Glucagon-like peptide 1 receptor agonists

Abstract

In one embodiment, the present invention provides a compound of the formula: or a pharmaceutically acceptable salt thereof, and methods of using the compound to treat type II diabetes. [Formula 1] JPEG2025537254000188.jpg22128

Description

[Technical Field]

[0001] The present invention relates to glucagon-like peptide 1 receptor agonists and the therapeutic use of the compounds for treating type II diabetes. [Background technology]

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

[0003] Most GLP-1R agonists approved for treating type 2 diabetes are injectable, and patients often prefer orally administered medications due to the drawbacks associated with injections, such as inconvenience, pain, and potential injection-site irritation.

[0004] WO 2018 / 109607 discloses certain benzimidazole derivatives, which are described as GLP-1R agonists. Further GLP-1 agonist compounds are disclosed in WO 2019 / 239371, WO 2019 / 239319, WO 2020 / 103815, WO 2020 / 207474, WO 2020 / 263695, WO 2021 / 018023, WO 2021 / 081207, WO 2021 / 096284, WO 2021 / 096304, WO 2021 / 112538, WO 2021 / 154796, and WO 2021 / 160127. , Chinese Patent No. 2021 / 187886, Chinese Patent No. 2021 / 197464, Chinese Patent No. 113480534, Chinese Patent No. 113493447, International Publication No. 2021 / 219019, International Publication No. 2021 / 244645, International Publication No. 2021 / 249492, Chinese Patent No. 113801136, International Publication No. 2021 / 254470, International Publication No. 2021 / 259309, International Publication No. 2022 / 007979, International Publication No. 2022 / 031994, International Publication No. 2022 / 028572 , Chinese Patent No. 2022 / 040600, Chinese Patent No. 2022 / 042691, Chinese Patent No. 2022 / 068772, Chinese Patent No. 2022 / 078407, Chinese Patent No. 2022 / 078380, Chinese Patent No. 2022 / 078152, Chinese Patent No. 114478497, International Publication No. 2022 / 109182, International Publication No. 2022 / 111624, Chinese Patent No. 114591296, International Publication No. 2022 / 116693, International Publication No. 2022 / 135572, Chinese Patent No. 1147633 52, International Publication No. 2022 / 165076, Chinese Patent No. 114907351, International Publication Nos. 2022 / 184849, 2022 / 192428, 2022 / 192430, 2022 / 202864, 2022 / 199458, 2022 / 199661, 2022 / 216094, 2022 / 219495, 2022 / 225914, and 2022 / 225941.

[0005] However, there is a need for alternative GLP-1R agonists. In particular, there is a need for GLP-1R agonists that can be administered orally. In particular, there is a need for potent GLP-1R agonists with a favorable toxicological profile and / or a pharmacokinetic profile that supports once-daily dosing. Summary of the Invention

[0006] Thus, the present invention provides a compound of formula:

[0007] [ka] A compound of the formula wherein -A- is a C3-C4 alkylene or C3-C4 alkenylene optionally substituted with OH, halo, or oxo;

[0008] [ka] but,

[0009] [ka] wherein a is the point of attachment to linker A and 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 and X 1 , X 2 , X 3 , and X 4 At most two of the are N and X 1 , X 2 , X 3 , and X 4 Two or fewer of the 1 and X 5 is N, CH, or CR 1a and X6 , X 7 , and X 8 are independently N, CH, or CR 1 and X 5 , X 6 , X 7 , and X 8 At most two of the are N and X 5 , X 6 , X 7 , and X 8 Two or fewer of the 1a or CR 1 and R 1 independently at each occurrence CN, halo, C1-C3 alkyl optionally substituted with OH, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C5 cycloalkyl, -SO2C1-C3 alkyl,

[0010] [ka] wherein each X 9 are independently CH or N, and there is not more than one X in the ring 9 is N, and each R e is independently selected from H, C1-C3 haloalkyl, halo, C3-C5 cycloalkyl, and C1-C3 alkyl optionally substituted with OH; R h H, C1-C3 haloalkyl, halo, C3-C5 cycloalkyl, OH, -NR c R d or C1-C3 alkyl optionally substituted with OH; 5- or 6-membered heteroaryl or phenyl, wherein the heteroaryl or phenyl is C1-C3 alkoxy, C3-C5 cycloalkyl, -CH2-C3-C5 cycloalkyl, -SO2C1-C3 alkyl, C4-C5 heterocyclyl, -CH2-C4-C5 heterocyclyl, halo, C1-C3 haloalkyl, C1-C3 haloalkoxy, CN, -CONR c R d , -NR c R dor C1-C3 alkyl optionally substituted with OH; R 1a is CN, halo, C1-C3 alkyl optionally substituted with OH, C1-C3 haloalkyl, or C1-C3 alkoxy; -B- is -CH2O-, -OCH2-, or -CH2NH-; Y 1 , Y 2 , and Y 7 are independently N, CH, or CR 2 and Y 1 , Y 2 , and Y 7 At most one of the following is N and Y 1 , Y 2 , and Y 7 Two or fewer of the 2 and Y 3 , Y 4 , Y 5 , and Y 6 are independently N, CH, or CR 2 and Y 3 , Y 4 , Y 5 , and Y 6 At most two of the 3 , Y 4 , Y 5 , and Y 6 Two or fewer of the 2 and R 2 is independently at each occurrence halo or methyl; Z 1 , Z 2 , and Z 3 are independently N, CH, or CR 3 and Z 1 , Z 2 , and Z 3 At most two of the 1 , Z 2 , and Z 3 Two or fewer of the 3 and R 3are independently selected from the group consisting of halo, C1-C4 alkyl, C1-C2 alkoxy, -OC4-C6 cycloalkyl optionally substituted with OH, C1-C3 alkyl, or C1-C3 haloalkyl, C1-C2 alkoxy, -OC4-C6 heterocyclyl optionally substituted with OH, C1-C3 alkyl, or C1-C3 haloalkyl, C1-C2 alkoxy, -OC4-C6 heterocyclyl optionally substituted with OH, C1-C2 alkyl, or C1-C3 haloalkyl, C1-C2 alkoxy, -OH, -NR f R g , -CONR c R d , CN, halo, or 5- or 6-membered heteroaryl optionally substituted with C1-C3 alkyl; R 4 but,

[0011] [ka] and R 5 But -CO2H,

[0012] [ka] and R c and R d are each independently H or C1-C3 alkyl; R f is H or C1-C3 alkyl, R g is H, C1-C3 alkyl, C1-C3 haloalkyl, C3-C5 cycloalkyl, C(O)C1-C3 alkyl, or C1-C3 alkylC3-C5 cycloalkyl; or a pharmaceutically acceptable salt thereof.

[0013] Formula I includes all individual enantiomers, diastereomers and mixtures thereof, as well as racemates.

[0014] In one embodiment, the formula:

[0015] [ka] or a pharmaceutically acceptable salt thereof.

[0016] In one embodiment, the formula:

[0017] [ka] or a pharmaceutically acceptable salt thereof.

[0018] In one embodiment,

[0019] [ka] teeth,

[0020] [ka] In one embodiment,

[0021] [ka] teeth,

[0022] [ka] and X 1 , X 3 , and X 4 is CH and X 2 is CR 1 In an alternative embodiment,

[0023] [ka] teeth,

[0024] [ka] and X 1 is N and X 2 is CR 1 and X 3 and X 4 is CH. In a further alternative embodiment,

[0025] [ka] teeth,

[0026] [ka] and X 1 and X 4 is CH and X 2 is CR 1 and X 3 is N. In a further alternative embodiment,

[0027] [ka] teeth,

[0028] [ka] and X 1 and X 3 is CH and X 2 is CR 1 and X 4 is N.

[0029] In one embodiment, X 1 , X 2 , X 3 , and X 4One and only one of them is N.

[0030] In an alternative embodiment,

[0031] [ka] teeth,

[0032] [ka] In one embodiment,

[0033] [ka] teeth,

[0034] [ka] and X 5 is N and X 6 is CR 1 and X 7 and X 8 is CH.

[0035] In one embodiment, X 5 , X 6 , X 7 , and X 8 One and only one of them is N.

[0036] In one embodiment, R 1 is CN or halo.

[0037] In one embodiment,

[0038] [ka] teeth,

[0039] [ka] and X 1 , X 3 , and X 4 is CH and X 2 is CR 1 and R 1 is CN or Cl.

[0040] In an alternative embodiment,

[0041] [ka] teeth,

[0042] [ka] and X 1 is N and X 2 is CR 1 and X 3 and X 4 is CH and R 1 is CN.

[0043] In an alternative embodiment,

[0044] [ka] teeth,

[0045] [ka] and X 1 and X 4 is CH and X 2 But, CR 1 and X 3 is N and R 1 is CN.

[0046] In an alternative embodiment,

[0047] [ka] teeth,

[0048] [ka] and X 1 and X 3 is CH and X 2 But, CR 1 and X 4 is N and R 1 is Cl.

[0049] In an alternative embodiment,

[0050] [ka] teeth,

[0051] [ka] and X 5 is N and X 6 is CR 1 and X 7 and X 8 is CH and R 1 is CN or Cl.

[0052] In one embodiment, -A- is CH2CH(OH)CH2CH2-, -CH(OH)CH2CH2-, -CH2CH2CH2-, CH2CH2CH2CH2-, -C(O)CH2CH2-, or -CH=CHCH2-.

[0053] In one embodiment, -B- is -CH2O-.

[0054] In one embodiment, Y 3is N.

[0055] In one embodiment, Y 4 is CH.

[0056] In one embodiment, Y 5 is CH.

[0057] In one embodiment, Y 6 is CH.

[0058] In one embodiment, Y 3 is N and Y 4 , Y 5 , and Y 6 is CH.

[0059] In one embodiment, Y 1 is CH or CR 2 is.

[0060] In one embodiment, Y 2 is CH.

[0061] In one embodiment, Y 7 is CH.

[0062] In one embodiment, R 2 is methyl.

[0063] In one embodiment, Y 1 , Y 2 , and Y 7 are all CH. In an alternative embodiment, Y 1 is CR 2 and Y 2 is CH and Y 7 is CH and R 2 is methyl.

[0064] In one embodiment, Y 4 , Y 5 , Y 6 , and Y 7 are all CH.

[0065] In one embodiment, Z 1 is CH or CR 3 is.

[0066] In one embodiment, Z 2 is CH.

[0067] In one embodiment, Z 3 is CH.

[0068] In certain embodiments, Z 2 and Z 3 are both CH.

[0069] In one embodiment, R 3 is halo, or C1-C4 alkoxy, preferably R 3 is F, —OCH3, or —OCH2CH3.

[0070] In one embodiment, Z 1 is CR 3 and R 3 is halo, or C1-C4 alkoxy, preferably R 3 is F, —OCH3, or —OCH2CH3.

[0071] In one embodiment, R 5 is CO2H.

