KR20230173166A - Macrocyclic glucagon-like peptide 1 receptor agonist - Google Patents

Abstract

또는 그의 제약상 허용되는 염, 및 제II형 당뇨병을 치료하기 위한 상기 화합물의 사용 방법을 제공한다.In one embodiment, the invention provides a compound of the formula:

or pharmaceutically acceptable salts thereof, and methods of using said compounds for treating type II diabetes.

Description

Macrocyclic glucagon-like peptide 1 receptor agonist

The present invention relates to glucagon-like peptide-1 receptor agonists and the therapeutic use of said compounds for treating type II diabetes.

Glucagon-like peptide-1 (GLP-1) is a member of the incretin family of peptide hormones secreted by intestinal enteroendocrine L-cells. GLP-1 induces the release of insulin from beta cells in a glucose-dependent manner. However, GLP-1 is rapidly metabolized so that only a small proportion of GLP-1 is available to induce insulin secretion. To offset this, GLP-1 receptor (GLP-1R) agonists were developed to enhance insulin secretion as a treatment for type II diabetes.

Most GLP-1R agonists approved to treat type II diabetes are injectable agents. Patients often prefer orally administered medications because of the drawbacks associated with injections, such as discomfort, pain, and the potential for injection site irritation.

WO2018/109607 discloses certain benzimidazole derivatives described as GLP-1R agonists. Additional GLP-1 agonist compounds include WO2019/239371, WO2019/239319, WO2020/103815, WO2020/207474, WO2020/263695, WO2021/018023, WO2021/081207, WO2021/096284, WO 2021/096304, WO2021/112538, WO2021 /154796, WO2021/160127, WO2021/187886, WO2021/197464, CN113480534, WO2021/219019, WO2021/244645, WO2021/249492, CN113801136, WO2021/2 54470, WO2021/259309, WO2022/007979, WO2022/031994, WO2022/028572 , WO2022/040600, WO2022/042691, WO2022/068772, WO2022/078407, WO2022/078380 and WO2022/078152. However, alternative GLP-1R agonists are needed. In particular, there is a need for a GLP-1R agonist that can be administered orally. In particular, there is a need for potent GLP-1R agonists with favorable toxicological and/or pharmacokinetic profiles that support once-daily administration.

Accordingly, the present invention provides a compound of the formula:

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 is independently at each occurrence H, halo, C ₁ -C ₂ alkyl, OH or C ₁ -C ₃ alkoxy;

R ^b is independently at each occurrence H, halo or C ₁ -C ₂ alkyl;

은

이고, 여기서 a는 링커 A에 대한 부착 지점이고; b는 링커 B의 부착 지점이고;

silver

, where a is the point of attachment to linker A; b is the point of attachment of linker B;

X ¹ , ^{X 2} , ^{X 3} and ^{X 4} are independently N ^, CH or CR ¹ , ^where at most two ^of X ¹ , and no more than two of X ⁴ are CR ¹ ;

X ^{5 is} N, ^{CH or} CR ^{1a , and X 6 ,} Up to two of X ⁵ , X ⁶ , X ⁷ and X ⁸ are CR ^1a or CR ¹ ;

R ¹ is independently at each occurrence: CN; halo; C ₁ -C ₃ alkyl optionally substituted with OH; C ₁ -C ₃ haloalkyl; C ₁ -C ₃ alkoxy; C ₃ -C ₅ cycloalkyl; -SO ₂ C ₁ -C ₃ alkyl;

, 여기서 각각의 X⁹는 독립적으로 CH 또는 N이고, 고리 내의 1개 이하의 X⁹는 N이고, 각각의 R^e는 독립적으로 H, C₁-C₃할로알킬, 할로, C₃-C₅시클로알킬, 및 OH로 임의로 치환된 C₁-C₃알킬로부터 선택되고, R^h는 H, C₁-C₃할로알킬, 할로, C₃-C₅시클로알킬, OH, -NR^cR^d, 또는 OH로 임의로 치환된 C₁-C₃알킬임;

, _wherein each ^{X 9} is independently _CH or N, _{up to} ^one is selected from cycloalkyl, and C ₁ -C ₃ alkyl optionally substituted with OH, and R ^h is H, C ₁ -C ₃ haloalkyl, halo, C ₃ -C ₅ cycloalkyl, OH, -NR ^c R ^d , or C ₁ -C ₃ alkyl optionally substituted with OH;

5- or 6-membered heteroaryl or phenyl, where heteroaryl or phenyl is C ₁ -C ₃ alkoxy, C ₃ -C ₅ cycloalkyl, -CH ₂ -C ₃ -C ₅ cycloalkyl, -SO ₂ C ₁ - C ₃ alkyl, C ₄ -C ₅ heterocyclyl, -CH ₂ -C ₄ -C ₅ heterocyclyl, halo, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ haloalkoxy, CN, -CONR ^c R optionally substituted with 1 or 2 substituents independently selected from ^d , -NR ^c R ^d , or C ₁ -C ₃ alkyl optionally substituted with OH;

R ^1a is CN; halo; C ₁ -C ₃ alkyl optionally substituted with OH; C ₁ -C ₃ haloalkyl; or C ₁ -C ₃ alkoxy;

-B- is -CH ₂ O-, -OCH ₂ - or -CH ₂ NH-;

Y ¹ , Y ² and Y ⁷ are independently N, CH or CR ² , where at most one of Y ¹ , Y ² and Y ⁷ is N, and at most two of Y ¹ , Y ² and Y ⁷ are CR ² ;

Y ³ , Y ⁴ , Y ⁵ and Y ⁶ are independently N, CH or CR ² , where at most two of Y ³ , Y ⁴ , Y ⁵ and Y ⁶ are N, and Y ³ , Y ⁴ , Y ⁵ and up to two of Y ⁶ are CR ² ;

R ² is independently halo or methyl at each occurrence;

Z ¹ , Z ² and Z ³ are independently N, CH or CR ³ , where at most two of Z ¹ , Z ² and Z ³ are N, and at most two of Z ¹ , Z ² and Z ³ are CR ³ ;

R ³ is independently halo at each occurrence; C ₁ -C ₄ alkyl; _-OC 4 -C ₆ cycloalkyl optionally substituted with C ₁ -C ₂ alkoxy, OH, C ₁ -C ₃ alkyl or C ₁ -C ₃ haloalkyl; _-OC 4 -C ₆ heterocyclyl optionally substituted with C ₁ -C ₂ alkoxy, OH, C ₁ -C ₃ alkyl or C ₁ -C ₃ haloalkyl; or _{1 or} 2 selected from 5- or 6-membered heteroaryl optionally substituted with C 1 -C ₂ alkoxy, OH, -NR ^f R ^g , -CONR ^c R ^d , CN, halo, or C ₁ -C ₃ alkyl C ₁ -C ₄ alkoxy optionally substituted with substituents;

이고;R ⁴ is

ego;

이고;R ⁵ is -CO ₂ H,

ego;

R ^c and R ^d are each independently H or C ₁ -C ₃ alkyl;

R ^f is H or C ₁ -C ₃ alkyl;

R ^g is H, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₃ -C ₅ cycloalkyl, C(O)C ₁ -C ₃ alkyl or C ₁ -C ₃ alkylC ₃ -C ₅ It is cycloalkyl.

Formula IX includes all individual enantiomers, and mixtures thereof, as well as racemates.

In one embodiment, provided is a compound of the formula:

.

.

In one embodiment, provided is a compound of the formula:

.

.

In one embodiment, provided is a compound of the formula:

In embodiments of Formulas V, Va and VI, Y ⁴ , Y ⁵ , Y ⁶ and Y ⁷ are all CH.

은

이다. 한 실시양태에서, 은

이고; X¹, X³ 및 X⁴는 CH이고; X²는 CR¹이다. 대안적 실시양태에서, 은

이고; X¹은 N이고; X²는 CR¹이고; X³ 및 X⁴는 CH이다. 추가의 대안적 실시양태에서, 은

이고; X¹, X³ 및 X⁴는 CH이고; X²는 N이다. 추가의 대안적 실시양태에서, 은

이고; X¹ 및 X⁴는 CH이고; X²는 CR¹이고; X³은 N이다. 추가의 대안적 실시양태에서, 은

이고; X¹ 및 X³은 CH이고; X²는 CR¹이고; X⁴는 N이다. 추가의 대안적 실시양태에서, 은

이고; X¹ 및 X³은 CH이고; X² 및 X⁴는 CR¹이다.In one embodiment,

silver

am. In one embodiment, silver

ego; X ¹ , X ³ and X ⁴ are CH; X ² is CR ¹ . In an alternative embodiment, silver

ego; X ¹ is N; X ² is CR ¹ ; X ³ and X ⁴ are CH. In a further alternative embodiment, silver

ego; X ¹ , X ³ and X ⁴ are CH; X ² is N. In a further alternative embodiment, silver

ego; X ¹ and X ⁴ are CH; X ² is CR ¹ ; X ³ is N. In a further alternative embodiment, silver

ego; X ¹ and X ³ are CH; X ² is CR ¹ ; X ⁴ is N. In a further alternative embodiment, silver

ego; X ¹ and X ³ are CH; X ² and X ⁴ are CR ¹ .

In one embodiment, only one of X ¹ , X ² , X ³ and X ⁴ is N.

이다. 한 실시양태에서, 은

이고; X⁵, X⁷ 및 X⁸은 CH이고; X⁶은 CR¹이다. 대안적 실시양태에서, 은

이고; X⁵는 N이고; X⁶은 CR¹이고; X⁷ 및 X⁸은 CH이다.In an alternative embodiment, silver

am. In one embodiment, silver

ego; X ⁵ , X ⁷ and X ⁸ are CH; X ⁶ is CR ¹ . In an alternative embodiment, silver

ego; X ⁵ is N; X ⁶ is CR ¹ ; X ⁷ and X ⁸ are CH.

In one embodiment, only one of X ⁵ , X ⁶ , X ⁷ and X ⁸ is N.

In one embodiment, R ¹ is: CN; halo; C ₁ -C ₃ alkyl optionally substituted with OH; C ₁ -C ₃ haloalkyl;

, 여기서 각각의 R^e는 독립적으로 H, C₁-C₃알킬 또는 할로로부터 선택되고, R^h는 H 또는 할로임;

, where each R ^e is independently selected from H, C ₁ -C ₃ alkyl or halo, and R ^h is H or halo;

5- or 6-membered heteroaryl or phenyl, where heteroaryl or phenyl is C ₁ -C ₃ alkoxy, C ₃ -C ₅ cycloalkyl, -SO ₂ C ₁ -C ₃ alkyl, C ₄ -C ₅ heterocyclyl , -CH ₂ -C ₄ -C ₅ heterocyclyl, halo, -CONR ^c R ^d , -NR ^c R ^d , or C ₁ -C ₃ alkyl optionally substituted with OH, where R ^c and R ^d are each independently H or C ₁ -C ₃ alkyl.

이다. 바람직하게는, R¹은 CN, Cl, F, CF₃,

이다. 한 실시양태에서, R¹은 CN; 할로; OH로 임의로 치환된 C₁-C₃알킬; C₁-C₃할로알킬;

(여기서, 각각의 R^e는 독립적으로 H 또는 C₁-C₃알킬로부터 선택됨); 5- 또는 6-원 헤테로아릴 또는 페닐 (여기서, 헤테로아릴 또는 페닐은 C₁-C₃알콕시, C₃-C₅시클로알킬, -SO₂-C₁-C₃알킬, -CH₂-C₄-C₅헤테로시클릴, -CONR^cR^d, 또는 OH로 임의로 치환된 C₁-C₃알킬로부터 선택된 1개의 치환기로 임의로 치환되고, 여기서 R^c 및 R^d는 각각 독립적으로 H 또는 C₁-C₃알킬임)이다. 한 실시양태에서, R¹은 CN, 할로, CF₃, -CH₂OH,

이다. 바람직하게는, R¹은 CN, Cl, F, CF₃,

이다. 추가 실시양태에서, R¹은 CN, 할로, C₁-C₃알킬 또는 C₁-C₃할로알킬이다. 한 실시양태에서, R¹은 CN, 할로 또는 CF₃이다. 한 실시양태에서, R¹은 CN 또는 할로이다.In one embodiment, R ¹ is CN, halo, CF ₃ , -CH ₂ OH,

am. Preferably, R ¹ is CN, Cl, F, CF ₃ ,

am. In one embodiment, R ¹ is CN; halo; C ₁ -C ₃ alkyl optionally substituted with OH; C ₁ -C ₃ haloalkyl;

(wherein each R ^e is independently selected from H or C ₁ -C ₃ alkyl); 5- or 6-membered heteroaryl or phenyl, wherein heteroaryl or phenyl is C ₁ -C ₃ alkoxy, C ₃ -C ₅ cycloalkyl, -SO ₂ -C ₁ -C ₃ alkyl, -CH ₂ -C ₄ -C ₅ heterocyclyl, -CONR ^c R ^d , or C ₁ -C ₃ alkyl optionally substituted with OH, wherein R ^c and R ^d are each independently H or C ₁ - C ₃ alkyl). In one embodiment, R ¹ is CN, halo, CF ₃ , -CH ₂ OH,

am. Preferably, R ¹ is CN, Cl, F, CF ₃ ,

am. In a further embodiment, R ¹ is CN, halo, C ₁ -C ₃ alkyl or C ₁ -C ₃ haloalkyl. In one embodiment, R ¹ is CN, halo, or CF ₃ . In one embodiment, R ¹ is CN or halo.

은

이고; X¹, X³ 및 X⁴는 CH이고; X²는 CR¹이고; R¹은 CN; 할로; OH로 임의로 치환된 C₁-C₃알킬; C₁-C₃할로알킬;

(여기서 각각의 R^e는 독립적으로 H, C₁-C₃알킬 또는 할로로부터 선택되고, R^h는 H 또는 할로임); 5- 또는 6-원 헤테로아릴 또는 페닐 (여기서 헤테로아릴 또는 페닐은 C₁-C₃알콕시, C₃-C₅시클로알킬, -SO₂C₁-C₃알킬, C₄-C₅헤테로시클릴, -CH₂-C₄-C₅헤테로시클릴, 할로, -CONR^cR^d, -NR^cR^d, 또는 OH로 임의로 치환된 C₁-C₃알킬로부터 선택된 1개의 치환기로 임의로 치환되고, 여기서 R^c 및 R^d는 각각 독립적으로 H 또는 C₁-C₃알킬임)이다. 바람직하게는, R¹은 CN, 할로, CF₃, -CH₂OH,

이다. 보다 바람직하게는, R¹은 CN, Cl, F, CF₃,

이다.In one embodiment,

silver

ego; X ¹ , X ³ and X ⁴ are CH; X ² is CR ¹ ; R ¹ is CN; halo; C ₁ -C ₃ alkyl optionally substituted with OH; C ₁ -C ₃ haloalkyl;

(wherein each R ^e is independently selected from H, C ₁ -C ₃ alkyl or halo, and R ^h is H or halo); 5- or 6-membered heteroaryl or phenyl, wherein heteroaryl or phenyl is C ₁ -C ₃ alkoxy, C ₃ -C ₅ cycloalkyl, -SO ₂ C ₁ -C ₃ alkyl, C ₄ -C ₅ heterocyclyl , -CH ₂ -C ₄ -C ₅ heterocyclyl, halo, -CONR ^c R ^d , -NR ^c R ^d , or C ₁ -C ₃ alkyl optionally substituted with OH, where R ^c and R ^d are each independently H or C ₁ -C ₃ alkyl. Preferably, R ¹ is CN, halo, CF ₃ , -CH ₂ OH,

am. More preferably, R ¹ is CN, Cl, F, CF ₃ ,

am.

은

이고; X¹, X³ 및 X⁴는 CH이고; X²는 CR¹이고; R¹은 CN; 할로; OH로 임의로 치환된 C₁-C₃알킬; C₁-C₃할로알킬;

(여기서, 각각의 R^e는 독립적으로 H 또는 C₁-C₃알킬로부터 선택됨); 5- 또는 6-원 헤테로아릴 또는 페닐 (여기서, 헤테로아릴 또는 페닐은 C₁-C₃알콕시, C₃-C₅시클로알킬, -SO₂C₁-C₃알킬, -CH₂-C₄-C₅헤테로시클릴, -CONR^cR^d, 또는 OH로 임의로 치환된 C₁-C₃알킬로부터 선택된 1개의 치환기로 임의로 치환되고, 여기서 R^c 및 R^d는 각각 독립적으로 H 또는 C₁-C₃알킬임)이다. 바람직하게는, R¹은 CN, 할로, CF₃, -CH₂OH,

이다. 보다 바람직하게는, R¹은 CN, Cl, F, CF₃,

이다. 추가 실시양태에서, X¹, X³ 및 X⁴는 CH이고; X²는 CR¹이고; R¹은 CN이다. 추가 실시양태에서, X¹, X³ 및 X⁴는 CH이고; X²는 CR¹이고; R¹은 Cl이다. 추가 실시양태에서, X¹, X³ 및 X⁴는 CH이고; X²는 CR¹이고; R¹은 CF₃이다.In one embodiment,

silver

ego; X ¹ , X ³ and X ⁴ are CH; X ² is CR ¹ ; R ¹ is CN; halo; C ₁ -C ₃ alkyl optionally substituted with OH; C ₁ -C ₃ haloalkyl;

(wherein each R ^e is independently selected from H or C ₁ -C ₃ alkyl); 5- or 6-membered heteroaryl or phenyl, wherein heteroaryl or phenyl is C ₁ -C ₃ alkoxy, C ₃ -C ₅ cycloalkyl, -SO ₂ C ₁ -C ₃ alkyl, -CH ₂ -C ₄ - C ₅ heterocyclyl, -CONR ^c R ^d , or C ₁ -C ₃ alkyl optionally substituted with OH, wherein R ^c and R ^d are each independently H or C ₁ -C ₃ alkyl). Preferably, R ¹ is CN, halo, CF ₃ , -CH ₂ OH,

am. More preferably, R ¹ is CN, Cl, F, CF ₃ ,

am. In a further embodiment, X ¹ , X ³ and X ⁴ are CH; X ² is CR ¹ ; R ¹ is CN. In a further embodiment, X ¹ , X ³ and X ⁴ are CH; X ² is CR ¹ ; R ¹ is Cl. In a further embodiment, X ¹ , X ³ and X ⁴ are CH; X ² is CR ¹ ; R ¹ is CF ₃ .

은

이고; X¹은 N이고; X²는 CR¹이고; X³ 및 X⁴는 CH이고; R¹은 CF₃이다.In an alternative embodiment,

silver

ego; X ¹ is N; X ² is CR ¹ ; X ³ and X ⁴ are CH; R ¹ is CF ₃ .

이고; X¹ 및 X⁴는 CH이고; X²는 CR¹이고; X³은 N이고; R¹은 CF₃이다.In an alternative embodiment, silver

ego; X ¹ and X ⁴ are CH; X ² is CR ¹ ; X ³ is N; R ¹ is CF ₃ .

이고; X¹ 및 X³은 CH이고; X²는 CR¹이고; X⁴는 N이고; R¹은 CN이다.In an alternative embodiment, silver

ego; X ¹ and X ³ are CH; X ² is CR ¹ ; X ⁴ is N; R ¹ is CN.

이고; X¹ 및 X³은 CH이고; X² 및 X⁴는 CR¹이고; 각각의 R¹은 독립적으로 할로 및 CN으로부터 선택된다. 바람직하게는, 각각의 R¹은 독립적으로 F, Cl 및 CN으로부터 선택된다.In an alternative embodiment, silver

ego; X ¹ and X ³ are CH; X ² and X ⁴ are CR ¹ ; Each R ¹ is independently selected from halo and CN. Preferably, each R ¹ is independently selected from F, Cl and CN.

이고; X⁵, X⁷ 및 X⁸은 CH이고; X⁶은 CR¹이고; R¹은 CN 또는 Cl이다. 특히, R¹은 CN이다.In an alternative embodiment, silver

ego; X ⁵ , X ⁷ and X ⁸ are CH; X ⁶ is CR ¹ ; R ¹ is CN or Cl. In particular, R ¹ is CN.

이고; X⁵는 N이고; X⁶은 CR¹이고; X⁷ 및 X⁸은 CH이고; R¹은 CN이다.In an alternative embodiment, silver

ego; X ⁵ is N; X ⁶ is CR ¹ ; X ⁷ and X ⁸ are CH; R ¹ is CN.

In one embodiment, -A- is -CH ₂ CH ₂ CH ₂ O-, -OCH ₂ CH ₂ O-, -CH 2 CH ₂ OCH ₂ -, -CH _{2 OCH 2} CH ₂ -, -CH ₂ OCH ₂ -, -CH ₂ CH ₂ O-, -OCH ₂ CH ₂ - or -CF ₂ CH ₂ OCH ₂ -. In certain embodiments, -A- is -CH ₂ CH ₂ CH ₂ O-, -CH ₂ OCH ₂ -, -CH ₂ CH ₂ OCH ₂ -, CH ₂ OCH ₂ CH ₂ - or -CF ₂ CH ₂ OCH ₂ -am.

In one embodiment, -A- is -CHR ^a CHR ^a CHR ^b O-, -CHR ^b OCHR ^b - or -OCHR ^b CHR ^b O-. In a further embodiment, -A- is -CHR ^a CHR ^a CHR ^b O-. In certain embodiments, -A- is -CHR ^a CHR ^a CHR ^b O- and each of R ^a and R ^b is H. In an alternative embodiment, -A- is -CHR ^b OCHR ^b -. In certain embodiments, -A- is -CHR ^b OCHR ^b - and each R ^b is H. In an alternative embodiment, -A- is -OCHR ^b CHR ^b O-. In certain embodiments, -A- is -OCHR ^b CHR ^b O- and each R ^b is H. In certain embodiments, -A- is -CH ₂ CH ₂ CH ₂ O-, -OCH ₂ CH ₂ O-, -CH ₂ CH ₂ OCH ₂ -, -CH ₂ OCH ₂ - or -CH ₂ CH ₂ O- ego; Preferably, A- is -CH ₂ CH ₂ CH ₂ O- or -CH ₂ OCH ₂ -.

In one embodiment, -B- is -CH ₂ O- or -CH ₂ NH-. In an alternative embodiment, B is -CH ₂ O- or -OCH ₂ -. In a further embodiment, -B- is -CH ₂ O-.

In one embodiment, Y ³ is N or CH. In one embodiment, Y ³ is N. In an alternative embodiment, Y ³ is CH.

In one embodiment, Y ⁴ is CH.

In one embodiment, Y ⁵ is CH.

In one embodiment, Y ⁶ is CH or CR ² .

In one embodiment, Y ³ is N; Y ⁴ , Y ⁵ are CH; Y ⁶ is CH or CR ² . In a further embodiment, Y ³ is N; Y ⁴ , Y ⁵ are CH; Y ⁶ is CH. In a further embodiment, Y ³ is N; Y ⁴ , Y ⁵ are CH; Y ⁶ is CR ² and preferably R ² is F. In an alternative embodiment, Y ³ , Y ⁴ , Y ⁵ and Y ⁶ are all CH. In a further alternative embodiment, Y ³ and Y ⁶ are N; Y ⁴ and Y ⁵ are CH.

In one embodiment, Y ¹ is CH or CR ² .

In one embodiment, Y ² is CH.

In one embodiment, Y ⁷ is CH.

In one embodiment, R ² is F or methyl.

In one embodiment, Y ¹ , Y ² and Y ⁷ are all CH. In an alternative embodiment, Y ¹ is CR ² ; Y ² is CH; Y ⁷ is CH; R ² is F. In a further alternative embodiment, Y ¹ is CR ² ; Y ² is CH; Y ⁷ is CH; R ² is methyl.

In one embodiment, Y ¹ and Y ² are both CH. In an alternative embodiment, Y ¹ is CR ² , Y ² is CH, and R ² is F. In a further alternative embodiment, Y ¹ is CR ² , Y ² is CH and R ² is methyl.

In one embodiment, Y ⁴ , Y ⁵ , Y ⁶ and Y ⁷ are all CH.

In one embodiment, Z ¹ is CH or CR ³ .

In one embodiment, Z ² is CH.

In one embodiment, Z ³ is CH. In an alternative embodiment, Z ³ is N.

In certain embodiments, Z ² and Z ³ are both CH.

In one embodiment, R ³ is halo; -OC ₄ -C ₆ heterocyclyl optionally substituted with C ₁ -C ₃ alkyl; or optionally with _{1 or 2} substituents selected from 5- or 6-membered heteroaryl optionally substituted with C 1 -C 2 alkoxy, OH, -NR ^f R ^g , -CONR ^c R ^d , or C ₁ -C ₃ alkyl. substituted C ₁ -C ₄ alkoxy; where R ^c and R ^d are each independently H or C ₁ -C ₃ alkyl, R ^f is H or C ₁ -C ₃ alkyl, and R ^g is H, C ₁ -C ₃ alkyl or C ₁ -C ₃ It is a haloalkyl. In certain embodiments, R ³ is halo, or C ₁ -C ₄ alkoxy optionally substituted with 1 or 2 substituents selected from C ₁ -C ₂ alkoxy, OH, or -NR ^f R ^g , where R _f and R _g are both CH ₃ ; Preferably, R ³ is F, -OCH ₃ , -OCH ₂ CH ₂ OCH ₃ , OCH ₂ CH ₂ OH or OCH ₂ CH ₂ N(CH ₃ ) ₂ .

In one embodiment, R ³ is halo, C ₁ -C ₄ alkoxy, or —C ₁ -C ₃ alkoxyC ₁ -C ₂ alkoxy; Preferably, R ³ is F, -OCH ₃ or -OCH ₂ CH ₂ OCH ₃ . In alternative embodiments, R ³ is halo, C ₁ -C ₂ alkyl, or methoxy.

In one embodiment, Z ¹ is CR ³ and R ³ is halo; -OC ₄ -C ₆ heterocyclyl optionally substituted with C ₁ -C ₃ alkyl; or optionally with _{1 or 2} substituents selected from 5- or 6-membered heteroaryl optionally substituted with C 1 -C 2 alkoxy, OH, -NR ^f R ^g , -CONR ^c R ^d , or C ₁ -C ₃ alkyl. substituted C ₁ -C ₄ alkoxy; where R ^c and R ^d are each independently H or C ₁ -C ₃ alkyl, R ^f is H or C ₁ -C ₃ alkyl, and R ^g is H, C ₁ -C ₃ alkyl or C ₁ -C ₃ It is a haloalkyl. In a further embodiment, Z ¹ is CR ³ and R ³ is halo or C _{1 -C 4} alkoxy optionally substituted with 1 or 2 substituents selected from C 1 -C ₂ alkoxy, OH or -NR ^f R ^g , where R _f and R _g are both CH ₃ ; Preferably, R ³ is F, -OCH ₃ , -OCH ₂ CH ₂ OCH ₃ , OCH ₂ CH ₂ OH or OCH ₂ CH ₂ N(CH ₃ ) ₂ . In one embodiment, Z ¹ is CR ³ and R ³ is F. In an alternative embodiment, Z ¹ is CH. In a further alternative embodiment, Z ¹ is CR ³ and R ³ is methoxy.

이다.In one embodiment, R ⁵ is -CO ₂ H. In an alternative embodiment, R ⁵ is

am.

In one embodiment, provided is a compound of the formula:

Here -A- is -CH ₂ CH ₂ CH ₂ O-, -OCH ₂ CH ₂ O-, -CH ₂ CH ₂ OCH ₂ -, -CH ₂ OCH ₂ CH ₂ -, -CH ₂ OCH ₂ -, -CH ₂ CH ₂ O-, -OCH ₂ CH ₂ - or -CF ₂ CH ₂ OCH ₂ -;

은

이고, 여기서 a는 링커 A에 대한 부착 지점이고; b는 링커 B의 부착 지점이고;

silver

, where a is the point of attachment to linker A; b is the point of attachment of linker B;

X ¹ , ^{X 2} , ^{X 3} and ^{X 4} are independently N ^, CH or CR ¹ , where at most ^{one of} X ¹ , and no more than two of X ⁴ are CR ¹ ;

X ⁵ is N ^or CH, ^{X 6} , ^{X 7} and X ⁸ are independently N, CH or ^{CR 1} , where at most one of X ⁵ , One or less of X ⁷ and X ⁸ is CR ¹ ;

R ¹ is independently at each occurrence: CN; halo; C ₁ -C ₃ alkyl optionally substituted with OH; C ₁ -C ₃ haloalkyl;

, 여기서 각각의 R^e는 독립적으로 H, C₁-C₃알킬 또는 할로로부터 선택되고, R^h는 H 또는 할로임;

, where each R ^e is independently selected from H, C ₁ -C ₃ alkyl or halo, and R ^h is H or halo;

5- or 6-membered heteroaryl or phenyl, where heteroaryl or phenyl is C ₁ -C ₃ alkoxy, C ₃ -C ₅ cycloalkyl, -SO ₂ C ₁ -C ₃ alkyl, C ₄ -C ₅ heterocyclyl , -CH ₂ -C ₄ -C ₅ heterocyclyl, halo, -CONR ^c R ^d , -NR ^c R ^d , or C ₁ -C ₃ alkyl optionally substituted with OH;

-B- is -CH ₂ O- or -CH ₂ NH-;

Y ¹ is CH or CR ² ;

Y ³ is N or CH;

Y ⁶ is N, CH or CR ² ;

R ² is independently halo or methyl at each occurrence;

Z ¹ is CH or CR ³ ;

Z ³ is N or CH;

R ³ is halo; -OC ₄ -C ₆ heterocyclyl optionally substituted with C ₁ -C ₃ alkyl; or optionally with _{1 or 2} substituents selected from 5- or 6-membered heteroaryl optionally substituted with C 1 -C 2 alkoxy, OH, -NR ^f R ^g , -CONR ^c R ^d , or C ₁ -C ₃ alkyl. substituted C ₁ -C ₄ alkoxy;

이고;R ⁴ is

ego;

이고;R ⁵ is -CO ₂ H,

ego;

R ^c and R ^d are each independently H or C ₁ -C ₃ alkyl;

R ^f is H or C ₁ -C ₃ alkyl;

R ^g is H, C ₁ -C ₃ alkyl or C ₁ -C ₃ haloalkyl.

In one embodiment of Formula VIII, -A- is -CH ₂ CH ₂ CH ₂ O-, -CH ₂ OCH ₂ -, -CH ₂ CH ₂ OCH ₂ -, CH ₂ OCH ₂ CH ₂ - or -CF ₂ CH ₂ OCH ₂ -is.

은

이고; X¹, X³ 및 X⁴는 CH이고; X²는 CR¹이다. 화학식 VIII의 대안적 실시양태에서, 은

이고; X¹은 N이고; X²는 CR¹이고; X³ 및 X⁴는 CH이다. 화학식 VIII의 추가의 대안적 실시양태에서, 은

이고; X¹, X³ 및 X⁴는 CH이고; X²는 N이다. 화학식 VIII의 추가의 대안적 실시양태에서, 은 이고; X¹ 및 X⁴는 CH이고; X²는 CR¹이고; X³은 N이다. 화학식 VIII의 추가의 대안적 실시양태에서, 은

이고; X¹ 및 X³은 CH이고; X²는 CR¹이고; X⁴는 N이다. 화학식 VIII의 추가의 대안적 실시양태에서, 은

이고; X¹ 및 X³은 CH이고; X² 및 X⁴는 CR¹이다.In one embodiment of Formula VIII,

silver

ego; X ¹ , X ³ and X ⁴ are CH; X ² is CR ¹ . In an alternative embodiment of Formula VIII, silver

ego; X ¹ is N; X ² is CR ¹ ; X ³ and X ⁴ are CH. In a further alternative embodiment of formula VIII, silver

ego; X ¹ , X ³ and X ⁴ are CH; X ² is N. In a further alternative embodiment of formula VIII, silver ego; X ¹ and X ⁴ are CH; X ² is CR ¹ ; X ³ is N. In a further alternative embodiment of formula VIII, silver

ego; X ¹ and X ³ are CH; X ² is CR ¹ ; X ⁴ is N. In a further alternative embodiment of formula VIII, silver

ego; X ¹ and X ³ are CH; X ² and X ⁴ are CR ¹ .

이고; X⁵, X⁷ 및 X⁸은 CH이고; X⁶은 CR¹이다. 화학식 VIII의 대안적 실시양태에서, 은

이고; X⁵는 N이고; X⁶은 CR¹이고; X⁷ 및 X⁸은 CH이다.In one embodiment of Formula VIII, silver

ego; X ⁵ , X ⁷ and X ⁸ are CH; X ⁶ is CR ¹ . In an alternative embodiment of Formula VIII, silver

ego; X ⁵ is N; X ⁶ is CR ¹ ; X ⁷ and X ⁸ are CH.

이다. 바람직하게는, R¹은 CN, Cl, F, CF₃,

이다.In one embodiment of Formula VIII, R ¹ is CN, halo, CF ₃ , -CH ₂ OH,

am. Preferably, R ¹ is CN, Cl, F, CF ₃ ,

am.

이다. 바람직하게는, R¹은 CN, Cl, F, CF₃,

이다.In one embodiment of Formula VIII, silver ego; X ¹ , X ³ and X ⁴ are CH; X ² is CR ¹ ; R ¹ is CN, halo, CF ₃ , -CH ₂ OH,

am. Preferably, R ¹ is CN, Cl, F, CF ₃ ,

am.

이고; X¹은 N이고; X²는 CR¹이고; X³ 및 X⁴는 CH이고; R¹은 CF₃이다.In an alternative embodiment of Formula VIII, silver

ego; X ¹ is N; X ² is CR ¹ ; X ³ and X ⁴ are CH; R ¹ is CF ₃ .

이고; X¹, X³ 및 X⁴는 CH이고, X²는 N이다.In an alternative embodiment of Formula VIII, silver

ego; X ¹ , X ³ and X ⁴ are CH, and X ² is N.

이고; X¹ 및 X⁴는 CH이고; X²는 CR¹이고; X³은 N이고; R¹은 CF₃이다.In an alternative embodiment of Formula VIII, silver

ego; X ¹ and X ⁴ are CH; X ² is CR ¹ ; X ³ is N; R ¹ is CF ₃ .

이고; X¹ 및 X³은 CH이고; X²는 CR¹이고; X⁴는 N이고; R¹은 CN이다.In an alternative embodiment of Formula VIII, silver

ego; X ¹ and X ³ are CH; X ² is CR ¹ ; X ⁴ is N; R ¹ is CN.

이고; X¹ 및 X³은 CH이고; X² 및 X⁴는 CR¹이고; 각각의 R¹은 독립적으로 할로 및 CN으로부터 선택된다. 바람직하게는, 각각의 R¹은 독립적으로 F, Cl 및 CN으로부터 선택된다.In an alternative embodiment of Formula VIII, silver

ego; X ¹ and X ³ are CH; X ² and X ⁴ are CR ¹ ; Each R ¹ is independently selected from halo and CN. Preferably, each R ¹ is independently selected from F, Cl and CN.

이고; X⁵, X⁷ 및 X⁸은 CH이고; X⁶은 CR¹이고; R¹은 CN 또는 Cl이다. 특히, R¹은 CN이다.In an alternative embodiment of Formula VIII, silver

ego; X ⁵ , X ⁷ and X ⁸ are CH; X ⁶ is CR ¹ ; R ¹ is CN or Cl. In particular, R ¹ is CN.

이고; X⁵는 N이고; X⁶은 CR¹이고; X⁷ 및 X⁸은 CH이고; R¹은 CN이다.In an alternative embodiment of Formula VIII, silver

ego; X ⁵ is N; X ⁶ is CR ¹ ; X ⁷ and X ⁸ are CH; R ¹ is CN.

In one embodiment of Formula VIII, -B- is -CH ₂ O-.

In one embodiment of Formula VIII, Y ⁶ is CH or CR ² .

In one embodiment of Formula VIII, R ² is F or methyl.

In one embodiment of Formula VIII, Y ³ is N and Y ⁶ is CH or CR ² . In a further embodiment of Formula VIII, Y ³ is N and Y ⁶ is CH. In a further embodiment, Y ³ is N, Y ⁶ is CR ² and preferably R ² is F. In an alternative embodiment, Y ³ and Y ⁶ are both CH. In a further alternative embodiment, Y ³ and Y ⁶ are both N.

In one embodiment of Formula VIII, Z ³ is CH.

In one embodiment of Formula VIII, R ³ is halo or C ₁ -C ₄ alkoxy optionally substituted with 1 or 2 substituents selected from C ₁ -C ₂ alkoxy, OH or -NR ^f R ^g , where R _f and R _g are both CH ₃ ; Preferably, R ³ is F, -OCH ₃ , -OCH ₂ CH ₂ OCH ₃ , OCH ₂ CH ₂ OH or OCH ₂ CH ₂ N(CH ₃ ) ₂ .

이다.In one embodiment of Formula VIII, R ⁴ is

am.

Certain compounds of formula VIII have the following characteristics:

i. -A- is -CH ₂ CH ₂ CH ₂ O-, -CH ₂ OCH ₂ -, -CH ₂ CH ₂ OCH ₂ -, CH ₂ OCH ₂ CH ₂ - or -CF ₂ CH ₂ OCH ₂ -;

이고, 여기서 X¹, X³ 및 X⁴는 CH이고, X²는 CR¹이고, R¹은 CN, Cl, F, CF₃,

이거나; 또는 X¹은 N이고, X²는 CR¹이고, X³ 및 X⁴는 CH이고, R¹은 CF₃이거나; 또는 X¹, X³ 및 X⁴는 CH이고, X²는 N이거나; 또는 X¹ 및 X⁴는 CH이고, X²는 CR¹이고, X³은 N이고, R¹은 CF₃이거나; 또는 X¹ 및 X³은 CH이고, X²는 CR¹이고, X⁴는 N이고, R¹은 CN이거나; 또는 X¹ 및 X³은 CH이고, X² 및 X⁴는 CR¹이고, 각각의 R¹은 독립적으로 F, Cl 및 CN으로부터 선택되거나;ii. silver

, where X ¹ , X ³ and X ⁴ are CH, X ² is CR ¹ , and R ¹ is CN, Cl, F, CF ₃ ,

This is; or X ¹ is N, X ² is CR ¹ , X ³ and X ⁴ are CH, and R ¹ is CF ₃ ; or X ¹ , X ³ and X ⁴ are CH and X ² is N; or X ¹ and X ⁴ are CH, X ² is CR ¹ , X ³ is N, and R ¹ is CF ₃ ; or X ¹ and X ³ are CH, X ² is CR ¹ , X ⁴ is N, and R ¹ is CN; or X ¹ and X ³ are CH, X ² and X ⁴ are CR ¹ and each R ¹ is independently selected from F, Cl and CN;

이고, 여기서 X⁵, X⁷ 및 X⁸은 CH이고, X⁶은 CR¹이고, R¹은 CN 또는 Cl이거나; 또는 X⁵는 N이고, X⁶은 CR¹이고, X⁷ 및 X⁸은 CH이고, R¹은 CN이고;or silver

where X ⁵ , X ⁷ and X ⁸ are CH, X ⁶ is CR ¹ and R ¹ is CN or Cl; or X ⁵ is N, X ⁶ is CR ¹ , X ⁷ and X ⁸ are CH, and R ¹ is CN;

iii. -B- is -CH ₂ O-;

iv. Y ¹ is CH or CR ² and R ² is F or methyl;

v. Y ⁶ is CH or CR ² and R ² is F;

vi. Z ³ is CH;

vii. Z ¹ is CH or CR ³ , R ³ is F, -OCH ₃ , -OCH ₂ CH ₂ OCH ₃ , OCH ₂ CH ₂ OH or OCH ₂ CH ₂ N(CH ₃ ) ₂ ;

이다.viii. R ⁴ is

am.

In one embodiment, provided is a compound of the formula:

.

.

In a preferred embodiment, a compound of the formula: or a pharmaceutically acceptable salt thereof is provided:

In one embodiment of Formulas VII and VIIa, X ² is CR ¹ and R ¹ is CN. In alternative embodiments of Formulas VII and VIIa, X ² is CR ¹ and R ¹ is CF ₃ .

In one embodiment of Formulas VII and VIIa, Y ³ is N. In an alternative embodiment, Y ³ is CH.

In one embodiment of Formulas VII and VIIa, Y ¹ is CH. In an alternative embodiment, Y ¹ is CR ² and R ² is methyl.

이다.In one embodiment of Formulas VII and VIIa, R ⁵ is -CO ₂ H. In an alternative embodiment, R ⁵ is

am.

In one embodiment, provided is a compound of the formula:

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 -;

R ^a is independently at each occurrence H, halo, C ₁ -C ₂ alkyl or OH;

R ^b is independently at each occurrence H, halo or C ₁ -C ₂ alkyl;

이고, 여기서 a는 링커 A에 대한 부착 지점이고; b는 링커 B의 부착 지점이고; silver

, where a is the point of attachment to linker A; b is the point of attachment of linker B;

X ¹ , ^{X 2} , ^{X 3} and ^{X 4} are independently N ^, CH or CR ¹ , ^where at most two ^of X ¹ , and no more than two of X ⁴ are CR ¹ ;

R ¹ is: CN; halo; C ₁ -C ₃ alkyl optionally substituted with OH; C ₁ -C ₃ haloalkyl; C ₁ -C ₃ alkoxy; C ₃ -C ₅ cycloalkyl; -SO ₂ C ₁ -C ₃ alkyl;

, 여기서 각각의 R^e는 독립적으로 H, OH로 임의로 치환된 C₁-C₃알킬, C₁-C₃할로알킬, 할로 및 C₃-C₅시클로알킬로부터 선택됨;

, where each R ^e is independently selected from C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, halo and C ₃ -C ₅ cycloalkyl optionally substituted with H, OH;

5- or 6-membered heteroaryl or phenyl, where heteroaryl or phenyl is C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₅ cycloalkyl, -CH ₂ -C, optionally substituted by OH. ₃ -C ₅ cycloalkyl, -SO ₂ C ₁ -C ₃ alkyl, -CH ₂ -C ₄ -C ₅ heterocyclyl, halo, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ haloalkoxy, CN or -CONR ^c R ^d , wherein R ^c and R ^d are each independently H or C ₁ -C ₃ alkyl;

-B- is -CH ₂ O-, -OCH ₂ - or -CH ₂ NH-;

Y ¹ and Y ² are independently N, CH or CR ² , where only one of Y ¹ and Y ² may be N;

Y ³ is N or CH;

R ² is halo or methyl;

Z ¹ is N, CH or CR ³ ;

Z ² is CH or CR ³ ;

Z ³ is N, CH or CR ³ ;

R ³ is halo, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or -C ₁ -C ₃ alkoxyC ₁ -C ₂ alkoxy;

이고;R ⁴ is

ego;

이다.R ⁵ is -CO ₂ H or

am.

In one embodiment, -A- is -CHR ^a CHR ^a CHR ^b O-, -OCHR ^b CHR ^a CHR ^a -, -OCHR ^b CHR ^b O-, -CHR ^a CHR ^b OCHR ^b -, -CHR ^b OCHR ^b CHR ^a -, -CHR ^b OCHR ^b -, -CHR ^a CHR ^b O- or -OCHR ^b CHR ^a -;

R ^a is independently at each occurrence H, halo, C ₁ -C ₂ alkyl or OH;

R ^b is independently at each occurrence H, halo or C ₁ -C ₂ alkyl;

이고, 여기서 a는 링커 A에 대한 부착 지점이고; b는 링커 B의 부착 지점이고; silver

, where a is the point of attachment to linker A; b is the point of attachment of linker B;

X ¹ , ^{X 2} , ^{X 3} and X ⁴ are independently N, CH or CR ¹ , where ^no more than ^{two of} X ¹ , Up to two of X ³ and X ⁴ may be CR ¹ ;

R ¹ is CN, halo, C ₁ -C ₃ alkyl or C ₁ -C ₃ haloalkyl;

-B- is -CH ₂ O-, -OCH ₂ - or -CH ₂ NH-;

Y ¹ and Y ² are independently N, CH or CR ² , where only one of Y ¹ and Y ² may be N;

Y ³ is N or CH;

R ² is halo or methyl;

Z ¹ is N, CH or CR ³ ;

Z ² is CH or CR ³ ;

Z ³ is N, CH or CR ³ ;

R ³ is halo, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or -C ₁ -C ₃ alkoxyC ₁ -C ₂ alkoxy;

이고;R ⁴ is

ego;

인R ⁵ is -CO ₂ H or

person

Compounds of formula IV or pharmaceutically acceptable salts thereof are provided.

In an alternative embodiment, provided is a compound of the formula:

here

-A- is -CHR ^a CHR ^a CHR ^b O-, -OCHR ^b CHR ^a CHR ^a -, -OCHR ^b CHR ^b O-, -CHR ^a CHR ^b OCHR ^b -, -CHR ^b OCHR ^b CHR ^a -, - CHR ^b OCHR ^b -, -CHR ^a CHR ^b O- or -OCHR ^b CHR ^a -;

R ^a is independently at each occurrence H, halo, C ₁ -C ₂ alkyl or OH;

R ^b is independently at each occurrence H, halo or C ₁ -C ₂ alkyl;

X ¹ , ^{X 2} , ^{X 3} and ^{X 4} are independently N ^, CH or CR ¹ , ^where only one of X ¹ , Up to two of X ³ and X ⁴ may be CR ¹ ;

R ¹ is CN or halo;

-B- is -CH ₂ O- or -OCH ₂ -;

Y ¹ and Y ² are independently N, CH or CR ² , where only one of Y ¹ and Y ² may be N;

R ² is halo or methyl;

Z ¹ is N, CH or CR ³ ;

Z ² is CH or CR ³ ;

Z ³ is N, CH or CR ³ ;

R ³ is halo, C ₁ -C ₂ alkyl or methoxy.

In one embodiment, provided is a compound of the formula:

.

.

In one embodiment, provided is a compound of the formula:

.

.

In a preferred embodiment, a compound of the formula: or a pharmaceutically acceptable salt thereof is provided:

.

.

In one embodiment, provided is a compound of the formula:

.

.

In a preferred embodiment, a compound of the formula: or a pharmaceutically acceptable salt thereof is provided:

.

.

In one embodiment, -A- is -CHR ^a CHR ^a CHR ^b O-. In a further embodiment, each R ^a and R ^b is H.

In one embodiment, X ¹ , X ³ and X ⁴ are CH and X ² is CR ¹ . In one embodiment, R ¹ is CN. In an alternative embodiment, R ¹ is Cl.

In one embodiment, -B- is -CH ₂ O-.

In one embodiment, Y ¹ and Y ² are both CH. In an alternative embodiment, Y ¹ is CR ² , Y ² is CH, and R ² is F.

In one embodiment, Z ² and Z ³ are both CH.

In one embodiment, Z ¹ is CH or CR ³ . In one embodiment, Z ¹ is CH. In an alternative embodiment, Z ¹ is CR ³ and R ³ is F.

In one embodiment, a compound selected from: or a pharmaceutically acceptable salt thereof is provided:

.

.

In linker A, the left end group as described is attached to the X ring and the right end group is attached to the Y ¹ , Y ² and Y ⁷ containing rings. For example, in the group -CR ^a R ^b CR ^a R ^b CR ^b R ^b O-, the oxygen is attached to the Y ¹ , Y ² and Y ⁷ containing rings. In linker B, the left end group is attached to the X ring and the right end group is attached to the Y ³ containing ring.

The term “halogen” or “halo” refers to fluorine, chlorine, bromine or iodine.

The term “C ₁ -C _n alkyl” refers to a straight or branched chain saturated hydrocarbon containing 1 to n carbon atoms. Examples of C ₁ -C ₄ -alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, and tert-butyl. Examples of C ₁ -C ₃ alkyl groups include, but are not limited to, methyl, ethyl, and propyl. The C ₁ -C ₂ alkyl group is methyl or ethyl.

The term “C ₁ -C _n haloalkyl” refers to a C ₁ -C _n alkyl group as defined herein substituted with one or more halogens. Examples of C ₁ -C ₃ haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, and pentafluoroethyl.

The term “C ₁ -C _n alkoxy” refers to a straight or branched chain saturated hydrocarbon containing 1 to n carbon atoms in the chain containing a terminal “O”, i.e. -O(alkyl). Examples of C ₁ -C ₄ alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, and butoxy.

The term “C ₁ -C _n haloalkoxy” refers to a C ₁ -C _n alkoxy group as defined herein substituted with one or more halogens. Examples of C ₁ -C ₃ haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, and pentafluoroethoxy.

The term “C ₃ -C ₅ cycloalkyl” refers to a monocyclic saturated carbon ring containing 3 to 5 carbon atoms. Specifically, it refers to cyclopropyl, cyclobutyl or cyclopentyl.

The term “C ₄ -C ₆ cycloalkyl” refers to a monocyclic saturated carbon ring containing 4 to 6 carbon atoms. Specifically, it refers to cyclobutyl, cyclopentyl or cyclohexyl.

The term “heteroaryl” refers to a monocyclic aromatic ring, preferably containing one or more heteroatoms selected from N, S and O. Examples of 5-membered heteroaryls include, but are not limited to, pyrazole, triazole, and thiazole. Examples of 6-membered heteroaryls include, but are not limited to, pyridine and pyridazine.

The term “C ₄ -C ₆ heterocyclyl” refers to a 4, 5 or 6 membered monocyclic saturated ring containing one or more heteroatoms, such as pyrrolidine.

The term “C ₄ -C ₅ heterocyclyl” refers to a 4 or 5 membered monocyclic saturated ring containing one or more heteroatoms, for example oxetane.

Formula IX encompasses formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, V, Va, Vb, VI, VII, VIIa and VIIb and is described below, for example in treatment methods and References to formula IX in therapeutic uses should also be interpreted as references to each and every of these subformulas.

In another embodiment, provided is a pharmaceutically acceptable composition comprising a compound of Formula IX, or a pharmaceutically acceptable salt thereof, and at least one of a pharmaceutically acceptable carrier, diluent, or excipient. In a preferred embodiment, the pharmaceutically acceptable composition is formulated for oral administration.

In another embodiment, a patient in need of treatment is administered a pharmaceutically acceptable composition comprising an effective amount of a compound of Formula IX, or a pharmaceutically acceptable salt thereof, and at least one of a pharmaceutically acceptable carrier, diluent, or excipient. A method of treating a patient for type II diabetes is provided, comprising administering. In one embodiment, the pharmaceutically acceptable composition is formulated for oral administration. Preferably, the patient is a human.

In another embodiment, a method of treating a patient for type II diabetes comprising administering to the patient in need thereof an effective amount of a compound of formula (IX), or a pharmaceutically acceptable salt thereof, provided. In a preferred embodiment, the patient is human.

In another embodiment, a method of lowering blood glucose levels in a patient is provided, comprising administering to the patient in need thereof an effective amount of a compound of Formula IX, or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the patient is human.

In another embodiment, a method of treating hyperglycemia in a patient is provided, comprising administering to the patient in need thereof an effective amount of a compound of Formula (IX), or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the patient is human.

In another embodiment, a method of treating obesity in a mammal is provided, comprising administering to a patient in need thereof an effective amount of a compound of Formula IX, or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the patient is human.

In another embodiment, treating non-alcoholic steatohepatitis (NASH) in a patient comprising administering to the patient an effective amount of a compound of Formula IX, or a pharmaceutically acceptable salt thereof, A treatment method is provided. In a preferred embodiment, the patient is human.

In one embodiment, provided is a compound of Formula IX, or a pharmaceutically acceptable salt thereof, for use in therapy.

In another embodiment, provided is a compound of Formula IX, or a pharmaceutically acceptable salt thereof, for use in the treatment of type II diabetes.

In another embodiment, provided is a compound of Formula IX, or a pharmaceutically acceptable salt thereof, for use in lowering blood glucose levels.

In another embodiment, also provided is a compound of Formula IX, or a pharmaceutically acceptable salt thereof, for use in treating hyperglycemia.

In another embodiment, provided is a compound of Formula IX, or a pharmaceutically acceptable salt thereof, for use in treating obesity.

In another embodiment, also provided is a compound of Formula IX, or a pharmaceutically acceptable salt thereof, for use in treating NASH.

In one embodiment, there is provided the use of a compound of formula (IX) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of type II diabetes.

In one embodiment, the use of a compound of formula (IX) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for lowering blood glucose levels is provided.

In one embodiment, there is provided the use of a compound of formula (IX) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of hyperglycemia.

In one embodiment, there is provided the use of a compound of formula (IX) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of obesity.

In one embodiment, there is provided the use of a compound of formula (IX) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of NASH.

Compounds of formula (IX) can be used simultaneously, individually or in sequential combination with one or more therapeutic agents. Examples of additional therapeutic agents include, but are not limited to, metformin, thiazolidinediones, sulfonylureas, dipeptidyl peptidase 4 inhibitors, sodium glucose co-transporters, and ketohexokinase inhibitors.

In a preferred embodiment, the compounds of formula (IX) are 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.

As used herein, the term “pharmaceutically acceptable salt” refers to a salt of a compound of the invention that is considered acceptable for clinical and/or veterinary use. Examples of pharmaceutically acceptable salts and common methodologies 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 S.M. Berge, et al., "Pharmaceutical Salts", Journal of Pharmaceutical Sciences, 1977, 66(1), 1-19.

The term “effective amount” refers to the amount or dose of a compound of formula (IX) or a pharmaceutically acceptable salt thereof that, upon administration to the patient in single or multiple doses, provides the desired effect in a patient undergoing diagnosis or treatment. The attending physician, as a person skilled in the art, can easily determine the effective amount by use of routine techniques and by observing results obtained under similar circumstances. Factors considered in determining an effective amount or effective dose of a compound include whether the compound or salt thereof will be administered; co-administration of other agents, if used; The patient's size, age, and general health; Degree of involvement or severity of the disorder; individual patient response; mode of administration; bioavailability characteristics of the administered agent; selected dosage regimen; and other related circumstances. Compounds of the invention are effective at daily doses ranging from about 0.01 to about 15 mg/kg of body weight.

As used herein, the terms “treating,” “for treating,” or “treatment” refer to the reduction, reduction or reversal of the progression or severity of an existing symptom, disorder or condition, such as hyperglycemia, which may include increased insulin secretion. do.

As used herein, the term “patient” includes mammals. The patient is preferably human.

Compounds of formula (IX) can be formulated as pharmaceutical compositions to be administered by any route that makes the compounds bioavailable. Preferably, such compositions are for oral administration. Preferably, the pharmaceutical composition is formulated as tablets, capsules or solutions. Tablets, capsules or solutions may contain a compound of formula (IX) in an amount effective to treat a patient in need thereof. Such pharmaceutical compositions and methods for their preparation are well known in the art (see, e.g., “Remington: The Science and Practice of Pharmacy”, A. Adejare Editor, 23 ^rd Ed., 2020, Elsevier Science) ).

Compounds of formula (IX) and pharmaceutically acceptable salts thereof are useful in the therapeutic applications of the present invention, and certain configurations are preferred.

Compounds of the invention include:

or a pharmaceutically acceptable salt thereof.

The invention contemplates all individual enantiomers, mixtures and racemates thereof, but particular preference is given to the compounds of formulas Ia, IIa, IIIa, Va and VIIa and their pharmaceutically acceptable salts.

Individual enantiomers can be identified by those skilled in the art at any convenient point in the synthesis of the compounds of the invention, using selective crystallization techniques, chiral chromatography (e.g., J. Jacques, et al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981, and E.L. Eliel and S.H. Wilen, "Stereochemistry of Organic Compounds", Wiley-Interscience, 1994], or supercritical fluid chromatography (SFC) (e.g. For example, it can be separated or decomposed by methods such as those described by T. A. Berger; "Supercritical Fluid Chromatography Primer," Agilent Technologies, July 2015.