[0072] In one embodiment, the formula:

[0073] [ka] A compound of the formula In the formula, X is

[0074] [ka] and X 1 , X 3 , and X 4are independently N or CH, and X 1 , X 3 , and X 4 At most one of is N, R 1 is CN or halo, Y 1 But CH or CR 2 and R 2 is methyl, Z 1 is N, CH, or CR 3 and R 3 is halo or C1-C4 alkoxy, or a pharmaceutically acceptable salt thereof.

[0075] In one embodiment, a compound selected from: 2-((5 6 -Cyano-1 6 -methyl-3-oxa-2(2,6),5(3,2)-dipyridina-1(1,3)-benzenacyclooctaphane-1 4 -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 2-((5 4 -cyano-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 2-((5 6 -Cyano-1 6 -methyl-3-oxa-2(2,6),5(3,4)-dipyridina-1(1,3)-benzenacyclooctaphane-1 4 -yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 2-((5 4 -cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4-yl)methyl)-4-methoxy-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 2-((5 4 -cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 -yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 2-((5 4 -cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 -yl)methyl)-4-ethoxy-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 2-((5 4 -cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 -yl)methyl)-4-fluoro-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 2-((5 4 -cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 -yl)methyl)-1-((oxetan-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid; 2-((5 5 -chloro-3-oxa-2,5(2,6)-dipyridina-1(1,3)-benzenacyclononaphane-1 4 -yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 2-((5 5 -cyano-3-oxa-2,5(2,6)-dipyridina-1(1,3)-benzenacyclononaphane-1 4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 2-((5 5 -cyano-3-oxa-2(2,6),5(2,3)-dipyridina-1(1,3)-benzenacyclooctaphane-1 4 -yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 2-((5 5 -chloro-3-oxa-2(2,6),5(2,3)-dipyridina-1(1,3)-benzenacyclooctaphane-1 4 -yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 2-((5 4 -chloro-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphan-6-ene-1 4 -yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 2-((5 4 -cyano-6-hydroxy-1 6 -methyl-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 -yl)methyl)-4-fluoro-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 2-((5 4 -cyano-6-hydroxy-1 6 -methyl-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 -yl)methyl)-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 2-((5 4 -chloro-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 2-((5 4 -Chloro-6-hydroxy-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 -yl)methyl)-4-methoxy-1-((oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 2-((5 4 -chloro-6-oxo-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 -yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; and 2-((5 4 -cyano-7-hydroxy-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane-1 4 -yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; or a pharmaceutically acceptable salt thereof.

[0076] In linker A, the left end group shown is attached to the X ring, and the right end group is attached to the Y ring. 1 , Y 2 , and Y 7 For example, in the -CH(OH)CHCH- group, the carbon substituted with the hydroxy group is attached to the X ring. In the linker B, the left terminal group is attached to the X ring and the right terminal group is attached to the Y ring. 3 It is attached to the containing ring.

[0077] The term "halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0078] "C1~C nThe term "alkyl" refers to a straight or branched chain saturated hydrocarbon containing 1 to n carbon atoms. Examples of C1-C4 alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, and tert-butyl. Examples of C1-C3 alkyl groups include, but are not limited to, methyl, ethyl, and propyl. A C1-C2 alkyl group is methyl or ethyl.

[0079] The term "C3-C4 alkylene" refers to a 3 or 4 carbon alkyl chain attached at each end. The term "C3-C4 alkenylene" refers to a 3 or 4 carbon alkenyl chain attached at each end.

[0080] "C1~C n The term "haloalkyl" refers to a C1-C3 alkyl group, as defined herein, substituted with one or more halogens. n It refers to an alkyl group. Examples of C1-C3 haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, and pentafluoroethyl.

[0081] "C1~C n The term "alkoxy" refers to a straight or branched chain saturated hydrocarbon containing 1 to n carbon atoms linked through an oxygen atom, i.e., refers to —O(alkyl). Examples of C1-C4 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, and butoxy.

[0082] "C1~C n The term "haloalkoxy" refers to a C1-C3 alkyl group, as defined herein, substituted with one or more halogens. n It refers to an alkoxy group. Examples of C1-C3 haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, and pentafluoroethoxy.

[0083] The term "C3-C5 cycloalkyl" refers to a monocyclic saturated carbocyclic ring containing from 3 to 5 carbon atoms, specifically cyclopropyl, cyclobutyl, or cyclopentyl.

[0084] The term "C4-C6 cycloalkyl" refers to a monocyclic saturated carbocyclic ring containing from 4 to 6 carbon atoms, specifically cyclobutyl, cyclopentyl, or cyclohexyl.

[0085] The term "heteroaryl" preferably refers to a monocyclic aromatic ring 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.

[0086] The term "C4-C6 heterocyclyl" refers to a 4-, 5-, or 6-membered monocyclic saturated ring containing one or more heteroatoms, for example, pyrrolidine.

[0087] The term "C4-C5 heterocyclyl" refers to a 4- or 5-membered monocyclic saturated ring containing one or more heteroatoms, for example, oxetane.

[0088] Formula I encompasses Formulas II, IIa, IIb, III, IIIa, and IIIb, and references to Formula I below, e.g., in methods of treatment and therapeutic uses, are also to be read as references to each and every one of these sub-formulae.

[0089] In another embodiment, there is provided a pharmaceutically acceptable composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient. In a preferred embodiment, the pharmaceutically acceptable composition is formulated for oral administration.

[0090] In another embodiment, a method of treating a patient for type II diabetes is provided, the method comprising administering to a patient in need thereof a pharmaceutically acceptable composition comprising an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and at least one of a pharmaceutically acceptable carrier, diluent, or excipient. In one embodiment, the pharmaceutically acceptable composition is formulated for oral administration. Preferably, the patient is human.

[0091] In another embodiment, there is provided a method of treating a patient for type II diabetes, the method comprising administering to a patient in need thereof an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the patient is human.

[0092] In another embodiment, there is provided a method of lowering blood glucose levels in a patient, the method comprising administering to a patient in need of treatment an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the patient is human.

[0093] In another embodiment, there is provided a method of treating hyperglycemia in a patient, the method comprising administering to a patient in need thereof an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the patient is human.

[0094] In another embodiment, there is provided a method of treating obesity in a mammal, the method comprising administering to a patient in need of treatment an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the patient is human.

[0095] In another embodiment, there is provided a method of treating nonalcoholic steatohepatitis (NASH) in a patient, the method comprising administering to a patient in need thereof an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the patient is human.

[0096] In one embodiment, there is provided a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in therapy.

[0097] In another embodiment, there is provided a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of type II diabetes.

[0098] In another embodiment, there is provided a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in lowering blood glucose levels.

[0099] In another embodiment, there is also provided a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of hyperglycemia.

[0100] In another embodiment, there is provided a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of obesity.

[0101] In another embodiment, there is also provided a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of NASH.

[0102] In one embodiment, there is provided the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of type II diabetes.

[0103] In one embodiment, there is provided the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for lowering blood glucose levels.

[0104] In one embodiment, there is provided the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of hyperglycemia.

[0105] In one embodiment, there is provided the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of obesity.

[0106] In one embodiment, there is provided the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of NASH.

[0107] The compounds of Formula I may be used in simultaneous, separate, or sequential combination with one or more additional therapeutic agents, including, but not limited to, metformin, thiazolidinediones, sulfonylureas, dipeptidyl peptidase 4 inhibitors, sodium glucose cotransporters, and ketohexokinase inhibitors.

[0108] In a preferred embodiment, the compound of formula I is administered orally. In a preferred embodiment, the compound of formula I is administered once daily. In another preferred embodiment, the therapeutic use is in humans.

[0109] As used herein, the term " pharmaceutically acceptable salt " refers to a salt of the compound of the present invention that is deemed acceptable for clinical and / or veterinary use. Examples of pharmaceutically acceptable salts and the general methodology 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.

[0110] The term "effective amount" refers to an amount or dose of a compound of Formula I, or a pharmaceutically acceptable salt thereof, that, upon single or multiple administration to a patient, provides the desired effect in the patient being diagnosed or treated. As a skilled artisan, the attending physician can readily determine an effective amount by using conventional techniques and observing results obtained under analogous circumstances. Factors to consider in determining the effective amount or dose of a compound include: whether the compound or a salt thereof is being administered; if used, the co-administration of other drugs; the size, age, and general health of the patient; the degree of involvement or severity of the disorder; the response of the individual patient; the mode of administration; the bioavailability characteristics of the administered preparation; the selected dosing regimen; and other relevant circumstances. The compounds of the present invention are effective at daily dosages falling within the range of about 0.01 to about 15 mg / kg of body weight.

[0111] As used herein, the terms "treating," "treat," or "treatment" refer to slowing, reducing, or reversing the progression or severity of an existing symptom, disorder, or condition, such as hyperglycemia, which may involve increased insulin secretion.

[0112] As used herein, the term "patient" includes mammals. The patient is preferably human.

[0113] The compound of formula I can be formulated as a pharmaceutical composition to be administered by any route that makes the compound bioavailable. Preferably, such a composition is for oral administration. Preferably, the pharmaceutical composition is formulated as a tablet, capsule, or solution. The tablet, capsule, or solution can contain the compound of formula I in an amount effective to treat a patient in need of treatment. Such pharmaceutical compositions and processes for their preparation are well known in the art (e.g., "Remington: The Science and Practice of Pharmacy," A. Adejare Editor, 23 rd Ed., 2020, Elsevier Science).

[0114] Compounds of Formula I and their pharmaceutically acceptable salts are useful in the therapeutic applications of the present invention, with certain stereoconfigurations being preferred.

[0115] The compounds of the present invention include

[0116] [ka] or a pharmaceutically acceptable salt thereof.

[0117] While the present invention contemplates all individual enantiomers, mixtures thereof, and racemates, the compounds of Formula IIa and Formula IIIa, and pharmaceutically acceptable salts thereof, are especially preferred.

[0118] Individual enantiomers can be separated or resolved by one of skill in the art at any convenient point in the synthesis of the compounds of the invention by methods such as selective crystallization techniques or chiral chromatography (see, 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) (see, e.g., T.A. Berger; "Supercritical Fluid Chromatography Primer," Agilent Technologies, July 2015).

[0119] Pharmaceutically acceptable salts of the compounds of the present invention can be formed, for example, by reacting a compound of formula I with an appropriate pharmaceutically acceptable base in a suitable solvent under standard conditions well known in the art (see, for example, Bastin, RJ, et al.; Org. Process. Res. Dev., 4, 427-435, 2000 and Berge, SM, et al.; J. Pharm. Sci., 66, 1-19, 1977).

[0120] 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, "AIBN" refers to azobisisobutyronitrile, "BHT" refers to butylated hydroxytoluene, "cAMP" refers to cyclic adenosine-3',5'-monophosphate, "DCM" refers to dichloromethane or methylene chloride, "DIPEA" refers to N,N-diisopropylethylamine, "DMEA" refers to 2-dimethylaminoethanol, "DMF" refers to N,N-dimethylformamide, "DMSO" refers to dimethyl sulfoxide, and "EC 50 " is the concentration of drug that produces a 50% response of target activity compared to a given positive control compound (absolute EC 50), "ES / MS" refers to electrospray mass spectrometry, "EtOAc" refers to ethyl acetate, "EtOH" refers to ethanol or ethyl alcohol, "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, and "HEPES" refers to 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid. "MeOH" refers to methanol or methyl alcohol, "min" refers to minutes, "MTBE" refers to methyl tert-butyl ether, "RT" refers to room temperature, and "S N "Ar" refers to a nucleophilic aromatic substitution, "TBAF" refers to tetrabutylammonium fluoride, "TEA" refers to triethylamine, "TFA" refers to trifluoroacetic acid, "THF" refers to tetrahydrofuran, and "TMSCN" refers to trimethylsilyl cyanide.

[0121] The compounds of the present invention can be prepared by a variety of procedures, some of which are illustrated in the following preparations and examples. Specific synthetic steps for each of the described routes may be combined in different ways to prepare the compounds of the present invention or their salts. The products of each of the following steps 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 can be separated or resolved at any convenient point in the synthesis by methods such as selective crystallization techniques or chiral chromatography (see, for example, 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). The following preparations and examples are provided to further illustrate the present invention without limiting its scope.

[0122] Scheme 1

[0123] [ka]

[0124] Scheme 1 shows two routes for preparing intermediate 5, which is used to prepare compounds of the invention. In the first route, alkyl bromide 1 is reacted with trimethylsilyl cyanide and TBAF to give intermediate 2, which undergoes acidic hydrolysis in the presence of an alcohol (R—OH) at elevated temperature to give intermediate 5. In the second route, acid intermediate 3 is iodinated with iodobenzene diacetate, palladium acetate, and iodine at elevated temperature to give intermediate 4, which undergoes Fischer esterification in the presence of an alcohol R—OH to give intermediate 5.

[0125] Scheme 2

[0126] [ka]

[0127] Scheme 2 illustrates the preparation of intermediate 9, which is used to prepare compounds of the present invention. Aryl fluoride 6 can be reacted with amine 7 and a carbonate base at elevated temperature to form a nucleophilic aromatic substituent (S N Ar) to give intermediate 8, which is then reduced to diamine intermediate 9 using a palladium catalyst and hydrogen gas.

[0128] Scheme 3

[0129] [ka]

[0130] Scheme 3 shows the preparation of intermediate 14 via two routes. In the first route, aryl difluoride 10 is reacted with amine 7 using a carbonate base at elevated temperature. N Ar to give intermediate 12, which is then reacted with the sodium alkoxide of alcohol 11 to give intermediate 13. N Upon receiving Ar, intermediate 14 is generated. In the second pathway, these two steps are carried out in the reverse order.

[0131] Scheme 4

[0132] [ka]

[0133] Scheme 4 illustrates the preparation of intermediates 19 and 20 used to prepare compounds of the invention. Intermediate 15 is brominated with N-bromosuccinimide and AIBN at elevated temperature to give intermediate 16, which is then alkylated with intermediate 25 using a carbonate base to give halogenated intermediate 17. Intermediate 17 undergoes Suzuki coupling with an allylboronic acid pinacol ester using a palladium catalyst and a carbonate base at elevated temperature to give allyl intermediate 18, which then undergoes a cross-coupling reaction with aryl halide 5 using a palladium catalyst and an organic base at elevated temperature (see Scheme 1) to give olefin intermediate 19. The alkene can be reduced under hydrogen gas using platinum oxide and acetic acid or a rhodium catalyst to give alkane intermediate 20.

[0134] Scheme 5

[0135] [ka]

[0136] Scheme 5 shows the preparation of intermediates 23 and 24 used to prepare compounds of the invention. Alkyl halide 41 is alkylated with intermediate 25 using a carbonate base to give intermediate 42, which is reduced using NaBH to give alcohol 43. Alcohol 43 is then oxidized using manganese dioxide to give aldehyde 21, which is then reacted with vinylmagnesium bromide to give alkene intermediate 22. Intermediate 22 undergoes a cross-coupling reaction with aryl halide 5 using a palladium catalyst and an organic base at elevated temperature (see Scheme 1) to give ketone intermediate 23. The ketone can then be reduced using NaBH to give alcohol intermediate 24.

[0137] Scheme 6

[0138] [ka]

[0139] Scheme 6 shows the preparation of intermediates 29, 30, and 33 used to prepare compounds of the invention. Intermediate 17 (see Scheme 4) first undergoes cross-coupling with olefin 31 using a palladium catalyst and a phosphate base at elevated temperature to give intermediate 32, which then undergoes another cross-coupling reaction with aryl halide 5 (see Scheme 1) using a palladium catalyst, a carbonate base, and silver oxide at elevated temperature to give intermediate 33.

[0140] Alternatively, intermediate 17 is coupled with 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane using a palladium catalyst and a phosphate base at elevated temperature to give intermediate 26, which is then converted under acidic conditions to aldehyde intermediate 27. Intermediate 27 is reacted with vinylmagnesium bromide to give alkene intermediate 28, which is then cross-coupled with aryl halide 5 (see Scheme 1) at elevated temperature using a palladium catalyst and an organic base to give intermediate 29. The ketone is then optionally reduced using NaBH to give intermediate 30.

[0141] Scheme 7

[0142] [ka]

[0143] Scheme 7 illustrates the preparation of compounds of the present invention starting from dihalo intermediate 34. Intermediate 34 can be cyclized to intermediate 36 via boronate ester intermediate 35, either in one pot or in two separate steps, by first coupling with bis(pinacolato)diboron using a palladium catalyst and a potassium carboxylate base, followed by an intramolecular cross-coupling reaction using a palladium catalyst and a phosphate base. Acid intermediate 36 is then hydrolyzed with an organic base in an aqueous / organic solvent mixture to give intermediate 37. For example, amide coupling with diamino intermediate 9 and acid intermediate 37 using HATU and an organic base gives intermediate 38, which is cyclized with acetic acid at elevated temperature to give intermediate 39. For example, when "W" represents a methyl or ethyl ester, hydrolysis using a guanidine base gives compound 40. For example, when "W" represents bromine, compound 40 can be obtained via carbonylation using a palladium catalyst, phenyl formate, and an organic base at elevated temperature.

[0144] Preparation 1 3,5-Difluoro-4-nitro-benzoic acid methyl ester

[0145] [ka]

[0146] 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. The reaction mixture was stirred at room temperature for 3 h, and then the temperature was gradually increased to 65° C. over 2 h. The mixture was filtered and concentrated under reduced pressure. The residue was dissolved in EtOAc (150 mL), and the organics were washed with saturated aqueous sodium bicarbonate (50 mL) and saturated aqueous NaCl (50 mL). The organic phase was dried over NaSO, 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 of the title compound (66%). 1H-NMR (400MHz, CDCl3) δ7.78(d,2H),4.0(s,3H).

[0147] Preparation 2 3-Fluoro-4-nitro-5-[[(2S)-oxetan-2-ylmethyl]amino]benzoic acid methyl ester

[0148] [ka]

[0149] A mixture of [(2S)-oxetan-2-yl]methanamine (545 mg, 6.13 mmol), methyl 3,5-difluoro-4-nitrobenzoate (1.4 g, 6.1 mmol), and potassium carbonate (1.7 g, 12 mmol) in ACN (14 mL) was stirred at 70 °C for 16 h. The reaction mixture was diluted with water (14 mL) and extracted with EtOAc (3 × 14 mL). The combined organic layers were washed with saturated aqueous NaCl (14 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography using a gradient of 0 to 30% EtOAc in petroleum ether to give 1.68 g of the title compound (79%). ES-MS m / z 285 (M+H).

[0150] Preparation 3 (S)-3-Ethoxy-4-nitro-5-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester

[0151] [ka]

[0152] Methyl 3-fluoro-4-nitro-5-[[(2S)-oxetan-2-ylmethyl]amino]benzoate (0.50 g, 1.7 mmol) was dissolved in THF (5 mL) and EtOH (1 mL). The reaction vessel was flushed with nitrogen, and the mixture was cooled in an ice bath. Then, sodium ethoxide in EtOH (2.68 M, 1.0 mL, 2.7 mmol) was added over approximately 10 min. After an additional 30 min, 1 M aqueous potassium phosphate dihydrate (25 mL) was added, and the mixture was allowed to stand at ambient temperature overnight. EtOAc (50 mL) was added, and the phases were separated. The organics were concentrated under reduced pressure, and the residue was coevaporated twice with THF (50 mL). The resulting residue was treated with sodium methoxide (0.5 M, 5.0 mL, 2.5 mmol) in MeOH. After 75 min, 1 M aqueous potassium phosphate monohydrate (25 mL) was added, followed by EtOAc (50 mL). The phases were separated and the organics were concentrated under reduced pressure to give the crude product, which was dissolved in DCM and purified by chromatography on silica (0-10% EtOAc in DCM) to give the title compound (0.29 g, 51%) as an orange oil. ES-MS m / z 311 (M+H) + .

[0153] Preparation 4 (S)-4-Amino-3-ethoxy-5-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester

[0154] [ka]

[0155] A solution of (S)-methyl 3-ethoxy-4-nitro-5-((oxetan-2-ylmethyl)amino)benzoate (0.29 g, 0.88 mmol) in EtOAc (5 mL) was charged into a glass tube, followed by a small amount of additional palladium on charcoal slurry in EtOAc (10 wt % dry basis, 57.5% water, 0.05 g, 0.02 mmol). The tube was attached to the inside of a glass pressure vessel, which was purged twice with 50 psi of hydrogen and then refilled with 50 psi of hydrogen. The mixture was stirred for 24 hours at ambient temperature and then vented. The contents of the tube were filtered through a plug of diatomaceous earth and rinsed with additional EtOAc (15 mL). The filtrate was concentrated under a stream of nitrogen at 40° C. to give the title compound (258 mg, quantitative yield) as an off-white solid. ES-MS m / z 281 (M+H) + .

[0156] Preparation 5 3-Fluoro-5-methoxy-4-nitro-benzoic acid methyl ester

[0157] [ka]

[0158] To a solution of methyl 3,5-difluoro-4-nitrobenzoate (0.3 g, 1.38 mmol) in MeOH (4 mL) was added a solution of sodium methylate (25% by weight in MeOH, 0.33 mL, 1.44 mmol), and the reaction mixture was heated at 65° C. for 2.5 h. The reaction mixture was cooled to room temperature, then water was added, and the mixture was extracted with EtOAc (3×5 mL). The combined organics were washed with saturated aqueous NaCl, dried over MgSO4, then filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using a gradient of EtOAc in heptane (0-10%) to afford 245 mg (76%) of the title compound as a yellow oil. ES-MS m / z 230 (M+H).

[0159] Preparation 6 (S)-3-Methoxy-4-nitro-5-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester

[0160] [ka]

[0161] The title compound was prepared essentially as described in Preparation 2 using methyl 3-fluoro-5-methoxy-4-nitro-benzoate. The residue was purified by silica gel chromatography using a gradient of 5-30% EtOAc in DCM to give the title compound. ES-MS m / z 296 (M+H).