Pharmaceutically acceptable salts of the compounds of the invention may be formed, for example, by reaction of a compound of formula IX and a suitable pharmaceutically acceptable base in a suitable solvent under standard conditions well known in the art (e.g. For example, Bastin, R.J., et al.; Org. Process. Res. Dev., 4, 427-435, 2000 and Berge, S.M., et al.; J. Pharm. Sci., 66, 1-19, 1977]).

Certain abbreviations used herein are defined according to Daub GH, et al., "The Use of Acronyms in Organic Chemistry" Aldrichimica Acta, 1984, 17(1), 6-23. Certain 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 azodicarboxylate; “DIAD” refers to diisopropyl azodicarboxylate; “DIPEA” refers to N,N-diisopropylethylamine; “DMF” refers to N,N-dimethylformamide; “DMSO” refers to dimethyl sulfoxide; “EC ₅₀ ” refers to the concentration of agent that produces a response of 50% of target activity compared to a predefined positive control compound (absolute EC 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 hexafluorophosphate; “HEK” refers to human embryonic kidney; “HEPES” refers to 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; “h” respectively refers to time; Ir[dF(CF3)ppy]2(dtbpy))PF6 is [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-N1,N1']bis[3,5- refers to difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate; “KOAc” refers to potassium acetate; “MeOH” refers to methanol or methyl alcohol; “min” refers to minutes; “MTBE” refers to methyl tert-butyl ether; “Pd(dppf)Cl ₂ ” refers to [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II); PdCl ₂ (dtbpf) refers to [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II); “RT” refers to room temperature; “S _N Ar” refers to nucleophilic aromatic substitution; “TBAF” refers to tetrabutylammonium fluoride; “TBS” refers to tert-butyl dimethylsilyl; “TEA” refers to triethylamine; “TFA” refers to trifluoroacetic acid; “THF” refers to tetrahydrofuran; “TMAD” refers to tetramethyl azodicarboxamide; “TMSCN” refers to trimethylsilyl cyanide.

Compounds of the present invention can be prepared by a variety of procedures, some of which are illustrated in the Preparations and Examples below. The specific synthetic steps for each route described can be combined in different ways to prepare the compounds of the invention or salts thereof. The products of each step below can be recovered by conventional methods including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization. Reagents and starting materials are readily available to those skilled in the art. Individual isomers, enantiomers and diastereomers may be separated or resolved by methods such as selective crystallization techniques or chiral chromatography at any convenient point in the synthesis (see, e.g., J. Jacques, et al., (see “Enantiomers, Racemates, and Resolutions”, John Wiley and Sons, Inc., 1981, and E.L. Eliel and S.H. Wilen, “Stereochemistry of Organic Compounds”, Wiley-Interscience, 1994). The following preparations and examples are provided to further illustrate the invention without limiting its scope.

Scheme 1

Scheme 1 shows the synthesis of intermediates 7, 8 and 9 used to prepare the compounds of the present invention. In Step 1, the hydroxyl group of intermediate 1 is methylated with iodomethane and carbonate base at elevated temperature to provide methoxy intermediate 2. Then, in step 2, the ester group of intermediate 2 is reduced to alcohol intermediate 3 using NaBH ₄ . The alcohol of intermediate 3 is converted to bromide intermediate 4 using PBr ₃ in step 3, which is 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 sulfuric acid in alcohol solution at elevated temperature to give ester intermediate 6, which is then demethylated with BBr ₃ in step 6 to give intermediate 7. Optionally, in Step 7, intermediate 7 is converted to the boronate using KOAc, and Pd(dppf)Cl ₂ , and bis(pinacolato)diborone or bis(neopentyl glycolate)diborone at elevated temperature, respectively. You can get 8 or 9.

Scheme 2

Scheme 2 shows the synthesis of intermediates 15, 18, 22 and 23, which are also used in the preparation of compounds of the present invention. In step 1, bromide 10 is converted to nitrile 11 using zinc cyanide and palladium catalysts at elevated temperature. In step 2a, nitrile intermediate 11 is converted to ester intermediate 12 using thionyl chloride in alcohol solution at elevated temperature, and then in step 3a, fluorine is replaced with amine 13 and carbonate base in S _N Ar reaction at elevated temperature to give intermediate Get 14. The nitro group was then reduced using Lindlar catalyst (5% Pd) in methanol under an atmosphere of hydrogen in step 4a to give intermediate 15. Intermediate 15 can be reacted with 2-chloroacetyl chloride using a tertiary amine base to obtain 2-chloromethylimidazole intermediate 23.

To access the tetrazole intermediate, intermediate 11 is reacted with amine 13 using an amine base in step 2b with S _N Ar to give intermediate 16, which is then reacted to tetrazole using tributyltin azide at elevated temperature in step 3b. Converted to intermediate 17. The nitro group was then reduced using a palladium on carbon catalyst under hydrogen pressure (4 bar) in step 4b to give intermediate 18. Alternatively, intermediate 11 is reacted with tributyltin azide in step 2c at elevated temperature to give tetrazole intermediate 19, which is then protected on the tetrazole nitrogen with a group such as SEM (trimethylsilylethoxymethyl) in step 3c. Intermediate 20 is obtained. Fluorine is replaced with amine 13 and a tertiary amine base in the S _N Ar reaction in step 4c to give intermediate 21, which is then reduced in step 5c with iron in acetic acid at elevated temperature to give the protected tetrazole intermediate 22. Obtain.

Scheme 3

Scheme 3 shows three routes for synthesizing intermediate 32 used in the preparation of the compounds of the present invention. In step 1a of the first pathway, halide intermediate 24 is Heck coupled with ethyl acrylate using palladium acetate and a carbonate base at elevated temperature to give intermediate 25, which is then converted to olefin under hydrogen (40 psi) in step 2a. Reduction provides intermediate 26. In step 3a, the alcohol group of intermediate 26 is converted to bromide using PBr ₃ and then reacted with intermediate 27 and Ag ₂ CO ₃ at elevated temperature to obtain intermediate 29. Reduction of the ester group with LiBH ₄ in step 4a gives intermediate 32.

In the second route, intermediate 33 (which can be prepared from intermediate 24 using PBr ₃ ) is first reacted with intermediate 27 using Ag ₂ CO ₃ at elevated temperature in step 1c to obtain intermediate 34, which is then Negishi coupling with bromo-[3-[tert-butyl(dimethyl)silyl]oxypropyl]zinc and palladium catalyst at elevated temperature in 2c gives intermediate 35. Subsequent deprotection using TBAF in step 3c yields intermediate 32.

In the third route, intermediate 24 is Sonogashira coupled with tert-butyldimethyl(2-propynyloxy)silane in step 1b using a palladium catalyst and a tertiary amine base to obtain intermediate 28, which is then Intermediate 30 is obtained by reacting intermediate 27 with Mitsunobu. After deprotection using TBAF in step 3b, the alkyne is hydrogenated using platinum oxide under an atmosphere of hydrogen in step 4b to obtain intermediate 32.

Scheme 4

Scheme 4 shows the synthesis of intermediate 42 used to prepare the compounds of the present invention. In Step 1, bromide intermediate 36 is reacted with potassium phthalimide at elevated temperature to give intermediate 37. In step 2, Sonogashira coupling with propargyl alcohol provides alkyne intermediate 38. In Step 3, the alkyne of intermediate 38 is reduced with a rhodium catalyst at elevated temperature under hydrogen pressure (90 psi) to give intermediate 39. In step 4, the phthalimide group is reacted with hydrazine at elevated temperature to obtain amine 40, which is then reacted with intermediate 41 and S _N Ar using DIPEA at elevated temperature in step 5 to obtain intermediate 42.

Scheme 5

Scheme 5 shows the synthesis of intermediate 47 used in the preparation of the compounds of the present invention. In Step 1, intermediate 43 is reacted with (2-bromoethoxy)-tert-butyldimethylsilane using a carbonate base at elevated temperature. The aldehyde of intermediate 44 is reduced using sodium borohydride in step 2 to obtain alcohol 45, which is then reacted with intermediate 27 and Mitsunobu in step 3 to obtain intermediate 46. Removal of the tert-butyldimethylsilyl group in step 4 using TBAF provides intermediate 47.

Scheme 6

Intermediate 32, as described in Scheme 3, can be prepared by the alternative route shown in Scheme 6. In step 1a, intermediate 48 is subjected to Negishi coupling with bromo-[3-[tert-butyl(dimethyl)silyl]oxypropyl]zinc and palladium catalyst at elevated temperature to give intermediate 49, which is then subjected to It is reduced to alcohol intermediate 50 using lithium aluminum hydride. In step 3a, intermediate 50 was reacted with intermediate 27 under Mitsunobu conditions to obtain intermediate 32.

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

Scheme 7

Scheme 7 shows two routes for synthesizing intermediate 55 used in the preparation of compounds of the present invention. In the first route, intermediate 51 is reacted by Mitsunobu with intermediate 8 or 9 in step 1a to provide intermediate 52. In step 2a, intermediate 52 is then intramolecularly cross-coupled with a palladium catalyst to form macrocyclic intermediate 54. In the second route, intermediate 51 is reacted by Mitsunobu with intermediate 7 in step 1b to give intermediate 53, followed by palladium-catalyzed intramolecular Stille coupling at elevated temperature in step 2b to provide intermediate 54. In step 3 the ester group of intermediate 54 is hydrolyzed using aqueous LiOH in ACN/water or guanidine base to give intermediate 55.

Scheme 8

Scheme 8 shows the synthesis of intermediate 64 used in the preparation of the compounds of the present invention. In step 1, intermediate 56 is reductively coupled with 3-bromo-1-propanol at elevated temperature to give intermediate 57, which is 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 obtain alcohol intermediate 59, which is then reacted with intermediate 27 and Mitsunobu in step 4 to obtain intermediate 60. In step 5, the TBS protecting group is removed with TBAF to obtain intermediate 61, which is then reacted with intermediate 8 and Mitsutobu in step 6 to obtain intermediate 62. In step 7, intermediate 62 is cyclized using a palladium catalyst and potassium phosphate to give intermediate 63, which is then hydrolyzed in step 8 using aqueous LiOH in ACN/water or guanidine base to give acid intermediate 64. .

Scheme 9

Scheme 9 shows the synthesis of intermediate 77 used in the preparation of compounds of the invention and shows two synthetic routes to common intermediate 74.

In the first route to intermediate 74, in step 1a, acid intermediate 65 is reduced using a borane-dimethylsulfide complex to give alcohol intermediate 66, which is then reacted with sodium hydride and bromide intermediate 67 in step 2a to give intermediate 68. obtain. In step 3a, ester reduction with lithium borohydride gives intermediate 73, which is then subjected to a Mitsunobu reaction with intermediate 27 in step 4a to give intermediate 74.

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

In Step 5, intermediate 74 is coupled with ethyl diazoacetate using a palladium catalyst at elevated temperature to provide intermediate 75. In step 6, intramolecular Steele coupling with a palladium catalyst at elevated temperature provides intermediate 76. Alternatively, step 6 is achieved by one-pot coupling and intramolecular cross-coupling with bis(neopentyl glycolate)diborone using a palladium catalyst and potassium pivalate to provide cyclic intermediate 76. . Intermediate 76 is then hydrolyzed in step 7 using aqueous LiOH in ACN/water or guanidine base to give acid intermediate 77.

Scheme 10

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

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

Scheme 11

Scheme 11 shows the preparation of intermediate 86 used in the preparation of the compounds of the present invention. In Step 1, aryl iodide 84 is negically coupled with (2-ethoxy-2-oxoethyl)zinc(II) bromide and a palladium catalyst at elevated temperature. In Step 2, intermediate 85 is photochemically brominated using N-bromosuccinimide in a flow reactor to provide bromide intermediate 86.

Scheme 12

Scheme 12 shows multiple routes for the preparation of 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 obtain intermediate 89. Alternatively, intermediate 83 can first be reacted with alkyl bromide 87 in step 1b under similar conditions as step 1a to give intermediate 88, which is then reacted at elevated temperature in step 1c with (2-ethoxy-2-oxoethyl)) Intermediate 89 can be obtained by negishi coupling with zinc bromide and a palladium catalyst. In Step 2a, intermediate 89 is subjected to palladium-catalyzed intramolecular Steele coupling at elevated temperature to provide intermediate 91. Alternatively, in step 2b, bromide 89 is converted to boronic acid ester intermediate 90 by cross-coupling with bis(pinacolato)diborone, Pd(dppf)Cl ₂ and potassium acetate at elevated temperature, followed by steps Cyclization in 2c by intramolecular cross-coupling with a palladium catalyst forms the macrocyclic intermediate 91 (steps 2b and 2c can be performed as a single reaction step). Finally in step 3 the ester is hydrolyzed using aqueous LiOH in ACN/water or guanidine base to give acid intermediate 92.

Scheme 13

Scheme 13 shows the preparation of intermediate 100 used in the preparation of the compounds of the present invention. In Step 1, intermediate 93 is first coupled to intermediate 27 using Mitsunobu conditions to obtain intermediate 94. In step 2, intermediate 94 is coupled with bromoethanol using a nickel and iridium catalyst, and the reaction is irradiated under blue light (456 nm) to give intermediate 95. Alternatively, intermediate 95 is prepared in a manner similar to the synthetic route shown for the preparation of intermediate 83 in Scheme 10, 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 boronic acid ester intermediate 98 by cross-coupling with bis(pinacolato)diborone, Pd(dppf)Cl ₂ and potassium acetate at elevated temperature. In step 5, intermediate 98 is then intramolecularly cross-coupled with a palladium catalyst to form macrocyclic intermediate 99. Alternatively, intermediate 97 is converted to intermediate 99 in one step via intramolecular Stille coupling using hexamethyldistin and palladium catalysts at elevated temperature. Intermediate 99 is then hydrolyzed in step 6 using aqueous LiOH in ACN/water or guanidine base to give acid intermediate 100.

Scheme 14

Scheme 14 shows the preparation of intermediate 109 used to prepare the compounds of the present invention. In Step 1, intermediate 101 is radically brominated with N-bromosuccinimide at elevated temperature, then reacted with trimethylsilyl cyanide and TBAF, and then treated with sulfuric acid in aqueous EtOH at elevated temperature to give ester intermediate 102. . In step 2, intermediate 102 is coupled with (E)-1-ethoxyethene-2-boronic acid pinacol ester using a palladium catalyst and a carbonate base to give intermediate 103, which is then processed in step 3. Converted to Alcohol 104 using mercuric acetate and sodium borohydride. Separately, aldehyde intermediate 43 is first protected, for example with a SEM group, and then reduced with sodium borohydride in step 4 to provide intermediate 105. In step 5, intermediate 105 is reacted with intermediate 27 by Mitsunobu to provide intermediate 106. Intermediates 104 and 106 were coupled via the Mitsunobu reaction to give intermediate 107, which was then subjected to step 2a (one-pot still coupling) or steps 2b and 2c (borylation followed by Pd-reaction) in Scheme 12 in step 7. Intramolecular cyclization in a manner similar to catalyzed cross-coupling) affords intermediate 108. This is followed by ester hydrolysis in step 8 using aqueous LiOH in ACN/water or guanidine base to give intermediate 109.

Scheme 15

Scheme 15 shows the preparation of intermediate 115 used to prepare the compounds of the present invention. In step 1a, alkyl bromide intermediate 144 is reacted with intermediate 27 using silver carbonate at elevated temperature, followed by ester reduction using Red-Al ^® in step 2a to obtain intermediate 112. Alternatively, intermediate 34 is carbonylated using potassium formate and palladium catalysts in step 1b to give intermediate 111, followed by reduction of the aldehyde using NaBH ₄ in step 2b to give intermediate 112. In Step 3, the alcohol of intermediate 112 is converted to an alkyl bromide using CBr ₄ and triphenylphosphine to give intermediate 113. In step 4, intermediates 113 and 104 are reacted with silver trifluoromethanesulfonate to obtain intermediate 114. Intermediate 114 is then reacted in step 5 in a manner similar to step 2a in Scheme 12 (one-pot still coupling), or in steps 5 and 6 in a manner similar to steps 2b and 2c in Scheme 12 (borylation followed by Pd -catalyzed cross-coupling) causes intramolecular cyclization. The resulting ester is hydrolyzed in step 7 using aqueous LiOH in ACN/water or guanidine base to give intermediate 115.

Scheme 16

Scheme 16 shows the preparation of intermediate 123 used in 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, which is then photochemically brominated using N-bromosuccinimide in a flow reactor in step 2 to give the alkyl bromide. Intermediate 118 is obtained. In step 3, intermediate 118 is reacted with intermediate 27 using a phosphate base at elevated temperature to give intermediate 119, which is then reduced with LiBH ₄ in step 4 to give alcohol intermediate 120. In step 5, intermediate 120 is treated with NaH and reacted with intermediate 124 to obtain intermediate 121. In step 6, intermediate 121 is negically coupled with (2-ethoxy-2-oxo-ethyl)zinc bromide and a palladium catalyst at elevated temperature to give intermediate 122. Intermediate 122 is then intramolecularly cyclized in step 7 in a manner similar to step 2a (one-pot Still coupling) or steps 2b and 2c (borylation followed by Pd-catalyzed cross-coupling) in Scheme 12. This is followed by ester hydrolysis in step 8 using aqueous LiOH in ACN/water or guanidine base to give intermediate 123.

Scheme 17

Scheme 17 shows the preparation of boronate intermediate 128 used in 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, step 2a (one-pot still coupling) or step 2b in Scheme 12 and 2c (borylation followed by Pd-catalyzed cross-coupling). Finally, in step 3, intermediate 127 is coupled with bis(pinacolato)diborone using a palladium catalyst and potassium acetate at elevated temperature to obtain boronate intermediate 128.

Scheme 18

Scheme 18 shows compounds of the invention via a number of different routes from intermediate 129 (formula encompassing intermediate 128) or intermediate 130 (formula encompassing intermediates 55, 64, 77, 92, 100, 109, 115 and 123). indicates the manufacture of.

To prepare the acid compound of formula IX', intermediate 129 is coupled with chloromethylimidazole intermediate 23 at elevated temperature using a palladium catalyst and a phosphate base in step 1a to give intermediate 143, which is then coupled with the ester in step 3a. Hydrolysis at elevated temperature using aqueous LiOH in ACN/water or guanidine base gives the acid of formula IX'. Alternatively, acid intermediate 130 is coupled with intermediate 15 in step 1c using an amide coupling reagent such as EDC or HATU to yield intermediate 132. Intermediate 132 is then cyclized with acetic acid at elevated temperature in step 2a to give intermediate 143, and the ester is then hydrolyzed as described in step 3a.

Compounds of formula IX" are prepared by coupling the acid of formula IX' with cyclopropylmethanesulfonamide using EDC and 4-dimethylaminopyridine in step 4a.

Compounds of formula I cyclization with acetic acid (if necessary, step 3b - tetrazole deprotection, for example using TBAF to remove the SEM group) at elevated temperature to give the tetrazole compound of formula IX'".

Scheme 19

Scheme 19 shows the preparation of compounds of formula IX"" of the invention. Intermediate 133 is reacted with alcohol intermediate 136 and Mitsunobu in step 1a to provide 135, and then reacted with amine 13 and tertiary amine base S _N Ar at elevated temperature in step 2 to provide intermediate 138. Alternatively, difluoro aryl intermediate 134 is first reacted with alcohol 136 in step 1b S _N Ar, which is first treated with NaH and then reacted with intermediate 134 at elevated temperature to provide intermediate 135. A second alternative provides intermediate 138 by S _N Ar reaction with intermediates 137 and 136 in step 1c in a similar manner to step 1b. In step 3, the nitro group of intermediate 138 is reduced with, for example, hydrogen gas and palladium on carbon to give aniline intermediate 139. Compounds of formula IX"" are then prepared in three steps from intermediates 139 and 130 in a manner similar to steps 1c, 2a and 3a of Scheme 18. If the "-OR" group shown in Scheme 19 carries a protecting group, for example a Boc group on nitrogen or a tert-butyldimethylsilyl group on oxygen, the protecting group can be removed as a final step (e.g. removing the Boc group (use TFA or TBAF to remove tert-butyldimethylsilyl group).

Scheme 20

Scheme 20 shows the preparation of compounds of the invention from halide intermediate 140. Intermediate 140 is subjected to a cross-coupling reaction (e.g. Suzuki) with an optionally substituted 5- or 6-membered aryl or heteroaryl boronic acid or boronic acid ester using a palladium catalyst and an inorganic base at elevated temperature to give 141. Alternatively, 140 can be converted to the boronate 142 using, for example, tetrahydroxydiborone and a palladium catalyst at elevated temperatures to obtain 142 as a boronic acid, which can then be converted to an optionally substituted 5- or 6-membered aryl Alternatively, 141 can be obtained by subjecting it to a cross-coupling reaction with a heteroaryl halide (e.g. Suzuki). These steps can be performed with protected or unprotected versions of R ⁵ , for example esters can act as protected functional groups which can be hydrolyzed to give R ⁵ =-CO ₂ H.

Preparation examples and examples

LC-ES/MS was performed on an AGILENT ^® HP1200 liquid chromatography system. Electrospray mass spectrometry measurements (acquired in positive and/or negative mode) are performed on a mass selective detector quadrupole mass spectrometer mounted on an HPLC, which may or may not have an ELSD. LC-ES/MS conditions (low pH): Column: PHENOMENEX ^® GEMINI ^® NX C18 2.0 x 50 mm 3.0 μm, 110 Å; Gradient: 5-95% B in 1.5 minutes, then 95% B in 0.5 minutes Column temperature: 50°C +/-10°C; Flow rate: 1.2 mL/min; 1 μL injection volume; Solvent A: deionized water containing 0.1% HCOOH; Solvent B: ACN, containing 0.1% formic acid; Wavelength 200-400 nm and 212-216 nm. If the HPLC is equipped with an ELSD, the settings are 45°C evaporator temperature, 40°C nebulizer temperature, and 1.6 SLM gas flow rate. Alternative LC-MS conditions (high pH): Column: Waters xBridge ^® C18 column 2.1x50 mm, 3.5 μm; Gradient: 5-95% B in 1.5 min, then 95% B in 0.50 min; Column temperature: 50°C +/-10°C; Flow rate: 1.2 mL/min; 1 μL injection volume; Solvent A: 10 mM NH ₄ HCO ₃ pH 9; Solvent B: ACN; Wavelength: 200-400 nm and 212-216 nm; With ELSD: 45°C evaporator temperature, 40°C nebulizer temperature, and 1.60 SLM gas flow rate.

Manufacturing Example 1

Methyl 4-bromo-5-fluoro-2-methoxy-benzoate

To a mixture of methyl 4-bromo-5-fluoro-2-hydroxy-benzoate (10.0 g, 40.1 mmol) and potassium carbonate (13.8 g, 100 mmol) in ACN (200 mL) was added iodomethane (5.0 mL). , 80.2 mmol) was added. The reaction was stirred at 60°C for 15 hours. The reaction mixture was diluted with water (150 mL) and extracted with DCM (3 x 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 (98%) of the title compound, which was used in crude form in Preparation Example 2. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.60 (d, J = 9 Hz, 1H), 7.15 (d, J = 5 Hz, 1H), 3.90 (s, 6H).

Production example 2

(4-Bromo-5-fluoro-2-methoxy-phenyl)methanol

Sodium borohydride (10.7 g, 272 mmol) in a solution of methyl 4-bromo-5-fluoro-2-methoxy-benzoate (14 g, 53.2 mmol) and MeOH (30 mL) in THF (300 mL). was added. The reaction was stirred at 50°C for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (300 mL) and washed with brine (2 x 100 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient from 0 to 20% EtOAc in hexane to give 11.5 g of the title compound (92%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.14 (d, J = 8 Hz, 1H), 7.0 (d, J = 6 Hz, 1H), 4.63 (s, 2H), 3.85 (s, 3H).

Production example 3

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

To a solution of (4-bromo-5-fluoro-2-methoxy-phenyl)methanol (11.5 g, 48.9 mmol) in DCM (200 mL) was added phosphorus tribromide (5.6 mL, 59 mmol). The reaction was stirred at RT for 1 hour. The reaction was quenched by addition of ice water (50 mL) and basified to pH 7 using saturated aqueous sodium bicarbonate 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 (86%) of the title compound, which was used in crude form in Preparation Example 4. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.13 (d, J = 8 Hz, 1H), 7.03 (d, J = 6 Hz, 1H), 4.46 (s, 2H), 3.89 (s, 3H).

Production example 4

2-(4-Bromo-5-fluoro-2-methoxy-phenyl)acetonitrile

TBAF in a solution of 1-bromo-4-(bromomethyl)-2-fluoro-5-methoxy-benzene (12.5 g, 42.0 mmol) and TMSCN (6.8 mL, 50.5 mmol) in ACN (250 mL) Solution (1.0 M in THF, 50 mL, 50 mmol) was added. The reaction was stirred at RT for 4 hours. The reaction was concentrated under reduced pressure. The residue was dissolved in EtOAc (200 mL) and washed with saturated aqueous sodium chloride (2 x 50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient from 0 to 10% EtOAc in petroleum ether to give 8.0 g (78%) of the title compound. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.19 (d, J = 8 Hz, 1H), 7.04 (d, J = 5 Hz, 1H), 3.86 (s, 3H), 3.64 (s, 2H).

Production example 5

Ethyl 2-(4-bromo-5-fluoro-2-methoxy-phenyl)acetate

To a solution of 2-(4-bromo-5-fluoro-2-methoxy-phenyl)acetonitrile (8.0 g, 32.8 mmol) in ethanol (100 mL) was added concentrated sulfuric acid (25 mL). The reaction was stirred at 80°C for 18 hours. The reaction was neutralized to pH 7 using saturated aqueous sodium bicarbonate solution. The reaction mixture was extracted with DCM (2 x 100 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 9.3 g (97%) of the title compound, which was used in crude form in Preparation Example 6. ¹ H-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).

Production example 6

Ethyl 2-(4-bromo-5-fluoro-2-hydroxy-phenyl)acetate

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 reaction was stirred at RT for 2 hours. The reaction mixture was cooled to 0° C. and the reaction was quenched with ice water (40 mL). The solution was basified to pH 7 using 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 (84%) of the title compound, which was used in crude form in Preparations 10, 54 and 60. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.69 (s, 1H), 7.14 (d, J = 6 Hz, 1H), 6.90 (d, J = 4 Hz, 1H), 4.22 (q, J = 7 Hz, 2H), 3.61 (s, 2H), 1.31 (t, J = 8 Hz, 3 H).

Production example 7

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

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

Production example 8

Methyl 2-[2-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate

Methyl 2-(4-bromo-2-hydroxy-phenyl)acetate (1.30 g, 5.30 mmol), bis(pinacolato)diborone (1.98 g, 7.72 mmol), KOAc (2.23 g, 22.5 mmol) and To a mixture of Pd(dppf)Cl ₂ (420 mg, 0.57 mmol) was added 1,4-dioxane (24 mL). The reaction mixture was stirred at 80° C. for 60 hours under nitrogen atmosphere. The mixture was filtered through a pad of ^Celite® and washed with EtOAc. The filtrate was concentrated under reduced pressure. The residue was dissolved in DCM, adsorbed onto silica, and purified via silica gel flash chromatography using a gradient of 0 to 55% EtOAc in hexane to give 748 mg (48%) of the title compound. ES-MS m/z 293 (M+H).

Production example 9

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

The title compound was prepared essentially as described in Preparation Example 8 using methyl 2-(4-bromo-2-hydroxy-5-methyl-phenyl)acetate. Purified via silica gel flash chromatography using a gradient of 5 to 80% EtOAc in hexanes. ES-MS m/z 304 (M-H).

Production example 10

Ethyl 2-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-fluoro-2-hydroxyphenyl]acetate

Ethyl 2-(4-bromo-5-fluoro-2-hydroxy-phenyl)acetate (2.43 g, 8.16 mmol), bis(neopentyl glycoloeito)diborone (2.82 g, 12.2 mmol) and KOAc The flask containing (2.04 g, 20.4 mmol) was purged with nitrogen. Anhydrous 1,4-dioxane (33 mL) was added and purged with nitrogen while stirring for 5 minutes. Dichlorobis(tricyclohexylphosphine)palladium(II) (0.31 g, 0.41 mmol) was added and stirred for 5 minutes while bubbling with nitrogen. After stirring at 90°C for 6 hours, the solid was washed with 1,4-dioxane (15 mL) and stirred at RT overnight. Diatomaceous earth was added and diluted with MTBE (0.1 L). Stirred for 30 minutes, filtered through a pad of ^Celite® and washed with MTBE (0.1 L). The filtrate was concentrated at 50° C. under reduced pressure. The residue was dissolved in toluene (0.1 L) and concentrated again at 50°C. The residue was purified by eluting through a pad of silica gel using a 1:1 mixture of EtOAc and heptane. Fractions containing the title compound were concentrated to a final volume of 30 mL and the resulting slurry was stirred at ambient temperature for 1 hour. The solid was collected by filtration, washed with heptane (0.1 L), and dried at 50° C. under reduced pressure for 19 hours to yield 1.77 g (64%) of the title compound as a light orange solid. ES-MS m/z 243 (M+H for boronic acid). ^1H -NMR (400 MHz, CDCl ₃ ) δ 7.28 (s, 1H), 7.27 (d, J = 5.2 Hz, 1H), 6.81 (d, J = 9.2 Hz, 1H), 4.22 (q, J = 7.2) Hz, 2H), 3.80 (s, 4H), 3.65 (s, 2H), 1.30 (t, J = 7.2 Hz, 3H), 1.05 (s, 6H).

Production example 11

Ethyl 2-[5-fluoro-2-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate

Bis(pinacolaito)diborone was used and the mixture was stirred at 90°C for 2 hours and then at 100°C for 18 hours to produce the title compound essentially as described in Preparation Example 10. The title compound was purified via silica gel flash chromatography using a gradient of 0 to 50% EtOAc in cyclohexane and then repurified via silica gel flash chromatography using a gradient of 0 to 40% EtOAc in cyclohexane. . ES-MS m/z 325 (M+H).

Production example 12

(5-bromo-4-fluoro-2-iodophenyl)methanol

To a solution of 5-bromo-4-fluoro-2-iodo-benzoic acid (6.3 g, 18.2 mmol) in THF (55 mL) was added borane dimethylsulfide complex (2 M in THF, 27 mL, 54 mmol). Added. 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 saturated aqueous ammonium chloride. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified via silica gel flash chromatography using a gradient of 10 to 30% EtOAc in heptane to give 5.1 g (85%) of the title compound. ES-MS m/z 313 and 315 (MH ₂ O).

Production Example 13

Methyl 3,5-difluoro-4-nitro-benzoate

A solution of thionyl chloride (37 mL, 74 mmol) in MeOH (110 mL) was cooled to -10°C and 3,5-difluoro-4-nitro-benzonitrile (2.8 g, 15 mmol) was added. . After stirring at RT for 3 hours, the temperature was slowly increased to 65° C. over 2 hours. The mixture was filtered and concentrated under reduced pressure. The residue was dissolved in EtOAc (150 mL). Washed with saturated aqueous sodium bicarbonate 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 via silica gel chromatography using 10% EtOAc in petroleum ether to give 2.24 g (66%) of the title compound. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.78 (d, 2H), 4.0 (s, 3H).

Production example 14

Methyl 3-fluoro-4-nitro-5-[[(2S)-oxetan-2-ylmethyl]amino]benzoate

[(2S)-oxetan-2-yl]methanamine (545 mg, 6.13 mmol, CAS 2091328-57-1), methyl 3,5-difluoro-4-nitro-benzoate in ACN (14 mL) (1.4 g, 6.1 mmol), and potassium carbonate (1.7 g, 12 mmol) was stirred at 70°C for 16 hours. The reaction mixture was diluted with water (14 mL) and extracted with EtOAc (3 x 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 via silica gel chromatography using a gradient from 0 to 30% EtOAc in petroleum ether to give 1.68 g (79%) of the title compound. ES-MS m/z 285 (M+H).

Production Example 15

Methyl (S)-3-methoxy-4-nitro-5-((oxetan-2-ylmethyl)amino)benzoate

The title compound was prepared essentially as described in Preparation Example 14 using methyl 3-fluoro-5-methoxy-4-nitro-benzoate. The residue was purified via silica gel chromatography using a gradient of 5 to 30% EtOAc in DCM to give the title compound. ES-MS m/z 296 (M+H).

Production example 16

Methyl 4-amino-3-fluoro-5-[[(2S)-oxetan-2-ylmethyl]amino]benzoate

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

Production Example 17

Methyl 4-amino-3-methoxy-5-[[(2S)-oxetan-2-yl]methylamino]benzoate

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

Production Example 18

Methyl 3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)-4-nitrobenzoate

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) (1-ethyl-1H-imi) Dazol-5-yl)methanamine dihydrochloride (339 mg, 1.6 mmol) was added. It was stirred at 35°C for 2 hours and then at 50°C for 16 hours. The crude reaction mixture was diluted with water and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with water and saturated aqueous NaCl, and the organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified via silica gel flash chromatography using a gradient from 0 to 100% EtOAc in heptane followed by 5% MeOH in DCM to give 395 mg (88%) of the title compound. ES-MS m/z 305 (M+H).

Production Example 19

Methyl 4-amino-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate

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-nitrobenzoate (117 mg, 0.38 mmol) in DMF (1 mL) was added. Stirred at 50°C for 15 minutes. The reaction was quenched to pH 8 with aqueous sodium carbonate solution and filtered through ^Celite® . The residue was washed with water (2 x 20 mL) and the aqueous layer was back-extracted with EtOAc (2 x 20 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 106 mg (100%) of the title compound, which was used in crude form in Preparation Example 95. ES-MS m/z 275 (M+H).

Production example 20

3-Fluoro-5-methoxy-4-nitrobenzonitrile

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) To a mixture of (317 mg, 0.27 mmol) was added DMF (17.8 mL). It was stirred at 100°C for 1.5 hours. The crude reaction mixture was diluted with water and extracted with EtOAc. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified via silica gel flash chromatography using a gradient from 0 to 15% EtOAc in heptane to give 479 mg (89%) of the title compound. ES-MS m/z 197 (M+H).

Production example 21

(S)-3-methoxy-4-nitro-5-((oxetan-2-ylmethyl)amino)benzonitrile

TEA (1.07 mL, 7.7 mmol) and (S)-oxetan-2-ylmethanamine (235 mg, 2.56 mmol) were dissolved in 3-fluoro-5-methoxy-4-nitrobenzonitrile in DMF (7 mL). (457 mg, 2.3 mmol) was added to the solution. Stirred at 35°C overnight. The crude reaction mixture was diluted with water and extracted with EtOAc. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified via silica gel flash chromatography using a gradient from 0 to 30% EtOAc in heptane to give 471 mg (77%) of the title compound. ES-MS m/z 264 (M+H).

Production example 22

(S)-3-methoxy-2-nitro-N-(oxetan-2-ylmethyl)-5-(1H-tetrazol-5-yl)aniline

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

Production example 23

(S)-3-methoxy-N1-(oxetan-2-ylmethyl)-5-(1H-tetrazol-5-yl)benzene-1,2-diamine

Palladium on carbon (20 mg, 0.009 mmol) was reacted with (S)-3-methoxy-2-nitro-N-(oxetan-2-ylmethyl)-5-(1H-tetrazol-5-yl)aniline ( 160 mg, 0.42 mmol) and MeOH (3 mL). Stirred under 4 bar hydrogen pressure at RT for 8 hours. The crude reaction mixture was filtered through ^Celite® and concentrated to give 120 mg of the title compound (52%), which was used in crude form in Preparation Example 96. ES-MS m/z 277 (M+H).

Manufacturing example 24

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

4-(Bromomethyl)-3-iodo-benzonitrile (2.88 g, 8.93 mmol), 6-bromopyridin-2-ol (1.10 g, 6.30 mmol), and silver carbonate (5.1 g, 18.0 mmol) 1,4-dioxane (50 mL) was added to the mixture. The reaction mixture was stirred at 60°C for 15 hours. The reaction was diluted with EtOAc (50 mL) and filtered through Celite. The filtrate was washed with water (2 x 50 mL) and saturated aqueous sodium chloride (50 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified via silica gel flash chromatography eluting with a gradient of 5 to 30% EtOAc in hexane to give 2.8 g (76%) of the title compound. ES-MS m/z 415 and 417 (M+H).

Production example 25

Ethyl 4-cyano-3-(3-hydroxypropyl)benzoate

Nickel (II) bromide (167 mg, 0.76 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (210 mg, 0.77) in anhydrous 1,4-dioxane (40 mL). The mixture was stirred at RT for 15 minutes while bubbling with nitrogen. Ethyl 3-bromo-4-cyanobenzoate (2 g, 7.71 mmol), 3-bromo-1-propanol (1.7 mL, 18 mmol) and cobalt (II) phthalocyanine (441 mg, 0.77 mmol) were added. did. The mixture was stirred at RT for 5 min while bubbling with nitrogen. Tetrakis(dimethylamino)ethylene (2.5 mL, 11 mmol) was added and the mixture was continued to stir at RT for 5 min while bubbling with nitrogen. The vessel was sealed and the mixture was stirred at 85° C. overnight. The mixture was cooled to RT, filtered through ^Celite® and concentrated under reduced pressure. The residue was purified via silica gel flash chromatography using a gradient of 20 to 50% EtOAc in cyclohexane to give the title compound (863 mg, 46%) as a green solid. ES-MS m/z 251 (M+NH ₄ ⁺ ).

Production example 26

Ethyl 3-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-4-cyano-benzoate

tert-Butyldimethylchlorosilane (615 mg, 3.96 mmol) and imidazole (298 mg, 4.33 mmol) were dissolved in ethyl 4-cyano-3-(3-hydroxypropyl)benzoate (863 mg) in DCM (15 mL). , 3.59 mmol) was added to the solution at RT. The mixture was stirred for 1 hour and concentrated under reduced pressure. The residue was purified via silica gel flash chromatography using a gradient from 0% to 50% EtOAc in cyclohexane to give the title compound (1.24 g, 94%) as a colorless oil. ES-MS m/z 348 (M+H).

Manufacturing Example 27

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

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

Manufacturing Example 28

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

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

Manufacturing Example 29

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

4-[(6-bromo-2-pyridyl)oxymethyl]-3-[3-[tert-butyl(dimethyl)silyl]oxypropyl]benzonitrile (1.32 g, 2.86 mmol) in THF (50 mL) To the mixture was added TBAF solution (1.0 M in THF, 2.9 mL, 2.9 mmol). The reaction mixture was stirred at RT for 1 hour. Diluted with EtOAc (50 mL) and washed with saturated aqueous ammonium chloride 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 via silica gel flash chromatography eluting with a gradient of 5 to 75% EtOAc in hexane to give 0.90 g (92%) of the title compound. ES-MS m/z 347 and 349 (M+H).

Production example 30

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

DIAD (915 μl, 4.5 mmol) was added slowly to a solution of triphenylphosphine (1.21 g, 4.61 mmol) in anhydrous THF (15 ml) at 0° C. under nitrogen atmosphere. The mixture was stirred for 30 min, then 2-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-4-(hydroxymethyl)benzonitrile (925 mg, 3.03 mmol) in dry THF (6 mL). A solution of and 2-bromo-6-hydroxypyridine (610 mg, 3.33 mmol) were added. The cooling bath was removed, stirred at RT for 2 hours and the mixture was concentrated under reduced pressure. The residue was purified via silica gel flash chromatography using a gradient from 0 to 30% EtOAc in cyclohexane to give 1.12 g of the title compound (78%). ES-MS m/z 461 and 463 (M+H).

Production example 31

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

TBAF solution (1.0 M in THF, 2.7 mL, 2.7 mmol) was dissolved in 4-[(6-bromo-2-pyridyl)oxymethyl]-2-[3-[tert-butyl(dimethyl) in THF (24 mL). )silyl]oxypropyl]benzonitrile (1.12 g, 2.43 mmol) was added slowly at RT. 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, washed with water and saturated aqueous NaCl, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified via silica gel flash chromatography using a gradient of 25 to 50% EtOAc in cyclohexane to give the title compound (790 mg, 89%) as a white solid. ES-MS m/z 347 and 349 (M+H).

Production example 32

3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-formylbenzonitrile

To a solution of 4-formyl-3-hydroxybenzonitrile (3.0 g, 18.8 mmol) in DMF (56 mL) was added sodium iodide (1.4 g, 9.3 mmol), potassium carbonate (3.8 g, 38 mmol), and (2-Bromoethoxy)-tert-butyldimethylsilane (6.1 mL, 28 mmol) was added. The mixture was stirred at 70° C. for 24 hours. The crude reaction mixture was diluted with water and EtOAc, and the aqueous layer was extracted with EtOAc. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified via silica gel flash chromatography using a gradient from 0 to 30% EtOAc in heptane to give 5.68 g (99%) of the title compound. ES-MS m/z 306 (M+H).

Production example 33

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

A solution of 3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-formylbenzonitrile (450 mg, 1.47 mmol) in MeOH (4.6 mL) was cooled to 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, adjusted to pH 7 using 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 pad of silica gel to give 350 mg of the title compound (77%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.32 (d, J = 7.7 Hz, 1H), 7.15 (d, J = 7.7 Hz, 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).

Production example 34

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

3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-(hydroxymethyl)benzonitrile (350 mg, 1.14 mmol), 6-bromopyridine-2- in THF (50 mL) To a solution of ol (1.4 g, 8.0 mmol), and triphenylphosphine (2.35 g, 8.96 mmol) was added DIAD (1.76 mL, 8.94 mmol). 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 via silica gel flash chromatography using a gradient from 0 to 20% EtOAc in heptane to give 247 mg (47%) of the title compound. ES-MS m/z 463 and 465 (M+H).

Production example 35

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

4-(((6-bromopyridin-2-yl)oxy)methyl)-3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)benzonitrile was used, and the reaction was incubated at RT for 2 hours. The title compound was prepared essentially as described in Preparation Example 31. The title compound was purified via silica gel flash chromatography using a gradient from 0 to 20% EtOAc in DCM. ES-MS m/z 349 and 351 (M+H).

Production example 36

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

(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 acetic acid in DMF (400 mL). To a mixture of palladium (1.47 g, 6.55 mmol) was added ethyl acrylate (10.3 mL, 94.8 mmol). The reaction mixture was stirred at 90°C for 6 hours under nitrogen atmosphere. The reaction mixture was filtered through a pad of ^Celite® and then rinsed with EtOAc (200 mL). The filtrate was diluted with EtOAc (200 mL) and washed with water (800 mL). The aqueous layer was back-extracted with EtOAc (250 mL). The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in DCM, adsorbed onto silica, and purified via silica gel chromatography using a gradient of 15 to 40% EtOAc in hexane to give 6.14 g (32%) of the title compound. ES-MS m/z 258 (M+NH ₄ ⁺ ).

Production example 37

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

To a mixture of platinum sulfide on carbon (5%, 220 mg, 0.056 mmol) in EtOAc (20 mL) was added ethyl (E)-3-[5-chloro-2-(hydroxymethyl)phenyl] in EtOAc (30 mL). Prop-2-enoate (2.21 g, 9.18 mmol) was added. Shake for 1 hour at RT on a Parr shaker at 40 psi hydrogen gas pressure. It was filtered through a pad of ^Celite® , and the filtrate was concentrated under reduced pressure to obtain 1.91 g (86%) of the title compound, which was used in crude form in Preparation Example 38. ES-MS m/z 225 (MH ₂ O).

Production example 38

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

To a mixture of ethyl 3-[5-chloro-2-(hydroxymethyl)phenyl]propanoate (1.90 g, 7.80 mmol) in diethyl ether (40 mL) was added phosphorus tribromide (0.80 mL, 8.5 mmol). It was added dropwise. The mixture was stirred at RT under nitrogen atmosphere for 1 hour. It was quenched by slowly adding saturated aqueous sodium bicarbonate solution (5 mL) dropwise. 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 obtain 2.40 g (100%) of the title compound, which was used in crude form in Preparation Example 45. ES-MS m/z 322 and 324 (M+NH ₄ ⁺ ).

Production example 39

4-[(1,3-dioxoisoindolin-2-yl)methyl]-3-iodo-benzonitrile

To a solution of 4-(bromomethyl)-3-iodobenzonitrile (10 g, 30.13 mmol) in DMF (100 mL) was added potassium phthalimide (6.14 g, 33.14 mmol). The reaction mixture was heated at 80° C. for 2 hours and then stirred at RT for 16 hours. The solvent was removed and the solid residue was triturated in 500 mL of water for 30 minutes. The white solid was filtered, washed with water, and the solid was dried under vacuum at 45° C. for 20 hours to give the title compound as a white solid (11.5 g, 88%). ES-MS m/z 405 (M+OH ^- ).

Production example 40

4-[(1,3-dioxoisoindolin-2-yl)methyl]-3-(3-hydroxyprop-1-ynyl)benzonitrile

Bis to a suspension of 4-[(1,3-dioxoisoindolin-2-yl)methyl]-3-iodo-benzonitrile (5.0 g, 11.7 mmol) in THF (50 mL) and TEA (50 mL). (triphenylphosphine)palladium dichloride (0.33 g, 0.47 mmol), cuprous iodide (0.18 g, 0.94 mmol) and propargyl alcohol (2.05 mL, 35.2 mmol) were added. The reaction mixture was heated at 40° C. for 3 hours. Cooled to RT, diluted with EtOAc (50 mL) and water (50 mL), and the mixture was filtered through ^Celite® . The phases were separated and the aqueous phase was extracted with additional EtOAc (2 x 50 mL). The organic portions were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 30% EtOAc to 100% EtOAc in cyclohexane to yield 3.2 g (79%) of the title compound as a cream-colored solid. ES-MS m/z 315 (MH).

Production example 41

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

In a 250 mL Buchi ^® miniclave reactor, 4-[(1,3-dioxoisoindolin-2-yl)methyl]-3-(3-hydroxyprop-1-) in MeOH (60 mL) 1,1'-bis(di-i-propylphosphino)ferrocene(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate (0.34%) in a suspension of inyl)benzonitrile (3 g, 9.48 mmol). g, 0.47 mmol) was added. The reactor was charged with 90 psi of hydrogen and heated at 50°C for 2 hours. The reaction mixture was cooled to RT, the solvent was evaporated and the residue was purified through a silica plug using EtOAc as solvent to give 2.4 g (75%) of the title compound as a light cream colored solid. ES-MS m/z 321 (M+H).

Production example 42

4-(Aminomethyl)-3-(3-hydroxypropyl)benzonitrile

Hydrazine monohydrate in a suspension of 4-[(1,3-dioxoisoindolin-2-yl)methyl]-3-(3-hydroxypropyl)benzonitrile (2.4 g, 7.49 mmol) in MeOH (45 mL) (1.90 mL, 37.6 mmol) was added and stirred at 60°C for 20 hours. The reaction mixture was cooled to RT and the solid was filtered. The filtrate was evaporated and the residue was diluted with water (30 ml) and extracted with DCM/MeOH 9:1 (3x20 ml). The organic portions were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as a reddish oil (880 mg, 49%). ES-MS m/z 191 (M+H).

Production example 43

Methyl 2-(((5-bromo-4-fluoro-2-iodobenzyl)oxy)methyl)-4-cyanobenzoate

Sodium hydride (60% in mineral oil, 362 mg, 9.1%) in a solution of (5-bromo-4-fluoro-2-iodophenyl)methanol (1.5 g, 4.5 mmol) in THF (24 mL) at 0°C. mmol) was added. It was stirred at 0°C for 30 minutes. Methyl 2-(bromomethyl)-4-cyano-benzoate (2.3 g, 9.1 mmol) was added and stirred at RT for 1 hour. The reaction was diluted with EtOAc and the organic layer was washed with water and saturated aqueous NaCl. The aqueous layer was back-extracted with EtOAc. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified using DCM through silica gel flash chromatography to obtain 2.5 g (67%) of the title compound, which was 61% pure and used in Preparation Example 44 without further purification. ES-MS m/z 504 and 506 (M+H).

Production example 44

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

Methyl 2-(((5-bromo-4-fluoro-2-iodobenzyl)oxy)methyl)-4-cyanobenzoate (Preparation Example 43) and a 10:1 mixture of THF:MeOH as the reaction solvent The title compound was prepared essentially as described in Preparation Example 27 using The reaction was stirred at RT for 20 hours, then an additional portion of lithium borohydride (0.5 equiv) was added and stirred at RT for 2 hours. The reaction mixture was diluted with EtOAc and the organic layer was washed with water and saturated aqueous NaCl. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified via silica gel flash chromatography using a gradient from 0 to 50% EtOAc in heptane to give the title compound. ES-MS m/z 476 and 478 (M+H).

Production example 45

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

Ethyl 3-[2-(bromomethyl)-5-chloro-phenyl]propanoate (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) of 1,4-dioxane (40 mL) was added to the mixture. The reaction mixture was stirred at 40° C. for 15 hours. Filtered through a pad of ^Celite® and the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM, adsorbed onto silica, and purified via silica gel chromatography using a gradient from 0 to 40% EtOAc in hexane to give 1.16 g (37%) of the title compound. ES-MS m/z 398, 400 and 402 (M+H).

Production example 46

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

Lithium borohydride to a mixture of ethyl 3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-chloro-phenyl]propanoate (1.16 g, 2.90 mmol) in THF (12 mL). (2.0 M in THF, 3.2 mL, 6.4 mmol) was added dropwise. The reaction mixture was stirred at RT for 6 hours. An additional amount of lithium borohydride (2.0 M in THF, 2.0 mL, 4.0 mmol) was added. The reaction mixture was stirred at RT for an additional 17 hours. The reaction was quenched by dropwise addition of water. The mixture was diluted with EtOAc (50 mL) and washed with water (40 mL). The aqueous layer was back-extracted with EtOAc (25 mL). The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in DCM, adsorbed onto silica, and purified by silica gel flash chromatography, eluting with a gradient of 0 to 55% EtOAc in hexane, to give 461 mg (35%) of the title compound. ES-MS m/z 356, 358 and 360 (M+H).

Production example 47

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

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

Production example 48

4-[(3-bromophenoxy)methyl]-3-iodo-benzonitrile

1 to a mixture of 4-(bromomethyl)-3-iodo-benzonitrile (2.0 g, 6.2 mmol), 3-bromophenol (1.10 g, 6.4 mmol), and potassium carbonate (2.6 g, 19.0 mmol) ,4-dioxane (20 mL) was added. The reaction mixture was stirred at RT for 15 hours. The reaction was diluted with EtOAc (100 mL) and filtered through ^Celite® . The filtrate was washed with water (2 x 50 mL) and saturated aqueous NaCl (50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified via silica gel flash chromatography eluting with a gradient of 0 to 30% EtOAc in hexane to give 2.4 g of the title compound (93%). ¹ H NMR (400.13 MHz, CDCl ₃ ) δ 8.16 (d, J= 1.5 Hz, 1H), 7.71 (dd, J= 1.5, 8.0 Hz, 1H), 7.64 (d, J= 8.0 Hz, 1H), 7.23 -7.17 (m, 3H), 6.92 (dt, J= 7.5, 2.1 Hz, 1H), 5.05 (s, 2H).

Production example 49

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

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

Production example 50

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

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

Production example 51

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

[2-iodo-4-(trifluoromethyl)phenyl]methanol (2.0 g, 6.6 mmol), 2-bromo-6-fluoro-pyridine (1.2 g, 6.6 mmol), and 1,4-di To a mixture of oxane (25 mL) was added potassium tert-butoxide (0.98 g, 8.6 mmol). The reaction mixture was stirred at 50°C for 2 hours. The reaction was diluted with EtOAc (100 mL) and filtered through ^Celite® . The filtrate was washed with water (2 x 50 mL) and saturated aqueous sodium chloride (50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified via silica gel flash chromatography eluting with a gradient of 10 to 50% EtOAc in hexane to give 2.0 g (66%) of the title compound. ES-MS m/z 458 and 460 (M+H).

Production example 52

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

The title compound was prepared essentially as described in Preparation Example 28 using 2-bromo-6-[[2-iodo-4-(trifluoromethyl)phenyl]methoxy]pyridine. The title compound was purified via silica gel flash chromatography eluting with a gradient of 0 to 10% EtOAc in hexanes. It was used directly in Preparation Example 53 without further characterization.

Production example 53

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

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

Production example 54

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

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

Production example 55

Methyl 2-[2-[3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-chloro-phenyl]propoxy]-4-(4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate

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

Production example 56

Methyl 2-[2-[3-[2-[[(6-bromopyridin-2-yl)oxy]methyl]-5-cyanophenyl]propoxy]-4-(4,4,5,5 -Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate

4-[(6-bromo-2-pyridyl)oxymethyl]-3-(3-hydroxypropyl)benzonitrile (14.5 g, 41.9 mmol) and methyl 2-[2-hydride in THF (250 mL) tri-n-butylphosphatase in a mixture of oxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate (18.7 g, 63.9 mmol) Pin (21 mL, 84 mmol) was added. 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 x 25 mL) to give 19.7 g (76%) of the title compound. ES-MS m/z 621, 623 (M+H).

Production example 57

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

4-[[(6-bromo-2-pyridyl)amino]methyl]-3-(3-hydroxypropyl)benzonitrile (380 mg, 1.04 mmol) and ethyl 2 in THF (5.2 mL) at 4°C. -[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-fluoro-2-hydroxyphenyl]acetate (0.38 g, 1.15 mmol) Phenylphosphine (0.30 g, 1.15 mmol) and di-tertbutyl azodicarboxylate (0.27 g, 1.15 mmol) were added. After stirring at RT for 22 h, the reaction mixture was concentrated and the residue was purified via silica gel chromatography using a gradient of 10 to 70% EtOAc in cyclohexane to give the title compound as a light brown solid (500 mg, 60%). It was obtained as. ES-MS m/z 570 and 572 (M+H for boronic acid).

Production example 58

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-dioxaborolan-2-yl)phenyl]acetate

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

Production example 59

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-dioxaborolan-2-yl)phenyl]acetate

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

Production example 60

Ethyl 2-(4-bromo-2-(2-(2-(((6-bromopyridin-2-yl)oxy)methyl)-5-cyanophenoxy)ethoxy)-5-fluoro phenyl)acetate

4-(((6-bromopyridin-2-yl)oxy)methyl)-3-(2-hydroxyethoxy)benzonitrile (640 mg, 1.83 mmol), ethyl 2-( 4-Bromo-5-fluoro-2-hydroxy-phenyl)acetate (506 mg, 1.83 mmol), and TMAD (671 mg, 3.70 mmol) in a solution of tri-N-butylphosphine (0.91 mL, 3.65 mmol) mmol) was added. It was stirred at 35°C for 2 hours. The reaction was quenched with MeOH and the crude mixture was concentrated. The residue was purified via silica gel flash chromatography using a gradient from 0 to 30% EtOAc in heptane to give 876 mg (79%) of the title compound. ES-MS m/z 607, 609, and 611 (M+H).

Production example 61

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

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

Production example 62

Ethyl 2-(4-bromo-2-(((2-(((6-bromopyridin-2-yl)oxy)methyl)-5-cyanobenzyl)oxy)methyl)-5-fluorophenyl )acetate

3-(((5-bromo-4-fluoro-2-iodobenzyl)oxy)methyl)-4-(((6-bromopyridin-2-yl)oxy)methyl in ACN (75 mL) ) 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) in a solution of benzonitrile (2.69 mg, 4.3 mmol). mmol) was added. The reaction was stirred at 70° C. and a solution of ethyl diazoacetate (2 M in DCM, 8.5 mL, 17 mmol) in ACN (25 mL) was added over 10 min. It was stirred at 70°C for 2 hours. A second portion of all reagents (half the initial addition) was added and heated for an additional 1.5 hours. The reaction mixture was diluted with EtOAc and the organic layer was washed with water. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified via silica gel flash chromatography using a gradient of 0 to 10% EtOAc in heptane to give 898 mg (36%) of the title compound. ES-MS m/z 591, 593, and 595 (M+H).