[0162] Preparation 7 4-Amino-3-fluoro-5-[[(2S)-oxetan-2-ylmethyl]amino]benzoic acid methyl ester

[0163] [ka]

[0164] To a solution of methyl 3-fluoro-4-nitro-5-[[(2S)-oxetan-2-ylmethyl]amino]benzoate (1.68 g, 4.84 mmol) in MeOH (17 mL) was added Lindlar's catalyst containing 5% palladium (600 mg, 0.28 mmol). The reaction mixture was stirred at room temperature under an atmosphere of hydrogen gas for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to give 1.4 g of the title compound (100%), which was carried forward without further purification. ES-MS m / z 255 (M+H).

[0165] Preparation 8 4-Amino-3-methoxy-5-[[(2S)-oxetan-2-yl]methylamino]benzoic acid methyl ester

[0166] [ka]

[0167] The title compound was prepared essentially as described in Preparation 7 using (S)-3-methoxy-4-nitro-5-((oxetan-2-ylmethyl)amino)methyl benzoate. The title compound was carried forward without further purification. ES-MS m / z 267 (M+H).

[0168] Preparation 9 6-Bromo-5-(bromomethyl)picolinonitrile

[0169] [ka]

[0170] A solution of 6-bromo-5-methyl-pyridine-2-carbonitrile (10 g, 51 mmol), N-bromosuccinimide (16 g, 91 mmol), and AIBN (1.1 g, 6.3 mmol) in 1,2-dichloroethane (170 mL) was stirred at 85 °C for 4 hours. The solution was concentrated in vacuo. To the residue was added THF (100 mL), diethyl phosphite (3.4 mL, 26 mmol), and DIPEA (9.0 mL, 52 mmol). The mixture was stirred at room temperature for 1 hour, then diluted with EtOAc (200 mL) and washed with water (100 mL). The aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 50% EtOAc in hexanes to give 13.6 g of the title compound (97%). 1H NMR (400MHz, CDCl3) δ7.94(d,J=8Hz,1H),7.70(d,J=8Hz,1H),4.59(s,2H).

[0171] Preparation 10 6-Bromo-5-(((6-chloropyridin-2-yl)oxy)methyl)picolinonitrile

[0172] [ka]

[0173] A suspension of 6-bromo-5-(bromomethyl)picolinonitrile (13.6 g, 49.4 mmol), 6-chloropyridin-2-ol (7.5 g, 58 mmol), and potassium carbonate (13.7 g, 98.8 mmol) in ACN (300 mL) was stirred at room temperature for 3 h. The suspension was filtered, and the solid was rinsed with ACN. The filtrate was concentrated, and the residue was purified by silica gel chromatography using a gradient of 20-80% EtOAc in hexanes to give 8.8 g of the title compound (55%). ES-MS m / z 325 (M+H).

[0174] Preparation 11 6-Allyl-5-(((6-chloropyridin-2-yl)oxy)methyl)picolinonitrile

[0175] [ka]

[0176] To a mixture of 6-bromo-5-(((6-chloropyridin-2-yl)oxy)methyl)picolinonitrile (5.9 g, 18 mmol), bis(triphenylphosphine)palladium(II) dichloride (640 mg, 0.91 mmol), and potassium carbonate (5.0 g, 36 mmol) was added a solution of allylboronic acid pinacol ester (5.3 mL, 27 mmol) in 1,4-dioxane (60 mL). Water (1.6 mL, 89 mmol) was added, and the mixture was stirred at 90 °C for 3 h. The mixture was diluted with EtOAc (150 mL) and washed with water (150 mL). The aqueous layer was extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 45% EtOAc in hexanes to give 2.4 g of the title compound (46%). ES-MS m / z 286 (M+H).

[0177] Preparation 12 2-(4-Bromo-2-iodo-5-methylphenyl)acetic acid

[0178] [ka]

[0179] A mixture of 2-(4-bromo-3-methyl-phenyl)acetic acid (14.7 g, 64.0 mmol), iodobenzene diacetate (15.6 g, 48.5 mmol), palladium acetate (1.5 g, 6.9 mmol), and iodine (12.2 g, 48.3 mmol) in DMF (275 mL) was stirred at 60 °C for 16 h protected from light. The mixture was diluted with EtOAc (200 mL) and washed with half-saturated aqueous sodium thiosulfate (500 mL). The pH of the aqueous layer was adjusted to pH = 1 and then extracted with EtOAc (2 × 100 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a 0-75% gradient of 1% AcOH in EtOAc in hexanes to give 19.8 g of the title compound (87%). ES-MS m / z 372 and 374 (M+water).

[0180] Preparation 13 2-(4-bromo-2-iodo-5-methylphenyl)acetic acid ethyl ester

[0181] [ka]

[0182] A mixture of 2-(4-bromo-2-iodo-5-methylphenyl)acetic acid (19.7 g, 55.5 mmol), EtOH (110 mL), and concentrated sulfuric acid (0.2 mL) was stirred at 75 °C for 7 h. The reaction mixture was diluted with EtOAc (200 mL) and washed with half-saturated aqueous sodium bicarbonate solution (100 mL). The aqueous layer was extracted with EtOAc (100 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 75% EtOAc in hexanes to give 18.0 g of the title compound (85%). ES-MS m / z 400 and 402 (M+water).

[0183] Preparation 14 2-(4-bromo-2-(3-(3-(((6-chloropyridin-2-yl)oxy)methyl)-6-cyanopyridin-2-yl)propyl)-5-methylphenyl)acetic acid ethyl ester

[0184] [ka]

[0185] To a solution of 6-allyl-5-(((6-chloropyridin-2-yl)oxy)methyl)picolinonitrile (1.85 g, 6.48 mmol) in THF (32 mL) was added 9-borabicyclo[3.3.1]nonane (14 mL, 7.0 mmol, 0.5 M in THF). The mixture was stirred at room temperature for 2 hours. To this solution was added a solution of ethyl 2-(4-bromo-2-iodo-5-methylphenyl)acetate (2.5 g, 6.5 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (276 mg, 0.373 mmol), potassium carbonate (2.69 g, 19.5 mmol), and water (1.2 mL, 67 mmol). The mixture was stirred at room temperature for 3 hours. An additional portion of water (0.6 mL, 34 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (220 mg, 0.30 mmol) was added, and the mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc (100 mL) and washed with 1:2 saturated aqueous NaCl:water (30 mL). The aqueous layer was extracted with EtOAc (30 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-60% EtOAc in hexanes to give 2.0 g of the title compound (58%). ES-MS m / z 542 and 544 (M+H).

[0186] Preparation 15 2-(2-(3-(3-(((6-chloropyridin-2-yl)oxy)methyl)-6-cyanopyridin-2-yl)propyl)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid ethyl ester

[0187] [ka]

[0188] A solution of ethyl 2-(4-bromo-2-(3-(3-(((6-chloropyridin-2-yl)oxy)methyl)-6-cyanopyridin-2-yl)propyl)-5-methylphenyl)acetate (1.9 g, 3.5 mmol), bis(pinacolato)diboron (1.4 g, 5.5 mmol), bis(triphenylphosphine)palladium(II) dichloride (286 mg, 0.407 mmol), and potassium 2-ethylhexanoate (1.95 g, 10.7 mmol) in 1,4-dioxane (15 mL) was stirred at 40° C. for 15.5 hours. The mixture was diluted with EtOAc (50 mL) and washed with water (10 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 reverse-phase chromatography using a gradient of 0-100% ACN in 10 mM aqueous ammonium bicarbonate containing 5% MeOH to give 420 mg of the title compound (20%). ES-MS m / z 590 (M+H).

[0189] Preparation 16 2-(5 6 -Cyano-1 6 -methyl-3-oxa-2(2,6),5(3,2)-dipyridina-1(1,3)-benzenacyclooctaphane-1 4 -yl)acetic acid ethyl ester

[0190] [ka]

[0191] To a mixture of ethyl 2-(2-(3-(3-(((6-chloropyridin-2-yl)oxy)methyl)-6-cyanopyridin-2-yl)propyl)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (420 mg, 0.712 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd Gen2, 57 mg, 0.070 mmol) was added 1,4-dioxane (14 mL). A solution of potassium phosphate (450 mg, 2.12 mmol) in water (3.5 mL) was then added, and the mixture was stirred at 50°C for 45 minutes. The mixture was diluted with EtOAc (30 mL) and washed with water (30 mL). The aqueous layer was extracted with EtOAc (25 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-100% EtOAc in hexanes to give 221 mg of the title compound (71%). ES-MS m / z 428 (M+H).

[0192] Preparation 17 2-(5 6 -Cyano-1 6 -methyl-3-oxa-2(2,6),5(3,2)-dipyridina-1(1,3)-benzenacyclooctaphane-1 4 -yl)acetic acid

[0193] [ka]

[0194] 2-(5-Methoxyphenyl)-2-(2-methyl-2-propanol) in ACN (2.6 mL), water (0.9 mL), and 1,4-dioxane (1.0 mL) 6 -Cyano-1 6 -methyl-3-oxa-2(2,6),5(3,2)-dipyridina-1(1,3)-benzenacyclooctaphane-1 4To a solution of ethyl (4-yl)acetate (220 mg, 0.514 mmol) was added 1,5,7-triazabicyclo[4.4.0]dec-5-ene (233 mg, 1.64 mmol). The mixture was stirred at 45° C. for 2 h, then quenched with aqueous citric acid (1 M, 4 mL) and diluted with EtOAc (10 mL). The aqueous layer was stripped and extracted with EtOAc (2×5 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 238 mg of the title compound (>100%), which was carried forward without further purification. ES-MS m / z 400 (M+H).

[0195] Preparation 18 (S)-4-(2-(5 6 -Cyano-1 6 -methyl-3-oxa-2(2,6),5(3,2)-dipyridina-1(1,3)-benzenacyclooctaphane-1 4 -yl)acetamido)-3-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester

[0196] [ka]

[0197] 2-(5 mL) in DMF (5 mL) 6 -Cyano-1 6 -methyl-3-oxa-2(2,6),5(3,2)-dipyridina-1(1,3)-benzenacyclooctaphane-1 4To a solution of (2S)-oxetan-2-yl)acetic acid (200 mg, 0.5 mmol) and methyl 4-amino-3-[[(2S)-oxetan-2-yl]methylamino]benzoate (prepared essentially as described in WO 2020 / 263695, 135 mg, 0.570 mmol), pyridine (0.40 mL, 4.9 mmol) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (1.7 M in THF, 0.75 mL, 1.3 mmol) were added. The mixture was stirred at room temperature for 2 hours and then diluted with water (20 mL). The resulting white solid was collected by vacuum filtration. The solid was washed with water and dried under vacuum to give 247 mg of the title compound (80%). ES-MS m / z 618 (M+H).

[0198] Preparation 19 (S)-2-((5 6 -Cyano-1 6 -methyl-3-oxa-2(2,6),5(3,2)-dipyridina-1(1,3)-benzenacyclooctaphane-1 4 -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester

[0199] [ka]

[0200] (S)-4-(2-(5)-(5-chloro-2-methyl-2-propanol) in 1,2-dichloroethane (2.0 mL) and acetic acid (2.0 mL) 6 -Cyano-1 6 -methyl-3-oxa-2(2,6),5(3,2)-dipyridina-1(1,3)-benzenacyclooctaphane-1 4 A solution of methyl ((oxetan-2-yl)acetamido)-3-((oxetan-2-ylmethyl)amino)benzoate (247 mg, 0.399 mmol) was stirred at 50° C. for 16 h. The crude reaction solution was loaded onto silica and purified by silica gel chromatography using a gradient of 0-100% EtOAc in DCM to give 186 mg of the title compound (78%). ES-MS m / z 600 (M+H).

[0201] Preparation 22 4-[(6-bromo-2-pyridyl)oxymethyl]-3-iodobenzonitrile

[0202] [ka]

[0203] To a mixture of 4-(bromomethyl)-3-iodobenzonitrile (2.88 g, 8.93 mmol), 6-bromopyridin-2-ol (1.10 g, 6.30 mmol), and silver carbonate (5.1 g, 18.0 mmol) was added 1,4-dioxane (50 mL). The reaction mixture was stirred at 60 °C for 15 h, then diluted with EtOAc (50 mL) and filtered through diatomaceous earth. The filtrate was washed with water (2 × 50 mL) and saturated aqueous sodium chloride solution (50 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradient of 5–30% EtOAc in hexane to give 2.8 g of the title compound (76%). ES-MS m / z 415 and 417 (M+H).

[0204] Preparation 23 3-Allyl-4-[(6-bromo-2-pyridyl)oxymethyl]benzonitrile

[0205] [ka]

[0206] Under nitrogen, to a solution of 4-[(6-bromo-2-pyridyl)oxymethyl]-3-iodobenzonitrile (3 g, 7.2 mmol) in 1,4-dioxane (155 mL) was added potassium carbonate (12 g, 86.8 mmol), bis(triphenylphosphine)palladium(II) dichloride (507 mg, 0.7 mmol), and allylboronic acid pinacol ester (2.1 mL, 10.9 mmol). The mixture was stirred at 80 °C for 6 h, then 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 silica gel chromatography using a gradient of 0-10% EtOAc in hexanes to give 1.4 g of the title compound (59%). ES-MS m / z 330 (M+H).

[0207] Preparation 24 2-(4-Bromo-2-iodophenyl)acetonitrile

[0208] [ka]

[0209] To a solution of 4-bromo-1-(bromomethyl)-2-iodobenzene (10 g, 25.5 mmol) and TMSCN (4.5 mL, 3.36 g, 33 mmol) in ACN (220 mL) was slowly added tetrabutylammonium fluoride hydrate (1 M solution in THF, 33 mL, 33 mmol) at 0 °C. The mixture was stirred at 40 °C for 4 h, and the solvent was removed under vacuum. The residue was dissolved in HO and extracted three times with EtOAc. The organic layer was washed with saturated aqueous NaCl, dried over MgSO, filtered, and evaporated under vacuum. To the residue was added TMSCN (3 mL, 2.07 g, 22.0 mmol) in ACN (220 mL), followed by the slow addition of tetrabutylammonium fluoride hydrate (20 mL, 20 mmol, 1 M) at 0 °C. The mixture was stirred at 40 °C for 7 h, and the solvent was then removed under vacuum. The residue was dissolved in HO and extracted three times with EtOAc. The organic layer was washed with saturated aqueous NaCl, dried over MgSO, filtered, and evaporated in vacuo. The crude mixture was purified by silica gel chromatography using a gradient of 0-15% EtOAc in heptane to afford the title compound (6.13 g, 74%) as a white solid. ES-MS m / z 322 (M+H).

[0210] Preparation 25 2-(4-bromo-2-iodo-phenyl)acetic acid ethyl ester

[0211] [ka]

[0212] Sulfuric acid (15 mL, 267 mmol) was slowly added to a suspension of 2-(4-bromo-2-iodophenyl)acetonitrile (6.13 g, 19.0 mmol) in EtOH (57 mL). The colorless solution was stirred at 80 °C for 24 h, then quenched with NaHCO3 until pH = 7-8, and the product was extracted three times with EtOAc. The organic layer was washed with saturated aqueous NaCl, dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified by silica gel chromatography using a gradient of 0-10% EtOAc in heptane to give the title compound (5.47 g, 78%) as a yellow oil. ES-MS m / z 369 (M+H).

[0213] Preparation 26 2-[4-bromo-2-[(E)-3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano-phenyl]prop-1-enyl]phenyl]acetic acid ethyl ester

[0214] [ka]

[0215] To a solution of 3-allyl-4-[(6-bromo-2-pyridyl)oxymethyl]benzonitrile (1.4 g, 4.3 mmol), ethyl 2-(4-bromo-2-iodo-phenyl)acetate (2 g, 5.4 mmol), and triethanolamine (TEA) (1.2 mL, 8.6 mmol) in DMF (15 mL) was added palladium(II) acetate (48 mg, 0.21 mmol) and (dicyclohexylphosphino)biphenyl (150 mg, 0.43 mmol). The solution was degassed with nitrogen and stirred at 90 °C for 18 h. The mixture was filtered through diatomaceous earth and then diluted with EtOAc and water. The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 100% DCM in heptane to give 1.1 g of the title compound (45%). ES-MS m / z 572 (M+H).

[0216] Preparation 27 2-[4-bromo-2-[3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano-phenyl]propyl]phenyl]acetic acid ethyl ester

[0217] [ka]

[0218] To a solution of ethyl 2-[4-bromo-2-[(E)-3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano-phenyl]prop-1-enyl]phenyl]acetate (1.1 g, 1.9 mmol) and acetic acid (0.011 mL, 0.2 mmol) in EtOAc (10 mL) was added platinum(IV) oxide (44 mg, 0.20 mmol), and the mixture was stirred at room temperature under a hydrogen balloon for 16 h. The mixture was filtered through diatomaceous earth, and the filtrate was diluted with EtOAc and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-100% DCM in heptane to give 0.49 g of the title compound (44%). ES-MS m / z 573 (M+H).

[0219] Preparation 28 2-(5 4 -cyano-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 -yl)acetic acid ethyl ester

[0220] [ka]

[0221] To a degassed solution of ethyl 2-[4-bromo-2-[3-[2-[(6-bromo-2-pyridyl)oxymethyl]-5-cyano-phenyl]propyl]phenyl]acetate (0.48 g, 0.8 mmol) and potassium acetate (247 mg, 2.5 mmol) in 1,4-dioxane (33.5 mL) was added bis(pinacolato)diboron (234 mg, 0.9 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride DCM complex (35 mg, 0.04 mmol). The mixture was stirred at 100 °C for 4 h and then filtered through diatomaceous earth and diluted with EtOAc. The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 100% DCM in heptane to give 90 mg of the title compound (30%). ES-MS m / z 413 (M+H).

[0222] Preparation 29 2-(5 4 -cyano-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 -yl)acetic acid

[0223] [ka]

[0224] 2-(5 mL) in ACN (6 mL) and water (4 mL) 4 -cyano-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 To a solution of ethyl (2-hydroxybenzoyl)acetate (90 mg, 0.2 mmol) was added 1,3,4,6,7,8-hexahydro-2h-pyrimido[1,2-a]pyrimidine (100 mg, 0.7 mmol). The mixture was stirred at 45 °C for 2 h, then quenched with formic acid to pH 6-7 and extracted with chloroform / isopropanol (3:1). The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 85 mg of the title compound (99%). ES-MS m / z 385 (M+H).

[0225] Preparation 30 (S)-4-(2-(5 4 -cyano-3-dioxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane-1 4 -yl)acetamido)-3-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester

[0226] [ka]

[0227] 2-(5 4 -cyano-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 To a solution of (2S)-oxetan-2-yl)acetic acid (85 mg, 0.22 mmol), methyl 4-amino-3-[[(2S)-oxetan-2-yl]methylamino]benzoate (55 mg, 0.23 mmol), HATU (130 mg, 0.34 mmol), and DMF (2 mL) under nitrogen, TEA (92 μL, 0.66 mmol) was added. The mixture was stirred at room temperature for 1.5 hours, then quenched with water and diluted with EtOAc. The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 127 mg of the title compound (97%). ES-MS m / z 603 (M+H).

[0228] Preparation 31 (S)-2-((5 4 -cyano-3-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 ester

[0229] [ka]

[0230] (S)-4-(2-54 -cyano-3-oxa-2(2,6)-pyridino-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 A solution of methyl ((oxetan-2-yl)acetamido)-3-((oxetan-2-ylmethyl)amino)benzoate (127 mg, 0.21 mmol) was stirred at 65° C. for 2 h and then concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-100% EtOAc in DCM to give 85 mg of the title compound (69%). ES-MS m / z 585 (M+H).

[0231] Preparation 32 2-(4-bromo-2-iodo-5-methylphenyl)acetic acid methyl ester

[0232] [ka]

[0233] To a solution of 2-(4-bromo-2-iodo-5-methylphenyl)acetic acid (0.20 g, 0.56 mmol) in MeOH (1.0 mL) was added concentrated sulfuric acid (0.09 mL) and the mixture was stirred at 80° C. for 1 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with saturated aqueous NaCl (2×20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 220 mg of the title compound (100%). 1 H NMR(d6-DMSO)δ8.00(s,1H),7.37(s,1H),3.77(s,2H),3.63(s,3H),2.28(s,3H).

[0234] Preparation 33 5-(Bromomethyl)-2-chloro-4-iodopyridine

[0235] [ka]

[0236] A solution of 2-chloro-4-iodo-5-methyl-pyridine (25 g, 97 mmol) and N-bromosuccinimide (19.3 g, 106 mmol) in ACN (483 mL) was passed through a photochemical flow reactor equipped with a 440-460 nM, 200 W lamp (reactor size = 15 m, 15 mL, flow rate = 1 mL / min, 25 °C). The reaction solution was diluted with water (300 mL) and extracted with EtOAc (2 × 300 mL). The combined organics were washed with saturated aqueous NaCl (2 × 300 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-100% EtOAc in petroleum ether to give 26.2 g of the title compound (74%). ES-MS m / z 333 (M+H).

[0237] Preparation 34 5-(((6-bromopyridin-2-yl)oxy)methyl)-2-chloro-4-iodopyridine

[0238] [ka]

[0239] 6-Bromopyridin-2-ol (2.8 g, 16 mmol) and silver carbonate (8.6 g, 31 mmol) were added to a solution of 5-(bromomethyl)-2-chloro-4-iodopyridine (5.0 g, 14 mmol) in toluene (73 mL). The mixture was stirred at 80 °C overnight. The crude suspension was concentrated, and the residue was purified by silica gel chromatography using a gradient of 0 to 100% EtOAc in petroleum ether to give 750 mg of the title compound (10%). ES-MS m / z 426 (M+H).