Production example 63

Methyl 2-[2-[3-[2-[(3-bromophenoxy)methyl]-5-cyano-phenyl]propoxy]-5-methyl-4-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate

4-[(3-bromophenoxy)methyl]-3-(3-hydroxypropyl)benzonitrile and methyl 2-[2-hydroxy-5-methyl-4-(4,4,5,5- Using tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate, using 1,4-dioxane as the reaction solvent, and adding DEAD as a 40% solution in toluene, essentially The title compound was prepared as described in Preparation Example 54. The title compound was purified via silica gel flash chromatography eluting with a gradient of 80 to 100% DCM in hexanes. ES-MS m/z 651 and 653 (M+NH ₄ ⁺ ).

Production example 64

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-dioxaborolan-2-yl)phenyl]acetate

3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-(trifluoromethyl)phenyl]propan-1-ol and methyl 2-[2-hydroxy-5-methyl- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate was used and DEAD was added to the reaction as a 40% solution in toluene to obtain essentially The title compound was prepared as described in Preparation Example 54. The title compound was purified via silica gel flash chromatography eluting with a gradient of 85 to 100% DCM in hexanes. ES-MS m/z 678 and 680 (M+H).

Production example 65

Ethyl 2-(5 ⁴ -cyano- ^{1 6} -fluoro-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclo Nonaphan-1 ⁴ -1) Acetate

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

Production example 66

Methyl 2-(5 ⁴ -Chloro-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphan-1 ⁴ -yl )acetate

Methyl 2-[2-[3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-chloro-phenyl]propoxy]-4-(4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-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 Gen 2, 28.9 mg, 0.036 mmol), and potassium phosphate (420 mg, To the mixture (1.94 mmol) was added THF (48 mL) and water (5.4 mL). The reaction mixture was stirred at 40°C for 15 hours under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was dissolved in DCM, adsorbed onto ^Celite® , and purified via silica gel flash chromatography, eluting with a gradient of 0 to 40% EtOAc in hexanes, to give 152 mg (74%) of the title compound. ES-MS m/z 424 and 426 (M+H).

Production example 67

Methyl 2-(5 ⁴ -Cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane-1 ⁴ - 1) Acetate

Methyl 2-[2-[3-[2-[[(6-bromopyridin-2-yl)oxy]methyl]-5-cyanophenyl]propoxy]-4-(4,4,5,5 -Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate (19.7 g, 31.7 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-tri Isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (XPhos Gen 2, 1.3 g, 1.6 mmol), and potassium phosphate (28.5 g, 132 mmol) was added THF (500 mL) and water (52 mL). The reaction mixture was stirred at 45°C for 2 hours and 15 minutes under nitrogen atmosphere. The reaction was diluted with EtOAc (200 mL) and washed with half-saturated brine (400 mL). The organic phase was dried over MgSO ₄ , 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 x 30 mL) to give 10.7 g (82%) of the title compound. ES-MS m/z 415 (M+H).

Production example 68

Ethyl 2-(5 ⁴ -cyano-1 ⁶ -fluoro-9-oxa-3-aza-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzena Cyclononaphan-1 ⁴ -yl)acetate

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

Production example 69

Methyl 2-(5 ⁴ -Cyano-1 ⁶ -methyl-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclonona Edition-1 ⁴ -day) Acetate

Methyl 2-[2-[3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano-phenyl]propoxy]-5-methyl-4-(4,4, The title compound was prepared essentially as described in Preparation Example 66 using 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate. Purified via silica gel flash chromatography using a gradient from 0 to 20% EtOAc in DCM. ES-MS m/z 429 (M+H).

Production example 70

Ethyl 2-(5 ⁴ -cyano-1 ⁶ -fluoro-3,9-dioxa-2(2,6)-pyridina-1,5(1,3)-dibenzenacyclononaphane- ^{1 4} -1) Acetate

Ethyl 2-[2-[3-[5-[(6-bromo-2-pyridyl)oxymethyl]-2-cyano-phenyl]propoxy]- in 1,4-dioxane (30 mL) A solution of 5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate (650 mg, 90% purity, 0.89 mmol) To which PdCl ₂ (dtbpf) (119 mg, 0.18 mmol) and 1M aqueous potassium phosphate 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. Dry over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified via silica gel flash chromatography using a gradient of 10 to 30% EtOAc in cyclohexane to give the title compound (150 mg, 38%) as a very light brown solid. ES-MS m/z 447 (M+H).

Production example 71

Ethyl 2-(5 ⁴ -cyano- ^{1 6} -fluoro-3,6,9-trioxa-2(2,6)-pyridina-1(1,3),5(1,2)-diben Zenacyclononaphan-1 ⁴ -yl)acetate

Ethyl 2-(4-bromo-2-(2-(2-(((6-bromopyridin-2-yl)oxy)methyl)-5-cyano in 1,4-dioxane (2.2 mL) Pd in a solution of phenoxy) ethoxy) -5-fluorophenyl) acetate (400 mg, 0.66 mmol), KOAc (0.2 g, 2.0 mmol), and bis(pinacolato)diborone (187 mg, 0.72 mmol). (dppf)Cl ₂ -DCM complex (27 mg, 0.032 mmol) was added. 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. To the residue was added THF (66 mL), potassium phosphate tribasic (0.6 g, 3.0 mmol), water (7.3 mL), and palladium(II) chloride (6.0 mg, 0.033 mmol) in THF (1 mL) and 2-dish. A previously prepared solution of chlorhexylphosphine-2',4',6'-triisopropylbiphenyl (32 mg, 0.066 mmol) was added. It was stirred at 45°C for 16 hours. 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 via silica gel flash chromatography using a gradient from 0 to 30% EtOAc in heptane to give 94 mg (32%) of the title compound. ES-MS m/z 449 (M+H).

Production example 72

Ethyl 2-(5 ⁴ -cyano- ^{1 6} -fluoro-3,7-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclo octaphane-1 ⁴ -yl)acetate

Ethyl 2-(4-bromo-2-(((2-(((6-bromopyridin-2-yl)oxy)methyl)-5-cyanobenzyl)oxy)methyl)-5-fluorophenyl ) acetate, using 1.1 equivalents of hexamethyldistin and Pd(dppf)Cl ₂ -DCM as catalyst, and stirring the reaction at 100° C. for 3.5 hours to prepare the title compound essentially as described in Preparation Example 65. did. 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 via silica gel flash chromatography using a gradient from 0 to 80% EtOAc in heptane to give the title compound. ES-MS m/z 433 (M+H).

Production example 73

Methyl 2-(5 ⁴ -cyano-1 ⁶ -methyl-3,9-dioxa-1,2(1,3),5(1,2)-tribenzenacyclononaphan-1 ⁴ -yl) acetate

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

Production example 74

Methyl 2-(1 ⁶ -methyl-5 ⁴ -(trifluoromethyl)-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)- Dibenzenacyclononaphan-1 ⁴ -yl)acetate

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-dioxaborolan-2-yl) phenyl] acetate, and the reaction was stirred at 40° C. for 1 hour to obtain a reaction mixture essentially as described in Preparation Example 66. The title compound was prepared similarly. The title compound was purified via silica gel flash chromatography eluting with a gradient from 0 to 20% EtOAc in DCM. ES-MS m/z 472 (M+H).

Production example 75

2-(5 ⁴ -cyano-1 ⁶ -fluoro-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclonona Edition-1 ⁴ -day) Acetic acid

ACN:ethyl 2-(5 ⁴ -cyano- ^{1 6} -fluoro-3,9-dioxa-2(2,6)-pyridina-1(1,3) in water (5 mL:0.5 mL) , ^1,3,4,6,7,8 -hexahydro-2H-pyrimido[ 1,2-a]pyrimidine (0.30 g, 2.0 mmol) was added. The reaction mixture was stirred at RT for 15 hours. The pH of the reaction mixture was adjusted to pH 7 using 1.0 M aqueous citric acid 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 aqueous NaCl (50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 238 mg (88%) of the title compound, which was used in crude form in Preparations 85 and 86. ES-MS m/z 419 (M+H).

Production example 76

2-(5 ⁴ -Chloro-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphan-1 ⁴ -yl) acetic acid

Methyl 2-(5 ⁴ -chloro-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2) in ACN (3.6 mL) and THF (3 mL) )-Dibenzenacyclononaphan-1 ⁴ -yl)acetate (152 mg, 0.36 mmol) was added to 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 aqueous citric acid solution (1.0 M, 2.2 mL) and then diluted with EtOAc. The aqueous layer was removed and extracted with EtOAc (2 x 3 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 150 mg (100%) of the title compound, which was used in crude form in Preparation Example 87. ES-MS m/z 410 (M+H).

Production example 77

2-(5 ⁴ -Cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane-1 ⁴ -yl )acetic acid

Methyl 2-(5 ⁴ Cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphan-1 ⁴ -yl ) The title compound was prepared essentially as described in Preparation Example 75, starting with acetate. After the reaction was completed, it was cooled to RT and neutralized with an aqueous solution of citric acid. The resulting precipitate was filtered and the resulting filter cake was dried under vacuum to obtain the title compound (100%). ES-MS m/z 401 (M+H)

Production example 78

2-(5 ⁴ -cyano-1 ⁶ -fluoro-9-oxa-3-aza-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclo Nonapan-1 ⁴ -1) Acetic acid

Ethyl 2-(5 ⁴ -cyano-1 6 -fluoro-9-oxa- ³ -aza-2(2,6)-pyri in ACN (3 mL), THF (1 mL) and water (1 mL) 1,5,7 ^- triazabicyclo [4.4. 0]des-5-ene (116 mg, 0.81 mmol) was added. Stirred at 45°C for 2 h, cooled to RT and quenched with 1M citric acid solution (2 mL). Extracted with EtOAc (3 x 3 mL). The organic portions were combined, washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a waxy light yellow solid (115 mg, 100%). ES-MS m/z 418 (M+H).

Production example 79

2-(5 ⁴ -Cyano-1 ⁶ -methyl-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane -1 ⁴ -day) Acetic acid

Methyl 2-(5 ⁴ -Cyano-1 ⁶ -methyl-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclonona The title compound was prepared essentially as described in Preparation Example 75 using Pan-1 ⁴ -yl)acetate. ES-MS m/z 415 (M+H).

Production example 80

2-(5 ⁴ -cyano-1 ⁶ -fluoro-3,9-dioxa-2(2,6)-pyridina-1,5(1,3)-dibenzenacyclononaphane-1 ⁴ - 1) Acetic acid

Ethyl 2-(5 ⁴ -cyano-1 ⁶ -fluoro-3,9-dioxa-2(2,6)-pyridina-1,5(1,3)-dibenzenacyclononaphane- ^{1 4} The title compound was prepared essentially as described in Preparation Example 78 using -yl)acetate. ES-MS m/z 419 (M+H).

Production example 81

2-(5 ⁴ -cyano-1 ⁶ -fluoro-3,6,9-trioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzena Cyclononaphan-1 ⁴ -yl)acetic acid

Ethyl 2-(5 ⁴ -cyano- ^{1 6} -fluoro-3,6,9-trioxa-2(2,6)-pyridina-1(1,3),5(1,2)-diben The title compound was prepared essentially as described in Preparation Example 75 using zenacyclononapan-1 ⁴ -yl)acetate and stirring the reaction at 45° C. for 3 hours. The reaction was quenched to pH 7 with formic acid and diluted with water. Extracted three times with EtOAc and then three times with 3:1 chloroform:isopropanol. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified via silica gel flash chromatography using a gradient of 10 to 80% EtOAc in DCM to give the title compound. ES-MS m/z 421 (M+H).

Production example 82

2-(5 ⁴ -cyano-1 ⁶ -fluoro-3,7-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacycloocta Edition-1 ⁴ -day) Acetic acid

Ethyl 2-(5 ⁴ -cyano- ^{1 6} -fluoro-3,7-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclo The title compound was prepared essentially as described in Preparation Example 75, using octapan-1 ⁴ -yl) and stirring the reaction at 45° C. for 1 hour. The reaction was quenched with formic acid to pH 6-7 and extracted with EtOAc followed by 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 in crude form in Preparation 98. ES-MS m/z 405 (M+H).

Production example 83

2-(5 ⁴ -cyano-1 ⁶ -methyl-3,9-dioxa-1,2(1,3),5(1,2)-tribenzenacyclononaphan-1 ⁴ -yl)acetic acid

Methyl 2-(5 ⁴ -cyano-1 ⁶ -methyl-3,9-dioxa-1,2(1,3),5(1,2)-tribenzenacyclononaphan-1 ⁴ -yl) The title compound was prepared essentially as described in Preparation Example 75 using acetate and stirring the reaction mixture at 45° C. for 1 hour. In Preparation Example 99, the crude form of the title compound was used. ES-MS m/z 412 (MH).

Manufacturing example 84

2-(1 ⁶ -methyl-5 ⁴ -(trifluoromethyl)-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-diben Zenacyclononaphan-1 ⁴ -yl)acetic acid

Methyl 2-(1 ⁶ -methyl-5 ⁴ -(trifluoromethyl)-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)- The title compound was prepared essentially as described in Preparation Example 75 using dibenzenacyclononaphan-1 ⁴ -yl)acetate and stirring the reaction at 50° C. for 1 hour. In Preparation Example 100, the crude form of the title compound was used. ES-MS m/z 458 (M+H).

Production example 85

Methyl (S)-4-(2-(5 ⁴ -cyano- ^{1 6} -fluoro-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1 ,2)-dibenzenacyclononaphan-1 ⁴ -yl)acetamido)-3-((oxetan-2-ylmethyl)amino)benzoate

2-(5 ⁴ -cyano- ^{1 6} -fluoro-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2) in pyridine (3 mL) )-Dibenzenacyclononapan-1 ⁴ -yl)acetic acid (crude, 0.170 g, 0.361 mmol) and methyl 4-amino-3-[[(2S)-oxetan-2-yl]methylamino]benzoate (prepared essentially as described in WO 2020/263695; 100 mg, 0.423 mmol) was added EDC (125 mg, 0.639 mmol). The reaction mixture was stirred at RT for 15 hours. The reaction was quenched to pH 6 with saturated aqueous ammonium chloride. The mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic portions were washed with saturated aqueous sodium chloride (10 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography, eluting with a gradient of 0 to 50% EtOAc in petroleum ether to yield 225 mg (71%) of the title compound. ES-MS m/z 637 (M+H).

Production example 86

Methyl (S)-4-(2-(5 ⁴ -cyano- ^{1 6} -fluoro-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1 ,2)-Dibenzenacyclononaphan-1 ⁴ -yl)acetamido)-3-fluoro-5-((oxetan-2-ylmethyl)amino)benzoate

2-(5 ⁴ -cyano- ^{1 6} -fluoro-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2) in DMF (5 mL) )-Dibenzenacyclononapan-1 ⁴ -yl)acetic acid (238 mg, 0.568 mmol) and methyl 4-amino-3-fluoro-5-[[(2S)-oxetan-2-ylmethyl]amino] To a mixture of benzoate (0.20 g, 0.79 mmol) was added DIPEA (0.15 mL, 0.86 mmol). HATU (0.20 g, 0.53 mmol) was added. Stirred at RT for 4 hours. The reaction was diluted with EtOAc (100 mL) and washed with water (50 mL) and saturated aqueous NaCl (50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 0.46 g (99%) of the title compound, which was used in crude form in Preparation Example 102. ES-MS m/z 655 (M+H).

Production example 87

Methyl (S)-4-(2-(5 ⁴ -chloro-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclo Nonapan-1 ⁴ -yl)acetamido)-3-((oxetan-2-ylmethyl)amino)benzoate

2-(5 ⁴ -Chloro-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphan-1 ⁴ -yl) Acetic acid and methyl 4-amino-3-[[(2S)-oxetan-2-yl]methylamino]benzoate (prepared essentially as described in WO 2020/263695) were used, followed by 16 h before work-up. The title compound was prepared essentially as described in Preparation Example 86 while the reaction was stirred. The title compound was used in crude form in Preparation Example 104. ES-MS m/z 628 (M+H).

Manufacturing example 88

Methyl (S)-4-(2-(5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzena Cyclononaphan-1 ⁴ -yl)acetamido)-3-((oxetan-2-ylmethyl)amino)benzoate

2-(5 ⁴ -Cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane-1 ⁴ -yl ) Preparation Example 86 essentially using acetic acid and methyl 4-amino-3-[[(2S)-oxetan-2-yl]methylamino]benzoate (prepared essentially as described in WO 2020/263695) The title compound was prepared as described. The crude title compound was obtained and used in Preparation Example 105 without purification. ES-MS m/z 619 (M+H)

Manufacturing example 89

Methyl (S)-4-(2-(5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzena Cyclononaphan-1 ⁴ -yl)acetamido)-3-methoxy-5-((oxetan-2-ylmethyl)amino)benzoate

2-(5 ⁴ -Cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane-1 ⁴ -yl ) Acetic acid and methyl 4-amino-3-methoxy-5-[[(2S)-oxetan-2-yl]methylamino]benzoate (Preparation 17) essentially as described in Preparation 86. The title compound was prepared. The residue was purified via silica gel chromatography using a gradient of 5 to 80% EtOAc in DCM to give the title compound. ES-MS m/z 649 (M+H).

Production example 90

Methyl (S)-5-(2-(5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzena Cyclononapan-14-yl)acetamido)-6-((oxetan-2-ylmethyl)amino)picolinate

2-(5 ⁴ -Cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane-1 ⁴ -yl )The title compound essentially as described in Preparation Example 86 using acetic acid (0.3 g, 0.75 mmol) and methyl (S)-5-amino-6-((oxetan-2-ylmethyl)amino)picolinate was manufactured. The title compound was used in the next step (Preparation Example 107) without purification. ES-MS m/z 620 (M+H)

Production example 91

Methyl (S)-4-(2-(5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzena Cyclononaphan-1 ⁴ -yl)acetamido)-3-fluoro-5-((oxetan-2-ylmethyl)amino)benzoate

2-(5 ⁴ -Cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane-1 ⁴ -yl ) The title compound was prepared essentially as described in Preparation Example 86 using acetic acid and methyl 4-amino-3-fluoro-5-[[(2S)-oxetan-2-ylmethyl]amino]benzoate . The title compound was used in the next step (Preparation Example 108) without purification. ES-MS m/z 637 (M+H)

Production example 92

Methyl (S)-4-(2-(5 ⁴ -cyano- ^{1 6} -fluoro-9-oxa-3-aza-2(2,6)-pyridina-1(1,3),5( 1,2)-dibenzenacyclononaphan-1 ⁴ -yl)acetamido)-3-((oxetan-2-ylmethyl)amino)benzoate

2-(5 ⁴ -cyano-1 ⁶ -fluoro-9-oxa-3-aza-2(2,6)-pyridina-1(1,3),5(1, 2)-Dibenzenacyclononapan-1 methyl ^4- amino-3-[[(2S)-oxetan-2-yl]methylamino]benzoate in a solution of 4-yl)acetic acid (115 mg, 0.27 mmol) (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. Stirred at RT for 2 hours, diluted with water (10 mL) and extracted with EtOAc (4 x 5 mL). The organics were combined, washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a brown solid (160 mg, 79%). ES-MS m/z 636 (M+H).

Production example 93

Methyl (S)-4-(2-(5 ⁴ -cyano-1 6 -methyl- ^3,9 -dioxa-2(2,6)-pyridina-1(1,3),5(1, 2)-Dibenzenacyclononaphan-1 ⁴ -yl)acetamido)-3-methoxy-5-((oxetan-2-ylmethyl)amino)benzoate

2-(5 ⁴ -Cyano-1 ⁶ -methyl-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane Preparation essentially using -1 ⁴ -yl)acetic acid and methyl 4-amino-3-methoxy-5-[[(2S)-oxetan-2-yl]methylamino]benzoate (Preparation Example 17) The title compound was prepared as described in 86. The title compound was used as crude product in the next step (preparation 103) without purification. ES-MS m/z 663 (M+H).

Production example 94

Methyl (S)-4-(2-(5 ⁴ -cyano-1 ⁶ -fluoro-3,9-dioxa-2(2,6)-pyridina-1,5(1,3)-diben Zenacyclononapan-1 ⁴ -yl)acetamido)-3-((oxetan-2-ylmethyl)amino)benzoate

2-(5 ⁴ -cyano-1 ⁶ -fluoro-3,9-dioxa-2(2,6)-pyridina-1,5(1,3)-dibenzenacyclononaphane-1 ⁴ - 1) Preparation example essentially using acetic acid and methyl 4-amino-3-[[(2S)-oxetan-2-yl]methylamino]benzoate (prepared essentially as described in WO 2020/263695) The title compound was prepared as described in 86. The title compound was used in its crude form without purification in Preparation Example 110. ES-MS m/z 637 (M+H).

Production example 95

Methyl 4-(2-(5 ⁴ -Cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane- 1 ⁴ -yl)acetamido)-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate

2-(5 ⁴ -Cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane-1 ⁴ -yl ) Acetic acid (100 mg, 0.25 mmol) and methyl 4-amino-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate (Preparation Example 19) The title compound was prepared as described in Example 86. The reaction was stirred at RT for 18 hours, then diluted with water and EtOAc, and the aqueous layer was extracted 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 in crude form in Preparation Example 111. ES-MS m/z 657 (M+H).

Production example 96

(S)-2-(5 ⁴ -Cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane- 1 ⁴ -yl)-N-(2-methoxy-6-((oxetan-2-ylmethyl)amino)-4-(1H-tetrazol-5-yl)phenyl)acetamide

2-(5 ⁴ -Cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane-1 ⁴ -yl ) Example of preparation essentially using acetic acid and (S)-3-methoxy-N1-(oxetan-2-ylmethyl)-5-(1H-tetrazol-5-yl)benzene-1,2-diamine The title compound was prepared as described in 86. Stirred at RT for 67 hours. The mixture was diluted with water and EtOAc, and the aqueous layer was extracted with EtOAc. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified via silica gel flash chromatography using a gradient of 0 to 100% EtOAc in heptane followed by 0 to 10% MeOH in DCM. ES-MS m/z 659 (M+H).

Production example 97

Methyl (S)-4-(2-(5 ⁴ -cyano- ^{1 6} -fluoro-3,6,9-trioxa-2(2,6)-pyridina-1(1,3),5 (1,2)-dibenzenacyclononaphan-1 ⁴ -yl)acetamido)-3-((oxetan-2-ylmethyl)amino)benzoate

2-(5 ⁴ -cyano-1 ⁶ -fluoro-3,6,9-trioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzena Cyclononapan-1 ⁴ -yl)acetic acid and methyl 4-amino-3-[[(2S)-oxetan-2-yl]methylamino]benzoate (prepared essentially as described in WO 2020/263695) The title compound was prepared essentially as described in Preparation Example 86 using and stirring the reaction at RT for 24 hours. The crude reaction was diluted with water and extracted three times with EtOAc. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound, which was used in crude form in Preparation Example 112. ES-MS m/z 639 (M+H).

Production example 98

Methyl (S)-4-(2-(5 ⁴ -cyano- ^{1 6} -fluoro-3,7-dioxa-2(2,6)-pyridina-1(1,3),5(1 ,2)-dibenzenacyclooctaphane-1 ⁴ -yl)acetamido)-3-((oxetan-2-ylmethyl)amino)benzoate

2-(5 ⁴ -cyano-1 ⁶ -fluoro-3,7-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacycloocta Pan-1 using ⁴ -yl)acetic acid and methyl 4-amino-3-[[(2S)-oxetan-2-yl]methylamino]benzoate (prepared essentially as described in WO 2020/263695) and the reaction was stirred at RT for 2 hours to prepare the title compound essentially as described in Preparation Example 86. The reaction was diluted with water and EtOAc, and the aqueous layer was extracted with EtOAc. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound, which was used in crude form in Preparation Example 113. ES-MS m/z 623 (M+H).

Manufacturing example 99

Methyl (S)-4-(2-(5 ⁴ -cyano-1 ⁶ -methyl-3,9-dioxa-1,2(1,3),5(1,2)-tribenzenacyclonona Pan-1 ⁴ -yl)acetamido)-3-methoxy-5-((oxetan-2-ylmethyl)amino)benzoate

2-(5 ⁴ -cyano-1 ⁶ -methyl-3,9-dioxa-1,2(1,3),5(1,2)-tribenzenacyclononaphan-1 ⁴ -yl)acetic acid (Preparation Example 83) and methyl 4-amino-3-methoxy-5-[[(2S)-oxetan-2-yl]methylamino]benzoate (Preparation Example 17), essentially as in Preparation Example 85. The title compound was prepared as described. The title compound was used in Preparation Example 114 without purification. ES-MS m/z 662 (M+H).

Production example 100

Methyl (S)-3-methoxy-4-(2-(1 ⁶ -methyl-5 ⁴ -(trifluoromethyl)-3,9-dioxa-2(2,6)-pyridina-1( 1,3),5(1,2)-dibenzenacyclononaphan-1 ⁴ -yl)acetamido)-5-((oxetan-2-ylmethyl)amino)benzoate

2-(1 ⁶ -methyl-5 ⁴ -(trifluoromethyl)-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-diben Zenacyclononaphan-1 ⁴ -yl) acetic acid (Preparation Example 84) and methyl 4-amino-3-methoxy-5-[[(2S)-oxetan-2-yl]methylamino]benzoate (Preparation Example The title compound was prepared essentially as described in Preparation Example 85 using 17). The title compound was used as crude product in Preparation Example 115 without purification. ES-MS m/z 706 (M+H).

Manufacturing Example 101

Methyl (S)-2-((5 ⁴ -cyano-1 ⁶ -fluoro-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2 )-Dibenzenacyclononapan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

Methyl (S)-4-(2-(5 ⁴ -cyano- ^{1 6} -fluoro-3,9-dioxa-2(2,6)-pyridina-1(1, 3),5(1,2)-dibenzenacyclononaphan-1 ⁴ -yl)acetamido)-3-((oxetan-2-ylmethyl)amino)benzoate (220 mg, 0.295 mmol) The solution was stirred at 80°C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to give 200 mg (87%) of the title compound, which was used in crude form in Example 1. ES-MS m/z 619 (M+H).

Manufacturing Example 102

Methyl (S)-2-((5 ⁴ -cyano-1 ⁶ -fluoro-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2 )-Dibenzenacyclononapan-1 ⁴ -yl)methyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

Methyl (S)-4-(2-(5 ⁴ -cyano- ^{1 6} -fluoro-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1 ,2)-Dibenzenacyclononaphan-1 ⁴ -yl)acetamido)-3-fluoro-5-((oxetan-2-ylmethyl)amino)benzoate (0.46 g, 0.56 mmol) was dissolved in acetic acid. (5.0 mL) and 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 via silica gel chromatography using a gradient of 5 to 60% EtOAc in hexane to give 0.24 g (67%) of the title compound. ES-MS m/z 637 (M+H).

Manufacturing Example 103

Methyl (S)-2-((5 ⁴ -cyano- ^{1 6} -methyl-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2) -Dibenzenacyclononapan-1 ⁴ -yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

Methyl (S)-4-(2-(5 ⁴ -cyano-1 6 -methyl- ^3,9 -dioxa-2(2,6)-pyridina-1(1,3),5(1, 2)-Dibenzenacyclononaphan-1 ⁴ -yl)acetamido)-3-methoxy-5-((oxetan-2-ylmethyl)amino)benzoate (Preparation Example 93) and 1:1 DCM :The title compound was prepared essentially as described in Preparation Example 102 using acetic acid. Purified via silica gel flash chromatography using a gradient of 5 to 60% EtOAc in DCM. ES-MS m/z 645 (M+H).

Manufacturing Example 104

Methyl (S)-2-((5 ⁴ -chloro-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane -1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

Methyl (S)-4-(2-(5 ⁴ -chloro-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclo Using nonapan-1 ⁴ -yl)acetamido)-3-((oxetan-2-ylmethyl)amino)benzoate, the reaction mixture was heated at 55°C for 3.5 hours, then at 65°C for 2 hours. The title compound was prepared essentially as described in Preparation Example 102 with stirring. The mixture was concentrated under reduced pressure and azeotroped with ACN. The residue was dissolved in DCM, adsorbed onto ^Celite® and purified via silica gel chromatography eluting with a gradient of 0 to 100% EtOAc in hexanes. ES-MS m/z 610 (M+H).

Manufacturing Example 105

Methyl (S)-2-((5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclonona Pan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

1:1 dichloroethane:methyl (S)-4-(2-(5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5 in acetic acid Preparation essentially using (1,2)-dibenzenacyclononaphan-1 ⁴ -yl)acetamido)-3-((oxetan-2-ylmethyl)amino)benzoate (Preparation Example 88) The title compound was prepared as described in 102. The residue was purified via silica gel chromatography using a gradient of 5 to 60% EtOAc in DCM to give the title compound. ES-MS m/z 601 (M+H).

Manufacturing Example 106

Methyl (S)-2-((5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclonona Pan-1 ⁴ -yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

1:1 dichloroethane:methyl (S)-4-(2-(5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5 in acetic acid Example of preparation essentially using (1,2)-dibenzenacyclononaphan- ¹⁴ -yl)acetamido)-3-methoxy-5-((oxetan-2-ylmethyl)amino)benzoate The title compound was prepared as described in 102. The residue was purified via silica gel chromatography using a gradient of 5 to 60% EtOAc in DCM to give the title compound. ES-MS m/z 631 (M+H).

Manufacturing Example 107

Methyl (S)-2-((5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclonona Pan-1 ⁴ -yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate

1:1 dichloroethane:methyl (S)-5-(2-(5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5 in acetic acid (1,2)-dibenzenacyclononaphan-14-yl)acetamido)-6-((oxetan-2-ylmethyl)amino)picolinate was used and the reaction time was increased to 48 hours. The title compound was prepared essentially as described in Preparation Example 102. The residue was purified via silica gel chromatography using a gradient of 5 to 60% EtOAc in DCM to give the title compound. ES-MS m/z 602 (M+H).

Manufacturing Example 108

Methyl (S)-2-((5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclonona Pan-1 ⁴ -yl)methyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

Methyl (S)-4-(2-(5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5 in 1:1 dichloroethane and acetic acid (1,2)-Dibenzenacyclononaphan-1 ⁴ -yl)acetamido)-3-fluoro-5-((oxetan-2-ylmethyl)amino)benzoate (0.38 g, 0.48 mmol) The title compound was prepared essentially as described in Preparation Example 102. The residue was purified via silica gel chromatography using a gradient of 5 to 60% EtOAc in DCM to give 0.24 g (67%) of the title compound. ES-MS m/z 619 (M+H).

Manufacturing Example 109

Methyl (S)-2-((5 ⁴ -cyano-1 ^{6 -fluoro-9-oxa-3} -aza-2(2,6)-pyridina-1(1,3),5(1, 2)-Dibenzenacyclononaphan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

Methyl (S)-4-(2-(5 ⁴ -cyano-1 6 -fluoro-9-oxa- ³ -aza-2() in 1,2-dichloroethane (1.5 mL) and acetic acid (1.25 mL) 2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononapan-1 ⁴ -yl)acetamido)-3-((oxetan-2-ylmethyl) A solution of amino)benzoate (160 mg, 0.20 mmol) was heated at 50° C. for 6 hours. The reaction mixture was cooled to RT, the solvents were concentrated under reduced pressure, and the residue was purified via silica gel chromatography using a gradient of 10 to 50% EtOAc in DCM to give 70 mg (53%) of the title compound as a white solid. Obtained. ES-MS m/z 618 (M+H).

Production example 110

Methyl (S)-2-((5 ⁴ -cyano- ^{1 6} -fluoro-3,9-dioxa-2(2,6)-pyridina-1,5(1,3)-dibenzenacyclo Nonapan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

Methyl (S)-4-(2-(5 ⁴ -cyano-1 ⁶ -fluoro-3,9-dioxa-2(2,6)-pyridina-1,5(1,3)-diben Zenacyclononaphan-1 ⁴ -yl) acetamido) -3-((oxetan-2-ylmethyl) amino) benzoate was used and the reaction mixture was stirred at 60° C. for 5.5 hours, essentially producing the preparation example. The title compound was prepared as described in 109. The mixture was cooled to RT and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 10 to 30% EtOAc in DCM. ES-MS m/z 619 (M+H).

Production example 111

Methyl 2-((5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane-1 ⁴ -yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate

Methyl 4-(2-(5 ⁴ -Cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane- 1 ⁴ -yl)acetamido)-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate (Preparation Example 95) was used, and the reactant was incubated at 65°C for 5 hours. followed by stirring at 80° C. for 17 hours to prepare the title compound essentially as described in Preparation Example 101. The solution was concentrated and azeotroped with ACN. The residue was purified via silica gel chromatography using a gradient of 0 to 100% EtOAc in heptane followed by a gradient of 0 to 10% MeOH in DCM. ES-MS m/z 639 (M+H).

Production example 112

Methyl (S)-2-((5 ⁴ -cyano- ^{1 6} -fluoro-3,6,9-trioxa-2(2,6)-pyridina-1(1,3),5(1 ,2)-Dibenzenacyclononaphan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

Methyl (S)-4-(2-(5 ⁴ -cyano- ^{1 6} -fluoro-3,6,9-trioxa-2(2,6)-pyridina-1(1,3),5 (1,2)-Dibenzenacyclononaphan-1 ⁴ -yl)acetamido)-3-((oxetan-2-ylmethyl)amino)benzoate was used, and the reaction was incubated at 65°C for 3 hours. With stirring, the title compound was prepared essentially as described in Preparation Example 101. The reaction was concentrated and azeotroped with ACN. The residue was purified via silica gel flash chromatography using a gradient from 0 to 100% EtOAc in heptane followed by a gradient from 0 to 2% MeOH in DCM to give the title compound. ES-MS m/z 621 (M+H).

Manufacturing Example 113

Methyl (S)-2-((5 ⁴ -cyano-1 ⁶ -fluoro-3,7-dioxa-2(2,6)-pyridina-1(1,3),5(1,2 )-Dibenzenacyclooctaphan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

Methyl (S)-4-(2-(5 ⁴ -cyano- ^{1 6} -fluoro-3,7-dioxa-2(2,6)-pyridina-1(1,3),5(1 ,2)-Dibenzenacyclooctaphan-1 ⁴ -yl)acetamido)-3-((oxetan-2-ylmethyl)amino)benzoate was used, and the reaction was stirred at 65°C for 1.5 hours. The title compound was prepared essentially as described in Preparation Example 101. The solution was concentrated, azeotroped with ACN, and the residue was purified via silica gel flash chromatography using a gradient from 0 to 60% EtOAc in heptane to give the title compound. ES-MS m/z 605 (M+H).

Production example 114

Methyl (S)-2-((5 ⁴ -cyano-1 ⁶ -methyl-3,9-dioxa-1,2(1,3),5(1,2)-tribenzenacyclononaphane- 1 ⁴ -yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

1:1 dichloroethane:methyl (S)-4-(2-(5 ⁴ -cyano-1 ⁶ -methyl-3,9-dioxa-1,2(1,3),5(1, 2) -Tribenzenacyclononaphan-1 ⁴ -yl)acetamido)-3-methoxy-5-((oxetan-2-ylmethyl)amino)benzoate (Preparation Example 99) The title compound was prepared as described in Preparation Example 102. ES-MS m/z 645 (M+H).

Manufacturing Example 115

Methyl (S)-4-methoxy-2-((1 ⁶ -methyl-5 ⁴ -(trifluoromethyl)-3,9-dioxa-2(2,6)-pyridina-1(1, 3),5(1,2)-dibenzenacyclononaphan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

1:1 dichloroethane:methyl (S)-3-methoxy-4-(2-(1 ⁶ -methyl-5 ⁴ -(trifluoromethyl)-3,9-dioxa-2(2, 6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononapan-1 ⁴ -yl)acetamido)-5-((oxetan-2-ylmethyl)amino) The title compound was prepared essentially as described in Preparation 102 using benzoate (Preparation 100). The title compound was purified via silica gel chromatography using a gradient from 80 to 100% DCM in hexane. ES-MS m/z 688 (M+H).

Manufacturing Example 116

Methyl 2-(4-bromo-2-methylphenyl)acetate

Thionyl chloride (2.5 mL, 34.3 mmol) was added dropwise over 15 min to a 4°C solution of 2-(4-bromo-2-methylphenyl)acetic acid (5 g, 20.74 mmol) in MeOH (42 mL). The reaction was stirred for 3 hours, then the solvent was evaporated under reduced pressure. To the residue was added water (50 mL) and saturated aqueous NaHCO ₃ to bring the solution to pH = 7-8 and then extracted with EtOAc (3 x 30 mL). The organics were combined, washed with water and saturated aqueous NaCl, dried over MgSO ₄ , filtered and concentrated under reduced pressure to give the title compound as an orange oil (5.06 g, 100%). The title compound did not ionize by LCMS and was used in Preparation 117 without further characterization.

Manufacturing Example 117

Methyl-4-bromo-2-(bromomethyl)phenyl acetate

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 illuminated with a 4 x 370 nm lamp. and a photochemical flow reactor (reactor size = 52 mL, residence time = 1.3 mL/min, 40°C) equipped with 4 x 440 nm lamps. The solution was collected over 2 hours, the solvent was evaporated, and then water (20 mL) and MTBE (20 mL) were added to the residue. The layers were separated and the aqueous phase was extracted with MTBE (2 x 20 mL). The organic portions were combined, washed with 20% aqueous NaHSO ₃ solution, water, and saturated aqueous NaCl, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 10 to 40% DCM in cyclohexane to give the title compound as a white waxy solid (5.1 g, 85% purity, 75% yield). ES-MS m/z 338/340/342 (M+NH ₄ ⁺ ).

Manufacturing Example 118

Methyl 3-fluoro-5-methoxy-4-nitro-benzoate

A solution of sodium methylate (25% by mass in MeOH, 0.33 mL, 1.44 mmol) was added to a solution of methyl 3,5-difluoro-4-nitro-benzoate (0.3 g, 1.38 mmol) in MeOH (4 mL). After addition, the reaction was heated at 65°C for 2.5 hours. The reaction mixture was cooled to RT, then water was added and extracted with EtOAc (3 x 5 mL). The organics were combined, washed with saturated aqueous NaCl, dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified via silica gel chromatography using a gradient of EtOAc in heptane (0 to 10%) to afford 245 mg (76%) of the title compound as a yellow oil. ES-MS m/z 230 (M+H).

Manufacturing Example 119

Ethyl 3-fluoro-5-methoxy-4-nitro-benzoate

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

Manufacturing example 120

Methyl 3-fluoro-5-(2-methoxyethoxy)-4-nitro-benzoate

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

Manufacturing example 121

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

Ethyl 3-fluoro-5-methoxy-4-nitro-benzoate (0.30 g, 1.0 mmol) and 1-(1,3-oxazol-2-yl)methanamine hydrochloride (0.20 g, 1.0 mmol) The title compound was prepared essentially as described in Preparation Example 14. The title compound was purified via silica gel chromatography using a gradient from 0 to 50% EtOAc in heptane. ES-MS m/z 322 (M+H).

Manufacturing example 122

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

Iron powder (0.33 g, 5.8 mmol) and NH ₄ Cl (0.015 g, 0.28 mmol) were suspended in water (4.4 mL) and acetic acid (0.07 mL, 1.18 mmol) was added. After stirring at 50° C. for 15 min, 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. Added. The mixture was stirred at 50° C. for 20 min, cooled to RT, and the mixture was filtered through ^Celite® and rinsed with EtOAc (100 mL). The organic portion was washed with saturated NaHCO ₃ solution (100 mL) and dried over MgSO ₄ . Filtration and concentration gave the title compound (0.11 g, 74%) as a yellow oil, which was used in Preparation 169 without purification. ES-MS m/z 292 (M+H).

Manufacturing Example 123

Methyl 3-(2-methoxyethoxy)-4-nitro-5-[[(2S)-oxetan-2-yl]-methylamino]benzoate

Essentially as described in Preparation Example 14 using methyl 3-fluoro-5-(2-methoxyethoxy)-4-nitro-benzoate and [(2S)-oxetan-2-yl]methanamine. The title compound was prepared. The title compound was purified via silica gel chromatography using a gradient from 0 to 30% EtOAc in heptane. ES-MS m/z 341 (M+H).

Manufacturing example 124

Methyl 4-amino-3-(2-methoxyethoxy)-5-[[(2S)-oxetan-2-yl]methylamino]benzoate

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

Manufacturing example 125

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

Cs in a solution of 4-[(6-bromo-2-pyridyl)oxymethyl]-3-iodo-benzonitrile (6 g, 14.45 mmol) in 1,4 dioxane (100 mL) under nitrogen bubbling. ₂ CO ₃ (9.5 g, 29 mmol), tetrakis(triphenylphosphine)palladium(0) (835 mg, 0.72 mmol) and (E)-1-ethoxyethene-2-boronic acid pinacol ester ( 4.2 mL, 18.8 mmol) was added. The reaction mixture was heated at 90° C. under nitrogen for 1 day, then added tetrakis(triphenylphosphine)palladium(0) (835 mg, 0.72 mmol) and (E)-1-ethoxyethene-2-. Boronic acid pinacol ester (1 mL, 4.48 mmol) was added. The mixture was continued to be heated at 90° C. for 2 days. The mixture was cooled, water (100 mL) was added and extracted with EtOAc (3 x 60 mL). The organic portions were combined, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0 to 10% EtOAc in cyclohexane to yield 3.6 g (60% yield) of the title compound as a pale yellow solid. ES-MS m/z 359/361 (M+H).

Production example 126

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

1 in a solution of 4-[(6-bromo-2-pyridyl)oxymethyl]-3-[(E)-2-ethoxyvinyl]benzonitrile (3.6 g, 8.5 mmol) in THF (54 mL) ,4M HCl in 4-dioxane (21 mL, 85 mmol) was added. The mixture was stirred at RT for 20 hours. The mixture was concentrated, water (50 mL) and 2M aqueous sodium carbonate were added until pH = 8, then extracted with EtOAc (3 x 40 mL). The organic portions were combined, dried over MgSO ₄ , filtered and concentrated under reduced pressure to give the title compound as a light orange solid (3.9 g, 97%). ES-MS m/z 331/333 (M+H).

Manufacturing Example 127

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

To a solution of 4-[(6-bromo-2-pyridyl)oxymethyl]-3-(2-oxoethyl)benzonitrile (3.9 g, 8.24 mmol) in MeOH (60 mL) was added sodium borohydride (550 mg). , 14.53 mmol) was added in batches. The mixture was stirred at RT for 1 h, the solvent was evaporated, DCM (30 mL) and 1M NaOH solution (10 mL) were added and stirred for 10 min. The phases were separated and the aqueous phase was extracted with additional DCM (2 x 5 mL). The organics were combined, washed with water and saturated aqueous NaCl, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 10 to 40% EtOAc in cyclohexane to give the title compound as a white waxy solid (1.71 g, 60%). ES-MS m/z 333/335 (M+H).

Manufacturing example 128

2-Bromo-4-(hydroxymethyl)benzonitrile

Lithium borohydride (7.7 mL, 15.4 mmol, 2.0 mol/L) in THF was added to a solution of ethyl 3-bromo-4-cyanobenzoate (2 g, 7.71 mmol) in anhydrous THF (20 mL) at 0°C. Added under nitrogen atmosphere. The mixture was allowed to reach RT and stirred overnight. Most of the THF was removed and citric acid (5% aqueous) was carefully added at 0°C. The aqueous layer was extracted with EtOAc, the organic layers were combined, washed with water and saturated aqueous NaCl, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient from 30 to 100% EtOAc in cyclohexane to give the title compound (1.56 g, 92% purity, 88%) as a white solid. ^1H NMR (400 MHz, DMSO) δ 7.91 (d, J = 7.9 Hz, 1H), 7.80 (s, 1H), 7.51 (d, J = 7.5 Hz, 1H), 5.57 (t, J = 5.8 Hz, 1H), 4.59 (d, J = 5.9 Hz, 2H).

Manufacturing example 129

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

The title compound was prepared essentially as described in Preparation Example 30 using 2-bromo-4-(hydroxymethyl)benzonitrile and 6-chloropyridin-2-ol. The title compound was purified via silica gel chromatography using a gradient of 10 to 30% EtOAc in cyclohexane. ES-MS m/z 323, 325, 327 (M+H).

Production example 130

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

The vial was charged with 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). The vial was purged with nitrogen and anhydrous 1,2-dimethoxyethane (3 mL) was added. The mixture was stirred for 15 minutes.

In another vial, Na ₂ CO ₃ (335 mg, 3.13 mmol), 2-bromo-4-[(6-chloro-2-pyridyl)oxymethyl]benzonitrile (502 mg, 1.55 mmol) and (Ir[ dF(CF ₃ )ppy] ₂ (dtbpy))PF ₆ (18 mg, 0.016 mmol) was charged. The vial was purged with nitrogen and mixed with anhydrous 1,2-dimethoxyethane (12 mL), 2-bromoethanol (1.1 mL, 15 mmol), tris(trimethylsilyl)silane (740 μL, 2.33 mmol) and previously prepared Ni catalyst was added. The mixture was bubbled with nitrogen for 5 minutes and illuminated overnight with fanned Kessil LED light at 456 nm in an EvoluChem ^™ photoredox box. The solid was filtered, washed with DCM and the filtrate was concentrated. The residue was purified via silica gel chromatography using a gradient from 0 to 10% EtOAc in DCM as the eluent system to give the title compound (190 mg, 42%) as a yellow waxy solid. ES-MS m/z 289, 291 (M+H).

Manufacturing Example 131

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

(4-Fluoro-2-iodo-phenyl)methanol (2.0 g, 7.9 mmol), 2-bromo-6-fluoro-pyridine (1.4 g, 7.9 mmol) and 1,4-dioxane (25 mL ) Potassium tert-butoxide (1.20 g, 10.0 mmol) was added to the mixture. The reaction mixture was stirred at 60°C for 16 hours. The reaction was diluted with EtOAc (100 mL) and filtered through ^Celite® . The filtrate was washed with water (2 x 50 mL) and saturated aqueous sodium chloride (50 mL). The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified via silica gel flash chromatography eluting with a gradient of 5 to 50% DCM in hexane to give 2.16 g (67%) of the title compound. ES-MS m/z 408 and 410 (M+H).

Manufacturing Example 132

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

The title compound was prepared essentially as described in Preparation Example 28 using 2-bromo-6-[(4-fluoro-2-iodo-phenyl)methoxy]pyridine. The title compound was purified via silica gel flash chromatography eluting with a gradient of 0 to 10% EtOAc in hexane to give a non-ionized oil by ES-MS, which was used directly in Preparation 133 without further confirmation.

Production example 133

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

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

Production example 134

Methyl 2-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-6-(trifluoromethyl)pyridine-3-carboxylate

The title compound was prepared essentially as described in Preparation Example 28 using methyl 2-bromo-6-(trifluoromethyl)pyridine-3-carboxylate. The title compound was purified via silica gel chromatography using a gradient from 0 to 10% EtOAc in DCM. ES-MS m/z 378 (M+H).

Manufacturing Example 135

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

A mixture of methyl 2-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-6-(trifluoromethyl)pyridine-3-carboxylate (2.0 g, 5.3 mmol) was cooled and incubated in THF (40 mL) was added in an ice/salt bath at -10°C. Lithium aluminum hydride (0.20 g, 5.3 mmol) was added to this mixture, and stirred for 1 hour while cooling. The reaction was quenched by dropwise addition of water (1 mL) and then diluted with EtOAc (50 mL). The resulting mixture was filtered through ^Celite® and washed with EtOAc (100 mL). The filtrate was washed with water (100 mL) and saturated aqueous NaCl (100 mL) and then dried over Na ₂ SO ₄ . Filtered and concentrated to give the title compound (1.66 g, 84%) as a tan oil, which was used in Preparation 136 without further purification. ES-MS m/z 350 (M+H).

Production example 136

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

Using [2-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-6-(trifluoromethyl)-3-pyridyl]methanol and 2-bromo-6-fluoro-pyridine, The reaction was stirred at 60° C. for 16 hours to prepare the title compound essentially as described in Preparation Example 51. The title compound was purified via silica gel flash chromatography eluting with a gradient of 5 to 50% DCM in hexanes. ES-MS m/z 506 and 508 (M+H).

Manufacturing Example 137

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

3-[3-[(6-bromo-2-pyridyl)oxymethyl]-6-(trifluoromethyl)-2-pyridyl]propoxy-tert-butyl-dimethyl-silane, essentially The title compound was prepared as described in Preparation Example 29. The title compound was purified via silica gel flash chromatography eluting with a gradient of 5 to 50% EtOAc in hexane. ES-MS m/z 390 and 392 (M+H).

Manufacturing Example 138

(3-iodo-4-pyridyl)methanol

A mixture of methyl 3-iodopyridine-4-carboxylate (5.0 g, 19 mmol) in THF (40 mL) and MeOH (10 mL) was cooled to -10°C using an ice/salt bath and then hydrogenated. Sodium boron (1.52 g, 40.2 mmol) was added and stirred for 1 hour while cooling. The reaction was quenched by dropwise addition of water (1 mL) and then diluted with EtOAc (50 mL). The resulting mixture was filtered through ^Celite® and washed with EtOAc (100 mL). The filtrate was washed with water (100 mL) and saturated aqueous NaCl (100 mL) and then dried over Na ₂ SO ₄ . The residue was purified via silica gel chromatography using a gradient of 5 to 50% (1:4 MeOH:EtOAc) in DCM to give the title compound (1.63 g, 36%) as a tan solid. ES-MS m/z 236 (M+H).

Manufacturing Example 139

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

Using (3-iodo-4-pyridyl)methanol and 2-bromo-6-fluoro-pyridine, the reaction was stirred at 60° C. for 16 hours to give the title compound essentially as described in Preparation Example 51. Manufactured. The title compound was purified via silica gel chromatography using a gradient of 5 to 50% EtOAc in DCM. ES-MS m/z 390 and 392 (M+H).

Production example 140

3-[4-[(6-bromo-2-pyridyl)oxymethyl]-3-pyridyl]propoxy-tert-butyl-dimethyl-silane

The title compound was prepared essentially as described in Preparation Example 28 using 2-bromo-6-[(3-iodo-4-pyridyl)methoxy]pyridine. The title compound was purified via silica gel chromatography using a gradient from 0 to 80% EtOAc in hexane and used in Preparation 141 without further characterization.

Manufacturing Example 141

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

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

Production example 142

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

4-[(6-bromo-2-pyridyl)oxymethyl]-3-(2-hydroxyethyl)benzonitrile (1 g, 2.85 mmol) and methyl-4- in DCM (15 mL) at 4°C. In a solution of bromo-2-(bromomethyl)phenyl acetate (1.65 g, 4.10 mmol) was added 2,6-di-tert-butylpyridine (0.93 mL, 4.24 mmol) and silver trifluoromethanesulfonate (1.10 g). , 4.24 mmol) was added. The mixture was stirred at low temperature for 1 hour and then at RT. After 5 hours, additional silver trifluoromethanesulfonate (220 mg, 0.85 mmol) was added. After 20 hours, the reaction mixture was filtered through ^Celite® and rinsed 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).

Production example 143

Methyl 2-[2-[2-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano-phenyl]ethoxymethyl]-4-(4,4,5,5 -Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate

Methyl 2-[4-bromo-2-[2-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cya in anhydrous 1,4-dioxane (8.2 mL) under nitrogen. Bis(pinacolato)diborone (260 mg, 1 mmol) and KOAc (202 mg, 2.01 mmol) in a solution of nor-phenyl]ethoxymethyl]phenyl]acetate (630 mg, 0.83 mmol, 75% purity). was added. After 5 minutes, Pd(dppf)Cl ₂ and DCM complex (40 mg, 0.048 mmol) were added and the reaction mixture was heated at 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 x 5 mL). The organic portions were combined, washed with water and saturated aqueous NaCl, dried over MgSO ₄ , filtered and concentrated under reduced pressure to give the title compound as a brown oil (850 mg, 60% purity), which was further purified in Preparation 150. It was used without. ES-MS m/z 621/623 (M+H).

Production example 144

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

4-[(6-chloro-2-pyridyl)oxymethyl]-2-(2-hydroxyethyl)benzonitrile was used and activated 3 Å molecular sieves were added to the reaction mixture to produce essentially Preparation Example 142. The title compound was prepared as described. The title compound was purified via silica gel chromatography using a gradient of 50% to 100% DCM in cyclohexane. ES-MS m/z 529, 531, 533 (M+H).

Production example 145

Methyl 2-[2-[2-[5-[(6-chloro-2-pyridyl)oxymethyl]-2-cyano-phenyl]ethoxymethyl]-4-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate

Essentially using methyl 2-[4-bromo-2-[2-[5-[(6-chloro-2-pyridyl)oxymethyl]-2-cyano-phenyl]ethoxymethyl]phenyl]acetate The title compound was prepared as described in Preparation Example 143. After the reaction was complete, cooled to RT, saturated NaHCO ₃ and EtOAc were added and the mixture was filtered through ^Celite® . The aqueous layer was separated, the organic layer was washed with water and saturated aqueous NaCl, dried over anhydrous Na ₂ SO ₄ , filtered and the solvent was removed. The residue was purified via silica gel chromatography using a gradient from 0 to 2% EtOAc in DCM to afford the title compound as a colorless waxy solid. ES-MS m/z 577 and 579 (M+H).

Production example 146

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-dioxaborolan-2-yl)phenyl]acetate

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

Manufacturing Example 147

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-dioxaborolan-2-yl)phenyl]acetate

3-[3-[(6-bromo-2-pyridyl)oxymethyl]-6-(trifluoromethyl)-2-pyridyl]propan-1-ol in 1,4-dioxane as solvent and essentially using methyl 2-[2-hydroxy-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate The title compound was prepared as described in Preparation Example 55. The reaction mixture was stirred at RT for 15 hours, then the reaction was quenched with MeOH and concentrated under reduced pressure. The title compound was purified via silica gel flash chromatography eluting with a gradient of 85 to 100% DCM in hexane. ES-MS m/z 678 and 680 (M+H).

Manufacturing example 148

Methyl 2-[2-[3-[4-[(6-bromo-2-pyridyl)oxymethyl]-3-pyridyl]propoxy]-5-methyl-4-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate

3-[4-[(6-bromo-2-pyridyl)oxymethyl]-3-pyridyl]propan-1-ol and methyl 2-[2-hydroxy- in 1,4-dioxane as solvent. 5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate was used and the reaction was stirred at RT for 15 h to achieve essential The title compound was prepared as described in Preparation Example 55. The reaction was quenched with MeOH and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 85 to 100% DCM in hexane to give the title compound. ES-MS m/z 611 and 613 (M+H).

Manufacturing Example 149

Methyl 2-(5 ⁴ -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,9-dioxa-2(2,6)-pyri dina-1(1,3),5(1,2)-dibenzenacyclononaphan-1 ⁴ -yl)acetate

Bis(pinacolato)diborone (3.93 g, 15.2 mmol) and KOAc (3.04 g, 30.4 mmol) were reacted with methyl 2-(5 ⁴ -chloro-3,9-di in 1,4-dioxane (0.2 L). Oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononapan-1 ⁴ -yl)acetate (4.33 g, 10.1 mmol) was added to the slurry. . The mixture was sparged with nitrogen for 5 minutes, then [chloro(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino -1,1'-biphenyl-2-yl) palladium(II)] (0.25 g, 0.31 mmol) was added. The mixture was stirred at 85° C. for 2.5 hours under positive pressure of nitrogen, 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 portion was extracted with additional DCM (50 mL). The combined organic phases were washed with 2M aqueous K ₂ CO ₃ (50 mL) followed by brine (50 mL), then dried over MgSO ₄ and filtered. The filtrate was concentrated to a volume of 30 mL, MeOH (0.2 L) was added, and then concentrated 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 MeOH (30 mL). The filter cake was dried under reduced pressure at 50° C. for 13 hours to yield 4.95 g (94%) of the title compound as a gray solid. ES-MS m/z 515 and 516 (M+H).