[0240] Preparation 35 4-Allyl-5-(((6-bromopyridin-2-yl)oxy)methyl)-2-chloropyridine

[0241] [ka]

[0242] To a mixture of 5-(((6-bromopyridin-2-yl)oxy)methyl)-2-chloro-4-iodopyridine (11 g, 25 mmol) and lithium chloride (3.2 g, 76 mmol) in 1,4-dioxane (130 mL) was added allyltributyltin (10 g, 29 mmol) and tetrakis(triphenylphosphine)palladium (1.5 g, 1.3 mmol). The mixture was stirred at 100 °C for 30 min. The reaction was quenched with saturated aqueous KF solution (300 mL) and extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with saturated aqueous NaCl solution (300 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0–8% EtOAc in petroleum ether to give 7.2 g of the title compound (80%). ES-MS m / z 341 (M+H).

[0243] Preparation 36 (E)-2-(4-bromo-2-(3-(5-(((6-bromopyridin-2-yl)oxy)methyl)-2-chloropyridin-4-yl)prop-1-en-1-yl)-5-methylphenyl)acetate methyl

[0244] [ka]

[0245] A mixture of 4-allyl-5-(((6-bromopyridin-2-yl)oxy)methyl)-2-chloropyridine (0.85 g, 2.4 mmol), methyl 2-(4-bromo-2-iodo-5-methylphenyl)acetate (1.2 g, 3.1 mmol), palladium acetate (54 mg, 0.24 mmol), 2-(cyclohexylphosphino)biphenyl (170 mg, 0.47 mmol), and TEA (0.67 mL, 4.8 mmol) in DMF (24 mL) was stirred at 90 °C for 1 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with saturated aqueous NaCl solution (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0–9% EtOAc in petroleum ether to give 519 mg of the title compound (33%). ES-MS m / z 581(M+H).

[0246] Preparation 37 2-(4-bromo-2-(3-(5-(((6-bromopyridin-2-yl)oxy)methyl)-2-chloropyridin-4-yl)propyl)-5-methylphenyl)acetic acid methyl ester

[0247] [ka]

[0248] A mixture of (E)-2-(4-bromo-2-(3-(5-(((6-bromopyridin-2-yl)oxy)methyl)-2-chloropyridin-4-yl)prop-1-en-1-yl)-5-methylphenyl)methyl acetate (0.41 g, 0.62 mmol) and chlorotris(triphenylphosphine)rhodium (0.34 g, 0.36 mmol) in MeOH (3 mL) was stirred overnight at 60 °C under an atmosphere of hydrogen gas (15 psi). The mixture was concentrated, then diluted with water (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with saturated aqueous NaCl (30 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0–18% EtOAc in petroleum ether to afford 196 mg of the title compound (49%). ES-MS m / z 583 (M+H).

[0249] Preparation 38 2-(5 6 -chloro-1 6 -methyl-3-oxa-2(2,6),5(3,4)-dipyridina-1(1,3)-benzenacyclooctaphane-1 4 -yl)acetic acid methyl

[0250] [ka]

[0251] A mixture of 2-(4-bromo-2-(3-(5-(((6-bromopyridin-2-yl)oxy)methyl)-2-chloropyridin-4-yl)propyl)-5-methylphenyl)methyl acetate (0.14 g, 0.22 mmol), potassium acetate (72 mg, 0.73 mmol), bis(pinacolato)diboron (96 mg, 0.36 mmol), and dichlorobis(tricyclophosphine)palladium (20 mg, 0.026 mmol) in 1,4-dioxane (5.0 mL) was stirred at 90° C. for 5 h. The mixture was diluted with water and extracted with EtOAc (3×30 mL). The combined organics were washed with saturated aqueous NaCl (2×30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0–13% EtOAc in petroleum ether to afford 38 mg of the title compound (33%). ES-MS m / z 423 (M+H).

[0252] Preparation 39 2-(5 6 -chloro-1 6 -methyl-3-oxa-2(2,6),5(3,4)-dipyridina-1(1,3)-benzenacyclooctaphane-1 4 -yl)acetic acid

[0253] [ka]

[0254] 2-(5-methyl-2-phenylpropanol) in ACN (3.5 mL), water (1.7 mL), and 1,4-dioxane (3.5 mL) 6 -chloro-1 6 -methyl-3-oxa-2(2,6),5(3,4)-dipyridina-1(1,3)-benzenacyclooctaphane-1 4 To a solution of methyl (-yl)acetate (165 mg, 0.323 mmol) was added aqueous lithium hydroxide (1 M, 0.7 mL, 0.7 mmol). The mixture was stirred at room temperature overnight and then quenched with 1 M citric acid solution to pH = 4. The solid was collected by vacuum filtration to give 95 mg of the title compound (68%). ES-MS m / z 409 (M+H).

[0255] Preparation 40 (S)-4-(2-(5 6 -chloro-1 6 -methyl-3-oxa-2(2,6),5(3,4)-dipyridina-1(1,3)-benzenacyclooctaphane-1 4 -yl)acetamido)-3-methoxy-5-((oxetan-2-ylmethyl)amino)benzoate methyl

[0256] [ka]

[0257] 2-(5 6 -chloro-1 6 -methyl-3-oxa-2(2,6),5(3,4)-dipyridina-1(1,3)-benzenacyclooctaphane-1 4 To a solution of 4-amino-3-methoxy-5-[[(2S)-oxetan-2-yl]methylamino]benzoic acid (95 mg, 0.22 mmol) and methyl 4-amino-3-methoxy-5-[[(2S)-oxetan-2-yl]methylamino]benzoate (80 mg, 0.29 mmol) was added HATU (150 mg, 0.39 mmol) and DIPEA (0.12 mL, 0.68 mmol). The mixture was stirred at room temperature overnight. The mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with saturated aqueous NaCl (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 272 mg, which was carried forward without further purification (>100%). ES-MS m / z 657 (M+H).

[0258] Preparation 41 (S)-2-((5 6 -chloro-1 6 -methyl-3-oxa-2(2,6),5(3,4)-dipyridina-1(1,3)-benzenacyclooctaphane-1 4 -yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester

[0259] [ka]

[0260] (S)-4-(2-(5)-(5-chloro-2-methyl-2-propanol) in 1,2-dichloroethane (1.0 mL) and acetic acid (1.0 mL) 6 -chloro-1 6 -methyl-3-oxa-2(2,6),5(3,4)-dipyridina-1(1,3)-benzenacyclooctaphane-1 4 A mixture of methyl 5-((oxetan-2-ylmethyl)acetamido)-3-methoxy-5-((oxetan-2-ylmethyl)amino)benzoate (272 mg, 0.25 mmol) was stirred at 55° C. overnight. The crude solution was concentrated under reduced pressure and azeotroped with 1:1 EtOAc:toluene (3×3 mL). The residue was purified by silica gel chromatography using a gradient of 0-3% MeOH in DCM to give 149 mg of the title compound (77%). ES-MS m / z 639 (M+H).

[0261] Preparation 42 (S)-2-((5 6 -Cyano-1 6 -methyl-3-oxa-2(2,6),5(3,4)-dipyridina-1(1,3)-benzenacyclooctaphane-1 4 -yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester

[0262] [ka]

[0263] (S)-2-((5 6 -chloro-1 6 -methyl-3-oxa-2(2,6),5(3,4)-dipyridina-1(1,3)-benzenacyclooctaphane-1 4To a mixture of methyl 4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (0.14 g, 0.18 mmol), zinc cyanide (0.11 g, 0.93 mmol), palladium trifluoroacetate (15 mg, 0.044 mmol), rac-2-(di-t-butylphosphino)-1,1'-binaphthyl (30 mg, 0.074 mmol), and zinc (40 mg, 0.60 mmol) was added N,N-dimethylacetamide (1.8 mL). The reaction was stirred at 80 °C overnight. The mixture was diluted with water (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organics were washed with saturated aqueous NaCl (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-33% EtOAc in petroleum ether to give 105 mg of the title compound (83%). ES-MS m / z 630 (M+H).

[0264] Preparation 43 2-chloro-6-[(4-chloro-2-iodo-phenyl)methoxy]pyridine

[0265] [ka]

[0266] A solution of 4-chloro-2-iodo-1-methyl-benzene (40.0 g, 159 mmol) and N-bromosuccinimide (27.3 g, 153 mmol) in ACN (500 mL) was transferred through a photochemical flow reactor (reactor size = 72 ft of 1 / 8" OD reaction tube, flow rate = 1.3 mL / min, 25 °C) equipped with a 4100 K, 42 W bulb. The product was added directly to a stirred suspension of 6-chloropyridin-2-ol (21.8 g, 168 mmol) and potassium carbonate (44.1 g, 319 mmol) in ACN (400 mL). The mixture was stirred at room temperature for 1 hour. The suspension was filtered and rinsed with ACN. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography using a gradient of 0-10% EtOAc in hexanes to give 45.8 g of the title compound (76%). ES-MS m / z 380 and 382 (M+H).

[0267] Preparation 44 5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]benzaldehyde

[0268] [ka]

[0269] To a mixture of 2-chloro-6-[(4-chloro-2-iodo-phenyl)methoxy]pyridine (25.0 g, 64.5 mmol) in THF (0.25 L) under nitrogen, n-butyllithium in hexane (36 mL, 90 mmol, 2.5 mol / L) was added over 30 min via syringe pump while cooling in a dry ice-acetone bath. After the addition was complete, the mixture was stirred for an additional 10 min, and then anhydrous DMF (10.0 mL, 129 mmol) was added. After 15 min, the flask was removed from the cooling bath and warmed with stirring for 30 min. Saturated aqueous ammonium chloride (50 mL) and water (50 mL) were added, and after 2.5 h, the mixture was transferred to a separatory funnel and diluted with EtOAc (0.5 L). The aqueous phase was drained and the organics washed with 10% aqueous lithium chloride (2 x 0.1 L) and saturated aqueous NaCl (0.1 L), then dried over MgSO, filtered, and partially concentrated under reduced pressure. When reduced to 0.1 L, the mixture was filtered and the filtrate was diluted with heptane and then concentrated under reduced pressure at 50 °C to give the crude title compound (81% pure, 18.51 g, 53.81 mmol) as a light brown oil. ES-MS m / z 282 and 284 (M+H). + .

[0270] Preparation 45 1-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]phenyl]prop-2-en-1-ol (racemic mixture)

[0271] [ka]

[0272] 5-Chloro-2-[(6-chloro-2-pyridyl)oxymethyl]benzaldehyde (81% purity, 18.51 g, 53.15 mmol) was dissolved in THF (0.20 L) in a round-bottom flask equipped with a stir bar, septum, and nitrogen inlet. The flask was cooled in an ice-water bath, and then a solution of vinylmagnesium bromide in THF (60 mL, 60 mmol, 1.0 mol / L) was added over 45 min using a syringe pump. Stirring was continued for an additional 30 min, and then saturated aqueous ammonium chloride (0.10 L) and saturated aqueous NaCl (0.10 L) were added to the mixture. The mixture was transferred to a separatory funnel and shaken with EtOAc (0.50 L). The aqueous phase was drained, and the organics were washed with 2 M aqueous potassium phosphate (0.10 L) followed by saturated aqueous NaCl (0.10 L), then dried over MgSO4, filtered, and concentrated under reduced pressure. When reduced to 0.10 L, the mixture was filtered, and the filtrate was diluted with heptane (0.20 L) and concentrated under reduced pressure. The crude product was purified by chromatography on silica (0-10% EtOAc in cyclohexane) to give the title compound (10.21 g, 62%) as a thick yellow oil. ES-MS m / z 292 and 294 (M-OH). + .