Production example 150

Methyl 2-(5 ⁴ -Cyano-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane-1 ⁴ - 1) Acetate

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

Manufacturing Example 151

Ethyl 2-(5 ⁴ -cyano-1 ⁶ -fluoro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclo octaphane-1 ⁴ -yl)acetate

4-[(6-bromo-2-pyridyl)oxymethyl]-3-(2-hydroxyethyl)benzonitrile (400 mg, 1.20 mmol) and triphenylphosphine (473) in a round bottom flask under nitrogen atmosphere. mg 1.80 mmol), and ethyl 2-[5-fluoro-2-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxabo) in anhydrous THF (10 mL) A solution of rolan-2-yl)phenyl]acetate (563 mg, 1.44 mmol) was added. The mixture was stirred until the solid dissolved and cooled in an ice bath. To the mixture was added a solution of di-tert-butyl azodicarboxylate (423 mg, 1.80 mmol) in THF (1.6 mL). The ice bath was removed and the reaction was left at RT for 2 hours. THF (26 mL) and aqueous potassium phosphate (1 M, 7.2 mL) were added to the reaction and the mixture was stirred for 5 minutes. Pd(dtbpf)Cl ₂ (80 mg, 0.12 mmol) was added to the reaction, flushed with nitrogen several times, and the reaction was heated to 80° C. for 3 hours. The reaction was cooled to RT, diluted with EtOAc, and ^Celite® was added.

The mixture was stirred for 10 minutes and the mixture was filtered through a pad of ^Celite® and the ^Celite® pad was washed with EtOAc. The filtrate was dried over MgSO ₄ , filtered and the filtrate was concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient from 0 to 100% EtOAc in cyclohexane to give the title product as a white solid (150 mg, 28.9%). ES-MS m/z 433 (M+H).

Manufacturing Example 152

Methyl 2-(5 ⁴ -cyano-3,8-dioxa-2(2,6)-pyridina-1,5(1,3)-dibenzenacyclononaphan- ^{1 4} -yl)acetate

Methyl 2-[2-[2-[5-[(6-chloro-2-pyridyl)oxymethyl]-2-cyano-phenyl]ethoxymethyl]-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate (132 mg, 0.20 mmol, 88 mass %), THF (5 mL) and aqueous tribasic potassium phosphate (1.0 M, 1 mL) , 1.0 mmol) was bubbled with nitrogen for 5 minutes. XPhos Pd(crotyl)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 aqueous NaCl, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified via silica gel chromatography using DCM to give the title compound (51 mg, 61%) as a white solid. ES-MS m/z 415 (M+H).

Manufacturing Example 153

Methyl 2-(5 ⁴ -fluoro-1 ⁶ -methyl-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclonona Edition-1 ⁴ -day) Acetate

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-dioxaborolan-2-yl)phenyl]acetate was used, and the reaction mixture was stirred at 40° C. for 1 hour under a nitrogen atmosphere to obtain a reaction mixture essentially as described in Preparation Example 66. The title compound was prepared as described. The title compound was purified via silica gel flash chromatography eluting with a gradient from 0 to 20% EtOAc in DCM. ES-MS m/z 422 (M+H).

Manufacturing Example 154

Methyl 2-(1 ⁶ -methyl-5 ⁶ -(trifluoromethyl)-3,9-dioxa-2(2,6),5(3,2)-dipyridina-1(1,3) -benzenacyclononaphan-1 ⁴ -yl)acetate

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-dioxaborolan-2-yl)phenyl]acetate was used and the reaction was stirred at 40° C. for 1 hour to essentially prepare the preparation example. The title compound was prepared as described in 66. The title compound was purified via silica gel chromatography using a gradient from 0 to 20% EtOAc in DCM. ES-MS m/z 473 (M+H).

Manufacturing Example 155

Methyl 2-(1 ⁶ -methyl-3,9-dioxa-2(2,6),5(4,3)-dipyridina-1(1,3)-benzenacyclononaphane-1 ⁴ - 1) Acetate

Methyl 2-[2-[3-[4-[(6-bromo-2-pyridyl)oxymethyl]-3-pyridyl]propoxy]-5-methyl-4-(4,4,5, The title compound was prepared essentially as described in Preparation Example 66 using 5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate and stirring the reaction at 40°C for 1 hour. did. The title compound was purified via silica gel chromatography using a gradient of 5 to 35% EtOAc in DCM. ES-MS m/z 405 (M+H).

Manufacturing Example 156

2-(5 ⁴ -Bromo-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane-1 ⁴ -yl )acetic acid

MeOH (20 mL) and water (5 mL) were dissolved in methyl 2-(5 ⁴ -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,9 -dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphan-1 ⁴ -yl)acetate (4.45 g, 8.55 mmol) and bromine Cupric topical (5.73 g, 25.7 mmol) was added to the mixture. The mixture was stirred at 80° C. for 30 hours. The mixture was cooled to ambient temperature, 30% aqueous NH ₄ OH was added and diluted with water to a final volume of approximately 0.5 L. The mixture was stirred for 0.5 h and the solid was collected by filtration and washed with 10% aqueous NH ₄ OH (0.1 L) followed by water (0.1 L). THF (0.14 L), MeOH (70 mL) and 1 M aqueous LiOH (35 mL) were added to the moist solid and stirred at 60° C. for 3.5 hours. 1 M aqueous KH ₂ PO ₄ (0.1 L) was added to the mixture and then diluted with water to a final volume of approximately 1 L. The mixture was left to cool naturally with stirring for 1 hour and the solid was collected by filtration and washed with 1:4 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 yield 3.66 g (92%) of the title compound as an off-white solid. ES-MS m/z 454 and 456 (M+H).

Manufacturing Example 157

2-(5 ⁴ -Cyano-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphan-1 ⁴ -yl ) Acetic acid

Methyl 2-(5 ⁴ -Cyano-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane-1 ⁴ - 1) The title compound was prepared essentially as described in Preparation 78 using acetate. ES-MS m/z 401 (M+H).

Manufacturing Example 158

2-(5 ⁴ -cyano-1 ⁶ -fluoro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacycloocta Edition-1 ⁴ -day) Acetic acid

Ethyl 2-(5 ⁴ -cyano-1 ⁶ -fluoro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclo The title compound was prepared essentially as described in Preparation Example 78 using octaphan-1 ⁴ -yl)acetate. ES-MS m/z 418 (M+H).

Manufacturing Example 159

2-(54Amino-cyano-3,8-dioxa-2(2,6)-pyridina-1,5(1,3)-dibenzenacyclononaphan-14amino-yl)acetic acid

Using methyl 2-(5 ⁴ -cyano-3,8-dioxa-2(2,6)-pyridina-1,5(1,3)-dibenzenacyclononaphan- ^{1 4} -yl)acetate The title compound was prepared essentially as described in Preparation Example 78. ES-MS m/z 401 (M+H).

Production example 160

2-(1 ⁶ -methyl-5 ⁴ -(fluoro)-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclo Nonapan-1 ⁴ -1) Acetic acid

Methyl 2-(1 ⁶ -methyl-5 ⁴ -(fluoro)-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzena The title compound was prepared essentially as described in Preparation Example 75 using cyclononaphan-1 ⁴ -yl)acetate and stirring the reaction at 50°C for 1 hour. The title compound was used without purification in Preparation Example 168. ES-MS m/z 408 (M+H).

Manufacturing example 161

Methyl 2-(1 ⁶ -methyl-5 ⁶ -(trifluoromethyl)-3,9-dioxa-2(2,6),5(3,2)-dipyridina-1(1,3) -benzenacyclononaphan-1 ⁴ -yl)acetic acid

Methyl 2-(1 ⁶ -methyl-5 ⁶ -(trifluoromethyl)-3,9-dioxa-2(2,6),5(3,2)-dipyridina-1(1,3) The title compound was prepared essentially as described in Preparation Example 75 using -benzenacyclononaphan-1 ⁴ -yl)acetate and stirring the reaction at 50° C. for 1 hour. The title compound was used in Preparation Example 171 without further purification. ES-MS m/z 459 (M+H).

Manufacturing example 162

2-(1 ⁶ -methyl-3,9-dioxa-2(2,6),5(4,3)-dipyridina-1(1,3)-benzenacyclononapan-1 ⁴ -yl )acetic acid

Methyl 2-(1 ⁶ -methyl-3,9-dioxa-2(2,6),5(4,3)-dipyridina-1(1,3)-benzenacyclononaphane-1 ⁴ - 1) Acetate was used and the reaction was stirred at 50° C. for 1 hour to prepare the title compound essentially as described in Preparation Example 75. The title compound was used in Preparation Example 172 without further purification. ES-MS m/z 391 (M+H).

Manufacturing example 163

Methyl (S)-4-(2-(5 ⁴ -cyano- ^{1 6} -fluoro-3,7-dioxa-2(2,6)-pyridina-1(1,3),5(1 ,2)-Dibenzenacyclooctaphan-1 ⁴ -yl)acetamido)-3-methoxy-5-((oxetan-2-ylmethyl)amino)benzoate

2-(5 ⁴ -cyano-1 ⁶ -fluoro-3,7-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacycloocta Pan-1 ⁴ -yl)acetic acid and methyl 4-amino-3-methoxy-5-[[(2S)-oxetan-2-yl]methylamino]benzoate were used, and the reaction was stirred for 16 hours. The title compound was prepared essentially as described in Preparation Example 86. The title compound was used in the next step (Preparation Example 173) without purification. ES-MS m/z 653 (M+H).

Manufacturing example 164

Methyl (S)-4-(2-(5 ⁴ -bromo-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzena Cyclononaphan-1 ⁴ -yl)acetamido)-3-((oxetan-2-ylmethyl)amino)benzoate

DMF (33 mL) and pyridine (6 mL) were dissolved in 2-(5 ⁴ -bromo-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2 )-Dibenzenacyclononapan-1 ⁴ -yl)acetic acid (3.10 g, 6.69 mmol) and methyl 4-amino-3-[[(2S)-oxetan-2-yl]methylamino]benzoate (essentially prepared as described in WO 2020/263695; 1.75 g, 7.41 mmol) and stirred for 30 minutes. 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (1.68 mol/L in EtOAc, 10 mL, 16.8 mmol ) was added and the mixture was stirred for 50 minutes. The reaction mixture was diluted with water to a final volume of 0.2 L and stirred for 20 minutes. The solid was collected by filtration and washed with water (0.1 L). The filter cake was dried at 50° C. under reduced pressure for 24 hours to yield 4.64 g of the title compound (99%) as a light pink solid. ES-MS m/z 672 and 674 (M+H).

Manufacturing example 165

Methyl (S)-4-(2-(5 ⁴ -cyano-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzena Cyclononaphan-1 ⁴ -yl)acetamido)-3-((oxetan-2-ylmethyl)amino)benzoate

2-(5 ⁴ -Cyano-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphan-1 ⁴ -yl ) Preparation Example 86 essentially using acetic acid and methyl 4-amino-3-[[(2S)-oxetan-2-yl]methylamino]benzoate (prepared essentially as described in WO 2020/263695) The title compound was prepared as described. The title compound was used in the next step (Preparation Example 175) without purification. ES-MS m/z 619 (M+H).

Manufacturing example 166

Methyl (S)-4-(2-(5 ⁴ -cyano- ^{1 6} -fluoro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1 ,2)-dibenzenacyclooctaphane-1 ⁴ -yl)acetamido)-3-((oxetan-2-ylmethyl)amino)benzoate

2-(5 ⁴ -cyano-1 ⁶ -fluoro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacycloocta Pan-1 using ⁴ -yl)acetic acid and methyl 4-amino-3-[[(2S)-oxetan-2-yl]methylamino]benzoate (prepared essentially as described in WO 2020/263695) The title compound was prepared essentially as described in Preparation Example 86. The title compound was used in crude form in Preparation Example 176. ES-MS m/z 623 (M+H).

Manufacturing Example 167

Methyl (S)-4-(2-(5 ⁴ -cyano-3,8-dioxa-2(2,6)-pyridina-1,5(1,3)-dibenzenacyclononaphane-1 ⁴ -yl)acetamido)-3-((oxetan-2-ylmethyl)amino)benzoate

2-(5 ⁴ -cyano-3,8-dioxa-2(2,6)-pyridina-1,5(1,3)-dibenzenacyclononaphan-1 ⁴ -yl)acetic acid and methyl 4 -amino-3-[[(2S)-oxetan-2-yl]methylamino]benzoate (prepared essentially as described in WO 2020/263695) and the title product essentially as described in Preparation Example 86 The compound was prepared. The title compound was used in crude form in Preparation Example 177. ES-MS m/z 619 (M+H).

Manufacturing example 168

Methyl (S)-3-methoxy-4-(2-(1 ⁶ -methyl-5 ⁴ -(fluoro)-3,9-dioxa-2(2,6)-pyridina-1(1, 3),5(1,2)-dibenzenacyclononaphan-1 ⁴ -yl)acetamido)-5-((oxetan-2-ylmethyl)amino)benzoate

2-(1 ⁶ -methyl-5 ⁴ -(fluoro)-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclo Essentially using nonaphan-1 ⁴ -yl)acetic acid (Preparation 160) and methyl 4-amino-3-methoxy-5-[[(2S)-oxetan-2-yl]methylamino]benzoate The title compound was prepared as described in Preparation Example 86. The title compound was used in Preparation Example 178 without purification. ES-MS m/z 656 (M+H).

Manufacturing example 169

Ethyl 4-(2-(5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane- 1 ⁴ -yl)acetamido)-3-methoxy-5-((oxazol-2-ylmethyl)amino)benzoate

2-(5 ⁴ -Cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane-1 ⁴ -yl ) The title compound was prepared essentially as described in Preparation 85 using acetic acid and ethyl-4-amino-3-methoxy-5-(oxazol-2-ylmethylamino)benzoate (Preparation 122) . The title compound was used in Preparation Example 179 without purification. ES-MS m/z 674 (M+H).

Production example 170

Methyl (S)-4-(2-(5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzena Cyclononaphan-1 ⁴ -yl)acetamido)-3-(2-methoxyethoxy)-5-((oxetan-2-ylmethyl)amino)benzoate

2-(5 ⁴ -Cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane-1 ⁴ -yl ) Acetic acid and methyl 4-amino-3-(2-methoxyethoxy)-5-[[(2S)-oxetan-2-yl]methylamino]benzoate (Preparation Example 124) The title compound was prepared as described in Example 85. The title compound was used in Preparation Example 180 without further purification. ES-MS m/z 693 (M+H).

Manufacturing example 171

Methyl (S)-3-methoxy-4-(2-(1 ⁶ -methyl-5 ⁶ -(trifluoromethyl)-3,9-dioxa-2(2,6),5(3,2 )-Dipyridina-1(1,3)-benzenacyclononapan-1 ⁴ -yl)acetamido)-5-((oxetan-2-ylmethyl)amino)benzoate

Methyl 2-(1 ⁶ -methyl-5 ⁶ -(trifluoromethyl)-3,9-dioxa-2(2,6),5(3,2)-dipyridina-1(1,3) -Benzenacyclononapan-1 ⁴ -yl)acetic acid (Preparation Example 161) and methyl 4-amino-3-methoxy-5-[[(2S)-oxetan-2-yl]methylamino]benzoate The title compound was prepared essentially as described in Preparation Example 86. The title compound of Preparation Example 183 was used without further purification. ES-MS m/z 707 (M+H).

Manufacturing example 172

Methyl (S)-3-methoxy-4-(2-(1 ^{6 -methyl} -3,9-dioxa-2(2,6),5(4,3)-dipyridina-1(1, 3)-benzenacyclononaphan-1 ⁴ -yl)acetamido)-5-((oxetan-2-ylmethyl)amino)benzoate

2-(1 ⁶ -methyl-3,9-dioxa-2(2,6),5(4,3)-dipyridina-1(1,3)-benzenacyclononapan-1 ⁴ -yl ) Acetic acid (Preparation 162) and methyl 4-amino-3-methoxy-5-[[(2S)-oxetan-2-yl]methylamino]benzoate essentially as described in Preparation 86. The title compound was prepared. The title compound was used in the next step (Preparation 184) without further purification. ES-MS m/z 639 (M+H).

Manufacturing example 173

Methyl (S)-2-((5 ⁴ -cyano-1 ⁶ -fluoro-3,7-dioxa-2(2,6)-pyridina-1(1,3),5(1,2 )-Dibenzenacyclooctaphan-1 ⁴ -yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

Methyl (S)-4-(2-(5 ⁴ -cyano- ^{1 6} -fluoro-3,7-dioxa-2(2,6)-pyridina-1(1,3),5(1 ,2)-Dibenzenacyclooctaphan-1 ⁴ -yl)acetamido)-3-methoxy-5-((oxetan-2-ylmethyl)amino)benzoate (from Preparation Example 163) was used , the reaction was heated at 65° C. for 9 hours to prepare the title compound essentially as described in Preparation Example 102. The mixture was cooled to RT, the solvent was evaporated under reduced pressure and ACN was added to aid removal of acetic acid. The residue was purified via silica gel chromatography using a gradient from 0 to 40% EtOAc in DCM followed by 10% MeOH in DCM to afford the title compound as a light orange solid. ES-MS m/z 635 (M+H).

Manufacturing example 174

Methyl (S)-2-((5 ⁴ -bromo-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclonona Pan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

Methyl (S)-4-(2-(5 ⁴ -bromo-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzena Essentially using cyclononaphan- ¹⁴ -yl)acetamido)-3-((oxetan-2-ylmethyl)amino)benzoate and 1:1 acetic acid:2-chlorotoluene as solvent. The title compound was prepared as described in Preparation Example 102. The reaction was stirred at 60°C for 32 hours under positive pressure of nitrogen. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM, concentrated over diatomaceous earth and purified by silica gel chromatography using a gradient of 0-50% EtOAc in DCM to give the title compound as a white solid. ES-MS m/z 654 and 656 (M+H).

Manufacturing example 175

Methyl (S)-2-((5 ⁴ -cyano-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclonona Pan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

Methyl (S)-4-(2-(5 ⁴ -cyano-3,8-dioxa-2(2,6)-pyridina-1() in 1:1 1,2-dichloroethane:acetic acid as solvent 1,3),5(1,2)-dibenzenacyclononaphan-1 ⁴ -yl)acetamido)-3-((oxetan-2-ylmethyl)amino)benzoate was used, and the reactant was The title compound was prepared essentially as described in Preparation Example 102 by heating at 50° C. for 5 hours. The reaction mixture was cooled to RT, the solvent was concentrated under reduced pressure and the residue was purified via silica gel chromatography using a gradient of 10 to 50% EtOAc in DCM to give the title compound as a white solid. ES-MS m/z 601 (M+H).

Manufacturing example 176

Methyl (S)-2-((5 ⁴ -cyano-1 ⁶ -fluoro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2 )-Dibenzenacyclooctaphan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

Methyl (S)-4-(2-(5 ⁴ -cyano-1 6 -fluoro-3,8-dioxa-2(2,6) in 1:1 ^1,2 -dichloroethane:acetic acid as solvent -Pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 ⁴ -yl)acetamido)-3-((oxetan-2-ylmethyl)amino)benzoate The title compound was prepared essentially as described in Preparation Example 102 using and heating to 52°C for 4 hours. The reaction was cooled to RT and the solvent was removed under reduced pressure. The residue was purified via silica gel chromatography using a gradient from 0 to 100% EtOAc in DCM to afford the title compound as a yellow solid. ES-MS m/z 605 (M+H).

Manufacturing example 177

Methyl (S)-2-((5 ⁴ -cyano-3,8-dioxa-2(2,6)-pyridina-1,5(1,3)-dibenzenacyclononaphane-1 ⁴ - 1) methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

Methyl (S)-4-(2-(5 ⁴ -cyano-3,8-dioxa-2(2,6)-pyridina-1, in 1:1 1,2-dichloroethane:acetic acid as solvent. 5(1,3)-dibenzenacyclononaphan-1 ⁴ -yl)acetamido)-3-((oxetan-2-ylmethyl)amino)benzoate was used, and the reaction was incubated at 60°C for 5 hours. The title compound was prepared essentially as described in Preparation Example 102. The reaction mixture was cooled to RT, the solvent was concentrated under reduced pressure and the residue was purified via silica gel chromatography using a gradient of 25 to 50% EtOAc in DCM to give the title compound as a white solid. ES-MS m/z 601 (M+H).

Manufacturing example 178

Methyl (S)-4-methoxy-2-((1 ⁶ -methyl-5 ⁴ -(fluoro)-3,9-dioxa-2(2,6)-pyridina-1(1,3) ,5(1,2)-dibenzenacyclononapan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

1:1 dichloroethane:methyl (S)-3-methoxy-4-(2-(1 ⁶ -methyl-5 ⁴ -(fluoro)-3,9-dioxa-2(2,6) in acetic acid -Pyridina-1(1,3),5(1,2)-dibenzenacyclononapan-1 ⁴ -yl)acetamido)-5-((oxetan-2-ylmethyl)amino)benzoate The title compound was prepared essentially as described in Preparation Example 102. The title compound was purified via silica gel chromatography using a gradient from 80 to 100% DCM in hexanes. ES-MS m/z 638 (M+H).

Manufacturing example 179

Ethyl 2-((5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane- ^{1 4} -yl)methyl)-4-methoxy-1-(oxazol-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

Ethyl 4-(2-(5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclonona in acetic acid Pan-1 The title compound was prepared essentially as described in Preparation Example 101 using ⁴ -yl)acetamido)-3-methoxy-5-((oxazol-2-ylmethyl)amino)benzoate . The reaction mixture was concentrated and the title compound was precipitated from heptane and used in Example 23 without further purification. ES-MS m/z 656 (M+H).

Production example 180

Methyl (S)-2-((5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclonona Pan-1 ⁴ -yl)methyl)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

Methyl (S)-4-(2-(5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)- in acetic acid Example of preparation essentially using dibenzenacyclononapan-1 ⁴ -yl)acetamido)-3-(2-methoxyethoxy)-5-((oxetan-2-ylmethyl)amino)benzoate The title compound was prepared as described in 101. The title compound was purified via silica gel chromatography using a gradient from 0 to 80% EtOAc in heptane. ES-MS m/z 675 (M+H).

Manufacturing example 181

Methyl (S)-2-((5 ⁴ -formyl-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclonona Pan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

A Schlenk tube was charged with bis(acetonitrile)dichloropalladium(II) (11 mg, 0.042 mmol) and butyldi-1-adamantylphosphine (48 mg, 0.13 mmol). The tube was purged with nitrogen (3 x vacuum/nitrogen cycles) and 4-methylmorpholine (3 mL, 27.24 mmol) was added. The tube was purged again with nitrogen with agitation (5 x vacuum/nitrogen cycles). The tube was closed and stirred at ambient temperature for 1 hour. The glass pressure vessel was filled with methyl (S)-2-((5 ⁴ -bromo-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)- Dibenzenacyclononapan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (290 mg, 0.42 mmol), and 4 -Charged with methylmorpholine (9 mL, 81.73 mmol, 100 mass%). It was capped with a septum and the mixture was bubbled with nitrogen while stirring. After 30 minutes, the catalyst suspension was transferred to a pressure vessel, which was purged three times with syngas to 80 psi and then recharged with syngas to 80 psi. The mixture was stirred and heated at 105° C. overnight. The reaction mixture was cooled to RT and the solvent was removed. The residue was partitioned between DCM (20 mL) and 2 M aqueous K ₂ CO ₃ (20 mL). The organic layer was separated and the aqueous layer was extracted with DCM (10 mL). The organic layers were combined, washed with saturated aqueous NaCl (10 mL), filtered, and concentrated to give 320 mg orange residue. The residue was purified via silica gel chromatography using a gradient from 0 to 50% EtOAc in DCM to give the title compound (250 mg, 89%) as a white solid. ES-MS m/z 604 (M+H).

Manufacturing example 182

(S)-2-((5 ⁴ -formyl-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane -1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

1 M aqueous LiOH (1.25 mL, 1.25 mmol) was dissolved in THF (5 mL) and MeOH (2.5 mL) with methyl (S)-2-((5 ⁴ -formyl-3,9-dioxa-2(2) ,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononapan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo [d]imidazole-6-carboxylate (0.25 g, 0.37 mmol, 90 mass%) was added to the stirred suspension. The reaction vessel was sealed and stirred at 60°C for 2 hours. The reaction was quenched with 1 M aqueous K ₂ HPO ₄ (5 mL), diluted with water to a volume of 60 mL, and the mixture was stirred at ambient temperature overnight. Adjust the reaction pH to 4 by adding 5% aqueous citric acid, dilute with saturated aqueous NaCl (50 mL), extract with DCM (50 mL), then 1:4 isopropanol:DCM (50 mL, 25 mL, 25 mL) ) was extracted three times. The organic extracts were combined and concentrated at 50° C. under reduced pressure. The residue was dissolved in 1:1 DCM:MeOH, concentrated on diatomaceous earth and then purified by silica gel chromatography using a gradient from 0 to 20% MeOH in DCM. Appropriate fractions were concentrated under reduced pressure at 50° C. to give a white residue, which was then stirred in EtOAc (5 mL) for 0.5 h. The solid was collected by filtration and washed with EtOAc (5 mL). The solid was dried at 45° C. under reduced pressure for 21 hours to give the title compound (125 mg, 51%) as a white solid. ES-MS m/z 590 (M+H).

Manufacturing example 183

Methyl (S)-4-methoxy-2-((1 ⁶ -methyl-5 ⁶ -(trifluoromethyl)-3,9-dioxa-2(2,6),5(3,2)- Dipyridina-1(1,3)-benzenacyclononapan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxyl rate

Methyl (S)-3-methoxy-4-(2-(1 ⁶ -methyl-5 ⁶ -(trifluoromethyl)-3,9-dioxa-2(2) in 1:1 DCM:acetic acid as solvent. ,6),5(3,2)-dipyridina-1(1,3)-benzenacyclononapan-1 ⁴ -yl)acetamido)-5-((oxetan-2-ylmethyl) The title compound was prepared essentially as described in Preparation Example 102 using amino)benzoate. The title compound was purified via silica gel chromatography using a gradient from 80 to 100% DCM in hexanes. ES-MS m/z 689 (M+H).

Manufacturing example 184

Methyl (S)-4-methoxy-2-((1 ⁶ -methyl-3,9-dioxa-2(2,6),5(4,3)-dipyridina-1(1,3) -Benzenacyclononapan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

Methyl (S)-3-methoxy-4-(2-(1 ⁶ -methyl-3,9-dioxa-2(2,6),5(4,3) in 1:1 dichloroethane:acetic acid as solvent. )-Dipyridina-1(1,3)-benzenacyclononapan-1 ⁴ -yl)acetamido)-5-((oxetan-2-ylmethyl)amino)benzoate (Preparation Example 172) The title compound was prepared essentially as described in Preparation Example 102. The title compound was purified via silica gel chromatography using a gradient from 80 to 100% EtOAc in DCM. ES-MS m/z 621 (M+H).

Manufacturing example 185

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

To a solution of 3-fluoro-4-nitro-benzonitrile (470 mg, 2.8 mmol) and TMSCN (4.5 mL, 33 mmol) in toluene (9 mL) was added tributyltin azide (2 mL, 7 mmol). Then, it was heated in a microwave reactor at 150°C for 2 hours. The reaction was quenched with saturated aqueous NaHCO ₃ and extracted with EtOAc. The organic phase was dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a mixture of DCM/MeOH/formic acid (9:1:0.1) to obtain 586 mg (99%) of the title compound. ES-MS m/z 210 (M+H).

Manufacturing example 186

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

To a solution of 5-(3-fluoro-4-nitro-phenyl)-1H-tetrazole (860 mg, 4.1 mmol) in THF (12 mL) was added sodium hydride (60% in mineral oil, 180 mg, 4.5 mmol). was added at 0°C. 2-(Chloromethoxy)ethyl-trimethyl-silane (0.79 mL, 4.5 mmol) was added to the mixture and stirred at RT for 16 hours. The reaction was quenched with water and extracted with EtOAc. The organic phase was dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified via 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).

Manufacturing Example 187

fumaric acid;[(2S)-oxetan-2-yl]methanamine

[(2S)-oxetan-2-yl]methanamine (3.6 wt% in EtOH, 1500 g, 620 mmol) and fumaric acid (72 g, 620 mmol) were mixed at 25° C. under nitrogen for 36 hours. The solid was filtered and the solid was dried under reduced pressure to give the title compound (65 g, 52%) as a white solid. ¹ H NMR (400.21 MHz, MeOH-d ₄ ) δ 6.72 (s, 2H), 5.02 (ddd, J= 14.8, 7.0, 3.7 Hz, 1H), 4.77-4.70 (m, 1H), 4.61 (dt, J = 9.0, 6.1 Hz, 1H), 3.27 (dd, J= 7.1, 13.4 Hz, 1H), 3.16 (dd, J= 3.7, 13.4 Hz, 1H), 2.87-2.81 (m, 1H), 2.60-2.54 ( m, 1H).

Manufacturing Example 188

2-nitro-N-[[(2R)-oxetan-2-yl]methyl]-5-[1-(2-trimethylsilylethoxymethyl)tetrazol-5-yl]aniline

A solution of fumaric acid;[(2S)-oxetan-2-yl]methanamine (160 mg, 0.79 mmol) and TEA (0.39 mL, 2.8 mmol) in N,N-dimethylacetamide (2 mL) was incubated at RT for 1 mL. Stirred for an hour. 2-[[5-(3-Fluoro-4-nitro-phenyl)tetrazol-1-yl]methoxy]ethyl-trimethyl-silane (240 mg, 0.7 mmol) was added and the mixture was incubated for 16 minutes at 35°C. Stirred for an hour. The reaction was quenched with water and extracted with EtOAc. The organic phase was dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified via 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).

Manufacturing Example 189

N2-[[(2R)-oxetan-2-yl]methyl]-4-[1-(2-trimethylsilylethoxymethyl)tetrazol-5-yl]benzene-1,2-diamine

A mixture of iron (100 mg, 2 mmol), ammonium chloride (7 mg, 0.1 mmol) and acetic acid (30 μL, 0.5 mmol) in water (3 mL) was stirred vigorously at 50°C for 15 min. 2-Nitro-N-[[(2R)-oxetan-2-yl]methyl]-5-[1-(2-trimethylsilylethoxymethyl)tetrazol-5-yl]aniline in DMF (1 mL) (100 mg, 0.2 mmol) was added and the mixture was stirred at 50°C for 1 hour. The reaction mixture was filtered through a pad of ^Celite® , then quenched with water and extracted with EtOAc. The organic phase was dried over MgSO ₄ , filtered and concentrated under reduced pressure to give 98 mg (99%) of the title compound. ES-MS m/z 377 (M+H).

Manufacturing example 190

(S)-2-(5 ⁴ -Cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane- 1 ⁴ -yl)-N-(2-((oxetan-2-ylmethyl)amino)-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-tetrazole-5- 1) phenyl) acetamide

2-(5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclonona in DMF (2 mL) Pan-1 ⁴ -yl)acetic acid (100 mg, 0.25 mmol), N2-[[(2R)-oxetan-2-yl]methyl]-4-[1-(2-trimethylsilylethoxymethyl)tetrazole To a solution of -5-yl]benzene-1,2-diamine (98 mg, 0.26 mmol) and TEA (104 μL, 0.75 mmol) was added HATU (142 mg, 0.37 mmol). The mixture was stirred at RT for 1 hour. The reaction was quenched with water and extracted with EtOAc. The organic phase was dried over MgSO ₄ , filtered and concentrated under reduced pressure to give 190 mg (99%) of the title compound. LC-MS retention time = 2.17 min.

Manufacturing Example 191

(S)-1 ⁴ -((1-(oxetan-2-ylmethyl)-6-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-tetrazol-5-yl)- 1H-benzo[d]imidazol-2-yl)methyl)-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclo Nonapan-5 ⁴ -Carbonitrile

(S)-2-(5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3) in 1:1 1,2-dichloroethane:acetic acid as solvent. ,5(1,2)-dibenzenacyclononapan-1 ⁴ -yl)-N-(2-((oxetan-2-ylmethyl)amino)-4-(1-((2-(trimethylsilyl )Ethoxy)methyl)-1H-tetrazol-5-yl)phenyl)acetamide was used and the reaction was heated at 85° C. for 16 hours to prepare the title compound essentially as described in Preparation Example 102. The mixture was concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient from 0 to 100% EtOAc in heptane to give the title compound. ES-MS m/z 741 (M+H).

Manufacturing Example 192

1-Bromo-4-(bromomethyl)-2-fluoro-5-iodo-benzene

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); 2,2'-Azobis(2-methylpropionitrile) (1.26 g, 7.54 mmol) was added and the reaction was heated at 80°C for 5 hours. Cool to RT, add saturated solution of NaHCO ₃ (300 mL) and extract with DCM (200 mL). The organic portions were combined, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography using heptane as eluent to give 16.04 g (54% yield) of the title compound. ¹ H NMR (400.13 MHz, CDCl ₃ ) δ 8.05 (d, J= 6.8 Hz, 1H), 7.29 (d, J= 9.00, 1H), 4.51 (s, 2H).

Manufacturing Example 193

2-(4-Bromo-5-fluoro-2-iodo-phenyl)acetonitrile

TBAF in a solution of 1-bromo-4-(bromomethyl)-2-fluoro-5-iodo-benzene (16.04 g, 40.74 mmol) and TMSCN (7.24 mL, 53 mmol) in ACN (110 mL) (1 M in THF, 53 mL, 53 mmol) was added slowly. The reaction was heated at 40°C for 3 hours. The solvent was evaporated under reduced pressure, the residue was dissolved in EtOAc (150 mL) and the organic portion was washed with saturated aqueous NaCl (3 x 50 mL). The organic portion was dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0 to 15% EtOAc in heptane to give the title compound as an orange oil (10.34 g, 69%). ES-MS m/z 340/342 (M+H).

Manufacturing Example 194

Ethyl 2-(4-bromo-5-fluoro-2-iodo-phenyl)acetate

To a solution of 2-(4-bromo-5-fluoro-2-iodo-phenyl)acetonitrile (10.34 g, 30.43 mmol) in 8 M EtOH (92 mL) in water was added sulfuric acid (24 mL) at RT. Added. The reaction mixture was heated at 80° C. for 18 hours. The mixture was cooled to RT, the reaction was basified to pH >7 by addition of saturated aqueous NaHCO ₃ and extracted with DCM (3 x 50 mL). The organics were combined, washed with water and saturated aqueous NaCl, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0 to 10% EtOAc in heptane to yield 8.88 g (75%) of the title compound as a white solid. ES-MS m/z 387/389 (M+H).

Manufacturing Example 195

Ethyl 2-[4-bromo-2-[2-ethoxyvinyl]-5-fluoro-phenyl]acetate

Tetrakis(triphenylphosphine)palladium(0) (1.3 g, 1.1 mmol), Cs ₂ CO ₃ (7.4 g, 23 mmol) and 2-(2-ethoxyvinyl)-4,4,5,5- Tetramethyl-1,3,2-dioxaborolane (3.3 mL, 15 mmol) was dissolved in ethyl 2-(4-bromo-5-fluoro-2-) in 1,4-dioxane (80 mL) under nitrogen. It was added to a solution of iodo-phenyl)acetate (4.37 g, 11.31 mmol). 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 portions were combined, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0 to 10% EtOAc in heptane to yield 2.51 g (67%) of the title compound as a yellow oil. ES-MS m/z 331/333 (M+H).

Manufacturing Example 196

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

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. was added mercuric acetate (6.3). g, 19 mmol) was added and stirred at 0°C for 2 hours. Meanwhile, sodium borohydride (520 mg, 13.75 mmol) was added to a solution of K ₂ CO ₃ (60 g) in water (56 mL) and this mixture was added to the previous reaction together with the starting materials. The reaction was stirred at RT for 40 min, then diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The organic portions were combined, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0 to 25% EtOAc in heptane to give the title compound as a colorless oil (1.31 g, 40% yield). ES-MS m/z 305/307 (M+H).

Manufacturing Example 197

4-formyl-3-hydroxy-benzonitrile

To a solution of 4-cyano-2-methoxybenzaldehyde (13 g, 79.86 mmol) in DCM (480 mL) was added boron tribromide (100 g, 399.16 mmol) in batches at -10°C. The reaction was stirred at RT for 3 days, cooled to 0° C., and water (21 mL) was added slowly. The reaction was diluted with water (100 mL) and extracted with DCM (3 x 100 mL). The organic portions were combined, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient from 0 to 20% EtOAc in heptane to yield 7.61 g (65%) of the title compound. ES-MS m/z 148 (M+H).

Manufacturing Example 198

4-formyl-3-(2-trimethylsilylethoxymethoxy)benzonitrile

DIPEA (9.5 mL, 54 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (5.3 mL, 30 mmol) were reacted with 4-formyl-3-hydroxy in DCM (68 mL) and diethyl ether (30 mL). -benzonitrile (4 g, 27.18 mmol) was added to the solution. The reaction mixture was stirred at RT for 3 hours. The reaction was diluted with saturated aqueous NH ₄ Cl and extracted with DCM (3 x 50 mL). The organics were combined, washed with water and saturated aqueous NaCl, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient from 0 to 20% EtOAc in heptane to give the title compound (5.67 g, 75%). ES-MS m/z 278 (M+H).

Manufacturing Example 199

4-(Hydroxymethyl)-3-(2-trimethylsilylethoxymethoxy)benzonitrile

Sodium borohydride (1.6 g, 42 mmol) was added in batches. The reaction mixture was stirred for 1 hour, then water (50 mL) was added and extracted with EtOAc (3 x 50 mL). The organics were combined, washed with water and saturated aqueous NaCl, dried over MgSO ₄ , filtered and concentrated under reduced pressure to give 5.55 g (97%) of the title compound. ES-MS m/z 280 (M+H).

Production example 200

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

Sodium hydride (60% in mineral oil, 500 mg, 12.5 mmol) was dissolved in 4-(hydroxymethyl)-3-(2-trimethylsilylethoxymethoxy)benzonitrile (2.65 g, 9.48 mmol) in THF (60 mL). was added to the solution 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 x 50 mL). The organics were combined, washed with water and saturated aqueous NaCl, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient from 0 to 10% EtOAc in heptane to give 3.18 g (77%) of the title compound. ¹ H NMR (400.13MHz, CDCl ₃ ) δ 7.57 (d, J= 7.6 Hz, 1H), 7.46 (m, 2H), 7.32 (d, J= 8 Hz, 1H), 7.11 (d, J= 7.2 Hz) , 1H), 6.77 (d, J= 8 Hz, 1H), 5.44 (s, 2H), 5.31 (s, 2H); 3.78 (t, J= 8.4 Hz, 2H), 0.98 (t, J= 8.4Hz, 2H). 0.02 (s, 9H).

Manufacturing Example 201

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

Carbon tetrabromide (364 mg, 1.1 mmol) was dissolved in 4-[(6-bromo-2-pyridyl)oxymethyl]-3-(2-trimethylsilylethoxymethoxy) in 2-propanol (75 ml). Benzonitrile (3.18 g, 7.31 mmol) was added to the solution. After heating the reaction mixture at 80° C. for 10 hours, the solvent was concentrated under reduced pressure and the residue was purified via silica gel chromatography using a gradient of 0 to 20% EtOAc in heptane to give the title compound as a white solid. (1.72 g, 57%). ES-MS m/z 305/307 (M+H).

Manufacturing Example 202

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

Ethyl 2-[4-bromo-5-fluoro-2-(2-hydroxyethyl)phenyl]acetate (519 mg, 1.70 mmol), 4-[(6-bromo-2) in THF (17 mL) -pyridyl)oxymethyl]-3-hydroxy-benzonitrile (500 mg, 1.64 mmol) and triphenylphosphine (645 mg, 2.46 mmol) in a solution of DEAD (40% in toluene) diluted in THF (1 mL). %, 0.97 mL, 2.46 mmol) was added at 0°C. The reaction mixture was stirred at RT overnight. After 14 hours, additional DEAD (40% in toluene, 0.53 mL, 1.36 mmol) diluted in THF (1 mL) at 0°C was added. After 20 hours at RT, the reaction mixture was diluted with water (25 mL) and extracted with EtOAc (3 x 10 mL). The organic portions were combined, filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 10 to 30% EtOAc in heptane to yield 444 mg (44%) of the title compound as a white solid. ES-MS m/z 591/593/595 (M+H).

Manufacturing Example 203

Ethyl 2-(5 ⁴ -cyano-1 ⁶ -fluoro-3,6-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclo octaphane-1 ⁴ -yl)acetate

In two different batches, ethyl 2-[4-bromo-2-[2-[2-[(6-bromo-2-pyridyl)oxymethyl]- in 1,4-dioxane (10 mL) Nitrogen was bubbled through a solution of 5-cyano-phenoxy]ethyl]-5-fluoro-phenyl]acetate (299 mg, 0.50 mmol), followed by hexamethyltin (0.16 mL, 0.76 mmol) and Pd( dppf)Cl ₂ and DCM complex (100 mg, 0.12 mmol) were added. The reaction mixture batch was heated at 100° C. for 3 hours. Both batches were cooled to RT and combined. Diluted with water and extracted three times with EtOAc. The organics were combined, washed with water and saturated aqueous NaCl, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 10 to 20% EtOAc in heptane to give the title compound as a white solid (90 mg, 41%). ES-MS m/z 433 (M+H).

Manufacturing example 204

2-(5 ⁴ -cyano-1 ⁶ -fluoro-3,6-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacycloocta Edition-1 ⁴ -day) Acetic acid

Ethyl 2-(5 ⁴ -cyano-1 ⁶ -fluoro-3,6-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclo The title compound was prepared essentially as described in Preparation Example 75 using octaphan-1 ⁴ -yl)acetate and heating the reaction at 45° C. for 3 hours. Formic acid was added to the mixture until pH = 5-6, diluted with water and extracted three times with 3:1 DCM:isopropanol. The organics were combined, washed with water and saturated aqueous NaCl, dried over MgSO ₄ , filtered and concentrated under reduced pressure to give the title compound as a white solid. ES-MS m/z 405 (M+H).

Manufacturing Example 205

Methyl (S)-4-(2-(5 ⁴ -cyano- ^{1 6} -fluoro-3,6-dioxa-2(2,6)-pyridina-1(1,3),5(1 ,2)-dibenzenacyclooctaphane-1 ⁴ -yl)acetamido)-3-((oxetan-2-ylmethyl)amino)benzoate

2-(5 ⁴ -cyano- ^{1 6} -fluoro-3,6-dioxa-2(2,6)-pyridina-1(1,3),5(1,2) in DMF (2 mL) )-Dibenzenacyclooctaphan-1 ⁴ -yl)acetic acid (82 mg, 0.20 mmol) and methyl 4-amino-3-[[(2S)-oxetan-2-yl]methylamino]benzoate (48 mg , 0.20 mmol), DIPEA (0.10 mL, 0.58 mmol) and HATU (115 mg, 0.30 mmol) were added. After stirring at RT for 24 h, additional 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 portions were combined, washed with water and saturated aqueous NaCl, dried over MgSO ₄ , filtered, and concentrated under reduced pressure to give the title compound (200 mg, >100%), which was used in Preparation 206 without further purification. . ES-MS m/z 623 (M+H).

Manufacturing Example 206

Methyl (S)-2-((5 ⁴ -cyano-1 ⁶ -fluoro-3,6-dioxa-2(2,6)-pyridina-1(1,3),5(1,2 )-Dibenzenacyclooctaphan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

Acetic acid (6 mL) was dissolved in methyl (S)-4-(2-(5 ⁴ -cyano- ^{1 6} -fluoro-3,6-dioxa-2(2,6)-pyridina-1(1, 3),5(1,2)-dibenzenacyclooctaphan-1 ⁴ -yl)acetamido)-3-((oxetan-2-ylmethyl)amino)benzoate (Preparation Example 205, 200mg, 0.32 mmol) and stirred at 65°C for 2 hours. The mixture was cooled to RT, the solvent was evaporated under reduced pressure and the residue was purified via silica gel chromatography using a gradient from 0 to 20% EtOAc in DCM to give 92 mg (47%) of the title compound. ES-MS m/z 605 (M+H).

Manufacturing Example 207

Ethyl 3-amino-5-bromo-pyridine-2-carboxylate

Sulfuric acid (52 mL, 927 mmol) was added slowly to a solution of 3-amino-5-bromopyridine-2-carboxylic acid (15 g, 65.66 mmol) in 8M ethanol in water (197 mL). The reaction was heated at 80°C for 18 hours. The mixture was cooled to RT, then NaOH (2 M aqueous) was added slowly until pH = 8 and extracted with EtOAc (3 x 100 mL). The organic portions were combined, dried over MgSO ₄ , filtered and concentrated under reduced pressure to give the title compound as a light yellow solid (13.93 g, 86%). ES-MS m/z 245/247 (M+H).

Manufacturing Example 208

(3-amino-5-bromo-2-pyridyl)methanol

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. was added lithium borohydride (3.75 g, 172 g). mmol) was added little by little. The reaction was stirred at RT for 1 hour. A saturated solution of NaHCO ₃ was added and extracted with EtOAc (5 x 100 mL). The organic portions were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. ACN was added to the residue, the resulting slurry was filtered, the solid was washed with ACN, and the solid was dried under vacuum to yield 9.87 g (81%) of the title compound as a beige solid. ES-MS m/z 203/205 (M+H).

Manufacturing Example 209

(5-bromo-3-iodo-2-pyridyl)methanol

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 NaHCO ₃ was added to the mixture and extracted with EtOAc (3 x 100 mL). The organic portions were combined, washed with 5% aqueous sodium bisulfite, water and saturated aqueous NaCl, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The resulting solid was triturated with ACN, then filtered, and the solid was dried under vacuum to give the title compound as a brownish solid (10.31 g, 61%). ES-MS m/z 314/316 (M+H).

Manufacturing Example 210

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

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 reacted with (5-bromo-3). To a solution of -iodo-2-pyridyl)methanol (11.78 g, 37.53 mmol) was added at RT under nitrogen. tert-Butyldimethyl(2-propynyloxy)silane (10 mL, 48 mmol) was added and the reaction was heated at 40° C. for 20 hours. The reaction was cooled to RT, water and brine were added and the mixture was extracted three times with EtOAc. The organic portions were combined, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient from 0 to 20% EtOAc in heptane to yield 9.03 g (67%) of the title compound as a brown oil. ES-MS m/z 356/358 (M+H).

Manufacturing Example 211

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

Zinc cyanide (2.09 g, 17.85 mmol) was dissolved in [5-bromo-3-[3-[tert-butyl(dimethyl)silyl]oxyprop-1-ynyl]-2-pyridyl] in DMF (180 mL). To a solution of methanol (9.03 g, 25.26 mmol) was added under nitrogen followed by tetrakis(triphenylphosphine)palladium(0) (2.93 g, 2.54 mmol). The reaction was heated at 100°C for 2 hours. The mixture was cooled to RT, water and saturated aqueous NaCl were added and the mixture was extracted three times with EtOAc. The organic portions were combined, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient from 0 to 25% EtOAc in heptane to afford 4.6 g (60%) of the title compound as a brown oil. ES-MS m/z 303 (M+H).

Manufacturing Example 212

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

The title compound essentially as described in Preparation Example 34 using 5-[3-[tert-butyl(dimethyl)silyl]oxyprop-1-ynyl]-6-(hydroxymethyl)pyridine-3-carbonitrile. was manufactured. After completion, the reaction was cooled to RT, the solvent was evaporated under reduced pressure and the residue was purified via silica gel chromatography using a gradient of 0 to 15% EtOAc in heptane to give the title compound as a light yellow solid. . ES-MS m/z 458/460 (M+H).

Manufacturing Example 213

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

1M TBAF (16.1 mL, 16.1 mmol) in THF was dissolved in 6-[(6-bromo-2-pyridyl)oxymethyl]-5-[3-[tert-butyl(dimethyl)silyl] in THF (40 mL). Oxyprop-1-ynyl] was added to a solution of pyridine-3-carbonitrile (6.15 g, 13.42 mmol). The mixture was stirred at RT for 7 hours. A saturated aqueous solution of NaHCO ₃ was added and the mixture was extracted three times with EtOAc. The organics were combined, washed with water and saturated aqueous NaCl, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient from 0 to 50% EtOAc in heptane to yield 3.04 g (66%) of the title compound as a colorless oil. ES-MS m/z 344/346 (M+H).

Manufacturing Example 214

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

Platinum oxide (0.06 g, 0.26 mmol) was dissolved in 6-[(6-bromo-2-pyridyl)oxymethyl]-5-(3-hydroxyprop-1) in MeOH (18 mL) and 2 drops of acetic acid. -ynyl)pyridine-3-carbonitrile (0.65 g, 1.88 mmol) was added to the solution. The reaction vessel was charged with an atmosphere of hydrogen (15 psi) and the mixture was stirred at RT for 5 hours. The reaction was filtered through a pad of ^Celite® , washing with MeOH and EtOAc. The filtrate was evaporated under vacuum and the residue was purified via silica gel chromatography using a gradient from 0 to 30% EtOAc in heptane to give the title compound (0.33 g, 51%). ES-MS m/z 348/350 (M+H).

Manufacturing Example 215

Ethyl 2-[4-bromo-2-[3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano-3-pyridyl]propoxy]-5-fluo rho-phenyl]acetate

6-[(6-bromo-2-pyridyl)oxymethyl]-5-(3-hydroxypropyl)pyridine-3-carbonitrile (1.01 g, 2.9 mmol) was used and MeOH was removed in the quenching step. The title compound was obtained as a white solid, prepared essentially as described in Preparation Example 60. ES-MS m/z 606/608 (M+H).

Manufacturing Example 216

Ethyl 2-(5 ⁵ -cyano-16amino-fluoro-3,9-dioxa-2(2,6),5(2,3)-dipyridina-1(1,3)-benzena Cyclononaphan-14amino-yl)acetate

Ethyl 2-[4-bromo-2-[3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano in 1,4-dioxane (55 mL) under nitrogen. A mixture of -3-pyridyl]propoxy]-5-fluoro-phenyl]acetate (0.75 g, 1.23 mmol), cesium fluoride (203 mg, 1.33 mmol), and hexamethyltin (321 mg, 0.98 mmol) To 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. The reaction mixture was heated at 100° C. for 18 hours. The mixture was cooled to RT, filtered through a pad of ^Celite® and washed with EtOAc (2 x 100 mL) and MeOH (2 x 100 mL). The filtrate was evaporated and the residue was purified via silica gel chromatography using a gradient of 0 to 50% EtOAc in heptane to yield 0.27 g (49%) of the title compound as a pale yellow solid. ES-MS m/z 448 (M+H).

Manufacturing Example 217

2-(5 ⁵ -Cyano-16amino-fluoro-3,9-dioxa-2(2,6),5(2,3)-dipyridina-1(1,3)-benzenacyclo nonaphan-14amino-yl)acetic acid

Ethyl 2-(5 ⁵ -cyano-1 ⁶ -fluoro-3,9-dioxa-2(2,6),5() in ACN (3.2 mL), THF (0.8 mL) and water (0.5 mL) 1,3,4,6,7,8- in a mixture of 2,3)-dipyridina-1(1,3)-benzenacyclononapan-1 ⁴ -yl)acetate (0.12 g, 0.27 mmol) Hexahydro-2H-pyrimido[1,2-a]pyrimidine (0.075 g, 0.54 mmol) was added. The suspension was heated at 45°C for 2 hours. The mixture was cooled to RT, formic acid was added until pH = 4 and extracted with EtOAc (3 x 5 mL). The organics were combined, washed with water and saturated aqueous NaCl, dried over MgSO ₄ , filtered and concentrated under reduced pressure to give the title compound as a white solid (0.11 g, 98%). ES-MS m/z 420 (M+H).

Manufacturing Example 218

Methyl (S)-4-(2-(5 ⁵ -cyano-16amino-fluoro-3,9-dioxa-2(2,6),5(2,3)-dipyridina-1( 1,3)-Benzenacyclononaphan-14amino-yl)acetamido)-3-methoxy-5-((oxetan-2-ylmethyl)amino)benzoate

2-(5 ⁵ -cyano-16amino-fluoro-3,9-dioxa-2(2,6),5(2,3)-dipyridina-1(1, 3)-Benzenacyclononaphan-14amino-yl)acetic acid (0.11 g, 0.26 mmol) and methyl 4-amino-3-methoxy-5-[[(2S)-oxetan-2-yl]methylamino ] To a solution of benzoate (0.077 g, 0.29 mmol) was added DIPEA (0.13 mL, 0.74 mmol) and HATU (0.16 g, 0.40 mmol). The reaction was stirred at RT for 16 hours. Saturated aqueous NaHCO ₃ solution was added and extracted with EtOAc (2 x 40 mL). The organic portions were combined, dried over MgSO ₄ , filtered, and concentrated under reduced pressure to give the title compound as a beige solid (0.22 g), which was used in Preparation 219 without further purification. ES-MS m/z 668 (M+H).

Manufacturing Example 219

Methyl (S)-2-((5 ⁵ -cyano-1 ⁶ -fluoro-3,9-dioxa-2(2,6),5(2,3)-dipyridina-1(1, 3)-Benzenacyclononaphan-1 ⁴ -yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

Methyl (S)-4-(2-(5 ⁵ -cyano- ^{1 6} -fluoro-3,9-dioxa-2(2,6),5(2,3)-dipyridina-1( 1,3)-Benzenacyclononaphan-1 ⁴ -yl)acetamido)-3-methoxy-5-((oxetan-2-ylmethyl)amino)benzoate (Preparation Example 218) was used. , the reaction was heated at 100° C. for 2 hours to prepare the title compound essentially as described in Preparation Example 102. After completion, the reaction was cooled to RT, ACN was added and evaporated. This operation was repeated three times to ensure acetic acid removal. The residue was purified via silica gel chromatography using a gradient from 0 to 100% EtOAc in heptane to afford the title compound as a light brown solid. ES-MS m/z 650 (M+H).

Manufacturing example 220

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

4-(bromomethyl)-3-iodo-benzonitrile (20.0 g, 62.1 mmol), 6-chloropyridin-2-ol (8.45 g, 65.2 mmol) in 1,4-dioxane (400 mL) and A mixture of silver carbonate (17.1 g, 62.0 mmol) was stirred at 70°C for 20 hours. Additional 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 hours. The mixture was cooled to RT and filtered through a silica gel plug using DCM as eluent to give the title compound as a light yellow solid (24.6 g, 107%). ES-MS m/z 371.0/373.0 (M+H).

Manufacturing example 221

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

4-[(6-chloro-2-pyridyl)oxymethyl]-3-iodo-benzonitrile (15.0 g, 40.5 mmol), 1,4-diazabicyclo[2.2.2] in DMF (180 mL) To a mixture of octane (460 mg, 4.06 mmol) and potassium formate (6.90 g, 81.2 mmol) was added tert-butyl isocyanide (5.52 mL, 48.6 mmol), methanesulfonato (tri-t-butylphosphino) (2 '-methylamino-1,1'-biphenyl-2-yl)palladium(II) [P(t-Bu)3 Pd G4, 775 mg, 1.29 mmol] and tri-tert-butylphosphonium tetrafluoroborate. (360 mg, 1.22 mmol) was added. The mixture was stirred at 75°C for 23 hours. The mixture was cooled to RT and filtered through a silica gel plug using DMF as eluent. The filtrate was cooled to 0°C, 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 min. The resulting solid was filtered to obtain the title compound as a light green solid (5.4 g, 77% purity, 37% yield). ES-MS m/z 273.0/275.0 (M+H).

Manufacturing Example 222

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

A solution of 4-[(6-chloro-2-pyridyl)oxymethyl]-3-formyl-benzonitrile (1.0 g, 3.67 mmol) in MeOH (20 mL) was cooled to 0° C. and dissolved in sodium borohydride ( 290 mg, 7.26 mmol) was added little by little. The mixture was stirred at RT for 30 min and then cooled to 0°C. To the mixture was added water (25 mL) followed by 5% aqueous citric acid solution until pH = 5, followed by additional water (50 mL). The reaction mixture was stirred at RT for 30 minutes. The resulting solid was filtered to obtain the title compound as a white solid (901 mg, 89%). ES-MS m/z 275.0/277.0 (M+H).

Manufacturing example 223

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

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 at 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 plug using DCM as eluent to give the compound as a light brown solid (1.25 g; 116% yield). ES-MS m/z 337.0/339.0/341.0 (M+H).

Manufacturing example 224

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

Ethyl 2-[4-bromo-5-fluoro-2-(2-hydroxyethyl)phenyl]acetate (750 mg, 2.46 mmol), 3-(bromomethyl)-4- in DCM (13.0 mL) A solution of [(6-chloro-2-pyridyl)oxymethyl]benzonitrile (1.24 g, 3.67 mmol) and 2,6-di-tert-butylpyridine (2.3 mL, 9.9 mmol) was stirred at RT. Silver trifluoromethanesulfonate (2.60 g, 10.0 mmol) was added in portions, 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 via silica gel chromatography using a gradient from 0 to 100% EtOAc in DCM to give the title compound as a yellow solid (480 mg, 34%). ES-MS m/z 561/563 (M+H).

Manufacturing example 225

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-dioxaborolan-2-yl)phenyl]acetate

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

Manufacturing Example 226

Ethyl 2-(5 ⁴ -cyano- ^{1 6} -fluoro-3,7-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclo Nonaphan-1 ⁴ -1) Acetate

Ethyl 2-[2-[2-[[2-[(6-chloro-2-pyridyl)oxymethyl]-5-cyano-phenyl]methoxy in THF (9.0 mL) while bubbling nitrogen through the mixture. A mixture of ]ethyl]-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate (160 mg, 0.26 mmol) 1N tribasic potassium phosphate (1.30 mL, 1.30 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2- (2'-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 21 mg, 0.03 mmol) was added and the reaction was stirred at 70°C for 30 minutes. The reaction mixture was cooled to RT, then MTBE (25 mL) and water (25 mL) were added. The phases were separated and the aqueous phase was extracted with MTBE (3 x 20 mL). The organic portions were combined, washed with water and saturated aqueous NaCl, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient from 0 to 100% EtOAc in DCM as eluent to give the title compound (45 mg, 34%) as a white solid. ES-MS m/z 447.0 (M+H).

Manufacturing example 227

2-(5 ⁴ -cyano-1 ⁶ -fluoro-3,7-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclonona Edition-1 ⁴ -day) Acetic acid

Ethyl 2-(5 ⁴ -cyano-1 ⁶ -fluoro-3,7-dioxa-2(2,6) in ACN (2.7 mL), THF (0.90 mL) and water (0.90 mL) under nitrogen bubbling. )-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphan-1 ⁴ -yl)acetate (91 mg, 0.24 mmol) in a mixture of 1,5,7-triazabicyclo [4.4.0]des-5-ene (96 mg, 0.67 mmol) was added little by little, and the reaction was stirred at 45°C for 1 hour. The reaction mixture was cooled to RT, water (5 mL), 5% aqueous citric acid solution was added until pH = 5 and the mixture was stirred at RT for 15 min. The resulting solid was filtered to give the title compound as a white solid (72 mg, 85%). ES-MS m/z 419.0 (M+H).

Manufacturing example 228

Methyl (S)-4-(2-(5 ⁴ -cyano- ^{1 6} -fluoro-3,7-dioxa-2(2,6)-pyridina-1(1,3),5(1 ,2)-dibenzenacyclononaphan-1 ⁴ -yl)acetamido)-2-methoxy-5-((oxetan-2-ylmethyl)amino)benzoate

2-(5 ⁴ -cyano- ^{1 6} -fluoro-3,7-dioxa-2(2,6)-pyridina-1(1,3),5(1,2) in DMF (2.5 mL) )-Dibenzenacyclononapan-1 ⁴ -yl)methyl 4-amino-3-methoxy-5-[[(2S)-oxetan-2-yl]methyl in a solution of 4-yl)acetic acid (70 mg, 0.167 mmol) Amino]benzoate (50 mg, 0.19 mmol), HATU (96 mg, 0.25 mmol) and DIPEA (0.1 mL, 0.60 mmol) were added. The mixture was stirred at RT for 2 hours, then water (10 mL) and EtOAc (10 mL) were added. The phases were separated and the aqueous phase was extracted with EtOAc (3 x 10 mL). The organics were combined, washed with 2M aqueous Na ₂ CO ₃ , water, and saturated aqueous NaCl, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give the title compound as a brown solid (193 mg, 48% purity, 83% yield), which was used in Preparation Example 229 without further purification. ES-MS m/z 667.2 (M+H).

Manufacturing Example 229

Methyl (S)-2-((5 ⁴ -cyano-1 ⁶ -fluoro-3,7-dioxa-2(2,6)-pyridina-1(1,3),5(1,2 )-Dibenzenacyclononaphan-1 ⁴ -yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

Methyl (S)-4-(2-(5 ⁴ -cyano-1 ⁶ -fluoro-3,7-dioxa-2(2) in 1,2-dichloroethane (3.0 mL) and acetic acid (1.5 mL) ,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononapan- ^{1 4} -yl)acetamido)-2-methoxy-5-((oxetane-2 A solution of -ylmethyl)amino)benzoate (Preparation Example 228, 190 mg, 0.28 mmol) was heated at 60°C for 6 hours. The reaction mixture was cooled to RT, the solvents were concentrated under reduced pressure and the residue was purified via silica gel chromatography using a gradient from 0 to 100% EtOAc in DCM to give the title compound (58 mg, 31%) as a white solid. It was obtained as. ES-MS m/z 649.2/650.2 (M+H).

Manufacturing Example 230

2-Bromo-4-chloro-6-fluoro-benzaldehyde

To a solution of 1,2-dibromo-5-chloro-3-fluorobenzene (50 g, 170 mmol) in heptane (130 mL) and THF (210 mL) at -45°C isopropylmagnesium chloride (in THF) The internal reaction temperature was maintained at -40°C to -45°C while adding dropwise 2 M solution, 94 mL, 188 mmol). After stirring at -40°C for 30 minutes, DMF (66 mL, 853 mmol) was added dropwise and stirred at -20°C for 1 hour. The reaction mixture was warmed to 0° C., 1 N HCl was added until pH = 7 and extracted with EtOAc (3 x 300 mL). The organics were combined, washed with water and saturated aqueous NaCl, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient from 0 to 12% EtOAc in petroleum ether to give the title compound (22.70 g, 52%) as a yellow solid. ES-MS m/z 238 (M+H).

Manufacturing Example 231

(2-Bromo-4-chloro-6-fluoro-phenyl)methanol

Sodium borohydride (5.16 g, 134 mmol) was added to a solution of 2-bromo-4-chloro-6-fluoro-benzaldehyde (22.70 g, 89.88 mmol) in MeOH (240 mL) at 0°C. Stirred at RT for 2 hours. Cooled to 0°C, added 1N HCl until pH = 7, concentrated most of the solvent, and extracted the mixture with EtOAc (3 x 150 mL). The organics were combined, washed with water and saturated aqueous NaCl, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound as an orange solid (22.3 g, 88%). ES-MS m/z 263 (M+Na).

Manufacturing Example 232

1-Bromo-2-(bromomethyl)-5-chloro-3-fluoro-benzene

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. did. The reaction mixture was brought to RT and stirred for 2 hours. The solvent was concentrated under reduced pressure and the residue was purified via silica gel chromatography using a gradient from 0 to 2% EtOAc in petroleum ether to give the title compound (26.83 g, 95%) as a colorless oil. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 7.75 (t, J = 2 Hz, 1H), 7.63 (dd, J = 9.5, 2 Hz, 1H), 4.70 (d, J = 2 Hz, 2H ).

Manufacturing Example 233

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

1-Bromo-2-(bromomethyl)-5-chloro-3-fluoro-benzene (34.1 g, 107 mmol) and 2-chloro-6-hydroxypyridine (57 g, Silver carbonate (180 g, 653 mmol) was added to a solution of 431 mmol). The reaction mixture was stirred at 40°C for 36 hours. The mixture was cooled to RT, then filtered and the filtrate was concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient from 0 to 5% EtOAc in petroleum ether to give the title compound as a white solid (22.8 g, 52%). ES-MS m/z 350/352 (M+H).

Manufacturing example 234

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

2-[(2-Bromo-4-chloro-6-fluoro-phenyl)methoxy]-6-chloro-pyridine (20.8 g, 50.4 mmol) and cesium carbonate in 1,4-dioxane (200 mL) (33 g, 101 mmol) was added to a mixture of 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (11.8 mL, 55.4 mmol) was added under nitrogen, followed by tetrakis(triphenylphosphine)palladium(0) (6.13 g, 5.0 mmol). The reaction was heated at 90° C. for 12 hours, then additional 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane ( 5.4 mL, 25 mmol) and tetrakis(triphenylphosphine)palladium(0) (3.1 g, 2.5 mmol) were added. The mixture was stirred at 90°C for another 4 hours. The mixture was cooled to RT, concentrated under reduced pressure, then water (150 mL) was added and extracted with EtOAc (3 x 150 mL). The organic portions were combined, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The residue was purified via silica gel chromatography using a gradient from 0 to 20% DCM in petroleum ether to give the title compound (13.71 g, 70%) as a white solid. ES-MS m/z 342 (M+H).

Manufacturing Example 235

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

2-Chloro-6-[[4-chloro-2-[(E)-2-ethoxyvinyl]-6-fluoro-phenyl]methoxy in THF (280 mL) and water (280 mL) at 0°C. ] Mercury acetate (37.53 g, 117.8 mmol) was added to a solution of pyridine (12.7 g, 35.3 mmol) and stirred at 0°C for 3 hours. 50% aqueous K ₂ CO ₃ (190 mL) and sodium borohydride (6 g, 158.59 mmol) were added to the mixture at 0°C and then stirred at 0°C for 3 hours. Water (200 mL) was added to the mixture and extracted with EtOAc (3 x 500 mL). The organic portions were combined, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient from 0 to 25% EtOAc in petroleum ether to give the title compound as a colorless oil (9.46 g, 78%). ES-MS m/z 316 (M+H).

Manufacturing Example 236

1-Bromo-5-(bromomethyl)-2-fluoro-4-iodobenzene

A solution of 5-bromo-4-fluoro-2-iodotoluene (50.2 g, 156 mmol) and N-bromosuccinimide (29.2 g, 164 mmol) in ACN (0.8 L) was prepared. A coiled PFA reaction tube (1/8" od, 52 mL volume) maintained at 40°C and surrounded by an array of four Kesil PR160-370 nm (40 W) and four Evoluchem 450 nm (30 W) lamps. ) at a flow rate of 2 mL/min to 3 mL/min. Once complete, ACN (60 mL) was pumped through the reactor at the same rate. The reactor output was stirred and 20% aqueous sodium bicarbonate. Sodium sulfate (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 minutes. The solid was collected by filtration and washed with water (0.5 L). 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 portions of water, saturated aqueous NaHCO ₃ and saturated aqueous NaCl, then dried over MgSO ₄ and filtered. Filtration The water was concentrated at 50° C. under reduced pressure to give 35.19 g (53%, 93% purity) of the title compound as a cream-colored solid. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.65 (d, J = 6.8 Hz, 1H ), 7.60 (J = 7.6 Hz, 1H), 4.51 (s, 2H) ^.19 F{1H}-NMR (386.5 MHz, CDCl3) -105.55 (s).

Manufacturing Example 237

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

Silver trifluoromethanesulfonate (8.30 g, 32 mmol) was dissolved in 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-ditertbutyl- It was added to a solution of 4-methylpyridine (5 g, 24 mmol). The reaction was stirred at RT for 5 hours. The reaction mixture was filtered through ^Celite® , diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The organic portions were combined, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient from 0 to 6% EtOAc in petroleum ether to give the title compound as a colorless oil (8.51 g, 76%). ES-MS m/z 628/630 (M+H).

Manufacturing Example 238

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

2-[[2-[2-[(5-bromo-4-fluoro-2-iodo-phenyl)methoxy]ethyl]-4-chloro-6-fluoro in THF (7 mL) under nitrogen. -phenyl]methoxy]-6-chloro-pyridine (1.49 g, 1.94 mmol) and chloro[(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'- Amino-1,1'-biphenyl)]palladium(II) (Xantphos-Pd-G2, 0.2 g, 0.2 mmol) in a mixture of (2-ethoxy-2-oxoethyl))zinc bromide (0.5 M in THF) , 8 mL, 4 mmol) was added. The mixture was heated in a microwave reactor at 65°C for 2 hours. The mixture was cooled to RT, saturated aqueous NH ₄ Cl solution (30 mL) was added, then diluted with water (30 mL) and extracted with EtOAc (3 x 50 mL). The organic portions were combined, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient from 0 to 15% EtOAc in petroleum ether to afford 0.57 g (45%) of the title compound as a colorless oil. ES-MS m/z 588/590 (M+H).

Manufacturing Example 239

Ethyl 2-(5 ⁴ -Chloro-1 ^{6,5 6} -difluoro-3,8-dioxa-2( ^2,6 )-pyridina-1(1,3),5(1,2)- Dibenzenacyclononaphan-1 ⁴ -yl)acetate

Ethyl 2-[4-bromo-2-[2-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]-3-fluoro-phenyl in THF (85 mL) under nitrogen. ]ethoxymethyl]-5-fluoro-phenyl]acetate (1.43 g, 2.19 mmol), potassium 2,2-dimethylpropanoate (0.78 g, 5.49 mmol) and bis(pinacolato)diborone (0.8 g) , 3 mmol) in a solution of 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. The reaction was heated at 55°C for 4 hours. Potassium phosphate tribasic (1.42 g, 6.57 mmol) in water (6.57 mL) was added to the reaction and heated at 55° C. for 2 hours. The mixture was cooled to RT, water (30 mL) was added and extracted with EtOAc (3 x 100 mL). The organic portions were combined, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient from 0 to 15% EtOAc in petroleum ether to afford the title compound as a beige solid (308 mg, 27%). ES-MS m/z 474 (M+H).

Manufacturing Example 240

2-(5 ⁴ -Chloro-1 ⁶ ,5 ⁶ -difluoro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-diben Zenacyclononaphan-1 ⁴ -yl)acetic acid

Ethyl 2-(5 ⁴ -Chloro-1 ^{6,5 6} -difluoro-3,8-dioxa-2( ^2,6 )-pyridina-1(1,3),5(1,2)- The title compound was prepared essentially as described in Preparation Example 227 using dibenzenacyclononaphan-1 ⁴ -yl)acetate. ES-MS m/z 446 (M+H).

Manufacturing Example 241

Methyl (S)-4-(2-(5 ⁴ -chloro-1 ⁶ ,5 ⁶ -difluoro-3,8-dioxa-2(2,6)-pyridina-1(1,3), 5(1,2)-dibenzenacyclononaphan-1 ⁴ -yl)acetamido)-3-(2-methoxyethoxy)-5-((oxetan-2-ylmethyl)amino)benzoate

2-(5 ⁴ -chloro-1 ⁶ ,5 ⁶ -difluoro-3,8-dioxa-2(2,6)-pyridina-1(1,3) in DMF (5.4 mL) under nitrogen; methyl 4-amino-3-(2-methoxy) in a solution of 5(1,2)-dibenzenacyclononaphan-1 ⁴ -yl)acetic acid (245 mg, 0.54 mmol) and HATU (356 mg, 0.91 mmol) Ethoxy)-5-[[(2S)-oxetan-2-yl]methylamino]benzoate (242 mg, 0.70 mmol) and DIPEA (0.28 mL, 1.62 mmol) were added. The mixture was stirred at RT for 2 hours, then water (10 mL) was added and extracted with EtOAc (3 x 25 mL). The organics were combined, washed with water and saturated aqueous NaCl, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound as a white solid (594 mg, 34% purity), prepared without further purification. Used in Example 242. ES-MS m/z 738 (M+H).

Manufacturing Example 242

Methyl (S)-2-((5 ⁴ -chloro-1 ⁶ ,5 ⁶ -difluoro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5( 1,2)-Dibenzenacyclononaphan-1 ⁴ -yl)methyl)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole -6-carboxylate

Methyl (S)-4-(2-(5 ⁴ -chloro-1 ^6,5 6 -difluoro-3,8-dioxa-2(2) in 1:1 ^1,2 -dichloroethane:acetic acid as solvent ,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononapan-1 ⁴ -yl)acetamido)-3-(2-methoxyethoxy)-5- The title compound was prepared essentially as described in Preparation Example 102 using ((oxetan-2-ylmethyl)amino)benzoate and heating the reaction at 60° C. for 6 hours. The reaction mixture was cooled to RT, the solvent was evaporated under reduced pressure and EtOAc/toluene (1:1) was added to aid removal of acetic acid in the concentrate. The residue was purified via silica gel chromatography using a gradient from 0 to 5% MeOH in DCM to give the title compound as a pale yellow solid (64% purity). ES-MS m/z 720 (M+H).

Manufacturing example 243

2-Bromo-6-(bromomethyl)nicotinonitrile

A solution of 2-bromo-6-methylnicotinonitrile (23 g, 113.2 mmol) and N-bromosuccinimide (30.8 g, 170 mmol) in ACN (560 mL) was heated at 440-460 nM with a 200 W lamp. Transferred through an equipped photochemical flow reactor (reactor size = 15 m, 15 mL, flow rate = 1 mL/min, 25°C). The reaction solvent was evaporated and the residue was partitioned between water and DCM. The organic layer was separated, washed with saturated aqueous NaCl, dried over anhydrous Na ₂ SO ₄ , 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 under N ₂ at 0° C. for 0.5 h. The reaction mixture was warmed to RT and stirred overnight to give a black solution. The reaction mixture was partitioned between water and EtOAc. The organic layer was separated, washed with saturated aqueous NaCl, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 25% EtOAc in petroleum ether to give the title compound (28.45 g, 84%) as a white solid. ES-MS m/z 275, 277, 279 (M+H).

Manufacturing example 244

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

Silver carbonate (10.5 g, 37.3 mmol) was dissolved in 2-bromo-6-(bromomethyl)nicotinonitrile (1.84 g, 6.33 mmol) and 2-chloro-6-hydroxypyridine in ACN (150 mL) at RT. (3.35 g, 25.3 mmol) was added to the solution. The mixture was stirred at 60°C for 48 hours. The solid was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient from 0 to 23% EtOAc in petroleum ether to give the title compound (957 mg, 91 wt% purity, 42%) as a white solid. ES-MS m/z 324, 326, 328 (M+H).

Manufacturing example 245

6-[(6-chloro-2-pyridyl)oxymethyl]-2-[(E)-2-ethoxyvinyl]pyridine-3-carbonitrile

2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (13.5 mL, 63.4 mmol) and 1,1'-bis( Diphenylphosphino)ferrocene-palladium(II)dichloride DCM complex (4.7 g, 5.65 mmol) was reacted with 2-bromo-6-[(6) in 1,4-dioxane (200 mL) and water (60 mL). -Chloro-2-pyridyl)oxymethyl]pyridine-3-carbonitrile (20.4 g, 56.6 mmol, 91 wt% purity) and tribasic potassium phosphate (24.5 g, 113 mmol). 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 x 4). The organic layers were combined, dried over anhydrous Na ₂ SO ₄ , filtered and the solvent was removed. The residue was purified by silica gel chromatography using a gradient from 0 to 20% EtOAc in petroleum ether to give the title compound (15.7 g, 83 wt% purity, 73%) as a yellow solid. ES-MS m/z 316, 318 (M+H).

Manufacturing example 246

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

The title compound was prepared essentially as described in Preparation Example 235 using 6-[(6-chloro-2-pyridyl)oxymethyl]-2-[(E)-2-ethoxyvinyl]pyridine-3-carbonitrile. was manufactured. After the reaction was complete, the solid was filtered and washed with EtOAc. From the filtrate, the organic layer was separated and the aqueous layer was extracted three times with EtOAc. The organic layers were combined, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 45% EtOAc in petroleum ether to afford the title compound as a pale yellow solid. ES-MS m/z 290, 292 (M+H)

Manufacturing example 247

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

6-[(6-chloro-2-pyridyl)oxymethyl]-2-(2-hydroxyethyl)pyridine-3-carbonitrile and methyl 2-[4-bromo-2-(bromomethyl)phenyl ]Acetate was used and the reaction was stirred at 40° C. overnight to prepare the title compound essentially as described in Preparation Example 224. After the reaction was completed, ACN was removed under reduced pressure, and the residue was diluted with water and extracted with EtOAc. The organic portion was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative HPLC [column: Phenomenex Luna C18 250 x 50 mm, 10 μm; Purification by mobile phase: 40 to 85% ACN (0.225%) in aqueous formic acid gave the title compound as a pale yellow waxy solid. ES-MS m/z 530, 532, 534 (M+H).

Manufacturing example 248

Methyl 2-(5 ⁵ -cyano-3,8-dioxa-2,5(2,6)-dipyridina-1(1,3)-benzenacyclononaphan-14amino-yl)acetate

Starting material: methyl 2-[4-bromo-2-[2-[6-[(6-chloro-2-pyridyl)oxymethyl]-3-cyano-2-pyridyl]ethoxymethyl]phenyl ]acetate and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-bi) as catalyst. Phenyl)]palladium(II) methanesulfonate (XPhos Pd G3) was used and the reaction was heated to 110° C. overnight to prepare the title compound essentially as described in Preparation Example 216. Once the reaction was complete, the reaction mixture was concentrated, water was added and extracted three times with EtOAc. The combined organic portions were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by HPLC [column: Welch Xtimate C18 150 x 40 mm, 10 μm; Purification by mobile phase: 40 to 80% ACN (0.225%) in aqueous formic acid gave the title compound as a white solid. ES-MS m/z 416 (M+H).

Manufacturing example 249

2-(5 ⁵ -Cyano-3,8-dioxa-2,5(2,6)-dipyridina-1(1,3)-benzenacyclononaphan-14amino-yl)acetic acid

Methyl 2-(5 ⁵ -cyano-3,8-dioxa-2,5(2,6)-dipyridina-1(1,3)-benzenacyclononaphan-1 ⁴ -yl)acetate The title compound was prepared essentially as described in Preparation Example 78. Once the reaction was complete, the organic solvent and water and aqueous citric acid (1 M) were removed to bring the pH to 5-6. The resulting solid was filtered and washed with water to obtain the title compound as a white solid. ES-MS m/z 402 (M+H).

Production example 250

Methyl (S)-4-(2-(5 ⁵ -cyano-3,8-dioxa-2,5(2,6)-dipyridina-1(1,3)-benzenacyclononaphane- 14amino-yl)acetamido)-3-(2-methoxyethoxy)-5-((oxetan-2-ylmethyl)amino)benzoate

2-(5 ⁵ -cyano-3,8-dioxa-2,5(2,6)-dipyridina-1(1,3)-benzenacyclononaphan-1 ⁴ -yl)acetic acid and methyl Using 4-amino-3-(2-methoxyethoxy)-5-[[(2S)-oxetan-2-yl]methylamino]benzoate and stirring the reaction at RT overnight, essentially The title compound was prepared as described in 86. The reaction mixture was diluted with water and extracted three times with EtOAc. The organic layers were combined, washed with water and saturated aqueous NaCl, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound as an orange waxy solid with 54 wt% purity. ES-MS m/z 694 (M+H).

Manufacturing Example 251

Methyl (S)-2-((55-amino-cyano-3,8-dioxa-2,5(2,6)-dipyridina-1(1,3)-benzenacyclononaphane-14 Amino-yl)methyl)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

Methyl (S)-4-(2-(5 ⁵ -cyano-3,8-dioxa-2,5(2,6)-dipyridina-1(1,3)-benzenacyclononaphane- 1 ⁴ -yl)acetamido)-3-(2-methoxyethoxy)-5-((oxetan-2-ylmethyl)amino)benzoate (54 wt% purity) was used, and under nitrogen atmosphere. The title compound was prepared essentially as described in Preparation Example 109 by stirring at 60° C. for 6 hours. Purification by silica gel chromatography using a gradient from 0 to 6% MeOH in DCM afforded the title compound as an orange waxy solid with 63 wt% purity. ES-MS m/z 676 (M+H).

Manufacturing Example 252

Methyl 2-chloro-5-(((6-chloropyridin-2-yl)oxy)methyl)benzoate

6-chloropyridin-2-ol (14.2 g, 110 mmol) in a solution of methyl 5-(bromomethyl)-2-chlorobenzoate (25 g, 95 mmol) in 1,4-dioxane (600 mL) 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 through ^Celite® and washed with EtOAc. The filtrate was concentrated under reduced pressure to obtain 29.4 g (99%) of the title compound, which was used in Preparation Example 253 without further purification. ES-MS m/z 312, 314 (M+H).

Manufacturing Example 253

(2-chloro-5-(((6-chloropyridin-2-yl)oxy)methyl)phenyl)methanol

A solution of methyl 2-chloro-5-(((6-chloropyridin-2-yl)oxy)methyl)benzoate (22 g, 71 mmol from Preparation 252) in THF (200 mL) was cooled to 0°C. Then, Red-Al ^® (60 wt% in toluene, 30 mL, 92 mL) was added dropwise. The mixture was stirred at 0° C. for 10 min, then the reaction was quenched with EtOAc (10 mL). The mixture was stirred at RT for 2 hours, then the reaction was diluted with water (200 mL) and EtOAc (200 mL). The aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic phases were dried over MgSO ₄ , filtered and concentrated under reduced pressure to give 20.7 g (100%) of the title compound, which was used in Preparation 254 without further purification. ES-MS m/z 284, 286 (M+H).

Manufacturing example 254

2-((3-(bromomethyl)-4-chlorobenzyl)oxy)-6-chloropyridine

(2-Chloro-5-(((6-chloropyridin-2-yl)oxy)methyl)phenyl)methanol (from Preparation Example 253, 1.5 g, 5.3 mmol) and triphenylphosphine ( A solution of 2.0 g, 7.5 mmol) 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 and then at RT for 30 min. The reaction solution was filtered through a pad of silica gel and rinsed with DCM. The filtrate was concentrated under reduced pressure to obtain 1.8 g (100%) of the title compound, which was used in Preparation Example 255 without further purification. ES-MS m/z 345/347/349 (M+H).

Manufacturing example 255

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

2-((3-(bromomethyl)-4-chlorobenzyl)oxy)-6-chloropyridine (from Preparation Example 254) and ethyl 2-[4-bromo-5-fluoro-2-(2- The title compound was prepared essentially as described in Preparation 224 using hydroxyethyl)phenyl]acetate and stirring the reaction at RT for 1 hour and 15 minutes. Filtered, the reaction mixture was concentrated under reduced pressure and then purified via silica gel chromatography using a gradient of 0 to 20% EtOAc in hexane to give the title compound. ES-MS m/z 570/572/574 (M+H).

Manufacturing Example 256

Ethyl 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-dioxaborolan-2-yl)phenyl)acetate

Ethyl 2-(4-bromo-2-(2-((2-chloro-5-(((6-chloropyridin-2-yl)oxy)methyl)benzyl)oxy)ethyl)-5-fluorophenyl ) Acetate (855 mg, 1.5 mmol), bis(pinacolato)diborone (480 mg, 1.87 mmol), KOAc (450 mg, 4.5 mmol), and dichlorobis(tricyclohexylphosphine)palladium (II) ( 225 mg, 0.30 mmol) of 1,4-dioxane (15 mL) was added to the mixture. The mixture was stirred at 90°C for 5 hours, then Pd(dppf)Cl ₂ (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 pad of silica gel and rinsed with EtOAc. The filtrate was concentrated under reduced pressure to obtain the title compound, which was used in Preparation Example 257 without further purification. ES-MS m/z 536 (M+H for boronic acid).

Manufacturing Example 257

Ethyl 2-(5 ⁴ -chloro-1 ⁶ -fluoro-3,7-dioxa-2(2,6)-pyridina-1,5(1,3)-dibenzenacyclononaphane-1 ⁴ - 1) Acetate

Ethyl 2-(2-(2-((2-chloro-5-(((6-chloropyridin-2-yl)oxy)methyl)benzyl)oxy)ethyl)-5-fluoro in THF (50 mL) -4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (from Preparation Example 256, 925 mg, 1.5 mmol) and XPhos Pd G2 ( To a solution of 145 mg, 0.18 mmol) was added a solution of potassium phosphate (1.6 g, 7.4 mmol) in water (5 mL). The reaction mixture was stirred at 60°C for 1.5 hours. The crude reaction mixture was diluted with EtOAc (50 mL) and 1:1 water:saturated aqueous NaCl (50 mL), and the aqueous layer was extracted with EtOAc (50 mL). The combined organic phases were dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0 to 40% EtOAc in hexane to give 140 mg of the title compound (20%). ES-MS m/z 456 (M+H).

Manufacturing example 258

2-(5 ⁴ -Chloro-1 ⁶ -fluoro-3,7-dioxa-2(2,6)-pyridina-1,5(1,3)-dibenzenacyclononaphan-1 ⁴ -yl )acetic acid

Ethyl 2-(5 ⁴ -chloro-1 ⁶ -fluoro-3,7-dioxa-2(2,6)-pyridina-1,5(1,3)-dibenzenacyclononaphane-1 ⁴ - 1) Using acetate, using 3:3:1 ACN:1,4-dioxane:water as solvent, and heating the reaction at 50° C. for 1 hour and 20 minutes, the title compound was obtained essentially as described in Preparation Example 75. Prepared as described. The reaction was diluted with water and quenched with 1 M aqueous citric acid solution. The precipitated material was collected by filtration and rinsed with water to obtain the title compound. ES-MS m/z 428 (M+H).

Manufacturing Example 259

Methyl (S)-4-(2-(5 ⁴ -chloro-1 ⁶ -fluoro-3,7-dioxa-2(2,6)-pyridina-1,5(1,3)-dibenzena Cyclononaphan-1 ⁴ -yl)acetamido)-3-(2-methoxyethoxy)-5-((oxetan-2-ylmethyl)amino)benzoate

2-(5 ⁴ -Chloro-1 ⁶ -fluoro-3,7-dioxa-2(2,6)-pyridina-1,5(1,3)-dibenzenacyclononaphan-1 ⁴ -yl )acetic acid and methyl 4-amino-3-(2-methoxyethoxy)-5-[[(2S)-oxetan-2-yl]methylamino]benzoate, and the reaction was incubated at RT for 17 hours. With stirring, the title compound was prepared essentially as described in Preparation Example 86. The reaction was diluted with EtOAc and water, the organic layer was washed with water and the aqueous layer was back-extracted twice with EtOAc. The combined organic phases were dried over MgSO ₄ , filtered and concentrated under reduced pressure to give the title compound, which was used in Preparation 260 without further purification. ES-MS m/z 720 (M+H).

Manufacturing Example 260

Methyl (S)-2-((5 ⁴ -chloro-1 ⁶ -fluoro-3,7-dioxa-2(2,6)-pyridina-1,5(1,3)-dibenzenacyclonona Pan-1 ⁴ -yl)methyl)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

Methyl (S)-4-(2-(5 ⁴ -chloro-1 ⁶ -fluoro-3,7-dioxa-2(2,6)-pyridina-1,5(1,3)-dibenzena Using cyclononaphan-1 ⁴ -yl) acetamido) -3- (2-methoxyethoxy) -5-((oxetan-2-ylmethyl) amino) benzoate (from Preparation Example 259) The title compound was prepared essentially as described in Preparation Example 109. Purification by silica gel chromatography using a gradient from 0 to 100% EtOAc in hexanes gave the title compound. ES-MS m/z 702 (M+H).

Manufacturing Example 261

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

Two batches were prepared on the same scale as follows: Na ₂ CO ₃ was dissolved in 4-(bromomethyl)-3-iodo-benzonitrile (22.4 g, 62.6 g) in acetone (340 mL) and water (340 mL). mmol) was added to the solution. Both batches were stirred at 80° C. overnight and then the two batches were combined. The mixture was concentrated to remove acetone and the solid was filtered and washed with water. The solid was dried under vacuum and then stirred in DCM (70 mL) for 30 minutes. The solid was filtered, rinsed with DCM, and dried under vacuum to give 4-(hydroxymethyl)-3-iodo-benzonitrile (23.6 g, 72%) as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.28 (d, J= 1.6 Hz, 1H), 7.88 (dd, J= 8.0, 1.6 Hz, 1H), 7.62 (d, J= 8.0 Hz, 1H) ), 5.71 (t, J= 5.6 Hz, 1H), 4.44 (d, J= 5.2 Hz, 2H).

4-(Hydroxymethyl)-3-iodo-benzonitrile (11.5 g, 43.5 mmol), 2-bromo-3,6-difluoro in 1,4-dioxane (80 mL) at 0°C under nitrogen. To a solution of rho-pyridine (7.08 g, 35.8 mmol) was added potassium tert-butoxide (1 M in THF, 43 mL, 43 mmol). The reaction was stirred at 0°C for 1 hour and then the reaction was stirred at RT for 7 hours. The reaction was diluted with a saturated aqueous solution of NH ₄ Cl (50 mL), then water (100 mL) was added and extracted with EtOAc (250 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl (60 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient from 0 to 45% DCM in petroleum ether to give the title compound as a white solid (14.28 g, 88%). ES-MS m/z 432 (M+H).

Manufacturing Example 262

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

Using 4-[(6-bromo-5-fluoro-2-pyridyl)oxymethyl]-3-iodo-benzonitrile as a starting material and K ₂ CO ₃ as a base, the reactants were reacted at 90° C. The title compound was prepared essentially as described in Preparation Example 245 by heating for an hour. After completion, the reaction mixture was concentrated under reduced pressure, then water was added and extracted three times with EtOAc. The organic layers were combined, washed with saturated aqueous NaCl, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient from 0 to 60% EtOAc in petroleum ether gave the title compound as a white solid. ES-MS m/z 377 (M+H).

Manufacturing Example 263

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

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

Manufacturing example 264

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

4-[(6-bromo-5-fluoro-2-pyridyl)oxymethyl]-3-(2-oxoethyl)benzonitrile (from Preparation 263, 8.54 g) in MeOH (80 mL) at 0°C , 22.0 mmol), sodium borohydride (3.59 g, 93.9 mmol) was added, and the reaction was stirred at RT for 4 hours. The reaction was quenched with a saturated aqueous solution of NH ₄ Cl and stirred at RT for 20 min. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with water (50 mL) and extracted with EtOAc (200 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl (60 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient from 0 to 30% EtOAc in petroleum ether to give the title compound as a yellow oil (7.1 g, 87%). ES-MS m/z 351/353 (M+H).

Manufacturing Example 265

Methyl 2-(4-bromo-2-((2-(((6-bromo-5-fluoropyridin-2-yl)oxy)methyl)-5-cyanophenethoxy)methyl)phenyl)acetate

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

Manufacturing Example 266

Methyl 2-(5 ⁴ -cyano-2 ³ -fluoro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclo Nonaphan-1 ⁴ -1) Acetate

Methyl 2-(4-bromo-2-((2-(((6-bromo-5-fluoropyridin-2-yl)oxy)methyl)-5-cyanophenethoxy)methyl) as starting material Phenyl) acetate was used as a catalyst, and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1, The title compound was prepared essentially as described in Preparation 216 using]palladium(II) methanesulfonate (XPhos Pd G3) and protecting the reaction mixture from light during heating. After completion, the reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with water and extracted three times with EtOAc. The organic layers were combined, washed with saturated aqueous NaCl, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient from 0 to 33% EtOAc in petroleum ether gave the title compound as a brown solid. ES-MS m/z 433 (M+H).

Manufacturing Example 267

2-(5 ⁴ -cyano- ^{2 3} -fluoro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclonona Edition-1 ⁴ -day) Acetic acid

Methyl 2-(5 ⁴ -cyano-2 ³ -fluoro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclo The title compound was prepared essentially as described in Preparation Example 78 using nonaphan-1 ⁴ -yl)acetate. After completion, the reaction was quenched with 1 M aqueous citric acid 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 in Preparation Example 268 without further purification. ES-MS m/z 419 (M+H).

Manufacturing Example 268

Methyl (S)-4-(2-(5 ⁴ -cyano- ^{2 3} -fluoro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1 ,2)-Dibenzenacyclononaphan-1 ⁴ -yl)acetamido)-3-(2-methoxyethoxy)-5-((oxetan-2-ylmethyl)amino)benzoate

2-(5 ⁴ -cyano- ^{2 3} -fluoro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclonona Pan-1 ⁴ -yl) acetic acid (Production Example 267) and methyl 4-amino-3-(2-methoxyethoxy)-5-[[(2S)-oxetan-2-yl]methylamino]benzoate and the reaction was stirred at RT overnight to prepare the title compound essentially as described in Preparation Example 86. After completion, the reaction was diluted with water and extracted three times with EtOAc. The organic layers were combined, washed with saturated aqueous NaCl, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give the title compound as a light brown oil, which was used in Preparation 269 without further purification. ES-MS m/z 711 (M+H).

Manufacturing Example 269

Methyl (S)-2-((5 ⁴ -cyano- ^{2 3} -fluoro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2 )-Dibenzenacyclononapan-1 ⁴ -yl)methyl)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6- carboxylate

Methyl (S)-4-(2-(5 ⁴ -cyano- ^{2 3} -fluoro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1 ,2)-Dibenzenacyclononaphan-1 ⁴ -yl)acetamido)-3-(2-methoxyethoxy)-5-((oxetan-2-ylmethyl)amino)benzoate (preparation example) 268) and 1:1 1,2-dichloroethane:acetic acid and heating the reaction at 55° C. for 5 hours to prepare the title compound essentially as described in Preparation Example 102. After the reaction was complete, the solvent was removed under reduced pressure, then 1:1 EtOAc:toluene was added to the residue and concentrated in vacuo. Purification by silica gel chromatography using a gradient from 0 to 6% MeOH in DCM afforded the title compound as an orange oil. ES-MS m/z 693 (M+H).

Manufacturing example 270

Methyl 2-(5-cyano-2-methyl-phenyl)-2,2-difluoro-acetate

3-Iodo-4-methylbenzonitrile (5 g, 19.96 mmol) and copper (12 g, 179.4 mmol) were stirred in THF (30 mL) and DMSO (80 mL). To this slurry, methyl bromodifluoroacetate (6 mL, 51.9 mmol) was added and the mixture was stirred under nitrogen at 30° C. for 18 hours. Then, 100 mL of saturated aqueous NaHCO ₃ solution was added followed by 100 mL of EtOAc. The mixture was filtered and the solid was washed with EtOAc (3 x 50 mL). The filtrate was then separated and the organic layer was washed with saturated aqueous NH ₄ Cl solution. The organic portion was dried over MgSO ₄ , filtered and concentrated. This residue was purified via silica gel chromatography (0-25% EtOAc in hexanes) to give the product as a clear crystalline solid (3.3 g, 73%). ¹ H NMR(DMSO-d ₆ ) δ 2.41 (s, 3H), 3.33 (s, 3H), 7.61 (d, J= 8.0 Hz, 1H), 7.99 (d, J= 7.9 Hz, 1H), 8.04 ( d, J = 1.2 Hz, 1H).

Manufacturing Example 271

Methyl 2-[2-(bromomethyl)-5-cyano-phenyl]-2,2-difluoro-acetate

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 reacted with ACN ( 100 mL). This solution was applied twice to a 4100K white bulb via flow conditions (1.0 mL/min; 72 feet of 1/8" outside diameter reaction tubing, wrapped around beaker; maintained at 30°C). After this treatment, the reaction liquid was After concentration to dryness, the residue was purified via silica gel chromatography (0-10% EtOAc in hexane) to give the product as a clear thick oil (3.7 g, 62%). ¹ H NMR (DMSO-d ₆ ) δ 3.41 (s, 3H), 3.89 (s, 2H), 7.61 (d, J= 7.9 Hz, 1H), 7.99 (d, J= 8.0 Hz, 1H), 8.03 (s, 1H).

Manufacturing Example 272

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

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) was dissolved in DMSO (50 mL). Potassium phosphate tribasic (6.6 g, 30 mmol) was added to this solution and heated to 60° C. for 2 hours. The reaction was then quenched with 1N HCl (to pH ~6) and extracted with EtOAc. The combined organics were dried over MgSO ₄ , filtered, and concentrated to give the product as a thick brown oil (7.8 g, 100%). ES-MS m/z ( ⁷⁹ Br/ ⁸¹ Br) 382.8/384.8 [M+H] ⁺ .

Manufacturing Example 273

Methyl 2-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano-phenyl]-2,2-difluoro-acetate

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

Manufacturing example 274

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

Methyl 2-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano-phenyl]-2,2-difluoro-acetate (8 g, 20.14 mmol) was dissolved in THF (100 mL). To this solution was added lithium borohydride (0.88 g, 40.4 mmol) and stirred for 2 hours under nitrogen at ambient temperature. The reaction was then quenched with saturated NH ₄ Cl solution and extracted with EtOAc. The organic portion was dried over MgSO ₄ , filtered and concentrated. This residue was purified via silica gel chromatography (0-50% EtOAc in hexane) to give the product as a thick clear oil (4.7 g, 63%). ES-MS m/z ( ⁷⁹ Br/ ⁸¹ Br) 368.8/370.8 [M+H] ⁺ .

Manufacturing Example 275

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

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). To this solution was added sodium hydride (0.6 g, 15 mmol; 60% mass in mineral oil) and stirred at ambient temperature under nitrogen for 5 minutes. 4-Bromo-2-(chloromethyl)-1-iodobenzene (4.8 g, 14 mmol) was then added and stirring was continued for 18 hours under nitrogen at ambient temperature. The reaction was then quenched with saturated aqueous NH ₄ Cl solution and extracted with EtOAc. The organic portion was dried over MgSO ₄ , filtered and concentrated. This residue was purified via silica gel chromatography (0-30% EtOAc in hexanes) to give the product as a thick clear oil (3.9 g, 48%). ES-MS m/z ( ⁷⁹ Br/ ⁸¹ Br) 663.0/665.0 [M+H] ⁺ .

Manufacturing Example 276

Ethyl 2-[4-bromo-2-[[2-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano-phenyl]-2,2-difluoro- Ethoxy]methyl]phenyl]acetate

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-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl) ]Palladium(II) methanesulfonate (XantPhos Pd G3, 0.6 g, 0.6 mmol) was dissolved in THF (30 mL). To this solution was added (2-ethoxy-2-oxo-ethyl)zinc bromide (0.5 M in ether) (18 mL, 9.0 mmol) and the mixture was heated to 60° C. under nitrogen for 18 hours. The reaction was then cooled to ambient temperature and the reaction was quenched with saturated aqueous NaHCO ₃ solution and extracted with EtOAc. The organic portion was dried over MgSO ₄ , filtered and concentrated. This residue was purified via silica gel chromatography (0-30% EtOAc in hexanes) to give the product as a thick light brown oil (1.6 g, 44%). ES-MS m/z ( ⁷⁹ Br/ ⁸¹ Br) 623.2/625.2 [M+H] ⁺ .

Manufacturing example 277

Ethyl 2-(54amino-cyano-6,6-difluoro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-diben Geneacyclonaphan-14amino-yl)acetate

Ethyl 2-[4-bromo-2-[[2-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano-phenyl]-2,2-difluoro- Ethoxy]methyl]phenyl]acetate (1.6 g, 2.9 mmol) was dissolved in 1,4-dioxane (30 mL). To this solution, KOAc (0.64 g, 6.39 mmol) and bis(pinacolato)diboron (0.8 g, 3.09 mmol) were added, and nitrogen was bubbled through it for 10 minutes. After this time 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride DCM complex (0.11 g, 0.132 mmol) was added and the mixture was heated at 80° C. under nitrogen for 18 hours. The reaction was then cooled to ambient temperature, diluted with saturated aqueous NaCl solution and extracted with EtOAc. The organic portion was dried over MgSO ₄ , filtered and concentrated. This residue was dissolved in 1,4-dioxane (50 mL) and water (3 mL) and tribasic potassium phosphate (1.4 g, 6.5 mmol) 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 ) was added. This mixture was heated to 60°C for 2 hours. The reaction was then cooled to ambient temperature and the reaction was quenched with saturated aqueous NH ₄ Cl solution and extracted with EtOAc. The organic portion was dried over MgSO ₄ , filtered and concentrated. This residue was purified via silica gel chromatography (0-50% EtOAc in hexane) to give the product as a white solid (249 mg, 21%). ES-MS (m/z) 465.2 (M+H).

Manufacturing example 278

Methyl (S)-2-((5 ⁴ -cyano-6,6-difluoro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1 ,2)-Dibenzenacyclonaphan-1 ⁴ -yl)methyl)-4-(2-methoxyethoxy)-1-(oxatan-2-ylmethyl)-1H-benzo[d]imidazole-6 -Carboxylates

Ethyl 2-(5 ⁴ -cyano-6,6-difluoro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-diben Geneacyclonaphan-1 ⁴ -yl)acetate (249 mg, 0.54 mmol) was dissolved in ACN (5 mL), THF (1.8 mL) and water (1.8 mL). To this solution was added 1,5,7-triazabicyclo[4.4.0]dec-5-ene (0.23 g, 1.62 mmol) and the mixture was stirred at ambient temperature for 2 hours. The reaction was then quenched with saturated aqueous NH ₄ Cl solution and extracted with EtOAc. The organic portion was dried over MgSO ₄ , filtered and concentrated. This residue was dissolved in DMF (2 mL) and methyl 4-amino-3-(2-methoxyethoxy)-5-[[(2S)-oxetan-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 stirred at ambient temperature for 18 hours. The reaction was then quenched with saturated aqueous NH ₄ Cl solution and extracted with EtOAc. The organic portion was dried over MgSO ₄ , filtered and concentrated. This 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 via silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound as an off-white solid (61 mg, 52.5%). ES-MS (m/z) 711.4 (M+H).

Manufacturing Example 279

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

To a solution of 2-chloropyrimidin-4-ol (8.50 g, 65.1 mmol) in DMF (150 mL) was added Cs ₂ CO ₃ (42.5 g, 130 mmol) and 4-(bromomethyl)-3-iodo- Benzonitrile (21.04 g, 65.35 mmol) was added. The reaction mixture was stirred at ambient temperature for 16 hours. The crude reaction was poured into water, and the precipitate was collected through filtration. The solid material was dissolved in DCM and washed twice with water. The organic phase was dried over MgSO ₄ , filtered, and concentrated under reduced pressure to give the title compound (20.3 g, 84%) as a light orange solid, which was used in Preparation Example 280 without further purification. ES/MS m/z 372 (M+H).

Manufacturing example 280

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

To a solution of 4-[(2-chloropyrimidin-4-yl)oxymethyl]-3-iodo-benzonitrile (10.1 g, 27.2 mmol) in THF (150 mL) was added potassium phosphate tribasic (40 mL, 80 ml). mmol, 2 M solution in water), 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7.5 mL, 35 mmol ), and bis(triphenylphosphine)palladium(II) dichloride (953 mg, 1.36 mmol) were added. The solution was aerated with nitrogen for 15 minutes and then stirred at 55°C for 4 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was dried over MgSO ₄ , 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 MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient from 0 to 30% EtOAc in hexane to give the title compound (5.97 g, 70%). ES/MS m/z ( ³⁵ Cl/ ³⁷ Cl) 315/317 [M+H] ⁺ .

Manufacturing Example 281

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

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) was added hydrochloric acid. (46 mL, 184 mmol, 4M solution in dioxane) was added. Stirred at ambient temperature for 2.5 hours. The reaction was concentrated under reduced pressure and then the residue was diluted with DCM. The mixture was adjusted to pH = 8 using saturated aqueous NaHCO ₃ solution and then extracted with DCM. The organic phase was dried over MgSO ₄ , 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 added slowly. The mixture was stirred at 0°C for 30 minutes. The reaction mixture was quenched with 1 M aqueous NaOH, then the solution was further diluted with water and DCM and extracted with DCM. The organic phase was dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient from 0 to 50% EtOAc in hexane to give the title compound (2.86 g, 44%). ES/MS m/z ( ³⁵ Cl/ ³⁷ Cl) 289/291 [M+H] ⁺ .

Manufacturing Example 282

Methyl 2-[4-bromo-2-[2-[2-[(2-chloropyrimidin-4-yl)oxymethyl]-5-cyano-phenyl]ethoxymethyl]phenyl]acetate

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 in an ice bath at 0°C. Cooled, methyl 2-[4-bromo-2-(bromomethyl)phenyl]acetate (556 mg, 1.73 mmol) was added, and then 2,6-di-tert-butylpyridine (0.31 mL, 1.38 mL). mmol) and silver trifluoromethanesulfonate (354 mg, 1.38 mmol) were added. The mixture was stirred at 0° C. for 1 hour and then allowed to stir at ambient temperature for 16 hours. The reaction mixture was filtered through a pad of diatomaceous earth, and the pad was rinsed with DCM. The filtrate was concentrated under reduced pressure and the residue was purified via silica gel chromatography using a gradient from 0 to 40% EtOAc in hexane to give the title compound (128 mg, 35%). ES/MS m/z ( ⁷⁹ Br/ ⁸¹ Br) 529/531 [M+H] ⁺ .

Manufacturing Example 283

Methyl 2-[2-[2-[2-[(2-chloropyrimidin-4-yl)oxymethyl]-5-cyano-phenyl]ethoxymethyl]-4-(4,4,5,5 -Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate

Methyl 2-[4-bromo-2-[2-[2-[(2-chloropyrimidin-4-yl)oxymethyl]-5-cyano-phenyl in 1,4-dioxane (7.5 mL) ]Ethoxymethyl]phenyl]acetate (566 mg, 0.715 mmol) was added to a solution of bis(pinacolato)diborone (222 mg, 0.86 mmol), KOAc (177 mg, 1.80 mmol), and 1,1'-bis. (Diphenylphosphino)ferrocene palladium(II) dichloride dichloromethane complex (30 mg, 0.036 mmol) was added. The solution was aerated with nitrogen for 10 minutes and then heated to 80°C. Stirred for 19 hours. The reaction was cooled to ambient temperature, filtered through a silica gel plug, and the silica gel plug was washed with DCM. The filtrate was concentrated under reduced pressure to obtain the title compound, which was used in Preparation Example 284 without further purification. ES/MS m/z ( ³⁵ Cl/ ³⁷ Cl) 496/498 [M+H] ⁺ (as boronic acid).

Manufacturing example 284

Methyl 2-(5 ⁴ -Cyano-3,8-dioxa-2(2,4)-pyrimidina-1(1,3),5(1,2)-dibenzenacyclononaphane-1 ⁴ -1) Acetate

Methyl 2-[2-[2-[2-[(2-chloropyrimidin-4-yl)oxymethyl]-5-cyano-phenyl]ethoxymethyl]-4-(4) in THF (5.6 mL) ,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate (Preparation Example 283, 130 mg, 0.225 mmol) was added to tribasic potassium phosphate (0.68 mL, 0.68 mmol, 1 M aqueous solution) was added. The solution was bubbled with nitrogen for 10 minutes, then chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino) -1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 8.9 mg, 0.011 mmol) was added and aeration resumed for an additional 5 minutes. The solution was heated 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 MgSO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified via silica gel chromatography using a gradient from 0 to 40% EtOAc in hexane to give the title compound (21 mg, 22%). ES/MS m/z 416 (M+H).

Manufacturing Example 285

2-(54amino-cyano-3,8-dioxa-2(2,4)-pyrimidina-1(1,3),5(1,2)-dibenzenacyclononaphane-14amino- 1) Acetic acid

Methyl 2-(5 ⁴ -Cyano-3,8-dioxa-2(2,4)-pyrimidina-1(1,3),5(1,2)-dibenzenacyclononaphane-1 ⁴ The title compound was prepared essentially as described in Preparation Example 217 using -1)acetate and stirring the reaction at ambient temperature for 2 hours. After completion, the reaction was quenched with 5% aqueous citric acid to pH 4 and then the mixture was diluted with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic phases were washed with saturated aqueous NaCl solution. The organic phase was dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting solid was triturated with water to obtain the title compound. ES/MS m/z 402 (M+H).

Manufacturing Example 286

Methyl (S)-4-(2-(5 ⁴ -cyano-3,8-dioxa-2(2,4)-pyrimidina-1(1,3),5(1,2)-diben Zenacyclononapan-1 ⁴ -yl)acetamido)-3-methoxy-5-((oxetan-2-ylmethyl)amino)benzoate

2-(5 ⁴ -Cyano-3,8-dioxa-2(2,4)-pyrimidina-1(1,3),5(1,2)-dibenzenacyclononaphane-1 ⁴ - mono)acetic acid and methyl 4-amino-3-methoxy-5-[[(2S)-oxetan-2-yl]methylamino]benzoate were used as starting materials and 2,4 as a 50% solution in DMFm. ,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide was added and the solution was heated to 42° C. for 24 hours to essentially The title compound was prepared as described in Preparation Example 164. The reaction was cooled to ambient temperature and then water was added. The aqueous layer was extracted with EtOAc, then the organic portion was washed with saturated aqueous NaHCO ₃ solution. The organic portion was dried over MgSO ₄ , filtered, and concentrated under reduced pressure to obtain the title compound, which was used in Preparation Example 287 without further purification (23.6 mg, 83%). ES/MS m/z 650 (M+H).

Manufacturing Example 287

Methyl (S)-2-((5 ⁴ -cyano-3,8-dioxa-2(2,4)-pyrimidina-1(1,3),5(1,2)-dibenzenacyclo Nonapan-1 ⁴ -yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

Methyl (S)-4-(2-(5 ⁴ -cyano-3,8-dioxa-2(2,4)-pyrimidina-1(1,3),5(1,2)-diben Zenacyclononapan-1 ⁴ -yl) acetamido) -3-methoxy-5-((oxetan-2-ylmethyl) amino) benzoate (Preparation Example 286) was used and 1,2-dichloroethane The title compound was prepared essentially as described in Preparation Example 102, using a 5:1 mixture of :acetic acid as solvent and heating the reaction to 53° C. for 22 hours. After completion, the reaction mixture was cooled to ambient temperature, diluted with DCM and concentrated under reduced pressure. The residue was dissolved in EtOAc and concentrated twice under reduced pressure. The residue was purified via silica gel chromatography using a gradient from 0 to 5% MeOH in DCM to give the title compound. ES/MS m/z 632 (M+H).

Manufacturing Example 288

Ethyl 4-[(E)-2-ethoxyvinyl]-6-(trifluoromethyl)pyridine-3-carboxylate

Ethyl 4-chloro-6-(trifluoromethyl)nicotinate (15 g, 57.4 mmol) and Cs ₂ CO ₃ (37 g, 112.4) in 1,4-dioxane (130 mL) and water (45 mL) 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (13.4 mL, 62.9 mmol) was added to the solution of (mmol) Next, tetrakis(triphenylphosphine)palladium(0) (7 g, 5.75 mmol) was added. The solution was sparged with nitrogen and the mixture was heated to 90° C. and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure and then diluted with water. The aqueous layer was extracted with EtOAc and the combined organics were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0 to 23% EtOAc in petroleum ether to give the title compound (14.5 g, 84%). ES/MS m/z 290 (M+H).