[0273] Preparation 46 2-[4-bromo-2-[3-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]phenyl]-3-oxo-propyl]phenyl]acetic acid ethyl ester

[0274] [ka]

[0275] Ethyl 2-(4-bromo-2-iodophenyl)acetate (13.31 g, 36.07 mmol) and 1-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]phenyl]prop-2-en-1-ol (racemic mixture, 10.20 g, 31.24 mmol) were dissolved in 0.10 L of ACN in a round-bottom flask equipped with a stir bar. TEA (11 mL, 79 mmol) was added, and the resulting solution was purged with nitrogen (using a subsurface needle) while stirring for 20 minutes. Palladium(II) acetate (0.14 g, 0.62 mmol) was added to the mixture, and the nitrogen purge was maintained for an additional 10 minutes. The mixture was heated at 82°C for 22 hours, after which the mixture was partially cooled and filtered through paper, using 0.10 L of ACN as a rinse. The filtrate was stirred and diluted to 0.60 L with water. The mixture was seeded with the purified product, and a dark solid formed. After 10 min, the solid was collected by filtration and washed with water (0.20 L). The wet solid was dissolved in EtOAc (0.20 L), dried over MgSO4, and eluted under suction through a pad of EtOAc-washed silica (6 cm diameter × 4 cm depth). The pad was eluted with additional EtOAc (0.40 L). The eluate was concentrated under reduced pressure to a volume of 0.10 L and then exchanged into EtOH by put-and-take distillation under reduced pressure at 50 °C to a final volume of 0.20 L. The flask was transferred to a 50 °C heating block, the heat was turned off, and the mixture was allowed to cool slowly with stirring. After 22 h, the solid was collected by filtration and rinsed with EtOH (70 mL) until the filtrate was clear. The filter cake was dried in a vacuum oven (10 mbar, 50° C.) for 26 h to give the title compound (11.78 g, 68%) as a light grey solid. ES-MS m / z 550, 552 and 552 (M+H). + .

[0276] Preparation 47 Ethyl 2-[4-bromo-2-[3-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]phenyl]-3-hydroxypropyl]phenyl]acetate (racemic mixture)

[0277] [ka]

[0278] Ethyl 2-[4-bromo-2-[3-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]phenyl]-3-oxo-propyl]phenyl]acetate (4.99 g, 8.87 mmol) was dissolved in THF (25 mL) with stirring in a round-bottom flask placed in an ambient temperature water bath. EtOH (50 mL) was added to the mixture, followed by sodium borohydride (0.17 g, 4.5 mmol). After 1.5 h, aqueous acetic acid (10% v / v, 25 mL) was added, and the mixture was stirred for 1 h. The mixture was diluted with EtOAc (0.20 L) and water (0.20 L), and the phases were separated. The organic phase was washed successively with water, 2 M aqueous potassium phosphate trihydrate, and saturated aqueous NaCl (50 mL each), then dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and, when near completion, heptane (50 mL) was added to give the crude title compound (5.11 g, 96%) as a thick brown oil. ES-MS m / z 552, 554 and 556 (M+H). + .

[0279] Preparation 48 Ethyl 2-[2-[3-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]phenyl]-3-hydroxypropyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate (racemic mixture)

[0280] [ka]

[0281] Bis(pinacolato)diboron (3.41 g, 13.2 mmol) and potassium 2-ethylhexanoate (3.35 g, 17.5 mmol) were added to a stirred solution of ethyl 2-[4-bromo-2-[3-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]phenyl]-3-hydroxypropyl]phenyl]acetate (racemic mixture, 5.02 g, 8.35 mmol) in 1,4-dioxane (0.10 L) in a round-bottom flask. A septum equipped with a nitrogen needle was attached to the flask, and the solution was purged with nitrogen for 20 minutes. Bis(triphenylphosphine)palladium(II) dichloride (0.33 g, 0.46 mmol) was added, and the mixture was heated to 50 °C for 3 hours. The mixture was concentrated under reduced pressure, dissolved in EtOAc (0.15 L), washed successively with 2 M aqueous potassium phosphate trihydrate, water, and saturated aqueous NaCl (70 mL each), and then concentrated under reduced pressure. The residue was dissolved in DCM and chromatographed on silica (0-10% EtOAc in DCM) to give the title compound (3.85 g, 69%) as a thick, pale yellow oil containing 8% residual solvent by weight. ES-MS m / z 600 and 602 (M+H). + .

[0282] Preparation 49 2-(5 4 -Chloro-6-hydroxy-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 -yl) ethyl acetate (racemic mixture)

[0283] [ka]

[0284] Ethyl 2-[2-[3-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]phenyl]-3-hydroxypropyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate (racemic mixture, 3.85 g, 5.77 mmol, 90% by weight) was dissolved in THF (0.60 L). Anisole (1.26 mL, 11.6 mmol, internal standard) was added, and the mixture was heated to 50 °C. 1 M aqueous potassium phosphate tribasic solution (60 mL, 60 mmol) was added, and the mixture was purged with argon using a subsurface PTFE cannula. After 20 min, [chloro(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.23 g, 0.29 mmol) was added and argon purging continued for an additional 5 min. After 3 h, the mixture was cooled, diluted with EtOAc (0.60 L), and the phases were separated. The organic phase was washed successively with 2 M aqueous potassium phosphate tribasic (50 mL), water (0.10 L), and saturated aqueous NaCl (2 x 50 mL), then dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (0-20% EtOAc in DCM) to give the title compound (1.62 g, 62%) as an off-white foam. ES-MS m / z 438 and 440 (M+H). + .

[0285] Preparation 50 2-(5 4 -cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 -yl) ethyl acetate (racemic mixture)

[0286] [ka]

[0287] 2-5 4 -Chloro-6-hydroxy-3-oxa-2(2,6)-pyridino-1(1,3),5(1,2)-dibenzenacyclooctaphane-14 A mixture of ethyl acetate (racemic mixture, 1.01 g, 2.24 mmol), potassium ferrocyanide trihydrate (0.41 g, 1.1 mmol), 1 M aqueous potassium acetate (0.66 mL, 0.66 mmol), 1,4-dioxane (40 mL), and water (20 mL) was purged with argon using a subsurface needle while stirring. After 5 min, chloro(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (92 mg, 0.115 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl) (27 mg, 0.055 mmol) were added, and the reaction mixture was heated to 90 °C under a balloon of argon for 5.5 h. The mixture was cooled and combined with material from a test reaction (0.22 mmol scale). The mixture was diluted with EtOAc (50 mL), filtered through diatomaceous earth, and the filter cake was rinsed with additional EtOAc (50 mL). The phases of the filtrate were separated, and the aqueous phase was extracted with additional EtOAc (2 x 25 mL). The organic portions were combined, washed with saturated aqueous NaCl (50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (0-20% EtOAc in DCM). The purified product was dissolved in DCM, diluted with cyclohexane, and concentrated to give the title compound (1.04 g, 87%) as a white solid. ES-MS m / z 429 (M+H) + .

[0288] Preparation 51 2-(5 4 -cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 -yl)acetic acid (racemic mixture)

[0289] [ka]

[0290] 2-(5 4-cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 Ethyl (4-yl)acetate (1.0 g, 2.1 mmol, racemic mixture) was dissolved in ACN (20 mL), THF (7 mL), and water (7 mL) in a glass tube. Triazabicyclo[4.4.0]dec-5-ene (0.88 g, 6.2 mmol) was added, and a septum equipped with a nitrogen injection needle was attached. The solution was purged with nitrogen for 5 minutes, then heated to 40 °C and stirred under a positive nitrogen pressure. After 2 hours, the reaction mixture was poured into water (50 mL). 5% aqueous citric acid solution (30 mL) was added, and the mixture was extracted three times with DCM (60 mL, 30 mL, 30 mL). The extracts were combined, washed with saturated aqueous NaCl (30 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was dissolved in DCM and filtered through a pad of diatomaceous earth. The filtrate was diluted with cyclohexane and then concentrated under reduced pressure to give the title compound (0.947 g, quantitative yield) as a white solid, which contained 5% by weight of residual solvent. ES-MS m / z 401 (M+H) + .

[0291] Preparation 52 2-((5 4 -cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 -yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (Isomer 1 and Isomer 2)

[0292] [ka]

[0293] 2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (1.68 M, 0.67 mL, 1.1 mmol) in EtOAc was dissolved in 2-(5-chloro-2-methyl-2-oxo-1,3,5,2,4,6-trioxatriphosphorinane)-2,4,6-trioxide in anhydrous DMF (2 mL) and pyridine (0.4 mL, 5 mmol). 4-cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 To a stirred solution of methyl 4-amino-3-[[(2S)-oxetan-2-yl]methylamino]benzoate (121 mg, 0.512 mmol) was added. The reaction vessel was purged with nitrogen, sealed, and stirred at ambient temperature for 10 minutes. The mixture was diluted with water to a final volume of 13 mL, shaken for 5 minutes, and then centrifuged. The supernatant was removed by pipette, and the solid was reslurried / centrifuged twice from water (12 mL each). Material from the test reaction (0.112 mmol scale) was added. The wet solid was suspended in THF (25 mL) and concentrated under reduced pressure at 50° C., and this process was then repeated two more times to give the crude amide intermediate. ES-MS m / z 619 (M+H) + .

[0294] The crude amide intermediate was dissolved in acetic acid (7 mL) and 2-chlorotoluene (7 mL) and stirred under nitrogen in a heating block at 60° C. for 8 h, then concentrated under reduced pressure at 50° C. The residue was purified by chromatography on silica (0-10% EtOH in DCM) to afford a diastereomeric mixture of the title compounds (315 mg, 79%) as a white solid, which contained 12% residual solvent by weight.

[0295] A portion of the diastereomeric mixture (270 mg, 84% wt purity, 0.378 mmol) was separated using supercritical fluid chromatography [Column: Chiralcel® OD (20 × 250 mm, 5 μm); Mobile phase: Carbon dioxide (A), (MeOH + 0.5% DMEA) (B), isocratic 40% B; Column temperature 40 °C; Flow rate: 80 mL / min] to give Isomer 1 (first eluting isomer, 102 mg, 40%) and Isomer 2 (second eluting isomer, 103 mg, 40%). Both Isomer 1 and Isomer 2: ES-MS m / z 601 (M+H) + .