Manufacturing Example 289

[4-[(E)-2-ethoxyvinyl]-6-(trifluoromethyl)-3-pyridyl]methanol

Ethyl 4-[(E)-2-ethoxyvinyl]-6-(trifluoromethyl)pyridine-3-carboxylate (14.5 g, 48.1 mmol) in THF (100 mL) at -78°C under an inert atmosphere. To the solution was added diisobutylaluminum hydride (150 mL, 150 mmol, 1M solution in toluene). The reaction vessel was removed from the cooling bath and allowed to stir at ambient temperature for 5 hours. The reaction was quenched by adding a saturated aqueous solution of potassium sodium tartrate (200 mL) at 0° C., followed by the addition of DCM (100 mL). The mixture was extracted with DCM, then the combined organic phases were washed with saturated aqueous NaCl solution. The organic phase was dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography, eluting with a gradient of 0 to 30% EtOAc in petroleum ether to give the title compound (11 g, 90%). ES/MS m/z 247 (M ⁺ ).

Manufacturing Example 290

5-[(6-bromo-2-pyridyl)oxymethyl]-4-[(E)-2-ethoxyvinyl]-2-(trifluoromethyl)pyridine

[4-[(E)-2-ethoxyvinyl]-6-(trifluoromethyl)-3-pyridyl]methanol (10.5 g, 40.4 mmol) and 2 in 1,4-dioxane (100 mL) To a solution of -bromo-6-fluoropyridine (5.4 mL, 51 mmol) was added potassium tert-butoxide (52 mL, 52 mmol, 1M solution in THF) at 0°C. The reaction was stirred at 0° C. for 30 minutes and then at ambient temperature for 2 hours. The reaction was quenched with saturated aqueous NH ₄ Cl solution (100 mL) and then extracted with EtOAc. The organic portion was dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient from 0 to 30% EtOAc in petroleum ether to give the title compound (17 g, 96%). ES/MS m/z ( ⁷⁹ Br/ ⁸¹ Br) 402/404 [M+H] ⁺ .

Manufacturing Example 291

2-[5-[(6-bromo-2-pyridyl)oxymethyl]-2-(trifluoromethyl)-4-pyridyl]ethanol

5-[(6-bromo-2-pyridyl)oxymethyl]-4-[(E)-2-ethoxyvinyl]-2-(trifluoro) in THF (300 mL) and water (500 mL) To a solution of methyl)pyridine (16.5 g, 39.3 mmol) was added mercuric acetate (14.45 g, 44.89 mmol) at 0°C. The mixture was stirred at 0° C. for 30 min, then 50% aqueous K ₂ CO ₃ solution (210 mL) and sodium borohydride (6.31 g, 165 mmol) were added. The mixture was stirred at 0°C for 2.5 hours. The reaction mixture was filtered and the filter was washed with EtOAc. The filtrate was transferred to a separatory funnel and extracted with EtOAc. The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient from 0 to 25% EtOAc in petroleum ether to give the title compound (12.1 g, 81%). ES/MS m/z ( ⁷⁹ Br/ ⁸¹ Br) 376/378 [M+H] ⁺ .

Manufacturing Example 292

4-[2-[(5-bromo-2-chloro-phenyl)methoxy]ethyl]-5-[(6-bromo-2-pyridyl)oxymethyl]-2-(trifluoromethyl) pyridine

2-[5-[(6-bromo-2-pyridyl)oxymethyl]-2-(trifluoromethyl)-4-pyridyl]ethanol (5.46 g) in 1,2-dichloroethane (100 mL) , 14.3 mmol), 4-bromo-1-chloro-2-(chloromethyl)benzene (5.19 g, 21.4 mmol), and 2,6-di-tert-butyl-4-methylpyridine (6 g, 28.64 mmol) ) was added silver trifluoromethanesulfonate (12 g, 46.24 mmol) at ambient temperature under an inert atmosphere. The reaction was heated to 70° C. and stirred for 18 hours. The crude reaction was concentrated under reduced pressure, and then the resulting residue was diluted with water. After extraction from the aqueous phase with EtOAc, the combined organic phases were washed with saturated aqueous NaCl solution. The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography eluting with a gradient of 0 to 20% EtOAc in petroleum ether to give the title compound (3.3 g, 37%). ES/MS m/z 580 (M+H).

Manufacturing Example 293

1 ⁴ -Chloro-5 ⁶ -(trifluoromethyl)-3,8-dioxa-2(2,6),5(3,4)-dipyridina-1(1,3)-benzenacyclo nonapan

As starting material 4-[2-[(5-bromo-2-chloro-phenyl)methoxy]ethyl]-5-[(6-bromo-2-pyridyl)oxymethyl]-2-(trifluoro Romethyl)pyridine was used as a catalyst, and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1) ,1'-biphenyl)]palladium(II) methanesulfonate (XPhos Pd G3) was used and the reaction was heated at 110° C. for 15 hours to prepare the title compound essentially as described in Preparation Example 216. The crude reaction was concentrated under reduced pressure, and then the residue was diluted with water. After extraction from the aqueous phase with EtOAc, the combined organic phases were washed with saturated aqueous sodium chloride solution. The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified via reverse phase HPLC chromatography using a gradient of 30-100% ACN in aqueous formic acid to give the title compound (403 mg, 14%) as a white solid. ES/MS m/z 421 (M+H).

Manufacturing Example 294

1 ⁴ -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5 ⁶ -(trifluoromethyl)-3,8-dioxa-2( 2,6),5(3,4)-dipyridina-1(1,3)-benzenacyclononaphane

1 ⁴ -Chloro-5 ⁶ -(trifluoromethyl)-3,8-dioxa-2(2,6),5(3,4)-dipyridina in 1,4-dioxane (6.5 mL) -1(1,3)-Benzenacyclononaphane (275 mg, 0.62 mmol), KOAc (155 mg, 1.56 mmol), and bis(pinacolato)diborone (321 mg, 1.24 mmol) (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium ( II) (XPhos Pd G2, 50 mg, 0.06 mmol) was added. The solution was sparged with nitrogen, then heated to 80° C. and stirred for 18 hours. The reaction mixture was concentrated under reduced pressure, and then the residue was diluted with water. After extraction from the aqueous phase with EtOAc, the combined organic phases were washed with saturated aqueous NaCl solution. The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography, eluting with a gradient of 0 to 30% EtOAc in petroleum ether to give the title compound (274 mg, 70%). ES/MS m/z 513 (M+H).

Manufacturing Example 295

Methyl 2-(chloromethyl)-7-(2-methoxyethoxy)-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate

Methyl 4-amino-3-(2-methoxyethoxy)-5-[[(2S)-oxetan-2-yl]methylamino]benzoate (310 mg, 0.93 mmol) in EtOH (6 mL) To the solution was added 2-chloro-1,1,1-trimethoxyethane (710 mg, 4.50 mmol) at ambient temperature. The mixture was heated to 90° C. for 2 hours and then the reaction was concentrated under reduced pressure. The residue was purified via silica gel chromatography eluting with a gradient of 0 to 5% MeOH in DCM to give the title compound (360 mg, 94%). ES/MS m/z 369 (M+H).

Manufacturing Example 296

Methyl (S)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)-2-((5 ⁶ -(trifluoromethyl)-3,8-dioxa-2 (2,6),5(3,4)-dipyridina-1(1,3)-benzenacyclononapan-1 ⁴ -yl)methyl)-1H-benzo[d]imidazole-6-car voxylate

1 ⁴ -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5 ⁶ in 2-methyltetrahydrofuran (1.6 mL) and water (0.32 mL) -(trifluoromethyl)-3,8-dioxa-2(2,6),5(3,4)-dipyridina-1(1,3)-benzenacyclononaphane (160 mg, 0.25 mmol, 81% by weight), methyl 2-(chloromethyl)-7-(2-methoxyethoxy)-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-car Chloro(2-dicyclohexylphosphino-2',4',6'-triiso) in a solution of boxylate (256 mg, 0.62 mmol, 89 mass %), and potassium phosphate tribasic (172 mg, 0.79 mmol). Propyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 26 mg, 0.03 mmol) was added. The solution was buffed with nitrogen and the reaction was heated to 80° C. for 18 hours. The reaction mixture was concentrated under reduced pressure, and then the residue was diluted with water. The mixture was extracted with EtOAc and then the combined organic phases were washed with saturated aqueous NaCl solution. The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography, eluting with a gradient of 0 to 60% EtOAc in petroleum ether to give the title compound (100 mg, 53%). ES/MS m/z 719 (M+H).

Manufacturing Example 297

Ethyl 2-(2-methyloxazol-4-yl)acetate

Ethyl 4-chloro-3-oxo-butanoate (40 g, 243 mmol) was added to a solution of acetamide (15 g, 254 mmol) in toluene (80 ml) at RT. Heated to 130°C and stirred for 12 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified via silica gel chromatography, eluting with a gradient of 10 to 15% EtOAc in petroleum ether to give the title compound as a yellow oil (19 g, 13%) with 30% purity. ES/MS m/z 170 (M+H).

Manufacturing Example 298

2-(2-methyloxazol-4-yl)ethanol

Calcium chloride (26 g, 234 mmol) was added to a solution of ethyl 2-(2-methyloxazol-4-yl)acetate (20 g, 35.5 mmol) in EtOH (400 mL). The mixture was stirred for 20 minutes, cooled to 0° C. and then sodium borohydride (10 g, 265 mmol) was added. The reaction mixture was stirred at RT for 12 hours and then the pH was adjusted to 7 using 1 M aqueous HCl. The mixture was extracted with DCM (3 x 200 mL) and the combined organics were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified via silica gel chromatography eluting with a gradient of 50 to 100% EtOAc in petroleum ether followed by a gradient of 0 to 15% MeOH in DCM to give the title compound as a yellow oil (5 g, 78%) with 70% purity. %) was obtained. ES/MS m/z 128 (M+H).

Manufacturing Example 299

Methyl 3-fluoro-5-hydroxy-4-nitro-benzoate

At -40°C, boron tribromide (2 M solution in DCM, 65.4 mL, 131 mmol) was dissolved in methyl 3-fluoro-5-methoxy-4-nitro-benzoate (30 g, 131 mmol) was added dropwise to the solution. The mixture was stirred at -40°C for 30 minutes and then at ambient temperature for 16 hours. The mixture was poured into ice water (2 L) and extracted with DCM (3 x 800 mL). The combined organic layers were washed with saturated aqueous NaCl solution (2 x 300 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified via silica gel chromatography, eluting with a gradient of 0 to 30% EtOAc in petroleum ether to give the title compound as a yellow solid (16.5 g, 59%). ¹ H NMR(CDCl ₃ ) δ 10.31 (s, 1H), 7.63 (s, 1H), 7.41 (d, 1H, J = 11), 3.98 (s, 3H). ¹⁹ F NMR(CDCl ₃ ) δ -113.37 (s).

Manufacturing Example 300

Methyl 3-fluoro-5-[2-(2-methyloxazol-4-yl)ethoxy]-4-nitro-benzoate

At 0° C., diisopropylazodicarboxylate (5.6 g, 28 mmol) was dissolved in methyl 3-fluoro-5-hydroxy-4-nitro-benzoate (3 g, 13.9 mmol) in THF (30 mL). and 2-(2-methyloxazol-4-yl)ethanol (3 g, 16.5 mmol). The mixture was allowed to warm to ambient temperature and stirred for 12 hours. The mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 50 mL). The combined organics were washed with saturated aqueous NaCl (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified via silica gel chromatography, eluting with a gradient of 0 to 50% EtOAc in petroleum ether to give the title compound as a pale yellow solid (6 g, 23%) with 17% purity. ES/MS m/z 325 (M+H).

Manufacturing Example 301

Methyl 3-[2-(2-methyloxazol-4-yl)ethoxy]-4-nitro-5-[[(2S)-oxetan-2-yl]methylamino]benzoate

(S)-Oxetan-2-ylmethanamine (15 g, 6.29 mmol) and TEA (1 ml, 7.17 mmol) were dissolved in methyl 3-fluoro-5-[2-(2-methyl) in DMSO (150 ml). Oxazol-4-yl)ethoxy]-4-nitro-benzoate (6 g, 3.15 mmol) was added to the solution. The mixture was stirred at 80° C. for 12 hours, cooled to ambient temperature, diluted with water (300 mL) and extracted with EtOAc (3 x 400 mL). The combined organic layers were washed with saturated aqueous NaCl solution (3 x 500 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified via silica gel chromatography, eluting with a gradient of 0 to 60% EtOAc in petroleum ether to afford the title compound as a yellow oil in 24% purity (2 g, 39%). ES/MS m/z 392 (M+H).

Manufacturing Example 302

Methyl 4-amino-3-[2-(2-methyloxazol-4-yl)ethoxy]-5-[[(2S)-oxetan-2-yl]methylamino]benzoate

Palladium on carbon (1 g, 10 wt% Pd) was dissolved in methyl 3-[2-(2-methyloxazol-4-yl)ethoxy]-4-nitro-5-[[(2S) in EtOAc (150 mL). -oxetan-2-yl]methylamino]benzoate (2 g, 1.23 mmol) was added to the solution. The reaction vessel was purged with hydrogen gas and evacuated three times. A hydrogen gas balloon was attached to the container and stirred for 2 hours. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0 to 100% EtOAc in petroleum ether and then purified by preparative HPLC [column: Phenomenex C18 75 x 40 mm, 3 μm; Mobile phase: 18 to 48% ACN in aqueous NH ₄ HCO ₃ (10 mM)] to give the title compound as a white solid (88 mg, 19%). ES/MS m/z 362 (M+H).

Manufacturing Example 303

Methyl (S)-4-(2-(5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzena Cyclononapan-1 ⁴ -yl)acetamido)-3-(2-(2-methyloxazol-4-yl)ethoxy)-5-((oxetan-2-ylmethyl)amino)benzoate

Methyl 4-amino-3-[2-(2-methyloxazol-4-yl)ethoxy]-5-[[(2S)-oxetan-2-yl]methylamino]benzoate (80 mg, 0.215 mmol) and 2-(5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane-1 The title compound was prepared essentially as described in Preparation 86 using ⁴ -yl)acetic acid and the product was used in Preparation 304 without further purification. ES/MS m/z 744 (M+H).

Manufacturing Example 304

Methyl (S)-2-((5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclonona Pan-1 ⁴ -yl)methyl)-4-(2-(2-methyloxazol-4-yl)ethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole -6-carboxylate

Methyl (S)-4-(2-(5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzena Cyclononapan-1 ⁴ -yl)acetamido)-3-(2-(2-methyloxazol-4-yl)ethoxy)-5-((oxetan-2-ylmethyl)amino)benzoate The title compound was prepared essentially as described in Preparation 102 using Preparation 303 and a 1:1 mixture of 1,2-dichloroethane:acetic acid. After completion, the reaction was cooled to ambient temperature and volatiles were removed under vacuum. 1:1 EtOAc/toluene was added and concentrated three times to remove residual acetic acid. The residue was purified via silica gel chromatography eluting with a gradient of 0 to 6% MeOH in DCM to afford the title compound as an orange solid. ES/MS m/z 726 (M+H).

Manufacturing Example 305

tert-Butyl N-(2-hydroxyethyl)-N-(2,2,2-trifluoroethyl)carbamate

A mixture of 2-bromoethanol (5 g, 38.8 mmol) and 2,2,2-trifluoroethylamine (9.66 g, 97.0 mmol) in ethanol (50 mL) was reacted in a sealed tube in a microwave reactor at 60°C. After heating for 3 hours, the reaction mixture was concentrated. To the residue were added TEA (5.2 mL, 3.7 g, 37 mmol) and di-tert-butyl pyrocarbonate (5.6 mL, 5.3 g, 24 mmol) and the mixture was stirred under N ₂ at 55° C. overnight. The reaction mixture was partitioned between EtOAc and water and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient from 0 to 38% EtOAc in petroleum ether to give the title compound (2.5 g, 50%) as a yellow oil. ^1H NMR (400 MHz, DMSO) δ 4.76 (m, 1H), 4.06 (q, J = 9.5 Hz, 2H), 3.67 (m, 2H), 3.30 (q, J = 6 Hz, 2H), 1.41 ( s, 9H).

Manufacturing Example 306

Methyl 3-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]ethoxy]-5-fluoro-4-nitro-benzoate

Methyl 3-fluoro-5-hydroxy-4-nitro-benzoate (1.5 g, 6.6 mmol), tert-butyl N-(2-hydroxyethyl)-N-(2,2) in THF (10 mL) To a solution of ,2-trifluoroethyl)carbamate (2.1 g, 7.8 mmol) and triphenylphosphine (3.5 g, 13 mmol) was added DIAD (2.8 mL, 13 mmol) at 0°C. After addition, the mixture was stirred at 20°C for 18 hours. The mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification by silica gel chromatography eluting with a gradient of 0 to 20% EtOAc/petroleum ether gave the title compound as a yellow oil (3.2 g, 93%). ES/MS m/z 340.9 (M-Boc+H).

Manufacturing Example 307

Methyl 3-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]ethoxy]-4-nitro-5-[[(2S)-oxetan-2-yl] methylamino]benzoate

Methyl 3-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]ethoxy]-5-fluoro-4-nitro-benzoate and fumaric acid;(S)-oxide The title compound was prepared essentially as described in Preparation Example 301 using cetan-2-ylmethanamine and heating the reaction at 100° C. for 3 hours in a microwave reactor. ES/MS m/z 508.1 (M+H).

Manufacturing Example 308

Methyl 4-amino-3-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]ethoxy]-5-[[(2S)-oxetan-2-yl] methylamino]benzoate

Methyl 3-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]ethoxy]-4-nitro-5-[[(2S)-ox in MeOH (10 mL) To a solution of cetan-2-yl]methylamino]benzoate (1.1 g, 1.8 mmol) was added Pd/C (810 mg, 10 mass%). The mixture was stirred at ambient temperature under hydrogen (15 psi) for 2 hours. Diatomaceous earth was added, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0 to 9% MeOH in DCM to give the title compound (940 mg, >99%). ES/MS m/z 478.1 (M+H).

Manufacturing Example 309

Methyl (S)-4-(2-(5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzena Cyclononaphan-1 ⁴ -yl)acetamido)-3-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]ethoxy]-5-[[(2S )-oxetan-2-yl]methylamino]benzoate

2-(5 ⁴ -Cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane-1 ⁴ -yl ) Acetic acid and methyl 4-amino-3-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]ethoxy]-5-[[(2S)-oxetane-2 The title compound was prepared essentially as described in Preparation Example 86 using -yl]methylamino]benzoate. ES/MS m/z 860.2 (M+H).

Manufacturing example 310

Methyl (S)-4-(2-((tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino)ethoxy)-2-((5 ⁴ -cyano-3,9 -dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphan-1 ⁴ -yl)methyl)-1-(oxetane-2- Ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

Methyl (S)-4-(2-(5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzena Cyclononaphan-1 ⁴ -yl)acetamido)-3-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]ethoxy]-5-[[(2S )-oxetan-2-yl]methylamino]benzoate and a mixture of 1:1 DCM:acetic acid as solvent and heating the reaction at 55° C. for 18 hours to give the title compound essentially as described in Preparation Example 102. was manufactured. After completion, the reaction was cooled to ambient temperature, diluted with toluene and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient from 0 to 14% MeOH in DCM, to give the title compound as a brown oil. ES/MS m/z 842.2 (M+H).

Manufacturing Example 311

(S)-4-(2-((tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino)ethoxy)-2-((5 ⁴ -cyano-3,9- Dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononapan-1 ⁴ -yl)methyl)-1-(oxetan-2-yl Methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Methyl (S)-4-(2-((tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino)ethoxy)-2 in a 3:1:1 mixture of ACN:THF:water -((5 ⁴ -Cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphan-1 ⁴ -yl ) methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate 1,5,7-triazabicyclo[4.4.0]dec-5-ene The title compound was prepared essentially as described in Example 5 by heating the reaction at 55° C. for 2 hours. After completion, the reaction was cooled to ambient temperature and quenched with 1 M aqueous formic acid to obtain a precipitate. Filtration and collection of the precipitate gave the title compound, which was used in Example 54 without further purification. ES/MS m/z 828.2 (M+H).

Manufacturing Example 312

2-Chloro-6-[(4-chloro-2-iodo-phenyl)methoxy]pyridine

A solution of 4-chloro-2-iodo-1-methyl-benzene (40 g, 158 mmol) and N-bromosuccinimide (27.3 g, 153 mmol) in ACN (500 mL) was prepared. A 4100K white bulb (42W, 150W equivalent) was pumped around a 4100K white bulb (42W, 150W equivalent) at a flow rate of 1.3 mL/min through a photochemical reactor consisting of a coiled PFA reaction tube (1/8" outer diameter, 53 mL volume), and the system temperature was maintained between 30 and 40 C. Maintained at ° C. Upon completion, ACN (100 mL) was pumped through the reactor at the same rate.The product was purified with 6-chloropyridin-2-ol (21.8 g, 168 mmol) and K ₂ CO in ACN (400 mL). Was added dropwise to the flask containing the suspension of ₃ (44.1 g, 319 mmol).After the bromination material was added completely, it was stirred at RT for 1 hour.The crude reaction mixture was filtered and concentrated under reduced pressure.The residue was Purification via silica gel chromatography using 0 to 10% EtOAc in hexane gave 45.8 g (76%) of the title compound, ES-MS m/z 380 and 382 (M+H).

Manufacturing Example 313

2-chloro-6-[[4-chloro-2-[2-ethoxyvinyl]phenyl]methoxy]pyridine

To a solution of 2-chloro-6-[(4-chloro-2-iodo-phenyl)methoxy]pyridine (5.0 g, 13 mmol) in THF (70 mL) under N ₂ was added aqueous potassium phosphate (2 M, 150 ml). mL, 300 mmol) and 1-ethoxyethene-2-boronic acid pinacol ester (1/1.3 isomer mixture, 3.81 mL, 17.1 mmol) were added and the mixture was stirred for 5 minutes. Bis(triphenylphosphine)palladium(II) dichloride (470 mg, 0.663 mmol) was added and the mixture was heated to 65° C. for 21 hours. The mixture was cooled to RT and water (100 mL) and EtOAc (100 mL) were added. The mixture was stirred at RT for 5 min, the organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 100 mL). The organic layers were combined and washed with water (100 mL), saturated aqueous NaCl (100 mL). The organic portion was concentrated and the residue was purified by filtration through a plug of silica gel using DCM eluent to give the title compound as a brown solid (4.37 g, 100%). ES/MS m/z 324 (M+H).

Manufacturing Example 314

2-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]phenyl]acetaldehyde

Hydrochloric acid in a solution of 2-chloro-6-[[4-chloro-2-[2-ethoxyvinyl]phenyl]methoxy]pyridine (54.2 g, 161.1 mmol) in acetone (525 mL) and water (175 mL). (35 mL, 407 mmol, 36.5% in water) was added and heated to 65° C. for 1 hour. The reaction was cooled to RT and diluted with water (250 mL) and MTBE (250 mL). The organic phase was separated and the aqueous portion was extracted with MTBE (3 x 250 mL). The combined organic layers were washed with 2M aqueous Na ₂ CO ₃ (250 mL), water (250 mL), saturated aqueous NaCl (250 mL), dried over Na ₂ SO ₄ and the solvent was removed under vacuum to afford 44.5 g of the title compound. (93%) was obtained, which was used in Preparation Example 315 without further purification. ES-MS m/z 296.0, 298.0 (M+H).

Manufacturing Example 315

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

To a solution of 2-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]phenyl]acetaldehyde (Preparation 314, 44.5 g, 150.3 mmol) in EtOH (400 mL) at 5°C Sodium borohydride (11.85 g, 300.7 mmol) was added little by little, and stirred at RT for 1 hour. The reaction was cooled to 0° C., quenched with water (250 mL), and the pH was adjusted to 6 using 5% aqueous citric acid. MTBE (400 mL) was added, the organic phase was separated and the aqueous phase was extracted with MTBE (3 x 250 mL). The organic layers were combined, washed with water (250 mL), saturated aqueous NaCl (250 mL), dried over Na ₂ SO ₄ and the solvent was removed under vacuum. The crude material was purified by silica gel chromatography using a gradient of 20 to 40% EtOAc in cyclohexane to give 31.95 g of the title compound (71%), which crystallized on standing. ES-MS m/z 298.0, 300.0 (M+H).

Manufacturing Example 316

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

To a solution of 2-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]phenyl]ethanol (31.80 g, 106.6 mmol) in THF (360 mL) at 0° C. was added sodium hydride (mineral oil). 60 wt%, 8.14 g, 203 mmol) was added and stirred for 20 minutes. To this, 4-bromo-2-(bromomethyl)-1-iodo-benzene (49.4 g, 131 mmol) was added little by little, and the mixture was allowed to warm to RT and stirred for 18 hours. To this was added sodium hydride (60 wt% in mineral oil, 1.25 g, 31.3 mmol) followed by additional 4-bromo-2-(bromomethyl)-1-iodo-benzene (4.9 g, 13 mmol). was added and the mixture was stirred at RT for an additional 5 hours. The reaction was cooled to 0°C, quenched with 5% aqueous citric acid (250 mL), and MTBE (200 mL) was added. The organic phase was separated and the aqueous portion was extracted with MTBE (3 x 250 mL). The organic layers were combined, washed with water (200 mL), saturated aqueous NaCl (200 mL), dried over Na ₂ SO ₄ and the solvent was removed under vacuum. The residue was purified by silica gel chromatography using a gradient from 40 to 100% DCM in cyclohexane to yield 45.05 g of the title compound (71%) as a yellow oil. ES-MS m/z 593.8 (M+H).

Manufacturing Example 317

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

2-[[2-[2-[(5-bromo-2-iodo-phenyl)methoxy]ethyl]-4-chloro-phenyl]methoxy]-6-chloro-pyridine in THF (50 mL) (13.11 g, 22.1 mmol), and chloro[(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)] A solution of [palladium(II)](XantPhos Pd G2, 1.100 g, 1.107 mmol) was stirred at RT under N ₂ . To this mixture was added dropwise bromo-(2-ethoxy-2-oxo-ethyl)zinc (0.4 M in THF, 103 mL, 40 mmol) and the mixture was heated to 65° C. for 3 hours. The reaction mixture was cooled to 0° C., quenched with 5% aqueous citric acid (200 mL), and MTBE (200 mL) was added. The organic phase was separated and the aqueous phase was extracted with MTBE (3 x 100 mL). The combined organic layers were washed with water (200 mL), saturated aqueous NaCl (200 mL), dried over Na ₂ SO ₄ and the solvent was removed under vacuum. The residue was purified by silica gel chromatography using a gradient from 20 to 100% DCM in cyclohexane to give 9.15 g of the title compound (75%) as a dark brown oil. ES-MS m/z 552.0, 554.0 (M+H).

Manufacturing Example 318

Ethyl 2-[2-[2-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]phenyl]ethoxymethyl]-4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)phenyl]acetate

Ethyl 2-[4-bromo-2-[2-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]phenyl]ethoxymethyl]phenyl] in dioxane (270 mL) N ₂ gas was bubbled through a solution of acetate (7.50 g, 13.6 mmol), bis(pinacolato)diborone (4.39 g, 16.9 mmol), and KOAc (4.1 g, 41 mmol) for 15 minutes. Dichlorobis(tricyclohexylphosphine)palladium(II) (1.02 g, 1.35 mmol) was added to this mixture and heated to 90°C for 20 hours. To this mixture were added bis(pinacolato)diborone (0.439 g, 1.69 mmol), dichlorobis(tricyclohexylphosphine)palladium(II) (0.10 g, 0.13 mmol), and KOAc (0.410 g, 4.1 mmol). ) was added. The mixture was heated to 90° C. for 4 hours. The mixture was cooled to RT and filtered through a plug of silica gel, eluting with DCM, to give 9.11 g of the title compound as a crude dark brown oil (112%), which was used in Preparation 319 without further purification. ES-MS m/z 600.2, 602.2 (M+H).

Manufacturing Example 319

Ethyl 2-(5 ⁴ -chloro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphan-1 ⁴ -yl )acetate

Ethyl 2-[2-[2-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]phenyl]ethoxymethyl]-4-(4,4, A solution of 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate (9.10 g, 15.2 mmol) and aqueous tribasic potassium phosphate (1 M, 91 mL, 91 mmol) N ₂ gas was bubbled through for 15 minutes. In this mixture, [chloro(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl -2-day) palladium(II)] (XPhos-Pd-G2, 1.22 g, 1.52 mmol) was added and heated to 65°C for 1 hour. The reaction was cooled to RT, diluted with water (300 mL) and extracted with MTBE (3 x 250 mL). The combined organics were washed with water (250 mL), saturated aqueous NaCl (250 mL), dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using a gradient from 80 to 100% DCM in cyclohexane to yield 1.6 g of the title compound (24.1%) as a white solid. ES-MS m/z 438.2 (M+H).

Manufacturing example 320

2-(5 ⁴ -Chloro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphan-1 ⁴ -yl) acetic acid

Ethyl 2-(54-chloro-3,8-dioxa-2(2,6)-pyridina-1 in ACN (5 mL), 1,4-dioxane (5 mL), and water (5 mL) 1,3,4,6,7,8-hexahydro-2H in a solution of (1,3),5(1,2)-dibenzenacyclononaphan-14-yl)acetate (900 mg, 2.06 mmol) -Pyrimido[1,2-a]pyrimidine (500 mg, 3.52 mmol) was added and heated to 50°C for 3 hours. The reaction was cooled to RT, quenched with 1N HCl (2 mL), diluted with water and extracted with EtOAc (2 x 250 mL). The organics were combined, washed with saturated aqueous NaCl, dried over MgSO ₄ , filtered and concentrated in vacuo to give 835 mg (99%) of the title compound as a pale yellow solid. ES-MS m/z 410.9 (M+H).

Manufacturing Example 321

Methyl 3-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-5-fluoro-4-nitro-benzoate

Methyl 3-fluoro-5-hydroxy-4-nitro-benzoate (2 g, 9.3 mmol), 2-((tert-butyldimethylsilyl)oxy)ethanol (2.6 g, 14 mmol) in THF (30 mL) ) and DIAD (3.8 g, 19 mmol) were added to a 0°C solution of triphenylphenylphosphine (3.5 g, 13 mmol). It was allowed to warm to 20°C and stirred for 12 hours. Diluted with water (50 mL) and extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-20% EtOAc/petroleum ether to give the title compound as a colorless oil (4 g, 92%). ^1H NMR(CDCl ₃ ) δ 7.59 (s, 1H), 7.51 (d, J = 24 Hz, 1H), 4.25 (t, J = 5 Hz, 2H), 3.98 (t, J = 5 Hz, 2H) , 3.97 (s, 3H), 0.88 (s, 9H), 0.07 (s, 6H).

Manufacturing Example 322

Methyl 3-(2-hydroxyethoxy)-4-nitro-5-[[(2S)-oxetan-2-yl]methylamino]benzoate

To a solution of methyl 3-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-5-fluoro-4-nitro-benzoate (2 g, 4.32 mmol) in DMSO (200 mL) was added TEA (2.5 mmol). mL, 18 mmol) and (S)-oxetan-2-ylmethanamine (21 g, 8.7 mmol) were added. It was stirred at 80°C for 12 hours. Diluted with water (200 mL) and extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (400 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with 0-50% EtOAc/petroleum ether to give the title compound (320 mg, 18%). ^1H NMR(CDCl ₃ ) δ 7.16 (s, 1H), 6.93 (s, 1H), 6.39 (s, 1H), 5.11 (m, 1H), 4.72 (m, 1H), 4.59 (m, 1H), 4.24 (t, j = 4 Hz, 2H), 3.97 - 3.93 (m, 5H), 3.50 (t, j = 4 Hz, 2H), 2.73 (m, 1H), 2.58 (m, 1H).

Manufacturing Example 323

Methyl 3-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-4-nitro-5-[[(2S)-oxetan-2-yl]methylamino]benzoate

Methyl 3-(2-hydroxyethoxy)-4-nitro-5-[[(2S)-oxetan-2-yl]methylamino]benzoate (320 mg, 0.78 mmol) in DCM (10 mL) To the solution were added tert-butyldimethylchlorosilane (200 mg, 1.29 mmol) and imidazole (130 mg, 1.90 mmol). The mixture was stirred at 20°C for 2 hours. Diluted with water (20 mL) and extracted with DCM (3 x 30 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0-20% EtOAc/petroleum ether to give the title compound (400 mg, 93%). ES/MS (m/z): 441.1 (M+H).

Manufacturing example 324

Methyl 4-amino-3-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-5-[[(2S)-oxetan-2-yl]methylamino]benzoate

Methyl 3-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-4-nitro-5-[[(2S)-oxetan-2-yl]methylamino]benzoate in EtOAc (100 mL) Pd/C (300 mg, 10 mass%) was added to a solution of (670 mg, 1.22 mmol). It was purged three times with hydrogen gas and stirred for 1 hour at 20°C under a balloon filled with hydrogen. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-10% MeOH/DCM to give the title compound (475 mg, 95%). ES/MS (m/z): 411.4 (M+H).

Manufacturing example 325

Methyl (S)-3-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-4-(2-(5 ⁴ -chloro-3,8-dioxa-2(2,6)-pyri dina-1(1,3),5(1,2)-dibenzenacyclononapan- ^{1 4} -yl)acetamido)-5-((oxetan-2-ylmethyl)amino)benzoate

2-(5 ⁴ -chloro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane in DMF (3 mL) -1 ⁴ -yl)acetic acid (80 mg, 0.20 mmol) and methyl 4-amino-3-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-5-[[(2S)-oxetane- To a solution of 2-yl]methylamino]benzoate (87 mg, 0.21 mmol) was added DIEA (0.07 mL, 0.4 mmol) followed by HATU (124 mg, 0.32 mmol). The mixture was stirred at 20° C. for 2 hours and then diluted with water (20 mL) to form a solid. The solid was filtered and dried under vacuum to give the title compound (132 mg, 84%). ES/MS m/z ( ³⁵ Cl/ ³⁷ Cl) 802.4/804.4 [M+H].

Manufacturing example 326

Methyl (S)-4-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-2-((5 ⁴ -chloro-3,8-dioxa-2(2,6)-pyridina- 1(1,3),5(1,2)-dibenzenacyclononaphan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6 -Carboxylates

Methyl (S)-3-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-4-(2-(54-chloro-3,8-dioxa-2(2) in acetic acid (3 mL) ,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphan-14-yl)acetamido)-5-((oxetan-2-ylmethyl)amino) A solution of benzoate (132 mg, 0.165 mmol) was heated to 80° C. for 1.5 hours, then cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 50 to 100% EtOAc/toluene followed by 2 to 5% MeOH/EtOAc to give the title compound (62 mg, 48%). The product eluted at 1.8 min by LC-ES/MS, but was not ionized. Conditions _for LCMS analysis: ₂ x 50

Manufacturing example 327

Methyl 3-[2-(dimethylamino)ethoxy]-5-fluoro-4-nitro-benzoate

N,N-dimethylethanolamine (994 mg, 11.15 mmol) in a solution of methyl 3-fluoro-5-hydroxy-4-nitro-benzoate (2 g, 9.30 mmol) in THF (20 mL), triphenyl Phosphine (2.92 g, 11.15 mmol) and DIAD (2.25 g, 11.15 mmol) were added. The reaction was stirred at ambient temperature for 18 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified via silica gel flash chromatography eluting with a gradient of 0 to 10% MeOH in DCM to give the title compound as a yellow oil (690 mg, 26%). ES/MS m/z 287 (M+H).

Manufacturing example 328

Methyl 3-[2-(dimethylamino)ethoxy]-4-nitro-5-[[(2S)-oxetan-2-yl]methylamino]benzoate

To a solution of methyl 3-[2-(dimethylamino)ethoxy]-5-fluoro-4-nitro-benzoate (690 mg, 2.41 mmol) in DMSO (8 mL) (2S)-oxetane-2- Il-methanamine (420 mg, 4.8 mmol) and TEA (1.46 g, 14.4 mmol) were added. The reaction mixture was stirred at 80° C. for 18 hours. The mixture was cooled to ambient temperature, diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The organic portion was combined, washed with water and saturated aqueous NaCl solution (2 x 50 mL), dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The residue was purified via silica gel flash chromatography eluting with a gradient of 0 to 20% MeOH in DCM to give the title compound as a colorless oil (1.03 g, 72%). ES/MS m/z 354 (M+H).

Manufacturing example 329

Methyl 4-amino-3-[2-(dimethylamino)ethoxy]-5-[[(2S)-oxetan-2-yl]methylamino]benzoate

Methyl 3-[2-(dimethylamino)ethoxy]-4-nitro-5-[[(2S)-oxetan-2-yl]methylamino]benzoate (1.03 g, 1.75 mmol) in EtOAc (100 mL) ) 10% Pd/C (200 mg, 0.18 mmol) was added to the solution. The mixture was stirred under hydrogen gas (14.5 psi) at ambient temperature for 2 hours, then filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound as a white solid (102 mg, 17%). [Column: Welch Extreme C18 75 x 40mm, 3 μm; Mobile phase A: H ₂ O, NH ₃ H ₂ O+NH ₄ HCO ₃ ; Mobile phase B: ACN; Gradient: B 22% to 52%). ES/MS m/z 324 (M+H).

Manufacturing example 330

Methyl (S)-4-(2-(5 ⁴ -chloro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclo Nonapan-1 ⁴ -yl)acetamido)-3-(2-(dimethylamino)ethoxy)-5-((oxetan-2-ylmethyl)amino)benzoate

2-(5 ⁴ -chloro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane in DMF (2 mL) -1 ⁴ -yl)acetic acid (75 mg, 0.18 mmol) and methyl 4-amino-3-[2-(dimethylamino)ethoxy]-5-[[(2S)-oxetan-2-yl]methylamino ]To a solution of benzoate (60 mg, 0.18 mmol) was added HATU (115 mg, 0.3 mmol) and DIPEA (0.10 mL, 0.5 mmol). The mixture was stirred at ambient temperature for 17 hours. The reaction was quenched with water and the white solid that precipitated was filtered. The filtrate was concentrated and extracted with EtOAc. The organic layers were combined and the organic portion was dried over MgSO ₄ , filtered and concentrated to give a solid residue. The first white solid was combined with the residue to give the title compound as a white solid (173 mg, 132%). ES/MS m/z 715 (M+H).

Manufacturing Example 331

Methyl (S)-2-((5 ⁴ -chloro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane -1 ⁴ -yl)methyl)-4-(2-(dimethylamino)ethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

Methyl (S)-4-(2-(5 ⁴ -chloro-3,8-dioxa-2(2,6)-pyridina- in acetic acid (2 mL) and 1,2-dichloroethane (1.5 mL) 1(1,3),5(1,2)-dibenzenacyclononaphan-1 ⁴ -yl)acetamido)-3-(2-(dimethylamino)ethoxy)-5-((oxetane- A mixture of 2-ylmethyl)amino)benzoate (130 mg; 0.18 mmol) was heated at 55° C. for 21 hours. The mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was purified via silica gel flash chromatography eluting with a gradient of 0 to 10% MeOH in DCM to give the title compound as a white solid (89 mg, 70%). ES/MS m/z 697 (M+H).

Manufacturing Example 332

Methyl 3-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]-5-fluoro-4-nitro-benzoate

Methyl 3-fluoro-5-hydroxy-4-nitro-benzoate (2 g, 9.30 mmol) and tert-butyl-(2-hydroxyethyl)methyl carbamate (3.43 g, To a solution of 18.6 mmol), triphenylphosphine (3.7 g, 14 mmol) and DIAD (2.82 g, 13.9 mmol) were added. The reaction was stirred at ambient temperature for 12 hours. The mixture was concentrated under reduced pressure and the residue was purified via silica gel chromatography eluting with a gradient of 0 to 20% EtOAc in petroleum ether to give the title compound as a yellow oil (2.3 g, 66%). ES/MS (m/z): 373 (M+H).

Manufacturing Example 333

Methyl 3-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]-4-nitro-5-[[(2S)-oxetan-2-yl]methylamino]benzoate

A solution of methyl 3-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]-5-fluoro-4-nitro-benzoate (1 g, 2.68 mmol) in DMSO (60 mL) in EtOH. A 3.6% w/w solution of (2S)-oxetan-2-yl-methanamine (13.0 g, 5.4 mmol) and TEA (1.6 g, 16 mmol) were added. The reaction mixture was stirred at 80°C for 12 hours. The mixture was cooled to ambient temperature, diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The organic portion was combined, washed with water and saturated aqueous NaCl solution (3 x 100 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography, eluting with a gradient of 0 to 20% EtOAc in petroleum ether to give the title compound as a yellow oil (750 mg, 62%). ES/MS (m/z): 440 (M+H-Boc).

Manufacturing Example 334

Methyl 4-amino-3-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]-5-[[(2S)-oxetan-2-yl]methylamino]benzoate

Methyl 3-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]-4-nitro-5-[[(2S)-oxetan-2-yl]methylamino] in EtOAc (50 mL) To a solution of benzoate (700 mg, 1.59 mmol) was added 10% Pd/C (200 mg, 0.18 mmol). The mixture was stirred at ambient temperature under hydrogen gas (15 psi) for 2 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give the title compound (536 mg, 82%). ES/MS (m/z): 410 (M+H).

Manufacturing Example 335

Methyl (S)-3-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-4-(2-(5 ⁴ -chloro-3,8-dioxa-2(2, 6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononapan-1 ⁴ -yl)acetamido)-5-((oxetan-2-ylmethyl)amino) benzoate

2-(5 ⁴ -chloro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane in DMF (2 mL) -1 ⁴ -yl)acetic acid (80 mg, 0.19 mmol) and methyl 4-amino-3-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]-5-[[(2S)-ox To a solution of cetan-2-yl]methylamino]benzoate (82 mg, 0.19 mmol) was added HATU (130 mg, 0.33 mmol) and DIEA (0.11 mL, 0.62 mmol). The mixture was stirred at ambient temperature for 15 hours, then quenched with water and extracted with EtOAc. The organic portion was dried over MgSO ₄ , filtered, and concentrated under reduced pressure to give the title compound as a solid (155 mg, 80%), which was used in Preparation 336 without further purification. ES/MS (m/z): 801 (M+H).

Manufacturing Example 336

Methyl (S)-4-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-2-((5 ⁴ -chloro-3,8-dioxa-2(2,6) -Pyridina-1(1,3),5(1,2)-dibenzenacyclononapan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d] Imidazole-6-carboxylate

Methyl (S)-3-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-4-(2- in acetic acid (1.5 mL) and 1,2-dichloroethane (1.5 mL) (5 ⁴ -Chloro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphan-1 ⁴ -yl)acetami Figure) A mixture of -5-((oxetan-2-ylmethyl)amino)benzoate (Preparation Example 335, 155 mg, 0.19 mmol) was heated at 55°C for 18 hours. The reaction was cooled to ambient temperature and concentrated under reduced pressure. The residue was purified via silica gel chromatography eluting with a gradient of 0 to 10% MeOH in DCM to give the title compound as a white solid (150 mg, 99%). ES/MS (m/z): 783 (M+H).

Manufacturing Example 337

(S)-4-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-2-((5 ⁴ -chloro-3,8-dioxa-2(2,6)- Pyridina-1(1,3),5(1,2)-dibenzenacyclononapan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imi Dazole-6-carboxylic acid

Methyl (S)-4-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy in ACN (2 mL), 1,4-dioxane (2 mL), and water (0.4 mL) )-2-((5 ⁴ -Chloro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (150 mg, 0.19 mmol) in a nitrogen-degassed mixture of 1,5,7 -Triazabicyclo[4.4.0]des-5-ene (86 mg, 0.60 mmol) was added and the mixture was heated to 55° C. for 36 hours. The reaction mixture was cooled to ambient temperature, concentrated under reduced pressure and the residue was purified via reverse phase chromatography using a gradient of 10 to 90% ACN in water (0.1% formic acid was added to both solvents) to give the title compound. was obtained as a white solid (64 mg, 43%). ES/MS (m/z): 769 (M+H).

Manufacturing Example 338

Ethyl 2-(4-bromo-5-fluoro-2-methyl-phenyl)acetate

1-Bromo-2-fluoro-4-iodo-5-methyl-benzene (11 g, 34 mmol) and chloro[(4,5-bis(diphenylphosphino)-9) in THF (45 mL) ,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) (XantPhos-Pd-G2, 3.5 mg, 3.4 mmol) in a solution of (2-ethoxy -2-Oxoethyl)zinc(II) bromide (0.50 M in THF, 110 mL, 60 mmol) was added at RT and the mixture was stirred at 65° C. overnight under N ₂ . The reaction was quenched by addition of 1N HCl (100 mL) and then the mixture was extracted with EtOAc (3 x 100 mL). The organic layers were combined, washed with aqueous K ₂ CO ₃ (100 mL), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel chromatography using a gradient from 0 to 20% EtOAc in petroleum ether to give the title compound (9.73 g, 98%) as a light yellow oil. ES/MS m/z 274.8 (M+H)

Manufacturing Example 339

Ethyl 2-[4-bromo-2-(bromomethyl)-5-fluoro-phenyl]acetate

of ethyl 2-(4-bromo-5-fluoro-2-methyl-phenyl)acetate (5.9 g, 21 mmol) and N-bromosuccinimide (3.6 g, 20 mmol) in ACN (110 mL) A solution was prepared. The solution was pumped at a flow rate of 1.3 mL/min around a 4100K white bulb (42W, 150W equivalent) through a photochemical reactor consisting of a coiled PFA reaction tube (1/8" outer diameter, 53 mL volume), and the system temperature was adjusted to Maintained at 30-40° C. Once complete, ACN (100 mL) was pumped through the reactor at the same rate. The resulting mixture was diluted with water (500 mL) and heptane (200 mL). The aqueous layer was diluted with heptane (200 mL). mL) and the combined organic layers were washed with saturated aqueous sodium thiosulfate solution (2 x 100 mL).The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was diluted in 0 to 10 mL in hexanes. Purification via silica gel chromatography using a gradient of % EtOAc gave 7.0 g (92% yield, 90% purity) of the title compound, ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.59 (d, J = 7 Hz, 1H), 7.09 (d, J = 9 Hz, 1H), 4.50 (s, 2H), 4.20 (q, J = 7.5 Hz, 2H), 3.75 (s, 2H), 1.29 (t, J = 7.5 Hz, 3H).

Production example 340

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

4-[(6-chloro-2-pyridyl)oxymethyl]-2-(2-hydroxyethyl)benzonitrile (700 mg, 2.4 mmol), ethyl 2-[4-bromo-2- (bromomethyl)-5-fluoro-phenyl]acetate (1.3 g, 3.2 mmol, 88 mass %), anhydrous DCM (20 mL) and 2,6-di-tert-butylpyridine (835 μL, 3.61 mmol) filled with The mixture was cooled to 0° C. under nitrogen atmosphere and silver trifluoromethanesulfonate (878 mg, 3.38 mmol) was added. The mixture was allowed to reach RT and stirred overnight. The reaction mixture was filtered through ^Celite® , the filtrate was concentrated and the residue was purified by silica gel chromatography using a gradient from 20 to 100% DCM in cyclohexane to give the title compound (369 mg, 67 wt%). Purity, 18%) was obtained as a colorless waxy solid. ES-MS m/z 561, 563, 565 (M+H).

Manufacturing Example 341

Ethyl 2-[2-[2-[5-[(6-chloro-2-pyridyl)oxymethyl]-2-cyano-phenyl]ethoxymethyl]-5-fluoro-4-(4,4 ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate

In a reaction vessel, add ethyl 2-[4-bromo-2-[2-[5-[(6-chloro-2-pyridyl)oxymethyl]-2-cyano-phenyl]ethoxymethyl]-5-fluo Ro-phenyl]acetate (340 mg, 0.41 mmol, 67% purity by weight), KOAc (140 mg, 1.40 mmol), bis(pinacolato)diborone (190 mg, 0.73 mmol) and 1,4-dioxane anhydride. (4 mL) was charged. The mixture was bubbled with nitrogen, dichlorobis(tricyclohexylphosphine)palladium(II) (61 mg, 0.081 mmol) was added, and stirred in a preheated bath at 90° C. for 5 hours. The reaction mixture was cooled to RT, saturated aqueous NaHCO ₃ and EtOAc were added and the mixture was filtered through ^Celite® . The aqueous layer was separated and the organic layer was washed with water and saturated aqueous NaCl, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified via silica gel chromatography using a gradient from 0 to 100% EtOAc in DCM to afford the title compound (275 mg, 75 wt% purity, 84%) as a yellow waxy solid. ES-MS m/z 609 and 611 (M+H).

Manufacturing Example 342

Ethyl 2-(5 ⁴ -cyano-1 ⁶ -fluoro-3,8-dioxa-2(2,6)-pyridina-1,5(1,3)-dibenzenacyclononaphane- ^{1 4} -1) Acetate

The reaction vessel was filled with ethyl 2-[2-[2-[5-[(6-chloro-2-pyridyl)oxymethyl]-2-cyano-phenyl]ethoxymethyl]-5-fluoro-4-( Charged with 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate (190 mg, 0.23 mmol, 75 wt% purity) and THF (7.8 mL). The mixture was bubbled with nitrogen and then tribasic potassium phosphate (1.0 M in water, 1.2 mL, 1.2 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1). ,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 20 mg, 0.025 mmol) was added. The mixture was stirred in a preheated bath at 70° C. for 30 minutes. The reaction mixture was cooled to RT and water and EtOAc were added. The aqueous layer was separated, the organic layer was washed with water and saturated aqueous NaCl, dried over Na ₂ SO ₄ , filtered and the solvent was removed. The residue was purified via silica gel chromatography using a gradient from 0 to 5% EtOAc in DCM to afford the title compound (49 mg, 90 wt% purity, 42%) as a light brown solid. ES-MS m/z 447 (M+H).

Manufacturing example 343

2-(5 ⁴ -cyano-1 ⁶ -fluoro-3,8-dioxa-2(2,6)-pyridina-1,5(1,3)-dibenzenacyclononaphane-1 ⁴ - 1) Acetic acid

1,5,7-Triazabicyclo[4.4.0]dec-5-ene (62 mg, 0.44 mmol) was dissolved in ethyl 2-methylene in a mixture of ACN (1.5 mL), THF (500 μL) and water (500 μL). (5 ⁴ -cyano- ^{1 6} -fluoro-3,8-dioxa-2(2,6)-pyridina-1,5(1,3)-dibenzenacyclononaphane-1 ⁴ -yl) Acetate (72 mg, 0.145 mmol, 90 mass%) was added to the suspension. The mixture was purged with N ₂ and stirred at 50° C. for 15 minutes. The organic solvent was removed with a stream of nitrogen. EtOAc and aqueous citric acid (5%) were added. The aqueous layer was separated, the organic layer was washed with water and saturated aqueous NaCl, dried over Na ₂ SO ₄ , filtered and the solvent was removed to give the title compound (65 mg, 97%, 91 mass %) as a white solid. did. ES-MS m/z 419 (M+H).

Manufacturing example 344

Methyl (S)-2-((5 ⁴ -cyano- ^{1 6} -fluoro-3,8-dioxa-2(2,6)-pyridina-1,5(1,3)-dibenzenacyclo Nonapan-1 ⁴ -yl)methyl)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

2-(5 ⁴ -cyano- ^{1 6} -fluoro-3,8-dioxa-2(2,6)-pyridina-1,5(1,3)-dibenzena in anhydrous DMF (1.4 ml) Cyclononaphan-1 ⁴ -yl)acetic acid (65 mg, 0.14 mmol, 91 mass%) and methyl 4-amino-3-(2-methoxyethoxy)-5-[[(2S)-oxetane-2 To a solution of -yl]methylamino]benzoate (45 mg, 0.145 mmol) was added HATU (70 mg, 0.18 mmol) and DIPEA (74 μl, 0.42 mmol) under nitrogen atmosphere. The mixture was stirred at RT for 3 hours and diluted with water and EtOAc. The aqueous layer was separated, the organic layer was washed with water and saturated aqueous NaCl, dried over Na ₂ SO ₄ , filtered and the solvent was removed. The residue was dissolved in 1,2-dichloroethane (0.9 mL) and acetic acid (0.9 mL) and the mixture was heated at 60° C. under N2-oxide for 8 hours. The reaction mixture was cooled to RT, the solvents were concentrated under reduced pressure, dried at 35-40° C. under vacuum, and the residue was purified via silica gel chromatography using a gradient of 25 to 100% EtOAc in DCM to give the title compound. (50 mg, 49%) was obtained as a white solid. ES-MS m/z 693 (M+H).

Manufacturing example 345

Methyl 3-fluoro-5-((1-methylpyrrolidin-3-yl)oxy)-4-nitrobenzoate

Methyl 3-fluoro-5-hydroxy-4-nitrobenzoate (2.0 g, 9.3 mmol), 1-methylpyrrolidin-3-ol (1.13 g, 11.2 mmol), triphenyl in THF (80 mL) A solution of phosphine (2.93 g, 11.2 mmol), and DIAD (2.26 g, 11.2 mmol) was stirred at RT for 12 hours. Filtered, the reaction mixture was concentrated and the residue was purified via silica gel chromatography using a gradient from 0 to 10% MeOH in DCM to give 1.03 g (37%) of the title compound. ES-MS m/z 299 (M+H).

Manufacturing example 346

Methyl 3-((1-methylpyrrolidin-3-yl)oxy)-4-nitro-5-((((S)-oxetan-2-yl)methyl)amino)benzoate

Methyl 3-fluoro-5-(1-methylpyrrolidin-3-yl)oxy)-4-nitrobenzoate (1.03 g, 3.45 mmol) in DMSO (150 mL), [(2S)-oxetane- A solution of 2-yl]methanamine (20 g, 8.3 mmol), and TEA (2.1 g, 21 mmol) was stirred at 80°C for 12 hours. The reaction was diluted with water (50 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with saturated aqueous NaCl (5 x 40 mL). The organic layer was dried over MgSO ₄ , filtered and concentrated. The residue was purified via silica gel chromatography using a gradient of 0 to 20% MeOH in DCM, followed by reverse phase chromatography using a gradient of 30 to 60% MeCN in aqueous ammonium hydroxide (0.05%). 520 mg of the title compound (41%) was obtained as a yellow oil. ES-MS m/z 366 (M+H).

Manufacturing example 347

Methyl 4-amino-3-((1-methylpyrrolidin-3-yl)oxy)-5-((((S)-oxetan-2-yl)methyl)amino)benzoate

Methyl 3-((1-methylpyrrolidin-3-yl)oxy)-4-nitro-5-((((S)-oxetan-2-yl)methyl)amino)benzo in EtOAc (100 mL) A solution of nitrate (500 mg, 1.37 mmol) and palladium on carbon (10%, 200 mg, 0.19 mmol) was stirred for 2 hours at RT under an atmosphere of hydrogen gas. Filtered and the reaction mixture was concentrated to give 358 mg of the title compound (78%) as a pale yellow solid. ES-MS m/z 336 (M+H).

Manufacturing example 348

Methyl 4-(2-(5 ⁴ -Cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane- 1 ⁴ -yl)acetamido)-3-((1-methylpyrrolidin-3-yl)oxy)-5-((((S)-oxetan-2-yl)methyl)amino)benzoate

2-(5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclonona in DMF (1.8 mL) Pan-1 ⁴ -yl)methyl 4-amino-3-((1-methylpyrrolidin-3-yl)oxy)- in a solution of acetic acid (75 mg, 0.18 mmol) and HATU (100 mg, 0.26 mmol). 5-((((S)-oxetan-2-yl)methyl)amino)benzoate (67 mg, 0.20 mmol) and DIPEA (0.08 mL, 0.45 mmol) were added. It was stirred at 20°C for 2 hours. The mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with saturated aqueous NaCl (10 mL), dried over Na ₂ SO ₄ , filtered, and concentrated to give 425 mg of the title compound, which was used in Preparation 349 without further purification. ES-MS m/z 718 (M+H).

Manufacturing example 349

Methyl 2-((5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane-1 ⁴ -yl)methyl)-4-((1-methylpyrrolidin-3-yl)oxy)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole -6-carboxylate

Methyl 4-(2-(5 4-cyano-3,9-dioxa-2(2,6)-pyridina-1(1) in 1,2-dichloroethane (4 ^mL ) and acetic acid (4 mL) ,3),5(1,2)-dibenzenacyclononaphan-1 ⁴ -yl)acetamido)-3-((1-methylpyrrolidin-3-yl)oxy)-5-((( A solution of (S)-oxetan-2-yl)methyl)amino)benzoate (Preparation Example 348, 425 mg, 0.528 mmol) was stirred at 55°C for 12 hours. Diluted 1:1 toluene:ACN (10 mL) and concentrated the solution. The residue was purified via silica gel chromatography using a gradient from 0 to 10% MeOH in DCM to yield 100 mg of the title compound (27%) as a white solid. ES-MS m/z 700 (M+H).

Production example 350

Ethyl 2-(4-bromo-2-((2-(((6-bromo-5-fluoropyridin-2-yl)oxy)methyl)-5-cyanophenethoxy)methyl)-5- Fluorophenyl)acetate

4-[(6-bromo-5-fluoro-2-pyridyl)oxymethyl]-3-(2-hydroxyethyl)benzonitrile (4 g, 10.59 mmol), ethyl 2 in DCM (60 mL) -[4-Bromo-2-(bromomethyl)-5-fluoro-phenyl]acetate (8.3 g, 21 mmol) and 2,6-di-tert-butyl-4-methylpyridine (4.45 g, 21.2 To the solution of (mmol) was added silver trifluoromethanesulfonate (8.3 g, 32 mmol) at 20°C. The reaction was stirred at RT overnight, then the reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with water (100 mL) and extracted with EtOAc (100 mL x 2). The organic layers were combined, washed with saturated aqueous NaCl (60 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient from 0% to 100% DCM in petroleum ether to give the title compound as a pale yellow solid (2.15 g, 25%). ES-MS m/z 625 (M+H).

Manufacturing Example 351

Ethyl 2-(5 ⁴ -Cyano-1 ⁶ ,2 ³ -difluoro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2) -dibenzenacyclononaphan-1 ⁴ -yl)acetate

Ethyl 2-(4-bromo-2-((2-(((6-bromo-5-fluoropyridin-2-yl)oxy) in 1,4-dioxane (230 mL) at RT under nitrogen. (2-dicyclohexylphosphino-) to a mixture of methyl)-5-cyanophenethoxy)methyl)-5-fluorophenyl)acetate (2.15 g, 2.63 mmol) and cesium fluoride (795 mg, 5.18 mmol). 2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (XPhos Pd G3 , 450 mg, 0.521 mmol) and hexamethyltin (1.34 g, 4.05 mmol) were added. The reaction was protected from light, heated to 110° C., stirred for 15 hours, and then the reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl (60 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by preparative HPLC [column: Xtimate C18 150 x 40 mm, 10 μm; Mobile phase: gradient from 50 to 90% ACN in water (NH ₃ H ₂ O+NH ₄ HCO ₃ ) to give the title compound as a white solid. (360.1 mg, 29%) ES-MS m/z 465 (M+H).

Manufacturing Example 352

2-(54amino-cyano-16amino,23amino-difluoro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)- Dibenzenacyclononaphan-14amino-yl)acetic acid

Ethyl 2-(5 ⁴ -cyano-1 ⁶ ,2 ³ -difluoro-3,8-dioxa-2(2,6) in THF (2.47 mL), water (2.47 mL) and ACN (7.41 mL) )-pyridina-1(1,3),5(1,2)-dibenzenacyclononapan- ^{1 4} A solution of yl)acetate (345 mg, 0.74 mmol) was slowly purged with nitrogen, and 1,5 ,7-Triazabicyclo[4.4.0]des-5-ene (320 mg, 2.25 mmol) was added. The reaction vessel was sealed and purged with nitrogen. The reaction mixture was heated to 45° C. and stirred at this temperature for 2 hours, then the reaction was concentrated under reduced pressure to give the title compound as a white solid (385 mg, 100%), which was used in Preparation Example 353 without further purification. did. ES-MS m/z 437 (M+H).

Manufacturing Example 353

Methyl (S)-4-(2-(5 ⁴ -cyano-1 ⁶ ,2 ³ -difluoro-3,8-dioxa-2(2,6)-pyridina-1(1,3) ,5(1,2)-dibenzenacyclononaphan-1 ⁴ -yl)acetamido)-3-(2-methoxyethoxy)-5-((oxetan-2-ylmethyl)amino)benzo eight

2-(5 ⁴ -cyano-1 ⁶ ,2 ³ -difluoro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5 in DMF (6 mL) (1,2)-Dibenzenacyclononaphan-1 ⁴ -yl) In a solution of acetic acid (Preparation Example 352, 250 mg, 0.48 mmol) and HATU (378 mg, 0.97 mmol,) was added methyl 4-amino-3-( 2-methoxyethoxy)-5-[[(2S)-oxetan-2-yl]methylamino]benzoate (260 mg, 0.75 mmol) was added, then DIPEA (300 μL, 1.72 mmol) was added to the mixture. and stirred overnight at 20°C under N ₂ . The reaction was diluted with water (20 mL) and extracted with EtOAc (20 mL x 2). The organic layers were combined, washed with saturated aqueous NaCl (20 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give the title compound as a light yellow solid (1.2 g, 100%), which was prepared as Used in Example 354 without further purification. ES-MS m/z 729 (M+H).

Manufacturing example 354

Methyl (S)-2-((5 ⁴ -cyano-1 ⁶ ,2 ³ -difluoro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5 (1,2)-dibenzenacyclononaphan-1 ⁴ -yl)methyl)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imi Dazole-6-carboxylate

Methyl (S)-4-(2-(5 ⁴ -cyano-1 ⁶ ,2 ³ -difluoro-3,8-dioxa- in 1,2-dichloroethane (5 mL) at RT under N ₂ 2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphan-1 ⁴ -yl)acetamido)-3-(2-methoxyethoxy) Acetic acid (5 mL) was added to a solution of -5-((oxetan-2-ylmethyl)amino)benzoate (Preparation Example 353, 1.2 g, 0.49 mmol). The reaction was heated at 55° C. and stirred overnight. The reaction was diluted with toluene/ACN 1:1 (5 mL), the solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography using a gradient from 0 to 5% MeOH in DCM to give the title product as a white Obtained as a solid (270 mg, 35%). ES-MS m/z 711 (M+H).

Manufacturing Example 355

Methyl (S)-2-(chloromethyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

Methyl 4-amino-3-fluoro-5-[[(2S)-oxetan-2-ylmethyl]amino]benzoate (2.0 g, 7.9 mmol) and TEA in 1,2-dichloroethane (22 mL) (1.1 mL, 7.9 mmol) was cooled to 0°C and 2-chloroacetyl chloride (0.63 mL, 7.9 mL) was added. The mixture was stirred at RT for 2 hours. The reaction mixture was diluted with DCM and washed with water. The organic layer was dried over MgSO ₄ , filtered and concentrated. The resulting residue was dissolved in acetic acid (40 mL) and stirred at 70° C. for 2 hours. The crude reaction was concentrated and the residue was purified via silica gel chromatography using a gradient from 0 to 4% MeOH in DCM to afford 1.76 g (72%) of the title compound as a yellow oil. ES-MS m/z 313 (M+H).

Manufacturing Example 356

3-(2-((5-bromo-2-chlorobenzyl)oxy)ethyl)-4-(((6-bromopyridin-2-yl)oxy)methyl)benzonitrile

4-[(6-bromo-2-pyridyl)oxymethyl]-3-(2-hydroxyethyl)benzonitrile (2.3 g, 6.8 mmol), 4-bromo-2- in DCM (36 mL) A solution of (bromomethyl)-1-chloro-benzene (2.7 g, 9.5 mmol), and 2,6-di-tert-butylpyridine (2.2 mL, 9.7 mmol) was cooled to 0°C. Silver trifluoromethanesulfonate (3.0 g, 11.8 mmol) was added to the reaction mixture and stirred at 0°C for 15 minutes and then at RT for 18 hours. Additional silver trifluoromethanesulfonate (0.53 g, 2.1 mmol) was added to the reaction mixture and stirred at RT for 22 hours. The crude reaction mixture was filtered through ^Celite® , concentrated, and the residue was purified via silica gel chromatography using a gradient from 0 to 100% DCM in heptane to give 2.3 g (62%) of the title compound as a colorless, sticky solid. It was obtained as. ES-MS m/z 535/537/539 (M+H).

Manufacturing example 357

1 ⁴ -Chloro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane-5 ⁴ -carbonitrile

Using 3-(2-((5-bromo-2-chlorobenzyl)oxy)ethyl)-4-(((6-bromopyridin-2-yl)oxy)methyl)benzonitrile, 0 in heptane Purification of the title compound via silica gel chromatography using a gradient of 25% EtOAc yielded the title compound as a beige solid, preparing the title compound essentially as described in Preparation 216. ES-MS m/z 377 (M+H).

Manufacturing example 358

1 ⁴ -(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3,8-dioxa-2(2,6)-pyridina-1( 1,3),5(1,2)-dibenzenacyclononaphan-5 ⁴ -carbonitrile

1 ⁴ -Chloro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclo in 2-methyltetrahydrofuran (14 mL) Nonaphan-5 ⁴ -carbonitrile (170 mg, 0.45 mmol), (S)-1,2-propanediol (0.2 mL, 3 mmol), 2-dicyclohexylphosphino-2',4',6' -Triisopropylbiphenyl (XPhos, 44 mg, 0.09 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) [2- (2'-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd Gen 2, 35 mg, 0.045 mmol), bis(pinacolaito)diborone (0.34 g, 1.3 mmol), and KOAc A solution of (0.13 g, 1.3 mmol) was stirred at 80°C for 3 hours. Filtered and concentrated the reaction solution. The residue was dissolved in EtOAc and washed with water. The organic layer was dried over MgSO ₄ , filtered, and concentrated to give 210 mg (99%) of the title compound, which was used in Preparation 359 without further purification. ES-MS m/z 469 (M+H).

Manufacturing Example 359

Methyl (S)-2-((5 ⁴ -cyano-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclonona Pan-1 ⁴ -yl)methyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

1 ⁴ -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3 in 2-methyltetrahydrofuran (3 mL) and water (0.3 mL), 8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane-5 ⁴ -carbonitrile (0.12 g, 0.26 mmol), methyl ( S)-2-(chloromethyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (0.12 g, 0.38 mmol), 2 -Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos, 25 mg, 0.05 mmol), chloro(2-dicyclohexylphosphino-2',4',6'- triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd Gen 2 20 mg, 0.025 mmol), and tribasic phosphoric acid A solution of potassium (67 mg, 0.31 mmol) was stirred at 90°C for 7 hours. The reaction solution was filtered, diluted with EtOAc, washed with water and the organic layer was dried over MgSO ₄ , filtered and concentrated. The residue was purified via silica gel chromatography using a gradient from 0 to 50% EtOAc in DCM to yield 20 mg of the title compound (10%) as a yellow solid. ES-MS m/z 619 (M+H).

Manufacturing example 360

Methyl (S)-3-(2-(dimethylamino)-2-oxoethoxy)-4-nitro-5-((oxetan-2-ylmethyl)amino)benzoate

Sodium hydride (60 wt%, 211 mg, 5.28 mmol) in mineral oil was added to a solution of 2-hydroxy-N,N-dimethylacetamide (730 mg, 7.08 mmol) in THF (10 mL) at 0°C. Next, the cooling bath was removed and the mixture was stirred for 1 hour. The mixture was re-cooled to 0° C. and methyl 3-fluoro-4-nitro-5-[[(2S)-oxetan-2-ylmethyl]amino]benzoate (1 g, 3.52 mmol) was added. The cooling bath was removed and the mixture was stirred for 48 hours. The reaction was quenched with saturated NH ₄ Cl solution (30 mL) and extracted with EtOAc (3 x 50 mL). The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel chromatography using a gradient from 0 to 60% EtOAc in petroleum ether to give the title compound as a yellow oil (800 mg, 61%). ES-MS m/z 368 (M+H).

Manufacturing Example 361

Methyl (S)-4-amino-3-(2-(dimethylamino)-2-oxoethoxy)-5-((oxetan-2-ylmethyl)amino)benzoate

Methyl (S)-3-(2-(dimethylamino)-2-oxoethoxy)-4-nitro-5-((oxetan-2-ylmethyl)amino)benzoate (800 mg, 2.13 mmol), A vessel containing Pd/C (200 mg, 10 wt%), and EtOAc (60 mL) was purged three times with hydrogen gas. The mixture was stirred at ambient temperature under 1 atm of H ₂ for 4 hours. The mixture was filtered and concentrated under reduced pressure. The product was purified by silica gel chromatography using a gradient from 0 to 100% EtOAc in petroleum ether to afford the title compound as a yellow oil (636.4 mg, 88%). ES-MS m/z 338 (M+H).

Manufacturing Example 362

Methyl (S)-4-(2-(5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzena Cyclononaphan-1 ⁴ -yl)acetamido)-3-(2-(dimethylamino)-2-oxoethoxy)-5-((oxetan-2-ylmethyl)amino)benzoate

At ambient temperature, 1-propanephosphonic anhydride (50 wt% solution in DCM, 225 μL, 0.378 mmol) was reacted with 2-(5 ⁴ -cyano-3) in DMF (1 mL) and pyridine (150 μL, 1.85 mmol). ,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononapan- ^{1 4} -yl)acetic acid (75 mg, 0.187 mmol) and of methyl (S)-4-amino-3-(2-(dimethylamino)-2-oxoethoxy)-5-((oxetan-2-ylmethyl)amino)benzoate (69 mg, 0.20 mmol) was added to the solution. After stirring for 20 hours, additional 1-propanephosphonic anhydride (225 μL, 0.378 mmol) was added. After stirring for an additional 23 hours, the reaction was quenched by addition of water (2 mL). The mixture was stirred for 10 minutes, filtered, and the solid was collected, then the solid was dried under vacuum at 60° C. for 2 hours to give the title compound as a beige solid (75.1 mg, 56%). ES-MS m/z 720 (M+H).

Manufacturing Example 363

Methyl (S)-2-((5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclonona Pan-1 ⁴ -yl)methyl)-4-(2-(dimethylamino)-2-oxoethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6- carboxylate

Methyl (S)-4-(2-(5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1) in acetic acid (3 mL) ,2)-Dibenzenacyclononaphan-1 ⁴ -yl)acetamido)-3-(2-(dimethylamino)-2-oxoethoxy)-5-((oxetan-2-ylmethyl)amino ) A solution of benzoate (75 mg, 0.104 mmol) was stirred at 60°C for 20 hours. Acetic acid was removed under vacuum and the residue was purified via silica gel chromatography using a gradient of 0 to 20% isopropanol in chloroform to give 70 mg (70% purity, 72%) of the title compound. ES-MS m/z 703 (M+H).

Manufacturing example 364

Methyl 3-[(3-ethylimidazol-4-yl)methylamino]-5-methoxy-4-nitro-benzoate

TEA (2.2 mL, 16 mmol) was dissolved in methyl 3-fluoro-5-methoxy-4-nitro-benzoate (900 mg, 3.93 mmol) and (1-ethyl-1H-imidazole-) in DMF (20 mL). 5-yl)methylamine dihydrochloride (900 mg, 4.32 mmol) was added to a stirred solution. The mixture was stirred at 60° C. for 16 hours. The mixture was cooled to ambient temperature and poured into saturated aqueous NH ₄ Cl (100 mL). The mixture was extracted with DCM (3 x 100 mL) and washed with saturated aqueous NaCl (3 x 50 mL). The organic portion was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography using a gradient of 0 to 10% MeOH in EtOAc to give the title compound (800 mg, 61%) as a yellow oil. ES-MS m/z 335 (M+H).

Manufacturing example 365

Methyl 4-amino-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)-5-methoxybenzoate

Iron (801 mg, 14.34 mmol) and NH ₄ Cl (768 mg, 14.4 mmol) were reacted with methyl 3-[(3-ethylimidazol-4-yl)methylamino in MeOH (30 mL) and water (10 mL). ]-5-methoxy-4-nitro-benzoate (960 mg, 2.87 mmol) was added to the solution. Stirred at 80° C. for 2 hours, cooled to ambient temperature, filtered over a pad of ^Celite® , and the pad was washed with MeOH (30 mL). The filtrate was concentrated under reduced pressure and purified by flash chromatography using a gradient from 0 to 15% MeOH in EtOAc. Repurification by silica gel chromatography using a gradient from 0 to 10% MeOH in EtOAc gave the title compound as a brown solid (504 mg, 55%). ES-MS m/z 305 (M+H).

Manufacturing example 366

Methyl 4-(2-(5 ⁴ -Cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane- 1 ⁴ -yl)acetamido)-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)-5-methoxybenzoate

At ambient temperature, 1-propanephosphonic anhydride (50 wt% solution in DMF, 170 μL, 0.28 mmol) was incubated with 2-(5 ⁴ -cyano-3) in DMF (600 μL) and pyridine (400 μL, 5 mmol). ,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononapan-1 ⁴ -yl)acetic acid (76 mg, 0.1898 mmol) and Was added to a solution of methyl 4-amino-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)-5-methoxybenzoate (63 mg, 0.207 mmol). The reaction was stirred at RT for 72 h, then diluted with EtOAc (100 mL), the organics were washed with saturated NaHCO ₃ (100 mL), filtered over ^Celite® , and the filtrate was extracted three times with additional EtOAc. did. The organics were combined, washed twice with saturated aqueous NaCl, dried over MgSO ₄ , filtered, and concentrated under reduced pressure to give the title product (136 mg), which was used in Preparation 367 without further purification. ES-MS m/z 688 (M+H).

Manufacturing example 367

Methyl 2-((5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane-1 ⁴ -yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-4-methoxy-1H-benzo[d]imidazole-6-carboxylate

Methyl 4-(2-(5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1, 3),5(1,2)-dibenzenacyclononaphan-1 ⁴ -yl)acetamido)-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)-5 The title compound was prepared essentially as described in Preparation 102 using -methoxybenzoate (Preparation 366) and heating the reaction at 70° C. for 16 hours. The mixture was cooled to RT and concentrated under vacuum. 1:1 EtOAc/toluene was added and concentrated to remove residual acetic acid (twice). The resulting yellow solid was dried under vacuum for 2 hours. The solid was purified by silica gel chromatography using a gradient of 90 to 100% EtOAc in DCM followed by MeOH to afford the title compound as an off-white solid, which was used in Example 63 without further purification. ES-MS m/z 670 (M+H).

Manufacturing example 368

Methyl (S)-4-(2-(5 ⁴ -cyano-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzena Cyclononaphan-1 ⁴ -yl)acetamido)-3-(2-methoxyethoxy)-5-((oxetan-2-ylmethyl)amino)benzoate

2-(5 ⁴ -cyano-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclonona in DMF (1.2 mL) Pan-1 ⁴ -yl)methyl 4-amino-3-(2-methoxyethoxy)-5-[[(2S)-oxetan-2-yl]methyl in a solution of acetic acid (44 mg, 0.103 mmol) Amino]benzoate (32 mg, 0.103 mmol), HATU (59 mg, 0.155 mmol) and DIPEA (0.055 mL, 0.32 mmol) were added. The mixture was stirred at RT for 2 hours, then diluted with water (10 mL) and extracted with EtOAc (4 x 5 mL). The organics were combined, washed with water and saturated aqueous NaCl, dried over MgSO ₄ , filtered and concentrated in vacuo to give the title compound as a light brown solid (80 mg, 80% purity, 88% yield). ES-MS m/z 693 (M+H).

Manufacturing example 369

Methyl (S)-2-((5 ⁴ -cyano-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclonona Pan-1 ⁴ -yl)methyl)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

Methyl (S)-4-(2-(5 ⁴ -cyano-3,8-dioxa-2(2,6)-pyridina in 1,2-dichloroethane (0.7 mL) and acetic acid (0.7 mL) -1(1,3),5(1,2)-dibenzenacyclononaphan-1 ⁴ -yl)acetamido)-3-(2-methoxyethoxy)-5-((oxetane-2 A solution of -ylmethyl)amino)benzoate (80 mg, 80% purity, 0.092 mmol) was heated at 58° C. for 6 hours. The reaction mixture was cooled to RT, concentrated under reduced pressure and the residue was purified via silica gel chromatography using a gradient from 30 to 100% EtOAc in DCM to give 25 mg (40%) of the title compound as a white solid. . ES-MS m/z 675 (M+H).

Manufacturing example 370

Methyl (S)-2-((5 ⁴ -cyano-3,8-dioxa-2(2,6)-pyridina-1,5(1,3)-dibenzenacyclononaphane-1 ⁴ - 1) methyl)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

2-(5 ⁴ -cyano-3,8-dioxa-2(2,6)-pyridina-1,5(1,3)-dibenzenacyclononaphane in anhydrous DMF (1.5 mL) under nitrogen atmosphere. -1 ⁴ -yl)acetic acid (60 mg, 0.15 mmol) and methyl 4-amino-3-(2-methoxyethoxy)-5-[[(2S)-oxetan-2-yl]methylamino]benzo To a solution of ate (47 mg, 0.15) was added HATU (74 mg, 0.19 mmol) and DIPEA (0.08 mL, 0.45 mmol). The mixture was stirred at RT for 2.5 hours, then water and EtOAc were added. The aqueous layer was separated and the organic layer was washed with water and saturated aqueous NaCl, dried over Na ₂ SO ₄ , filtered and concentrated. A solution of the residue in 1,2-dichloroethane (0.9 ml) and acetic acid (0.9 ml) was heated at 60° C. for 8 hours under nitrogen atmosphere. The reaction mixture was cooled to RT, the solvent was concentrated under reduced pressure, dried at 35-40° C. under vacuum and the residue was purified via silica gel chromatography using a gradient of 25 to 100% EtOAc in DCM as eluent system. This gave the title compound (72 mg, 71%) as a white solid. ES-MS m/z 675 (M+H).

Manufacturing Example 371

(S)-(1 ⁴ -((6-(methoxycarbonyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-2-yl)methyl)-3,9 -dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphan-5 ⁴ -yl)boronic acid

The reaction vessel was filled with methyl (S)-2-((5 ⁴ -bromo-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-diben Zenacyclononapan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (500 mg, 0.72 mmol), anhydrous THF ( 5 mL) and MeOH (10 mL). The mixture was bubbled with N ₂ for 10 min and dry ethylene glycol (610 μL, 10.9 mmol) and DIPEA (315 μL, 1.82 mmol) were added. The mixture was bubbled with N ₂ for 5 min, tetrahydroxydiborone (139 mg, 1.47 mmol), tricyclohexylphosphine (5 mg, 0.018 mmol) and [(tricyclohexylphosphine)-2-( 2'-aminobiphenyl)]palladium(II) methanesulfonate [P(Cy3)Pd G3, 26 mg, 0.039 mmol) was added, the vessel was sealed, and stirred at 50°C for 2.5 hours in a preheated bath. . The reaction mixture was concentrated, then saturated aqueous NaHCO ₃ was added and stirred for 5 minutes. The solid was filtered and then washed with water, ACN and MeOH to give the title compound (500 mg, 90 wt% purity, 100%) as a gray solid. ES-MS m/z 620 (M+H).

Manufacturing Example 372

Methyl (S)-2-((54amino-(4-fluoro-1H-imidazol-1-yl)-3,9-dioxa-2(2,6)-pyridina-1(1,3 ),5(1,2)-dibenzenacyclononaphan-14amino-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

In a reaction vessel, (S)-(1 ⁴ -((6-(methoxycarbonyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-2-yl)methyl)- 3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphan-5 ⁴ -yl)boronic acid (21 mg, 0.03 mmol) , 90 wt% purity), 4-fluoro-1H-imidazole (14 mg, 0.15 mmol), copper (II) acetate (5.8 mg, 0.032 mmol), MeOH (245 μL) and pyridine (6 μL, 0.07 mmol) ) was filled. The reaction vessel was sealed and the suspension was stirred at 60°C for 10 hours. EtOAc and aqueous ammonia (28%) were added and the organic layer was separated, washed with aqueous ammonia (28%), water and saturated aqueous NaCl, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified via silica gel chromatography using a gradient of 20 to 100% EtOAc in DCM as the eluent system to give the title compound (8 mg, 10%) as a white solid. ES-MS m/z 660 (M+H).

Manufacturing Example 373

Methyl 2-(bromomethyl)-5-chlorobenzoate

The title compound was prepared essentially as described in Preparation Example 236 using methyl 5-chloro-2-methylbenzoate. The reactor output was stirred with water and aqueous sodium bisulfite, the layers were separated and the aqueous phase was extracted twice with heptane. The organics were combined and washed with water (3×), saturated aqueous NaHCO ₃ followed by saturated aqueous NaCl. The organic portion was dried over MgSO ₄ , filtered and concentrated to give the title compound (67.99 g, 87%) as a yellow oil. ¹ H NMR (400.21 MHz, CDCl ₃ ) δ 7.98 (d, J= 2.2 Hz, 1H), 7.49 (dd, J= 2.3, 8.3 Hz, 1H), 7.43 (d, J= 8.3 Hz, 1H), 4.94 (s, 2H), 3.97 (s, 3H).

Manufacturing example 374

Methyl 5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]benzoate

A solution of methyl 2-(bromomethyl)-5-chloro-benzoate (20.0 g, 67.5 mmol) in toluene (200 mL) was mixed with 6-chloropyridin-2-ol (10.9 g, 84.1 mmol) and silver carbonate ( 14.9 g, 54.0 mmol) was added to the mixture. The mixture was heated to 65° C. under N ₂ for 48 hours, the reaction vessel was protected from light using aluminum foil, and additional toluene (100 mL) was added. DCM (200 mL) was added to the reaction, filtered through a pad of ^Celite® , and the pad was rinsed with DCM (100 mL). The filtrate was concentrated to a volume of 100 mL and the first collection of solid material was filtered. The solid was washed with 1:1 toluene/heptane (50 mL) and heptane (2 x 50 mL). 100 mL heptane was added to the filtrate, then a second collection of solid material was filtered and washed with 1:1 toluene/heptane (50 mL) and heptane (2 x 50 mL) as before. The filtrate was concentrated and the residue was slurried in heptane (200 mL) at 50° C. for 30 minutes and then stirred at ambient temperature overnight. A third collection of solids was filtered and the solids were washed with heptane (2 x 50 mL). The first, second and third collections of solid material were combined and dried under reduced pressure at 50° C. for 5.5 hours to give the title compound (18.85 g, 89%) as a white solid. ES/MS m/z 312, 314 (M+H).

Manufacturing example 375

[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]phenyl]methanol

LiBH ₄ (2 M in _THF ; 35 mL, 70 mmol) was added. The reaction mixture was stirred at ambient temperature for 5 minutes, then MeOH (2.9 mL, 72 mmol) was added in portions over 1 hour. EtOAc (5 mL), water (10 mL), HCl (1 M aqueous, 100 mL), and MTBE (300 mL) were added to the mixture and the layers were separated. The layers were separated and the organics were washed with water (50 mL), aqueous K ₂ CO ₃ (2 M, 50 mL), and saturated aqueous NaCl (50 mL). The organic portion was dried over MgSO ₄ , filtered, and the filtrate was concentrated to give the title compound (13.54 g, 97%) as a waxy solid. ES/MS m/z 284, 286 (M+H).

Manufacturing example 376

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

THF (7.5 mL) was reacted with [5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]phenyl]methanol (0.50 g, 1.7 mmol) and 1-bromo-5-(bromo) under N ₂ To a mixture of parentmethyl)-2-fluoro-4-iodobenzene (0.89 g, 2.1 mmol) was added then potassium tert-butoxide (1 M solution in tert-butanol, 2.2 mL, 2.2 mmol) in portions. Added. The mixture was stirred at RT for 30 min, then water (30 mL) was added and the mixture was stirred at RT overnight, resulting in a mixture with a sticky lower phase. The supernatant was decanted, water was added, and the water was decanted. The remainder was dissolved in MeOH (55 mL) with heating at 60°C, SiliamethS triamine (1 g) was added and heating continued at 60°C for 3.5 hours. The reaction was filtered while hot through a pad of ^Celite® , the pad was rinsed with hot MeOH (15 mL) and the filtrate was concentrated. The residue was dissolved in MTBE (20 mL), filtered and concentrated. The residue was purified by silica gel chromatography using a gradient from 0 to 20% EtOAc in cyclohexane to give the title compound (0.75 g, 68%) as a colorless oil. ES/MS m/z 595, 597, 599 (M+H).

Manufacturing Example 377

Ethyl 2-[4-bromo-2-[[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]phenyl]methoxymethyl]-5-fluoro-phenyl]acetate

Under N ₂ , bromo-(2-ethoxy-2-oxo-ethyl)zinc (0.4 M in THF, 3.4 mL, 1.4 mmol) was reacted with 2-[[2-[(5-bro) in THF (1 mL). parent-4-fluoro-2-iodo-phenyl)methoxymethyl]-4-chloro-phenyl]methoxy]-6-chloro-pyridine (0.58 g, 0.91 mmol) and chloro[(4,5-bis) (diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) (Pd-179, Xantphos Pd G2, 45 mg, 0.045 mmol) was added to the mixture. The reaction mixture was heated to 60° C. for 10 hours. The reaction mixture was partitioned between water (15 mL), aqueous citric acid (5%, 5 mL) and MTBE. The organic phase was washed with 5 mL portions of water, aqueous K ₂ CO ₃ (2 M), and saturated aqueous NaCl. The organic portion was concentrated on ^Celite® and purified by silica gel chromatography using a gradient of 5 to 40% EtOAc in cyclohexane to give the title compound (311 mg, 58%) as a colorless oil. ¹ H NMR (400.13 MHz, CDCl ₃ ) δ 7.56-7.52 (m, 2H), 7.46-7.44 (m, 2H), 7.32 (dd, J= 2.2, 8.1 Hz, 1H), 7.07 (d, J= 9.0 Hz, 1H), 6.94 (d, J= 6.8 Hz, 1H), 6.66 (d, J= 7.6 Hz, 1H), 5.36 (s, 2H), 4.66 (s, 2H), 4.57 (s, 2H), 4.11 (q, J= 7.1 Hz, 2H), 3.68 (s, 2H), 1.22 (t, J= 7.1 Hz, 3H).

Manufacturing example 378

Ethyl 2-(5 ⁴ -chloro- ^{1 6} -fluoro-3,7-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacycloocta Edition-1 ⁴ -day) Acetate

N ₂ was purified with ethyl 2-[4-bromo-2-[[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]phenyl]methoxymethyl]- in anhydrous THF (40 mL). Spraying a mixture of 5-fluoro-phenyl]acetate (0.59 g, 1.0 mmol), bis(neopentyl glycolate)diborone (0.28 g, 1.2 mmol) and potassium pivalate (0.36 g, 2.5 mmol) for 10 minutes. Then, chloro(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl- 2-day) Palladium(II) (X-Phos-Pd-G2, 42 mg, 0.052 mmol) was added. The reaction mixture was heated at 45°C for 1.5 hours, then at 55°C for 1 hour, then additional bis(neopentyl glycolate)diborone (46 mg, 0.20 mmol) was added and heated at 55°C for 45 minutes. It continued for a while. Potassium phosphate tribasic (1.0 M solution in water, 3 mL, 3.0 mmol) was added and heating continued at 55° C. for 2 hours. The reaction mixture was partitioned between aqueous K ₂ CO ₃ (2 M, 25 mL) and DCM (100 mL) and the layers were separated. The aqueous layer was extracted with DCM (25 mL) and the organics were combined and filtered through ^Celite® . The filtrate was concentrated and the residue was purified by silica gel chromatography using DCM. The product was triturated with a mixture of DCM (5 mL) and heptane (20 mL) and the solid was dried under vacuum at 40° C. to give the title compound (144 mg, 32%) as a white solid. ES/MS m/z 442, 444 (M+H).

Manufacturing example 379

2-(5 ⁴ -Chloro-1 ⁶ -fluoro-3,7-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane -1 ⁴ -day) Acetic acid

LiOH (1M aqueous, 2.1 mL, 2.1 mmol) was dissolved in ethyl 2-(5 ⁴ -chloro-1 ⁶ -fluoro-3,7-dioxa-2( 2,6)-Pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphan- ^{1 4} -yl)acetate (227 mg, 0.51 mmol) was added to the suspension. The mixture was heated at 60° C. for 1 hour. The reaction mixture was concentrated and aqueous citric acid (5%) was added. The solid was filtered, washed with water and dried under vacuum at 40° C. to give the title compound (246 mg, 90 mass %, 100%) as a white solid. ES-MS m/z 414, 416 (M+H).

Production example 380

Methyl (S)-2-((5 ⁴ -chloro-1 ⁶ -fluoro-3,7-dioxa-2(2,6)-pyridina-1(1,3),5(1,2) -Dibenzenacyclooctaphan-1 ⁴ -yl)methyl)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-car voxylate

2-(5 ⁴ -chloro- ^{1 6} -fluoro-3,7-dioxa-2(2,6)-pyridina-1(1,3),5( 1,2)-Dibenzenacyclooctaphan-1 ⁴ -yl)acetic acid (246 mg, 0.535 mmol, 90 mass%) and methyl 4-amino-3-(2-methoxyethoxy)-5-[[( 2S)-oxetan-2-yl]methylamino]benzoate (183 mg, 0.59 mmol) in a solution of pyridine (492 μL, 6.08 mmol) and 2,4,6-tripropyl-1,3,5,2 ,4,6-Trioxatriphosphorinane-2,4,6-trioxide (1.68 M in EtoAc, 800 μL, 1.34 mmol) was added. The mixture was stirred at RT for 30 minutes and then water was added. The solid was filtered, washed with water and dried at 40°C overnight. A suspension of solids in 1,2-dichloroethane (6.4 mL) and acetic acid (6.4 mL) was heated at 60° C. overnight under N ₂ atmosphere. The reaction mixture was cooled, diluted with EtOAc and water and the solid was filtered. The organic layer was separated, dried over Na ₂ SO ₄ , filtered and the organic portion was concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient from 0 to 50% EtOAc in DCM to afford the title compound (291 mg, 75%) as a white solid. ES-MS m/z 688, 690 (M+H).

Example 1

(S)-2-((5 ⁴ -cyano-1 ⁶ -fluoro-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2) -Dibenzenacyclononapan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

ACN:Methyl (S)-2-((5 ⁴ -cyano- ^{1 6} -fluoro-3,9-dioxa-2(2,6)-pyridina-1 in water (4.0 mL:1.0 mL) (1,3),5(1,2)-dibenzenacyclononaphan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6- A mixture of carboxylate (200 mg, 0.257 mmol) and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (300 mg, 2.11 mmol) was stirred at 60°C for 5 hours. The mixture was adjusted to pH 6 using 1.0 M aqueous hydrochloric acid solution. The entire reaction mixture was purified via C18 reverse phase chromatography eluting with a gradient of 40 to 70% ACN in 0.225% aqueous formic acid to yield 33 mg (21%) of the title compound. ES-MS m/z 605 (M+H).

Example 2

(S)-2-((5 ⁴ -cyano-1 ⁶ -fluoro-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2) -Dibenzenacyclononapan-1 ⁴ -yl)methyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

ACN:Methyl (S)-2-((5 ⁴ -cyano- ^{1 6} -fluoro-3,9-dioxa-2(2,6)-pyridina-1 in water (5.0 mL:1.0 mL) (1,3),5(1,2)-dibenzenacyclononaphan-1 ⁴ -yl)methyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d] 1,3,4,6,7,8-hexahydro-2h-pyrimido[1,2-a]pyrimidine (50 mg, 0.40 mmol) was added. It was stirred at RT for 15 hours and then at 60°C for 4 hours. The reaction mixture was concentrated to half volume and neutralized to pH 7 using 1 M aqueous citric acid solution. The mixture was diluted with water (100 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with saturated aqueous sodium chloride (50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified via silica gel chromatography using a gradient of 5 to 100% solvent B in solvent A, where solvent B is 20% MeOH in EtOAc and solvent B is DCM. The product was further purified via C18 reverse phase chromatography using a gradient of 25 to 40% ACN in 10 mM aqueous ammonium bicarbonate containing 5% MeOH to yield 40 mg (17%) of the title compound. ES-MS m/z 623 (M+H).

Example 3

(S)-2-((5 ⁴ -Chloro-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane- 1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Methyl (S)-2-((5 ⁴ -chloro-3,9-dioxa-2(2,6)-pyridina-1(1) in ACN:THF:MeOH (0.80 mL:0.50 mL:0.50 mL) ,3),5(1,2)-dibenzenacyclononapan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxyl To a mixture of lithium hydroxide (45 mg, 0.074 mmol) was added aqueous lithium hydroxide solution (1.0 M, 0.75 mL). The mixture was stirred at 40°C for 6 hours and at 55°C for 30 minutes. The mixture was adsorbed onto ^Celite® and purified via C18 reverse phase chromatography, eluting with a gradient from 0 to 100% ACN in 10 mM aqueous ammonium bicarbonate containing 5% MeOH, to give 22 mg (49%) of the title compound. did. ES-MS m/z 596 (M+H).

Example 4

(S)-2-((5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane -1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

1,4-dioxane:ACN:methyl (S)-2-((5 ⁴ -cyano-3,9-dioxa-2(2,6)- in water (5:5:1, 11 mL) Pyridina-1(1,3),5(1,2)-dibenzenacyclononapan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imi A mixture of dazole-6-carboxylate (240 mg, 0.40 mmol) and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (170 mg, 1.20 mmol) was incubated at 60°C for 3 hours. , and stirred at 25°C for 16 hours, then at 50°C for 72 hours. The mixture was concentrated to 1/4 volume and purified via C18 reverse phase chromatography eluting with a gradient from 10 to 80% ACN in 10 mM aqueous ammonium bicarbonate containing 5% MeOH to give 160 mg (68%) of the title compound. Obtained. ES-MS m/z 587 (M+H).

Example 5

(S)-2-((5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane -1 ⁴ -yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

1,4-dioxane:ACN:methyl (S)-2-((5 ⁴ -cyano-3,9-dioxa-2(2,6)- in water (5:5:1, 11 mL) Pyridina-1(1,3),5(1,2)-dibenzenacyclononapan-1 ⁴ -yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H- A mixture of benzo[d]imidazole-6-carboxylate (230 mg, 0.28 mmol) and 1,5,7-triazabicyclo[4.4.0]des-5-ene (170 mg, 1.20 mmol) was added at 50 °C. It was stirred at ℃ for 16 hours, at 65℃ for 4 hours, and then at 50℃ for 72 hours. The mixture was concentrated to 1/4 volume and purified via C18 reverse phase chromatography, eluting with a gradient of 10 to 80% ACN in 10 mM aqueous ammonium bicarbonate containing 5% MeOH to give the title compound (170 mg, 72%). Obtained. ES-MS m/z 617 (M+H).

Example 6

(S)-2-((5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane -1 ⁴ -yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

Methyl (S)-2-((5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclonona Pan-1 essentially as described in Example 5 using ⁴ -yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate. The title compound was prepared as described. ES-MS m/z 588 (M+H).

Example 7

(S)-2-((5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane -1 ⁴ -yl)methyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Methyl (S)-2-((5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclonona Pan-1 essentially the same method as Example 5 using ⁴ -yl)methyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate. The title compound was prepared as described. ES-MS m/z 605 (M+H).

Example 8

(S)-2-((5 ⁴ -cyano-1 6 -fluoro-9-oxa- ³ -aza-2(2,6)-pyridina-1(1,3),5(1,2 )-Dibenzenacyclononaphan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

ACN:THF:methyl (S)-2-((5 ⁴ -cyano-1 ⁶ -fluoro-9-oxa-3-aza-2(2,6)-pyri in water (1:1:0.4) dina-1(1,3),5(1,2)-dibenzenacyclononapan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole The title compound was prepared essentially as described in Example 5 using -6-carboxylate. The mixture was heated at 50°C for 4 hours, cooled to RT and quenched with 1M citric acid solution. The mixture was extracted three times with EtOAc. The organic portions were combined, washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by C18 reverse phase chromatography using a gradient of 35 to 70% ACN in 20 mM aqueous ammonium bicarbonate to give the title compound as a white solid. ES-MS m/z 604 (M+H).

Example 9

(S)-2-((5 ⁴ -Cyano-16-methyl-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-diben Zenacyclononapan-14-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Methyl (S)-2-((5 ⁴ -cyano- ^{1 6} -methyl-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2) Essentially using -dibenzenacyclononaphan- ¹⁴ -yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate The title compound was prepared as described in Example 5. ES-MS m/z 631 (M+H).

Example 10

(S)-2-((5 ⁴ -cyano- ^{1 6} -fluoro-3,9-dioxa-2(2,6)-pyridina-1,5(1,3)-dibenzenacyclonona Pan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Methyl (S)-2-((5 ⁴ -cyano- ^{1 6} -fluoro-3,9-dioxa-2(2,6)-pyridina-1,5(1,3)-dibenzenacyclo Nonapan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate was prepared essentially as described in Example 5. The compound was prepared. The mixture was heated at 60° C. under nitrogen atmosphere for 2 hours, then cooled to RT and quenched with citric acid (5% aqueous). The solid was filtered and then washed with water and ACN to give the title compound as a white solid. ES-MS m/z 605 (M+H).

Example 11

2-((54amino-cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane-14amino- yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Methyl 2-((5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1) in ACN (0.75 mL), THF (0.19 mL), and water (0.12 mL) ,3),5(1,2)-dibenzenacyclononaphan-1 ⁴ -yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d ] 1,3,4,6,7,8-hexahydro-2h-pyrimido[1,2-a]pyrimidine (35 mg) in a solution of imidazole-6-carboxylate (39.7 mg, 0.06 mmol) , 0.25 mmol) was added. The mixture was stirred at 45°C for 3 hours. Additional 1,3,4,6,7,8-hexahydro-2h-pyrimido[1,2-a]pyrimidine (7.5 mg, 0.05 mmol) was added and the reaction was stirred at 50° C. for 1 hour. did. The reaction was quenched with formic acid to pH 6-7 and extracted with EtOAc. 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 C18 reverse phase chromatography using a gradient of 28 to 64% (1:1 ACN:MeOH) in (65 mM aqueous ammonium acetate:ACN 90:10 solution) to give 11.8 mg (30%) of the title compound. was obtained. ES-MS m/z 625 (M+H).

Example 12

(S)-1 ⁴ -((4-methoxy-1-(oxetan-2-ylmethyl)-6-(1H-tetrazol-5-yl)-1H-benzo[d]imidazole-2- 1) methyl)-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane-5 ⁴ -carbonitrile

(S)-2-(54Amino-cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane- 14amino-yl)-N-(2-methoxy-6-((oxetan-2-ylmethyl)amino)-4-(1H-tetrazol-5-yl)phenyl)acetamide (56 mg, 0.05 mmol) was stirred in acetic acid (1.0 mL) at 65°C for 12 hours. The solution was concentrated and azeotroped with ACN. The residue was purified by C18 reverse phase chromatography using a gradient of 41 to 83% 1:1 ACN:MeOH in 25 mM aqueous ammonium carbonate solution to give 9.4 mg (28%) of the title compound. ES-MS m/z 641 (M+H).

Example 13

(S)-2-((5 ⁴ -cyano- ^{1 6} -fluoro-3,6,9-trioxa-2(2,6)-pyridina-1(1,3),5(1, 2)-Dibenzenacyclononaphan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Methyl (S)-2-((5 ⁴ -cyano- ^{1 6} -fluoro-3,6,9-trioxa-2(2,6)-pyridina-1(1,3),5(1 ,2)-Dibenzenacyclononaphan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate was used, and the reactants were The title compound was prepared essentially as described in Example 1 with stirring at 45° C. for 2 hours. Upon completion, the reaction was quenched with formic acid to pH 7 and the crude mixture was diluted with water. The mixture was extracted three times with EtOAc. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified via silica gel flash chromatography using a gradient of MeOH containing 1% formic acid in 0 to 40% 9:1 DCM:DCM to give the title compound. ES-MS m/z 607 (M+H).

Example 14

(S)-2-((5 ⁴ -cyano-1 ⁶ -fluoro-3,7-dioxa-2(2,6)-pyridina-1(1,3),5(1,2) -Dibenzenacyclooctaphan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Methyl (S)-2-((5 ⁴ -cyano-1 ⁶ -fluoro-3,7-dioxa-2(2,6)-pyridina-1(1,3),5(1,2 )-Dibenzenacyclooctaphan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate was used, and the reactants were stored at 45°C. After stirring for 19 hours, 1,4-dioxane was added and stirred at 45° C. for 23 hours to prepare the title compound essentially as described for Example 2. The reaction was quenched with formic acid to pH 6-7 and extracted with EtOAc followed by 3:1 chloroform:2-propanol. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by C18 reverse phase chromatography using a gradient of 30 to 73% 1:1 ACN:MeOH in 25 mM aqueous ammonium carbonate solution to give the title compound. ES-MS m/z 591 (M+H).

Example 15

(S)-2-((5 ⁴ -cyano- ^{1 6} -methyl-3,9-dioxa-1,2(1,3),5(1,2)-tribenzenacyclononaphane-1 ⁴ -yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Methyl (S)-2-((5 ⁴ -cyano-1 ⁶ -methyl-3,9-dioxa-1,2(1,3),5(1,2)-tribenzenacyclononaphane- 1 Essentially as described in Example 4 using ⁴ -yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate. The title compound was prepared similarly. After completion, the reaction mixture was concentrated to 1/4 volume, neutralized with citric acid solution, and chromatographed via C18 reverse phase chromatography, eluting with a gradient from 10 to 80% ACN in 10 mM aqueous ammonium bicarbonate containing 5% MeOH. Purification gave the title compound. ES-MS m/z 630 (M+H).

Example 16

(S)-4-methoxy-2-((1 ⁶ -methyl-5 ⁴ -(trifluoromethyl)-3,9-dioxa-2(2,6)-pyridina-1(1,3 ),5(1,2)-dibenzenacyclononapan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Methyl (S)-4-methoxy-2-((1 ⁶ -methyl-5 ⁴ -(trifluoromethyl)-3,9-dioxa-2(2,6)-pyridina-1(1, 3),5(1,2)-dibenzenacyclononaphan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate The title compound was prepared essentially as described in Example 1, using dioxane:ACN:water (6:6:1) as solvent and stirring the reaction at 50°C for 2 hours. Once complete, neutralize with citric acid and concentrate the reaction mixture. The residue was diluted with EtOAc and washed with water and saturated aqueous NaCl. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified via silica gel chromatography using a gradient from 10 to 80% (20% MeOH in EtOAc) in DCM to give the title compound. ES-MS m/z 674 (M+H).

Example 17

(S)-2-((5 ⁴ -cyano-1 ⁶ -fluoro-3,7-dioxa-2(2,6)-pyridina-1(1,3),5(1,2) -Dibenzenacyclooctaphan-1 ⁴ -yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Methyl (S)-2-((5 ⁴ -cyano-1 ⁶ -fluoro-3,7-dioxa-2(2,6)-pyridina-1(1,3),5(1,2 )-Dibenzenacyclooctaphan-1 ⁴ -yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate The title compound was prepared essentially as described in Example 2. The reaction was stirred at 45°C for 4 hours. The mixture was cooled to RT, filtered and the filtrate was evaporated. The residue was purified by reverse phase chromatography using a gradient of 30-73% solvent B in solvent A (solvent A = [65mM NH4OAc + ACN (90:10)]; solvent B = ACN]) to give the title compound as a white Obtained as a solid. ES-MS m/z 621 (M+H).

Example 18

(S)-2-((5 ⁴ -bromo-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane -1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Methyl (S)-2-((5 ⁴ -bromo-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclonona Pan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate was used, and 2:1 THF:MeOH was used as the solvent. The title compound was prepared essentially as described in Example 3. Stirred at 65° C. for 1.5 hours and 1 M aqueous KH ₂ PO ₄ was added. The reaction was diluted 2.5 times with water and allowed to cool while stirring for 45 minutes. The solid was collected by filtration and washed with 1:3 MeOH:water followed by water. The filter cake was dried at 50° C. under reduced pressure for 20 hours to yield the title compound as a white solid. ES-MS m/z 640 and 642 (M+H).

Example 19

(S)-2-((5 ⁴ -cyano-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane -1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

3:1:1 ACN:THF:methyl (S)-2-((5 ⁴ -cyano-3,8-dioxa-2(2,6)-pyridina-1(1,3) in water, Using 5(1,2)-dibenzenacyclononaphan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate The title compound was prepared essentially as described in Example 1. The mixture was heated at 55°C for 3 hours, cooled to RT and quenched with 5% aqueous citric acid to pH = 4-5 to precipitate a white solid. The solid was filtered, washed with water (3 times) and ACN and dried under vacuum at 45° C. overnight to give the title compound as a white solid. ES-MS m/z 587 (M+H).

Example 20

(S)-2-((5 ⁴ -cyano-1 ⁶ -fluoro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2) -Dibenzenacyclooctaphan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

3:1:1 ACN:1,4-dioxane:methyl (S)-2-((5 ⁴ -cyano-1 ⁶ -fluoro-3,8-dioxa-2(2, 6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ The title compound was prepared essentially as described in Example 1 using d]imidazole-6-carboxylate. The reaction was heated to 60° C. for 3 hours, then cooled to RT and quenched with a solution of citric acid (5% in water). Diluted with EtOAc, the phases were separated and the aqueous phase was extracted twice with EtOAc. The organic phases were combined, washed with water and saturated aqueous NaCl, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by SFC [Column: Chiralpak 20x250mm, 5 μm; Purification by isocratic mobile phase: 35% CO ₂ in (MeOH + 0.5% dimethylethylamine) at 100 bar, flow rate 65 mL/min] gave the title compound as a white solid. ES-MS m/z 591 (M+H).

Example 21

(S)-2-((5 ⁴ -cyano-3,8-dioxa-2(2,6)-pyridina-1,5(1,3)-dibenzenacyclononaphan-1 ⁴ -yl )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

3:1:1 ACN:1,4-dioxane:methyl (S)-2-((5 ⁴ -cyano-3,8-dioxa-2(2,6)-pyridina- in water as solvent) 1,5(1,3)-dibenzenacyclononaphan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate ( The title compound was prepared essentially as described in Example 1 (90 mg, 0.14 mmol). The reaction was heated to 60° C. for 1 hour, cooled to RT and quenched with aqueous citric acid (5%). The solid was filtered and washed with water followed by ACN to give the title compound as a white solid. ES-MS m/z 587 (M+H).

Example 22

(S)-4-methoxy-2-((1 ⁶ -methyl-5 ⁴ -(fluoro)-3,9-dioxa-2(2,6)-pyridina-1(1,3), 5(1,2)-dibenzenacyclononaphan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Methyl (S)-4-methoxy-2-((1 ⁶ -methyl-5 ⁴ -(fluoro)-3,9-dioxa-2(2,6)-pyridina-1(1,3) ,5(1,2)-dibenzenacyclononapan- ¹⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate is used. and the reaction was stirred at 50° C. for 2 hours to prepare the title compound essentially as described in Example 4. The reaction was concentrated, neutralized with aqueous citric acid and purified via C18 reverse phase chromatography using a gradient of 10 to 80% ACN in 10 mM aqueous NH ₄ HCO ₃ containing 5% MeOH. ES-MS m/z 624 (M+H).

Example 23

2-((54amino-cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane-14amino- 1) methyl)-4-methoxy-1-(oxazol-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Ethyl 2-((5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane- ^{1 4} -yl)methyl)-4-methoxy-1-(oxazol-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate was used, and the reaction was stirred at 65°C for 72 hours. The title compound was prepared essentially as described in Example 1. The mixture was concentrated to 1/4 volume and adjusted to pH = 5 using formic acid. The resulting precipitate was collected and purified via C18 reverse phase chromatography eluting with a gradient from 10 to 80% ACN in 10 mM aqueous NH ₄ HCO ₃ containing 5% MeOH to give the title compound as a colorless solid. ES-MS m/z 628 (M+H).

Example 24

(S)-2-((5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane -1 ⁴ -yl)methyl)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Methyl (S)-2-((5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclonona Pan-1 using ⁴ -yl)methyl)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate , 5:5:1 1,4-dioxane:ACN:water was used as the solvent and the reaction was stirred at 45° C. for 16 hours to prepare the title compound essentially as described in Example 1. The mixture was concentrated to 1/4 volume and adjusted to pH = 5 using formic acid. The mixture was diluted with water and the organic portion was extracted with chloroform/isopropanol (3:1). The organic portion was dried over MgSO ₄ , filtered and concentrated. The title compound was purified via flash chromatography eluting with a gradient from 0 to 40% (10% formic acid in MeOH) in DCM. ES-MS m/z 661 (M+H).

Example 25

(S)-2-((5 ⁴ -(hydroxymethyl)-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzena Cyclononapan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Sodium borohydride (5.3 mg, 0.14 mmol) was dissolved in (S)-2-((5 ⁴ -formyl-3,9-dioxa-2(2, 6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononapan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d]imidazole-6-carboxylic acid (30 mg, 0.051 mmol) was added to the slurry at 0°C. The mixture was stirred for 5 minutes and then warmed to RT. The reaction was stirred for 20 minutes and then volatiles were removed with a stream of nitrogen at RT. Aqueous citric acid (5%) was added, stirred for 5 minutes and the solid was filtered and washed with water and MeOH. The solid was purified via silica gel chromatography using 10% MeOH in DCM to give the title compound (8 mg, 25%) as a white solid. ES-MS m/z 592 (M+H).

Example 26

(S)-4-methoxy-2-((1 ⁶ -methyl-5 ⁶ -(trifluoromethyl)-3,9-dioxa-2(2,6),5(3,2)-dip Ridina-1(1,3)-benzenacyclononaphan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid ;1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine

Methyl (S)-4-methoxy-2-((1 ⁶ -methyl-5 ⁶ -(trifluoromethyl)-3,9-dioxa-2(2,6),5(3,2)- Dipyridina-1(1,3)-benzenacyclononapan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxyl The title compound was prepared essentially as described in Example 4 using a rate and the reaction was stirred at 45° C. for 16 hours. The reaction was neutralized with aqueous citric acid and the mixture was concentrated and purified via C18 reverse phase chromatography using a gradient of 10 to 80% ACN in 10 mM aqueous NH ₄ HCO ₃ containing 5% MeOH. ES-MS m/z 675 (M+H).

Example 27

(S)-4-methoxy-2-((1 ⁶ -methyl-3,9-dioxa-2(2,6),5(4,3)-dipyridina-1(1,3)- Benzenacyclononapan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Methyl (S)-4-methoxy-2-((1 ⁶ -methyl-3,9-dioxa-2(2,6),5(4,3)-dipyridina-1(1,3) -Benzenacyclononapan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate was used, and the reactants were incubated at 50°C. The title compound was prepared essentially as described in Example 4 by stirring for 2 hours. The reaction was concentrated, neutralized with aqueous citric acid and purified via C18 reverse phase chromatography using a gradient of 10 to 80% ACN in 10 mM aqueous NH ₄ HCO ₃ containing 5% MeOH. The purified product was redissolved in DCM and neutralized with aqueous citric acid. The organic portion was washed with water and saturated aqueous NaCl. Dry over Na ₂ SO ₄ , filtered and concentrated to give the title compound. ES-MS m/z 607 (M+H).

Example 28

(S)-1-(oxetan-2-ylmethyl)-2-((5 ⁴ -(1-(oxetan-3-ylmethyl)-1H-pyrazol-4-yl)-3,9- Dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphan-1 ⁴ -yl)methyl)-1H-benzo[d]imidazole- 6-carboxylic acid

DMF (0.43 mL) and tripotassium phosphate (1 M aqueous solution, 0.13 mL, 0.13 mmol) were dissolved in (S)-2-((5 ⁴ -bromo-3,9-dioxa-2(2,6)-pyri dina-1(1,3),5(1,2)-dibenzenacyclononapan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole -6-carboxylic acid (30 mg, 0.0436 mmol), 1-(oxetan-3-ylmethyl)-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- It was added to a vessel containing pyrazole (19 mg, 0.0698 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (1.4 mg, 0.0021 mmol). The vessel was purged with nitrogen, the vessel was sealed and the mixture was stirred at 60°C for 2 hours. After cooling to ambient temperature, the mixture was purified directly via C18 reversed phase chromatography using ACN/10 mM aqueous NH ₄ HCO ₃ as eluent.

The material from a second similar reaction was combined and the resulting solid 1:1 DCM:EtOAc was suspended and partially concentrated under reduced pressure to remove DCM. The suspension was stirred at ambient temperature for 10 minutes, then the solid was collected by filtration and washed with EtOAc. Drying at 50° C. under reduced pressure for 16 hours gave 28 mg (41% average for each of the two reactions) of the title compound as a white solid. ES-MS m/z 698.

Example 29

(S)-2-((5 ⁴ -(6-methoxypyridin-3-yl)-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1 ,2)-Dibenzenacyclononaphan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

(S)-2-((5 ⁴ -bromo-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane -1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (30 mg, 0.0436 mmol), 2-methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (22 mg, 0.094 mmol) and 1,1'-bis(di-tert-butylphosphino) ) Ferrocene palladium dichloride (3 mg, 0.0045 mmol) was added to a glass tube with a stirring bar. The tube was purged with nitrogen and tripotassium phosphate (1 M aqueous solution, 0.13 mL, 0.13 mmol) and DMF (0.5 mL) were added. The mixture was stirred at 60° C. for 16 hours. Additional 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (3 mg, 0.0045 mmol) was added to the reaction and heated at 60°C for 3 hours, then at 90°C for 16 hours. . The mixture was cooled to ambient temperature, and then the reaction mixture was purified directly using C18 reverse phase chromatography using ACN/10 mM aqueous NH ₄ HCO ₃ as eluent to give the title compound (4.7 mg, 14%) as a solid. . ES-MS m/z 669.

The following examples were prepared essentially as described in Example 29 using the appropriate boronic acid or boronate ester.

Example 40

(S)-2-((5 ⁴ -(1-methyl-1H-pyrazol-4-yl)-3,9-dioxa-2(2,6)-pyridina-1(1,3), 5(1,2)-dibenzenacyclononaphan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Using 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole, the reaction was stirred at 60°C for 2 hours, The title compound was prepared essentially as described in Example 29 omitting the second addition of catalyst. The crude reaction mixture was loaded onto hydrophobic lipophilic balance (HLB) resin and eluted with 10 mM aqueous NH ₄ HCO ₃ buffer followed by 1:1 DCM:MeOH. Fractions containing the title compound were concentrated and then further purified using C18 reverse phase chromatography using a gradient of ACN in 10 mM aqueous NH ₄ HCO ₃ . ES-MS m/z 642.

Example 41

(S)-1 ⁴ -((1-(oxetan-2-ylmethyl)-6-(1H-tetrazol-5-yl)-1H-benzo[d]imidazol-2-yl)methyl)- 3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane-5 ⁴ -carbonitrile

(S)-1 ⁴ -((1-(oxetan-2-ylmethyl)-6-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-tetrazole in THF (2 mL) -5-yl)-1H-benzo[d]imidazol-2-yl)methyl)-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1, 2)-Dibenzenacyclononaphane-5 To a solution of ⁴ -carbonitrile (100 mg, 0.1 mmol) was added TBAF (1 M in THF, 0.3 mL, 0.3 mmol). The mixture was stirred at 60° C. for 16 hours. The reaction was quenched with water and diluted with EtOAc. The organic phase was dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was suspended in aqueous ammonia solution and stirred at 50° C. for 6 hours. Concentrated under reduced pressure and the solid was purified by C18 reverse phase chromatography using a gradient of 30 to 70% ACN in aqueous ammonium acetate solution to give 93 mg (10%) of the title compound. ES-MS m/z 611 (M+H).

Example 42

(S)-2-((5 ⁴ -cyano-1 ⁶ -fluoro-3,6-dioxa-2(2,6)-pyridina-1(1,3),5(1,2) -Dibenzenacyclooctaphan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Methyl (S)-2-((5 ⁴ -cyano- ^{1 6} -fluoro-3,6-dioxa-2(2,6)-pyridina- in ACN (8.4 mL) and water (4.8 mL) 1(1,3),5(1,2)-dibenzenacyclooctaphan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6 -1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine (87 mg, 0.61 mmol) in a solution of carboxylate (92 mg, 0.15 mmol) Added. Stirred at 45°C overnight. The mixture was cooled to RT, diluted with water and extracted three times with 3:1 DCM:isopropanol. The organics were combined, washed with water and saturated aqueous NaCl, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 30% EtOAc in DCM followed by 0 to 5% (10:1 MeOH: formic acid) in DCM. Repurification by reverse phase chromatography using 41-83% [1:1 ACN:MeOH] in 0.1% aqueous formic acid (pH 3) gave the title compound (12 mg, 13%) as a white solid. ES-MS m/z 591 (M+H).

Example 43

(S)-2-((55-amino-cyano-16amino-fluoro-3,9-dioxa-2(2,6),5(2,3)-dipyridina-1(1, 3)-benzenacyclononaphan-14amino-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid dipor mate salt

Methyl (S)-2-((5 ⁵ -cyano- ^{1 6} -fluoro-3,9-dioxa-2(2, 6),5(2,3)-dipyridina-1(1,3)-benzenacyclononapan-1 ⁴ -yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl )-1H-benzo[d]imidazole-6-carboxylate (66 mg, 0.10 mmol) in a suspension of 1,3,4,6,7,8-hexahydro-2H-pyrimido [1,2- a]pyrimidine (0.032 g, 0.23 mmol) was added. The suspension was stirred at 45°C for 6 hours. The mixture was cooled to RT, formic acid was added until pH = 4 and extracted with EtOAc (3 x 5 mL). The organic portions were combined, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0 to 50% solvent B in solvent A (where solvent B = (DCM/MeOH/formic acid 9:0.9:0.1) and solvent A = DCM), giving the title The compound was obtained as a beige solid (15 mg, 24%). ES-MS m/z 636 (M+H-formate salt).

Example 44

(S)-2-((5 ⁴ -cyano-1 ⁶ -fluoro-3,7-dioxa-2(2,6)-pyridina-1(1,3),5(1,2) -Dibenzenacyclononapan-1 ⁴ -yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Methyl (S)-2-((5 ⁴ -cyano-1 ⁶ -fluoro-3,7- in degassed ACN (0.9 mL), 1,4-dioxane (0.3 mL) and water (0.3 mL) Dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphan-1 ⁴ -yl)methyl)-4-methoxy-1-(ox 1,5,7-triazabicyclo[4.4.0]des-5- in a suspension of cetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (57 mg, 0.09 mmol) N (38 mg, 0.27 mmol) was added. The reaction mixture was heated at 60° C. for 2 h, cooled to RT and 5% aqueous citric acid solution was added until pH = 5, followed by water (2.0 mL) and the mixture was stirred at RT for 15 min. The resulting solid was filtered, washed with water (5 mL) and dried under vacuum at 45°C overnight. The solid was suspended in MeOH (1.0 mL) and the mixture was stirred at RT for 15 min. The resulting solid was filtered, washed with MeOH (0.5 mL), EtOAc (1.5 mL), and dried under vacuum at 45° C. overnight to give the title compound as a light brown solid (19 mg, 34%). ES-MS m/z 635.2/636.2 (M+H).

Example 45

(S)-2-((5 ⁴ -chloro-1 ⁶ ,5 ⁶ -difluoro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1 ,2)-Dibenzenacyclononaphan-1 ⁴ -yl)methyl)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole- 6-carboxylic acid

Methyl (S)-2-((5 ⁴ -chloro-1 ⁶ ,5 ⁶ -difluoro-3,8-di) in ACN (2.4 mL), water (0.8 mL) and THF (0.8 mL) at 55°C. Oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphan-1 ⁴ -yl)methyl)-4-(2-methoxyethoxy) 1,5,7-triazabicyclo in a solution of -1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (245 mg, 64% purity, 0.21 mmol) [4.4.0]des-5-ene (210 mg, 1.47 mmol) was added. The mixture was stirred at 55° C. for 2 hours, cooled to RT, 5% aqueous citric acid was added until pH = 4-5 and the white solid was filtered, which precipitated out. The solid was dissolved in ACN/MeOH and purified by preparative HPLC [column: Welch Extreme C18 150 x 30 mm x 5 μm; Purification by mobile phase: 30 to 70% ACN (0.225%) in aqueous formic acid gave the title compound as a white solid (31 mg, 20%). ES-MS m/z 706 (M+H).

Example 46

(S)-2-((55-amino-cyano-3,8-dioxa-2,5(2,6)-dipyridina-1(1,3)-benzenacyclononaphane-14amino -yl)methyl)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Methyl (S)-2-((55-amino-cyano-3,8-dioxa-2,5(2,6)-dipyridina in a mixture of ACN:THF:water (3:1:1) -1(1,3)-benzenacyclononaphan-14amino-yl)methyl)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d ]imidazole-6-carboxylate (63 wt% purity) was used and the reaction was heated at 55° C. for 2 hours under a nitrogen atmosphere to prepare the title compound essentially as described in Example 5. The reaction mixture was cooled to RT, quenched with aqueous citric acid (5%), then the solid was filtered and washed with water. Preparative HPLC [Column: Welch Extreme C18 150 x 30 mm, 5 μm; Purification by mobile phase: 25 to 65% ACN (0.225%) in aqueous formic acid gave the title compound as a white solid. ES-MS m/z 662 (M+H).

Example 47

(S)-2-((5 ⁴ -chloro-1 ⁶ -fluoro-3,7-dioxa-2(2,6)-pyridina-1,5(1,3)-dibenzenacyclononaphane -1 ⁴ -yl)methyl)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Methyl (S)-2-((5 ⁴ -chloro-1 ⁶ -fluoro-3,7-dioxa-2(2,6) in 10:5:3 ACN:1,4-dioxane:water as solvent )-pyridina-1,5(1,3)-dibenzenacyclononapan-1 ⁴ -yl)methyl)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl) The title compound was prepared essentially as described in Example 2 using -1H-benzo[d]imidazole-6-carboxylate and stirring the reaction mixture at 55° C. for 6 hours and 30 minutes. The crude reaction mixture was concentrated on ^Celite® and purified by C18 reverse phase chromatography using a gradient of 10 to 73% ACN in aqueous NH ₄ HCO ₃ (10 mM + 5% MeOH) to give the title compound. ES-MS m/z 688 (M+H).

Example 48

(S)-2-((5 ⁴ -cyano- ^{1 6} -fluoro-3,7-dioxa-2(2,6)-pyridina-1,5(1,3)-dibenzenacyclonona Pan-1 ⁴ -yl)methyl)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

(S)-2-((5 ⁴ -chloro-1 ⁶ -fluoro-3,7-dioxa-2(2,6)-pyridina-1,5(1,3)-dibenzenacyclononaphane -1 ⁴ -yl)methyl)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (15 mg, 0.022 mmol), 1 in a mixture of potassium ferrocyanide trihydrate (14.5 mg, 0.039 mmol), XPhos Pd(crotyl)Cl (Pd-170, 5.5 mg, 0.008 mmol), and KOAc (5.6 mg, 0.056 mmol) 4-Dioxane (1.0 mL) and water (0.4 mL) were added. The mixture was stirred at 90°C for 4 hours. The reaction mixture was concentrated on ^Celite® and purified by C18 reverse phase chromatography using a gradient of 10 to 73% ACN in aqueous NH ₄ HCO ₃ (10 mM + 5% MeOH) to give 8.2 mg of the title compound (55% ) was obtained. ES-MS m/z 679 (M+H).

Example 49

(S)-2-((5 ⁴ -cyano- ^{2 3} -fluoro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2) -Dibenzenacyclononapan-1 ⁴ -yl)methyl)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-car boxylic acid

Methyl (S)-2-((5 ⁴ -cyano- ^{2 3} -fluoro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2 )-Dibenzenacyclononapan-1 ⁴ -yl)methyl)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6- The title compound was prepared essentially as described in Example 45 using the carboxylate. Preparative HPLC [Column: Welch Extreme C18 150 x 25 mm, 5 μm; Mobile phase: 25 to 70% ACN in aqueous TFA (0.1%)]. The organic solvent was removed under reduced pressure and the remaining aqueous solution was lyophilized to give the title product as a white solid. ES-MS m/z 679 (M+H).

Example 50

(S)-2-((5 ⁴ -cyano-6,6-difluoro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1, 2)-Dibenzenacyclonaphan-1 ⁴ -yl)methyl)-4-(2-methoxyethoxy)-1-(oxatan-2-ylmethyl)-1H-benzo[d]imidazole-6- carboxylic acid

Methyl (S)-2-((5 ⁴ -cyano-6,6-difluoro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1 ,2)-Dibenzenacyclonaphan-1 ⁴ -yl)methyl)-4-(2-methoxyethoxy)-1-(oxatan-2-ylmethyl)-1H-benzo[d]imidazole-6 -Carboxylate (61 mg, 0.086 mmol) was dissolved in ACN (1 mL), 1,4-dioxane (0.3 mL), and water (0.3 mL). To this solution was added 1,5,7-triazabicyclo[4.4.0]des-5-ene (0.04 g, 0.28 mmol) and the mixture was stirred at ambient temperature for 18 hours. The reaction was then quenched with 1N HCl (to pH 5) and extracted with EtOAc. The organic portion was dried over MgSO ₄ , filtered and concentrated. This material was subjected to reverse phase HPLC [column: Phenomenex Kinetex EVO C18 100 x 30 mm, 5 μm; Mobile phase: 23 to 58% ACN in aqueous NH ₄ HCO ₃ (10 mM plus 5% MeOH)] to give the title compound as a white solid (14.5 mg, 24.1%). ES-MS (m/z) 697.4 (M+H).

Example 51

(S)-2-((5 ⁴ -cyano-3,8-dioxa-2(2,4)-pyrimidina-1(1,3),5(1,2)-dibenzenacyclonona Pan-1 ⁴ -yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Methyl (S)-2-((5 ⁴ -cyano-3,8-dioxa-2(2,4)-pyrimidina-1(1,3),5(1,2)-dibenzenacyclo Nonapan-1 ⁴ -yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate was used as a starting material, and solvent The title compound was prepared essentially as described in Example 2 using 5:2:1 ACN:1,4-dioxane:water and heating the reaction to 40° C. for 21 hours. After completion, the reaction was cooled to ambient temperature and quenched with 5% aqueous citric acid to bring the pH to 4. The resulting precipitate was filtered, and the solid was washed with water. The collected solid was dried under reduced pressure to obtain the title compound. ES/MS m/z 618 (M+H).

Example 52

(S)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)-2-((5 ⁶ -(trifluoromethyl)-3,8-dioxa-2( 2,6),5(3,4)-dipyridina-1(1,3)-benzenacyclononapan-1 ⁴ -yl)methyl)-1H-benzo[d]imidazole-6-carboxyl mountain

Methyl (S)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)-2-((5 ⁶ -(trifluoromethyl)-3,8-dioxa-2 (2,6),5(3,4)-dipyridina-1(1,3)-benzenacyclononapan-1 ⁴ -yl)methyl)-1H-benzo[d]imidazole-6-car The title compound was prepared essentially as described in Example 2 using 2.8:1:1 ACN:THF:water as the boxylate and solvent and heating the reaction at 45° C. for 2 hours. The reaction was quenched with 1 M aqueous citric acid to bring the pH to 4.5. The resulting colorless solid was filtered and dried under vacuum. Purification via reverse phase chromatography on a C18 column using a gradient of 42% to 75% ACN in aqueous formic acid (0.225%) afforded the title compound. ES/MS m/z 705 (M+H).

Example 53

(S)-2-((5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane -1 ⁴ -yl)methyl)-4-(2-(2-methyloxazol-4-yl)ethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole- 6-carboxylic acid

Methyl (S)-2-((5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclonona Pan-1 ⁴ -yl)methyl)-4-(2-(2-methyloxazol-4-yl)ethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole The title compound was prepared essentially as described in Example 5, using -6-carboxylate, using a 3:1:1 ACN:THF:water mixture as solvent, and stirring the reaction at 35° C. for 6 hours. did. After completion, the mixture was concentrated and the residue was dissolved in a minimal amount of DMSO. The DMSO solution was filtered and the filtrate was subjected to preparative HPLC [column: Welch Xtimate C18 150 x 30 mm, 5 μm; Mobile phase: gradient from 10 to 45% ACN in aqueous NH ₄ HCO ₃ (10mM)] to give the title compound as a white solid. ES/MS m/z 712 (M+H).

Example 54

(S)-2-((5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane -1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-4-(2-((2,2,2-trifluoroethyl)amino)ethoxy)-1H-benzo[d ]imidazole-6-carboxylic acid

(S)-4-(2-((tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino)ethoxy)-2-((5 ⁴ -cya) in toluene (7 mL) No-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphan-1 ⁴ -yl)methyl)-1-( Silica gel (750 mg) was added to a solution of oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Preparation Example 311, 75 mg, 0.058 mmol), and the mixture was incubated at 120 °C. Heated at ℃ for 18 hours. The mixture was cooled to ambient temperature, filtered and concentrated under vacuum. The residue was purified by preparative HPLC [column: Xtimate C18 100 x 30 mm, 10 μm; Mobile phase: gradient from 35 to 65% ACN in aqueous formic acid (0.2%) to give the title compound as a colorless solid (2.5 mg, 5.7%). ES/MS m/z 728.6 (M+H).

Example 55

(S)-4-[2-hydroxyethoxy]-2-((5 ⁴ -chloro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5( 1,2)-Dibenzenacyclononaphan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Methyl (S)-4-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-2-((54-chloro-3,8-dioxa) in THF (5 mL) and MeOH (2 mL) -2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononapan-14-yl)methyl)-1-(oxetan-2-ylmethyl)- To a solution of 1H-benzo[d]imidazole-6-carboxylate (62 mg, 0.079 mmol) was added LiOH (10 mg, 0.42 mmol) dissolved in water (2 mL) and incubated at 45°C for 1.5 h. Heated. Additional LiOH (12 mg, 0.050 mmol) dissolved in water (1 mL) was added, heated at 45° C. for a further 1 hour, cooled to ambient temperature and concentrated under reduced pressure. The crude material was suspended in water (20 mL) and the pH was adjusted to 5 using 1N HCl. The solid was filtered, collected and dried under reduced pressure. Purification via C18 reverse phase chromatography, eluting with 30-60% ACN in 10mM aqueous ammonium bicarbonate containing 5% MeOH, gave the title compound (7.5 mg, 14%). ES/MS (m/z): 656.4 (M+H).

Example 56

(S)-2-((5 ⁴ -chloro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane- 1 ⁴ -yl)methyl)-4-(2-(dimethylamino)ethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Methyl (S)-2-((5 ⁴ -chloro-3,8-dioxa-2(2,6)) in ACN (2 mL), 1,4-dioxane (1 mL) and water (0.22 mL) -Pyridina-1(1,3),5(1,2)-dibenzenacyclononapan-1 ⁴ -yl)methyl)-4-(2-(dimethylamino)ethoxy)-1-(oxetane -2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (89 mg, 0.12 mmol) in a nitrogen-aerated mixture of 1,5,7-triazabicyclo[4.4.0]dec. -5-N (60 mg, 0.42 mmol) was added. The reaction mixture was heated at 60° C. for 16 hours. The mixture was cooled to ambient temperature, concentrated under reduced pressure, and the residue was purified via reverse phase chromatography using a gradient of 10 to 80% ACN in water (0.1% formic acid was added to both ACN and water) to give the title The compound was obtained as a colorless solid (42 mg, 48%). ES/MS m/z 683 (M+H).

Example 57

(S)-2-((5 ⁴ -chloro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane- 1 ⁴ -yl)methyl)-4-(2-(methylamino)ethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

(S)-4-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-2-((5 ⁴ -chloro-3,8-dioxa-2 in DCM (2 mL) (2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononapan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H To -benzo[d]imidazole-6-carboxylic acid (12.3 mg, 0.016 mmol) was added TFA (0.1 mL, 1 mmol). The mixture was stirred at ambient temperature for 15 minutes, then the reaction was concentrated under reduced pressure and the residue was purified by reverse phase chromatography using a gradient of 10 to 90% ACN in water (0.1% formic acid was added to both solvents). and purified to obtain the title compound (2.2 mg, 21%). ES/MS (m/z): 669 (M+H).

Example 58

(S)-2-((5 ⁴ -cyano- ^{1 6} -fluoro-3,8-dioxa-2(2,6)-pyridina-1,5(1,3)-dibenzenacyclonona Pan-1 ⁴ -yl)methyl)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

1,5,7-Triazabicyclo[4.4.0]dec-5-ene (29 mg, 0.20 mmol) was dissolved in ACN (1.4 mL), 1,4-dioxane (0.5 mL) and water (0.5 mL). Methyl (S)-2-((5 ⁴ -cyano- ^{1 6} -fluoro-3,8-dioxa-2(2,6)-pyridina-1,5(1,3)-diben in the mixture Zenacyclononapan-1 ⁴ -yl)methyl)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (50 mg, 0.069 mmol) was added to the degassed suspension. The mixture was heated at 60° C. under N ₂ for 1.5 h, cooled to RT and quenched with aqueous citric acid (5%). The solid was filtered and washed with water followed by ACN to give the title compound (34 mg, 70%) as a colorless solid. ES-MS m/z 679 (M+H).

Example 59

2-((5 ⁴ -Cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane-1 ⁴ - yl)methyl)-4-((1-methylpyrrolidin-3-yl)oxy)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole- 6-carboxylic acid

Methyl 2-((5 ⁴ -cyano-3,9-dioxa-2( 2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononapan-1 ⁴ -yl)methyl)-4-((1-methylpyrrolidin-3-yl ) Oxy)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (90 mg, 0.12 mmol) and 1,5,7- A solution of triazabicyclo[4.4.0]des-5-ene (55 mg, 0.39 mmol) was stirred at 25°C for 6 hours. The mixture was adjusted to pH 7 with formic acid and concentrated. The residue was purified via reverse phase chromatography using a gradient of 6 to 46% MeCN in aqueous ammonium hydroxide (0.04%) + NH ₄ HCO ₃ (10 mM) to give 30.5 mg of the title compound (35%). ES-MS m/z 686 (M+H).

Example 60

(S)-2-((5 ⁴ -cyano-1 ⁶ ,2 ³ -difluoro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5( 1,2)-Dibenzenacyclononaphan-1 ⁴ -yl)methyl)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole -6-carboxylic acid

Methyl (S)-2-((5 ⁴ -cyano-1 ⁶ ,2 ³ -difluoro-3,8-dioxa- in THF (1.17 mL), water (1.17 mL) and ACN (3.51 mL) 2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononapan-1 ⁴ -yl)methyl)-4-(2-methoxyethoxy)-1 In a degassed solution of -(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (250 mg, 0.16 mmol), 1,5,7-triazabicyclo[4.4.0 ]des-5-ene (150 mg, 1.06 mmol) was added. The reaction vessel was sealed and purged with nitrogen. The reaction mixture was heated to 45° C. and stirred at this temperature for 2 hours. The reaction was quenched with 1 M aqueous citric acid to pH = 4.5, then the colorless solid was filtered and dried under reduced pressure. The solid was purified by preparative HPLC (column: Welch Xtimate C18 150x25 mm, 5 μm); Purification by mobile phase: gradient from 25 to 60% ACN in aqueous formic acid gave the title compound as a colorless solid (53.9 mg, 49%). ES-MS m/z 697 (M+H).

Example 61

(S)-2-((5 ⁴ -cyano-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane -1 ⁴ -yl)methyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Methyl (S)-2-((5 ⁴ -cyano-3,8-dioxa-2(2,6)-pyridina-1(1,3) in ACN (6 mL) and water (4 mL) ,5(1,2)-dibenzenacyclononapan-1 ⁴ -yl)methyl)-4-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6- A solution of carboxylate (20 mg, 0.03 mmol) and 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-A]pyrimidine (20 mg, 0.1 mmol) was added at 45 °C. It was stirred at ℃ for 7 hours. The pH was adjusted to 6 using formic acid, and extracted with 3:1 chloroform:isopropanol. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was purified via silica gel chromatography using a gradient from 0 to 10% (MeOH + 10% formic acid) in DCM to give 4 mg (20%) of the title compound. ES-MS m/z 605 (M+H).

Example 62

(S)-2-((5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane -1 ⁴ -yl)methyl)-4-(2-(dimethylamino)-2-oxoethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-car boxylic acid

Methyl (S)-2-((5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3) in 1,2-dichloroethane (1 mL) 5(1,2)-dibenzenacyclononaphan-1 ⁴ -yl)methyl)-4-(2-(dimethylamino)-2-oxoethoxy)-1-(oxetan-2-ylmethyl)- A solution of 1H-benzo[d]imidazole-6-carboxylate (50 mg, 0.0356 mmol) and trimethyltin hydroxide (34 mg, 0.178630 mmol) was stirred at 80°C for 16 hours. The temperature was increased to 90°C for 7 hours and then to 100°C for 72 hours. Additional trimethyltin hydroxide (34 mg, 0.179 mmol) was added and heated to 105° C. for 18 hours. The reaction mixture was allowed to cool to ambient temperature and concentrated under vacuum. 15% aqueous citric acid (1 mL) was added to form a gum, which was filtered slowly over a sintered funnel. The gum was washed with water (2 mL) and dried at 60°C in a vacuum oven. The crude product was subjected to preparative HPLC [column: Phenomenex Kinetex EVO C18 250 x 30 mm, 5 μm; Mobile phase: gradient from 0 to 100% ACN in aqueous NH ₄ HCO ₃ (10 mM + 5% MeOH) to give the title compound as a colorless solid (12.5 mg, 51%). ES-MS m/z 688 (M+H).

Example 63

2-((5 ⁴ -Cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane-1 ⁴ - yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-4-methoxy-1H-benzo[d]imidazole-6-carboxylic acid

1,5,7-triazabicyclo[4.4.0]dec-5-ene ( A solution of 28 mg, 0.197 mmol) was aerated for 10 minutes. The oxygen-free solution was placed in a reaction vessel with methyl 2-((5 ⁴ -cyano-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)- Dibenzenacyclononapan-1 ⁴ -yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-4-methoxy-1H-benzo[d]imidazole-6- Carboxylate (44 mg, 0.065 mmol) was added. The mixture was stirred at ambient temperature for 24 hours. The reaction mixture was partitioned between EtOAc and 0.1 M aqueous HCl. The organic layer was separated, washed with saturated aqueous NaCl, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was subjected to preparative HPLC [column: Phenomenex Kinetex ^® EVO C18 100 x 30 mm, 5 μm; Mobile phase: gradient from 14 to 48% ACN in aqueous formic acid (0.1%)] to give the title compound (8.2 mg, 19%). ES-MS m/z 655 (M+H).

Example 64

(S)-2-((5 ⁴ -cyano-3,8-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane -1 ⁴ -yl)methyl)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Methyl (S)-2-((5 ⁴ -cyano-3,8-dioxa-2(2,6)-pyri in degassed ACN (0.5 mL), THF (0.2 mL) and water (0.2 mL) dina-1(1,3),5(1,2)-dibenzenacyclononapan-1 ⁴ -yl)methyl)-4-(2-methoxyethoxy)-1-(oxetan-2-yl 1,5,7-triazabicyclo[4.4.0]dec-5-ene (15 mg, 0.11 mmol) was added. The mixture was heated to 55° C. for 3 hours, then cooled to RT and 5% aqueous citric acid was added to pH = 4-5. The resulting solid was filtered, the solid was washed with water (3 times) and ACN, and then dried under vacuum at 45° C. overnight to give the title compound as a beige solid (15 mg, 63%). ES-MS m/z 661 (M+H).

Example 65

(S)-2-((5 ⁴ -cyano-3,8-dioxa-2(2,6)-pyridina-1,5(1,3)-dibenzenacyclononaphan-1 ⁴ -yl )methyl)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

1,5,7-Triazabicyclo[4.4.0]dec-5-ene (26 mg, 0.18 mmol) was dissolved in ACN (1.4 mL), 1,4-dioxane (0.5 mL) and water (0.5 mL). Methyl (S)-2-((5 ⁴ -cyano-3,8-dioxa-2(2,6)-pyridina-1,5(1,3)-dibenzenacyclononaphane-1 in the mixture ⁴ -yl)methyl)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (45 mg, 0.067 mmol) ) was added to the degassed suspension. The mixture was heated at 60° C. under N ₂ for 1.5 h, cooled to RT and quenched with aqueous citric acid (5%). The solid was filtered and washed with water followed by ACN to give the title compound (26 mg, 59%) as a white solid. ES-MS m/z 661 (M+H).

Example 66

(S)-2-((54amino-(4-fluoro-1H-imidazol-1-yl)-3,9-dioxa-2(2,6)-pyridina-1(1,3) ,5(1,2)-dibenzenacyclononaphan-14amino-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Aqueous LiOH (1M, 120 μL, 0.12 mmol) was dissolved in methyl (S)-2-((5 ^4- (4-fluoro-1H-imidazole-1) in a mixture of MeOH (300 μL) and THF (600 μL). -yl)-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphan-1 ⁴ -yl)methyl)-1 -(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (30 mg, 0.045 mmol) was added to the suspension and stirred at 60°C for 12 hours. The reaction mixture was concentrated and aqueous citric acid (5%) was added. The solid was filtered and washed with water, ACN and MeOH to give the title compound (11 mg, 47%) as a light brown solid. ES-MS m/z 646 (M+H).

Example 67

(S)-2-((5 ⁴ -chloro-1 ⁶ -fluoro-3,7-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)- Dibenzenacyclooctaphan-1 ⁴ -yl)methyl)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxyl mountain

Aqueous LiOH (1 M, 1.6 mL, 1.6 mmol) was dissolved in methyl (S)-2-((5 ⁴ -chloro-1 ⁶ -fluoro-3,7) in a mixture of THF (8.5 mL) and MeOH (4.3 mL). -dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphan-1 ⁴ -yl)methyl)-4-(2-methoxy Toxi)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (285 mg, 0.39 mmol) was added to the suspension. The mixture was heated at 60° C. for 3 hours. The reaction mixture was concentrated, aqueous citric acid (5%) was added and the solid was filtered and washed with water and ACN. The solid was dried under vacuum at 40° C. to give the title compound (285 mg, 100%) as a white solid. ES-MS m/z 674, 676 (M+H).

Example 68

(S)-2-((5 ⁴ -cyano-1 ⁶ -fluoro-3,7-dioxa-2(2,6)-pyridina-1(1,3),5(1,2) -Dibenzenacyclooctaphan-1 ⁴ -yl)methyl)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-car boxylic acid

(S)-2-((5 ⁴ -chloro-1 ⁶ -fluoro-3,7-dioxa-2(2,6)-pyridina-1(1,3),5(1, 2)-Dibenzenacyclooctaphan-1 ⁴ -yl)methyl)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6 -Carboxylic acid (61 mg, 0.087 mmol), tetrapotassium hexacyanoferate trihydrate (57 mg, 0.135 mmol), KOAc (19 mg, 0.19 mmol) and chloro(crotyl)(2-dicyclohexylphos) Pino-2',4',6'-triisopropyl-1,1'-biphenyl) was charged with palladium(II) (Pd-170, XPhos Pd(crotyl)Cl, 6.2 mg, 0.009 mmol]. Reaction The mixture was purged with N ₂ and DMF (1.7 mL) and water (0.9 mL) were added. The mixture was purged again with N ₂ for 5 minutes, the vessel was sealed and stirred at 90° C. overnight. The mixture was heated to RT. Cooled _to Purification by gradient from 30 to 50% ACN in HCO ₃ (20 mM, pH9) gave the title compound (9 mg, 16%) as a white solid, ES-MS m/z 665 (M+H).

Example 69

(S)-N-((cyclopropylmethyl)sulfonyl)-2-((5 ⁴ -fluoro-1 ⁶ -methyl-3,9-dioxa-2(2,6)-pyridina-1( 1,3),5(1,2)-dibenzenacyclononaphan-1 ⁴ -yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imi Dazole-6-carboxamide

(S)-4-methoxy-2-((1 ⁶ -methyl-5 ⁴ -(fluoro)-3,9-dioxa-2(2,6)-pyridina-1 in DCM (2 mL) (1,3),5(1,2)-dibenzenacyclononaphan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6- To a solution of carboxylic acid (100 mg, 0.16 mmol) was added 4-dimethylaminopyridine (20 mg, 0.16 mmol), cyclopropylmethanesulfonamide (35 mg, 0.26 mmol), and TEA (0.1 mL, 0.7 mmol). , the mixture was gently purged with N ₂ for 10 minutes. EDC (50 mg, 0.26 mmol) was added to the reaction mixture and stirred at RT overnight, then the reaction was heated at 40° C. for 4 hours. The reaction was quenched with aqueous citric acid (5%) and diluted with DCM. The phases were separated and the aqueous layer was extracted twice with DCM. The organic phases were combined, washed with saturated aqueous NaCl, dried over Na ₂ SO ₄ , the solid was filtered off and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC [column: _{Xbridge C18} 150 Obtained as a white solid (28 mg, 23.6%). ES-MS m/z 741 (M+H).

Example 70

(S)-2-((5 ⁴ -cyano-1 ⁶ ,5 ⁶ -difluoro-3,8-dioxa-2(2,6)-pyridina-1(1,3),5( 1,2)-Dibenzenacyclononaphan-1 ⁴ -yl)methyl)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole -6-carboxylic acid

As starting material (S)-2-((5 ⁴ -chloro-1 ⁶ ,5 ⁶ -difluoro-3,8-dioxa-2(2,6)-pyridina-1(1,3), 5(1,2)-dibenzenacyclononaphan-1 ⁴ -yl)methyl)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d] Using imidazole-6-carboxylic acid and a 2.5:1 mixture of 1,4-dioxane:water as solvent, the reaction was heated to 90° C. for 4 hours to give the title product essentially as described in Example 68. The compound was prepared. Preparative HPLC [column: C18 100 x 30 mm, 5 μm; Mobile phase: gradient from 15 to 85% ACN in aqueous formic acid (0.225%) to give the title compound as a white solid. ES-MS m/z 697 (M+H).

Example 71

(S)-2-((5 ⁴ -(3-fluoro-4-oxopyridin-1(4H)-yl)-3,9-dioxa-2(2,6)-pyridina-1(1 ,3),5(1,2)-dibenzenacyclononapan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxyl mountain

(S)-2-((5 ⁴ -bromo-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzena Cyclononapan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (51 mg, 0.079 mmol), 3-fluoro Charged with pyridin-4-ol (14 mg, 0.12 mmol), copper (I) iodide (1.6 mg, 0.008 mmol) and K ₂ CO ₃ (22 mg, 0.156 mmol). The reaction vessel was purged with N ₂ and then dry DMSO (80 μL) and 2,2,6,6-tetramethyl-3,5-heptanedione (7 μL, 0.033 mmol) were added. The reaction mixture was stirred at 120°C for 9 hours. The mixture was cooled to RT, aqueous citric acid (5%) was added and the solid was filtered and washed with water. Preparative HPLC [Column: Xbridge C18 19 x 150 mm, 5 μm; Mobile phase: gradient from 30 to 60% ACN in aqueous NH ₄ HCO ₃ (20 mM, pH9) to give the title compound (10 mg, 18%) as a white solid. ES-MS m/z 673 (M+H).

Example 72

(S)-2-((54amino-(4-methyl-1H-imidazol-1-yl)-3,9-dioxa-2(2,6)-pyridina-1(1,3), 5(1,2)-dibenzenacyclononaphan-14amino-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Anhydrous DMSO (0.06 mL) was dissolved in (S)-2-((5 ⁴ -bromo-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2 )-Dibenzenacyclononapan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (20 mg, 0.031 mmol), 4-methylimidazole (10 mg, 0.119 mmol), tripotassium phosphate (13 mg, 0.059 mmol), N ¹ ,N ² -bis(furan-2-ylmethyl)oxalamide (3 mg, 0.012 mmol) and copper (I) oxide (5 mg, 0.034 mmol). The reaction vessel was purged with argon, the vessel was sealed and heated to 120° C. with stirring for 19 hours. The reaction mixture in DCM (20 mL) was mixed with a second mixture prepared under similar conditions using bis(tetrabutylammonium iodide)copper(I) iodide (7 mg, 0.006 mmol) instead of copper(I) oxide. and combined. Water (5 mL), 2-propanol (5 mL), aqueous citric acid (5%, 5 mL) and saturated aqueous NaCl (20 mL) were added, then the mixture was shaken and the phases were separated. The aqueous phase was extracted using 4:1 DCM:2-propanol (2 parts 50 mL). The aqueous pH was adjusted to 3 using aqueous tripotassium phosphate and extracted again using 4:1 DCM:2-propanol (15 mL). The organic extracts were combined and concentrated under reduced pressure. The residue was purified by reverse phase chromatography using a gradient from 30 to 60% ACN in aqueous NH ₄ HCO ₃ (10 mM, pH = 9) to give the title compound (6 mg, 15%) as a solid. ES-MS m/z 642 (M+H).

Example 73

(S)-2-((54amino-(1H-imidazol-1-yl)-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1, 2)-Dibenzenacyclononaphan-14amino-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Anhydrous DMSO (0.20 mL) was dissolved in (S)-2-((5 ⁴ -bromo-3,9-dioxa-2(2,6)-pyridina-1(1,3),5(1,2 )-Dibenzenacyclononapan-1 ⁴ -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (30 mg, 0.046 mmol), Imidazole (13 mg, 0.189 mmol), tripotassium phosphate (20 mg, 0.091 mmol), N ¹ ,N ² -bis(furan-2-ylmethyl)oxalamide (5 mg, 0.02 mmol) and copper oxide ( I) (3 mg, 0.02 mmol) was added to the mixture. The vessel was purged with argon, sealed and heated to 120° C. with stirring for 20 hours. The reaction mixture was transferred to a MeOH-washed strong anion exchange resin cartridge (Isolute ^® SAX) and washed sequentially with 7:3 MeOH/water, MeOH, DCM, and 1:1 DCM:MeOH (containing 3% acetic acid). It was eluted with Fractions containing the title compound were combined and concentrated under reduced pressure. The residue was dissolved in DMSO and then the mixture was purified by reverse phase chromatography using a gradient from 30 to 60% ACN in aqueous NH ₄ HCO ₃ (10 mM, pH = 9). Appropriate fractions were concentrated under reduced pressure. The solid residue was triturated in 1:1 DCM:EtOAc (4 mL) and the mixture was partially concentrated to remove DCM. The suspension was centrifuged, the supernatant was removed, and the residue was dried under reduced pressure at 50° C. for 24 hours to give 9.4 mg (29% yield) of the title compound as a white solid. ES-MS m/z 628 (M+H).

Example 74

(S)-1-(oxetan-2-ylmethyl)-2-((5 ⁴ -(4-oxopyridin-1(4H)-yl)-3,9-dioxa-2(2,6) -Pyridina-1(1,3),5(1,2)-dibenzenacyclononapan-1 ⁴ -yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Anhydrous DMSO (80 μL) and 2,2,6,6-tetramethyl-3,5-heptanedione (7 μL, 0.033 mmol) were dissolved in (S)-2-((5 ⁴ -bromo-3,9- Dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononapan-1 ⁴ -yl)methyl)-1-(oxetan-2-yl Methyl)-1H-benzo[d]imidazole-6-carboxylic acid (50 mg, 0.078 mmol), 4-hydroxypyridine (10 mg, 0.102 mmol), copper (I) iodide (1.6 mg, 0.008) mmol) and K ₂ CO ₃ (22 mg, 0.156 mmol). The vessel was sealed and stirred at 120°C for 16 hours. The mixture was cooled to RT, aqueous citric acid (5%) was added and the solid was filtered and washed with water. The solid was purified by preparative HPLC [column: Xbridge C18 19 x 150 mm, 5 μm; Mobile phase: gradient from 25 to 55% ACN in aqueous NH ₄ HCO ₃ (20 mM, pH = 9)] and then the solid product was washed with MeOH and ACN to give the title compound (11 mg, 18%) as a colorless Obtained as a solid. ES-MS m/z 655 (M+H).

Example 75

(S)-2-((1 ⁶ -fluoro-5 ⁴ -(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3,7-dioxa-2(2, 6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 ⁴ -yl)methyl)-4-(2-methoxyethoxy)-1-(oxetane -2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

(S)-2-((5 ⁴ -chloro-1 ⁶ -fluoro-3,7-dioxa-2(2,6)-pyridina-1(1,3),5(1, 2)-Dibenzenacyclooctaphan-1 ⁴ -yl)methyl)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6 -Carboxylic acid (61 mg, 0.087 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H )-one (43 mg, 0.174 mmol) and chloro(crotyl)(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) palladium(II) (Pd-170, XPhos Pd(crotyl)Cl, 6.2 mg, 0.009 mmol) was charged. The vessel was purged with N ₂ , DMF (860 μL) and aqueous potassium phosphate tribasic (1 M, 260 μL, 0.26 mmol) were added and the mixture was stirred at 90° C. for 2.5 hours. The mixture was cooled to RT, aqueous citric acid (5%) was added and the solid was filtered and washed with water and ACN. The solid was subjected to preparative HPLC [column: Xbridge C18, 19 x 150 mm, 5 μm; Mobile phase: gradient from 30 to 60% ACN in NH ₄ HCO ₃ (20 mM, pH = 9) to give the title compound (9.5 mg, 14%) as a light brown solid. ES-MS m/z 747 (M+H).

biological assay

Human GLP-1 receptor HEK293 cell cAMP assay

GLP-1 receptor functional activity was measured using the human GLP-1R (NCBI accession number NP_002053) at an expression density of 581 ± 94 (n=6) and 104 ± 12 (n=5) fmol/mg protein ([ ¹²⁵ I]GLP-1 cAMP formation in a HEK293 clonal cell line expressing (7-36)NH ₂ determined using a homology competition binding assay. hGLP-1R receptor ^expressing cells were incubated with 1 Methylxanthine, Acros Cat# 228420010) and compound in DMEM (Gibco Cat# 31053) supplemented with 20 mM HEPES (Gibco Cat# 15630) (20 point concentration-response curve in DMSO, 2.75x LabSite Echo (Labcyte Echo) direct dilution, 384 well plate Corning Cat# 3570) in a 20 μL assay volume (final DMSO concentration is 0.5%). After incubation at 37°C for 30 minutes, the increase in intracellular cAMP produced was quantitatively determined using the CisBio cAMP Dynamic 2 HTRF Assay Kit (62AM4PEJ). Briefly, intracellular cAMP levels were detected by adding cAMP-d2 conjugate in lysis buffer (10 μL) followed by antibody anti-cAMP-Eu ³⁺ -cryptate also in lysis buffer (10 μL). The resulting competition assay was incubated at RT for at least 60 minutes and then detected using a PerkinElmer ^Envision® instrument with excitation at 320 nm and emission at 665 nm and 620 nm. Envision units (emission at 665nm/620nm*10,000) were inversely proportional to the amount of cAMP present and were converted to nM of cAMP per well using a cAMP standard curve. The amount of cAMP produced in each well (nM) was converted to a percentage of the maximum response observed with human GLP-1(7-36)NH ₂ . Relative EC ₅₀ values and percent maximum (E _max ) were derived by non-linear regression analysis using percent maximum response versus concentration of added compound, fitted to a 4-parameter logistic equation. EC ₅₀ and E _max data when the compounds of Examples 1 to 80 were tested in the cAMP assay described above using HEK293 cells expressing 581 and 104 fmol/mg GLP-1R are shown in Tables 1 and 2, respectively. These data indicate that the compounds of Examples 1-80 are agonists of the human GLP-1 receptor.

Table 1. HEK293 cell line with GLP-1R expression density of 581 fmol/mg, intracellular cAMP response, relative EC ₅₀ and E _max

Table 2. HEK293 cell line with GLP-1R expression density of 104 fmol/mg, intracellular cAMP response, relative EC ₅₀ and E _max

EC ₅₀ , nM = geometric mean and number of observations according to SEM (delta method) (in parentheses).

E _max , % = arithmetic mean and number of observations (in parentheses) ± SEM for percent of maximal response to GLP-1(7-36)NH ₂ in hGLP-1R

GLP-1R CHO cell β-arrestin mobilization assay

Activated G-protein coupled receptors can interact with the β-arrestin family of signaling proteins. The potency of compounds on GLP-1R induced arrestin recruitment was determined using the PathHunter Enzyme Fragment Complementation approach as substantially described below (von Degenfeld et al., FASEB J. , 2007 (14):3819-26 and Hamdouchi et al., J. Med Chem., 2016 59(24):10891-10916). CHO-K1 cells expressing Pro-Link-tagged human GLP-1R and enzyme-acceptor-tagged β-arrestin-2 were obtained from DiscoverRx and prepared as assay-ready frozen cells. You can. Test compounds were solubilized in DMSO and serial dilutions were performed using an Echo Acoustic Dispenser (Labsite). Assay medium was Pathhunter Cell Assay Buffer (DiscoverX) containing 0.1% w/v hydrolyzed casein (Sigma). 100 nL of the test compound solution was distributed into 10 μL of assay medium in a 384 well plate, and then 10 μL of cells in assay medium were added to obtain 5000 cells per well. The plate was incubated in a 37°C/5% CO ₂ incubator for 90 minutes, 10 μL of Pathhunter detection reagent (DiscoverX) was added, and the plate was incubated at RT for 60 minutes. The luminescence signal was measured. Compound concentration-response curves were fit to a 4-parameter logistic model to calculate potency as EC ₅₀ and percent maximum (E _max ). Data normalization to % stimulation was performed using DMSO and GLP-1(7-36) as minimum and maximum controls (Campbell et al., Assay Guidance Manual 2017). The potency of sample compounds to stimulate GLP-1R induced β-arrestin recruitment is reported in Table 3.

Table 3. hGLP1R induced β-arrestin-2 mobilization relative EC ₅₀ and E _max

Claims (51)

A compound of the 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 is independently at each occurrence H, halo, C ₁ -C ₂ alkyl, OH or C ₁ -C ₃ alkoxy;
R ^b is independently at each occurrence H, halo or C ₁ -C ₂ alkyl;
silver , where a is the point of attachment to linker A; b is the point of attachment of linker B;
X ¹ , ^{X 2} , ^{X 3} and ^{X 4} are independently N ^, CH or CR ¹ , ^where at most two ^of X ¹ , and no more than two of X ⁴ are CR ¹ ;
X ^{5 is} N, ^{CH or} CR ^{1a , and X 6 ,} Up to two of X ⁵ , X ⁶ , X ⁷ and X ⁸ are CR ^1a or CR ¹ ;
R ¹ is independently at each occurrence: CN; halo; C ₁ -C ₃ alkyl optionally substituted with OH; C ₁ -C ₃ haloalkyl; C ₁ -C ₃ alkoxy; C ₃ -C ₅ cycloalkyl; -SO ₂ C ₁ -C ₃ alkyl;
, _wherein each ^{X 9} is independently _CH or N, _{up to} ^one is selected from cycloalkyl, and C ₁ -C ₃ alkyl optionally substituted with OH, and R ^h is H, C ₁ -C ₃ haloalkyl, halo, C ₃ -C ₅ cycloalkyl, OH, -NR ^c R ^d , or C ₁ -C ₃ alkyl optionally substituted with OH;
5- or 6-membered heteroaryl or phenyl, where heteroaryl or phenyl is C ₁ -C ₃ alkoxy, C ₃ -C ₅ cycloalkyl, -CH ₂ -C ₃ -C ₅ cycloalkyl, -SO ₂ C ₁ - C ₃ alkyl, C ₄ -C ₅ heterocyclyl, -CH ₂ -C ₄ -C ₅ heterocyclyl, halo, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ haloalkoxy, CN, -CONR ^c R optionally substituted with 1 or 2 substituents independently selected from ^d , -NR ^c R ^d , or C ₁ -C ₃ alkyl optionally substituted with OH;
R ^1a is CN; halo; C ₁ -C ₃ alkyl optionally substituted with OH; C ₁ -C ₃ haloalkyl; or C ₁ -C ₃ alkoxy;
-B- is -CH ₂ O-, -OCH ₂ - or -CH ₂ NH-;
Y ¹ , Y ² and Y ⁷ are independently N, CH or CR ² , where at most one of Y ¹ , Y ² and Y ⁷ is N, and at most two of Y ¹ , Y ² and Y ⁷ are CR ² ;
Y ³ , Y ⁴ , Y ⁵ and Y ⁶ are independently N, CH or CR ² , where at most two of Y ³ , Y ⁴ , Y ⁵ and Y ⁶ are N, and Y ³ , Y ⁴ , Y ⁵ and up to two of Y ⁶ are CR ² ;
R ² is independently halo or methyl at each occurrence;
Z ¹ , Z ² and Z ³ are independently N, CH or CR ³ , where at most two of Z ¹ , Z ² and Z ³ are N, and at most two of Z ¹ , Z ² and Z ³ are CR ³ ;
R ³ is independently halo at each occurrence; C ₁ -C ₄ alkyl; _-OC 4 -C ₆ cycloalkyl optionally substituted with C ₁ -C ₂ alkoxy, OH, C ₁ -C ₃ alkyl or C ₁ -C ₃ haloalkyl; _-OC 4 -C ₆ heterocyclyl optionally substituted with C ₁ -C ₂ alkoxy, OH, C ₁ -C ₃ alkyl or C ₁ -C ₃ haloalkyl; or _{1 or} 2 selected from 5- or 6-membered heteroaryl optionally substituted with C 1 -C ₂ alkoxy, OH, -NR ^f R ^g , -CONR ^c R ^d , CN, halo, or C ₁ -C ₃ alkyl C ₁ -C ₄ alkoxy optionally substituted with substituents;
R ⁴ is ego;
R ⁵ is -CO ₂ H, ego;
R ^c and R ^d are each independently H or C ₁ -C ₃ alkyl;
R ^f is H or C ₁ -C ₃ alkyl;
R ^g is H, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₃ -C ₅ cycloalkyl, C(O)C ₁ -C ₃ alkyl or C ₁ -C ₃ alkylC ₃ -C ₅ It is cycloalkyl. 2. The compound according to claim 1 of the formula:

or a pharmaceutically acceptable salt thereof. 3. The compound according to claim 2 of the formula:

or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1 of the formula:

or a pharmaceutically acceptable salt thereof. According to any one of claims 1 to 4,
go A phosphorus compound or a pharmaceutically acceptable salt thereof. The compound or pharmaceutically acceptable salt thereof according to claim 5, wherein X ¹ , X ³ and X ⁴ are CH and X ² is CR ¹ . The method of claim 6, wherein R ¹ is CN, Cl, F, CF ₃ , A phosphorus compound or a pharmaceutically acceptable salt thereof. The method of claim 5, wherein X ¹ is N; X ² is CR ¹ ; A compound where X ³ and X ⁴ are CH, or a pharmaceutically acceptable salt thereof. The compound or pharmaceutically acceptable salt thereof according to claim 8, wherein R ¹ is CF ₃ . The method of claim 5, wherein X ¹ , X ³ and X ⁴ are CH; A compound where X ² is N. The method of claim 5, wherein X ¹ and X ⁴ are CH; X ² is CR ¹ ; A compound where X ³ is N. The compound or pharmaceutically acceptable salt thereof according to claim 11, wherein R ¹ is CF ₃ . The method of claim 5, wherein X ¹ and X ³ are CH; X ² is CR ¹ ; A compound where X ⁴ is N. The compound or pharmaceutically acceptable salt thereof according to claim 13, wherein R ¹ is CN. The method of claim 5, wherein X ¹ and X ³ are CH; A compound where X ² and X ⁴ are CR ¹ . 16. The compound or pharmaceutically acceptable salt thereof according to claim 15, wherein each R ¹ is independently selected from F, Cl and CN. According to any one of claims 1 to 4,
go A phosphorus compound or a pharmaceutically acceptable salt thereof. The compound or pharmaceutically acceptable salt thereof according to claim 17, wherein X ⁵ , X ⁷ and X ⁸ are CH and X ⁶ is CR ¹ . The compound or pharmaceutically acceptable salt thereof according to claim 18, wherein R ¹ is CN. 20. The method of claim 19, wherein X ⁵ is N; X ⁶ is CR ¹ ; A compound wherein X ⁷ and X ⁸ are CH, or a pharmaceutically acceptable salt thereof. The compound or pharmaceutically acceptable salt thereof according to claim 20, wherein R ¹ is CN. 22. The method according to any one of claims 1 to 21, wherein -A- is -CH ₂ CH ₂ CH ₂ O-, -CH ₂ OCH ₂ -, -CH ₂ CH ₂ OCH ₂ -, CH ₂ OCH ₂ CH ₂ - or -CF ₂ CH ₂ OCH ₂ - compound or pharmaceutically acceptable salt thereof. The compound according to any one of claims 1 to 22, wherein -B- is -CH ₂ O-, or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 1 to 23, wherein Y ¹ , Y ² and Y ⁷ are all CH, or a pharmaceutically acceptable salt thereof. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 23, wherein Y ¹ is CR ² , Y ² is CH, Y ⁷ is CH, and R ² is F. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 23, wherein Y ¹ is CR ² , Y ² is CH, Y ⁷ is CH, and R ² is methyl. 27. The method of any one of claims 1 to 26, wherein Y ³ is N; Y ⁴ and Y ⁵ are CH; A compound where Y ⁶ is CH or CR ² or a pharmaceutically acceptable salt thereof. The compound according to claim 27, wherein Y ⁶ is CH, or a pharmaceutically acceptable salt thereof. The compound or pharmaceutically acceptable salt thereof according to claim 27, wherein Y ⁶ is CR ² and R ² is F. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 26, wherein Y ³ , Y ⁴ , Y ⁵ and Y ⁶ are all CH. 31. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 30, wherein Z ¹ is CH or CR ³ . The compound of claim 31, wherein Z ¹ is CR ³ and R ³ is F, -OCH ₃ , -OCH ₂ CH ₂ OCH ₃ , OCH ₂ CH ₂ OH or OCH ₂ CH ₂ N(CH ₃ ) ₂ or a compound thereof. Pharmaceutically acceptable salt. The compound according to claim 31, wherein Z ¹ is CH, or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 1 to 33, wherein Z ² is CH, or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 1 to 34, wherein Z ³ is CH, or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 1 to 35, wherein R ⁵ is -CO ₂ H, or a pharmaceutically acceptable salt thereof. The method according to any one of claims 1 to 35, wherein R ⁵ is A phosphorus compound or a pharmaceutically acceptable salt thereof. The compound according to claim 1 selected from:







or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising the compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent or excipient. A method of treating type II diabetes in a patient, comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof. A method of lowering blood glucose levels in a patient, comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof. A method of treating hyperglycemia in a patient, comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof. 43. The method of any one of claims 40-42, wherein the compound is administered orally. 39. A compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, for use in therapy. 39. A compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, for use in the treatment of type II diabetes. 39. A compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, for use in lowering blood glucose levels. 39. A compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, for use in the treatment of hyperglycemia. The compound or pharmaceutically acceptable salt thereof according to any one of claims 44 to 47, which is administered orally. Use of a compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of type II diabetes. Use of a compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for lowering blood glucose levels. Use of the compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of hyperglycemia.