[0296] Preparation 53 2-((54 -cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 -yl)methyl)-4-ethoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (Isomer 1 and Isomer 2)

[0297] [ka]

[0298] A diastereomeric mixture of the title compound was prepared essentially as described in Preparation 52 using methyl (S)-4-amino-3-ethoxy-5-((oxetan-2-ylmethyl)amino)benzoate and purified twice by silica gel chromatography (0-10% EtOH in DCM, then 20-100% EtOAc in cyclohexane). The diastereomeric mixture was then separated using supercritical fluid chromatography under the conditions described in Preparation 52 to give Isomer 1 (first eluting isomer, 86 mg, 42%) and Isomer 2 (second eluting isomer, 91 mg, 44%). ES-MS m / z 645 (M+H). + .

[0299] Preparation 54 2-((5 4 -cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 -yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (Isomer 1 and Isomer 2)

[0300] [ka]

[0301] A diastereomeric mixture of the title compound was prepared essentially as described in Preparation 52 using methyl 4-amino-3-fluoro-5-[[(2S)-oxetan-2-ylmethyl]amino]benzoate. The diastereomers were separated using supercritical fluid chromatography under the conditions described in Preparation 52 to give Isomer 1 (fastest eluting isomer) and Isomer 2 (second eluting isomer). ES-MS m / z 619 (M+H) + .

[0302] Preparation 55 (S)-5-Bromo-2-nitro-N-(oxetan-2-ylmethyl)pyridin-3-amine

[0303] [ka]

[0304] TEA (2.5 mL, 18 mmol) was added to a solution of 5-bromo-3-fluoro-2-nitropyridine (2.5 g, 11 mmol) in DMF (5 mL). [(2S)-oxetan-2-yl]methanamine (1.0 g, 10 mmol) was then added, and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (30 mL), and the resulting precipitate was collected by filtration to give the title compound (2.8 g, 86%). ES-MS m / z 288 and 290 (M+H). + .

[0305] Preparation 56 (S)-5-Bromo-N 3 -(Oxetan-2-ylmethyl)pyridine-2,3-diamine

[0306] [ka]

[0307] To a Parr shaker bottle was added 5% sulfided platinum on carbon (469 mg, 2.41 mmol) and EtOAc (60 mL), followed by (S)-5-bromo-2-nitro-N-(oxetan-2-ylmethyl)pyridin-3-amine (2.4 g, 8.3 mmol) as a solution in EtOAc (60 mL). The reaction vessel was pressurized with 60 psi of hydrogen gas and shaken at room temperature for 4 hours. The reaction mixture was filtered through diatomaceous earth and rinsed with EtOAc. The filtrate was concentrated under reduced pressure to give 2.3 g of the title compound (92%). ES-MS m / z 258 and 260 (M+H). + .

[0308] Preparation 57 1 4 -((6-bromo-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-6-hydroxy-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-5 4 -carbonitrile (mixture of diastereomers)

[0309] [ka]

[0310] In a flask, add 2-(5 4 -cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 -yl)acetic acid (racemic mixture, 290 mg, 0.652 mmol), (S)-5-bromo-N 3A mixture of 188 mg (0.728 mmol) of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (1.68 M, 0.97 mL, 1.63 mmol) in EtOAc was added and the solution was stirred at ambient temperature. After 30 minutes, additional 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (1.68 M, 0.97 mL, 1.63 mmol) in EtOAc was added to the mixture. After 30 minutes, water was added, the mixture was stirred for 5 minutes, and the solid was then collected by filtration and washed with water. The filter cake was dried under reduced pressure at 40°C overnight. The solid was dissolved in acetic acid (6.5 mL) and stirred at 60°C overnight. The resulting mixture was concentrated to dryness, water was added, and the solid was filtered and washed with water. The solid was purified by chromatography on silica gel (25-100% EtOAc in DCM) to give the title compound (82 mg, 20%) as a white solid. ES-MS m / z 622 and 624 (M+H) + .

[0311] Preparation 58 2-(but-3-en-1-yl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione

[0312] [ka]

[0313] A solution of but-3-enylboronic acid (19.1 g, 192 mmol) and 4-methylmorpholine-2,6-dione (49.5 g, 383 mmol) in 1,4-dioxane (500 mL) was stirred at 70 °C for 20 h. The suspension was filtered, and the solid was rinsed with EtOAc. The filtrate was concentrated under reduced pressure. The resulting solid was suspended in hot acetone (500 mL) and filtered through a pad of silica gel. The silica gel pad was eluted with acetone, and the filtrate was concentrated to give 34 g of the title compound (84%).1 H NMR(d6-DMSO)δ 5.89(m,1H),4.99(dd,J=17 and 1.5Hz,1H),4.88(dd,J=10.5 and 1.5Hz,1H),4.18 (d,J=17Hz,2H),3.98(d,J=17Hz,2H),2.84(s,3H),2.00(m,2H),0.61(m,2H).

[0314] Preparation 59 Methyl 6-bromo-5-chloropicolinate

[0315] [ka]

[0316] Bromotrimethylsilane (35.0 mL, 265 mmol) was added to a solution of methyl 5,6-dichloropyridine-2-carboxylate (27.0 g, 131 mmol) in propionitrile (250 mL). The mixture was heated to 100° C. for 17 h. The reaction mixture was diluted with EtOAc (300 mL) and washed with semi-saturated aqueous sodium bicarbonate (200 mL). The aqueous layer was extracted with EtOAc (100 mL), and the combined organic layers were then dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 42.0 g of the title compound (>100%), which was used without further purification. ES-MS m / z 250 and 252 (M+H).

[0317] Preparation 60 (6-Bromo-5-chloropyridin-2-yl)methanol

[0318] [ka]

[0319] A solution of methyl 6-bromo-5-chloropicolinate (42.0 g crude) in THF (300 mL) and MeOH (100 mL) was cooled to 0 °C. Sodium borohydride (10.2 g, 270 mmol) was added portionwise and stirred at 0 °C for 30 min. An additional portion of sodium borohydride (2.0 g, 53 mmol) was added, and the mixture was stirred at room temperature for 20 min. The reaction was quenched with water (20 mL), diluted with EtOAc (300 mL), and washed with water (200 mL). The aqueous layer was extracted with EtOAc (2 × 100 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 27.8 g of the title compound (95%). ES-MS m / z 222 and 224 (M+H).

[0320] Preparation 61 2-Bromo-3-chloro-6-(((6-chloropyridin-2-yl)oxy)methyl)pyridine

[0321] [ka]

[0322] A solution of (6-bromo-5-chloropyridin-2-yl)methanol (27.8 g, 125 mmol), 6-chloropyridin-2-ol (18.0 g, 139 mmol), and triphenylphosphine (49.9 g, 190 mmol) in THF (400 mL) was cooled to 0 °C. Diisopropyl azodicarboxylate (38.0 mL, 192 mmol) was added dropwise. The mixture was stirred at 0 °C for 10 min and then at room temperature for 4 h, diluted with EtOAc (600 mL), and washed with 1:2 saturated aqueous NaCl:water (300 mL). The aqueous layer was extracted with EtOAc (100 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 10–25% EtOAc in hexanes to give 25.2 g of the title compound (61%). ES-MS m / z 333, 335, and 337 (M+H).

[0323] Preparation 62 2-(4-(3-chloro-6-(((6-chloropyridin-2-yl)oxy)methyl)pyridin-2-yl)butyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione

[0324] [ka]

[0325] 9-Borabicyclo[3.3.1]nonane (50 mL, 25 mmol, 0.5 M in THF) was added to a solution of 2-(but-3-en-1-yl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (5.05 g, 23.9 mmol) in THF (150 mL). The mixture was stirred at room temperature for 2 hours. 2-Bromo-3-chloro-6-(((6-chloropyridin-2-yl)oxy)methyl)pyridine (7.91 g, 23.7 mmol), chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (RuPhos Pd Gen2, 1.3 g, 1.6 mmol), and anhydrous potassium phosphate (15 g, 69 mmol) were added to the resulting white suspension. The mixture was stirred at 50 °C for 7 h. The reaction was diluted with EtOAc (300 mL) and washed with water (200 mL). The aqueous layer was extracted with EtOAc (200 mL). The combined organic layer was washed with 1:1 water:saturated aqueous NaCl solution (100 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-30% EtOAc in hexanes followed by a gradient of 0-50% acetone in diethyl ether to give 5.8 g of the title compound (53%). ES-MS m / z 466 and 468 (M+H).

[0326] Preparation 63 2-(4-bromo-2-(4-(3-chloro-6-(((6-chloropyridin-2-yl)oxy)methyl)pyridin-2-yl)butyl)phenyl)acetic acid ethyl ester

[0327] [ka]

[0328] Aqueous sodium hydroxide (1 M, 13 mL, 13 mmol) was added to a solution of 2-(4-(3-chloro-6-(((6-chloropyridin-2-yl)oxy)methyl)pyridin-2-yl)butyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (2.0 g, 4.3 mmol) in THF (21 mL). The mixture was stirred at room temperature for 1 hour. The mixture was diluted with diethyl ether (25 mL) and washed with saturated aqueous ammonium chloride solution (40 mL). The aqueous layer was extracted with diethyl ether (2 x 25 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 1.9 g of crude boronic acid, which was used immediately. 2-(4-bromo-2-iodo-phenyl)ethyl acetate (1.6 g, 4.3 mmol) and 1,4-dioxane (42 mL) were added to the boronic acid. Potassium carbonate (3.5 g, 25 mmol), silver oxide (3.0 g, 13 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (410 mg, 0.554 mmol) were added. The mixture was placed under a nitrogen atmosphere and heated to 60°C for 4 h. Water (0.2 mL, 10 mmol) was added, and the reaction mixture was heated at 60°C for 14 h. The reaction was filtered through diatomaceous earth, rinsed with EtOAc, and concentrated. The residue was purified by silica gel chromatography using a gradient of 0 to 45% EtOAc in hexanes to give 1.3 g of the title compound (56%). ES-MS m / z 551 and 553 (M+H).

[0329] Preparation 64 2-(5 5 -chloro-3-oxa-2,5(2,6)-dipyridina-1(1,3)-benzenacyclononaphane-1 4 -yl)acetic acid ethyl ester

[0330] [ka]

[0331] To a mixture of ethyl 2-(4-bromo-2-(4-(3-chloro-6-(((6-chloropyridin-2-yl)oxy)methyl)pyridin-2-yl)butyl)phenyl)acetate (952 mg, 1.72 mmol), bis(pinacolato)diboron (550 mg, 2.17 mmol), potassium acetate (577 mg, 5.88 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (130 mg, 0.175 mmol), 1,4-dioxane (8.5 mL) was added. The mixture was stirred at 90° C. for 4.5 hours. An additional portion of bis(pinacolato)diboron (560 mg, 2.21 mmol) was added, and the mixture was stirred at 95° C. for 2 hours. The suspension was cooled and filtered through a pad of silica. The solution was eluted with THF (60 mL). A solution of chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd Gen2, 150 mg, 0.186 mmol) and potassium phosphate (1.0 g, 4.7 mmol) in water (11 mL) was added to this solution. The mixture was stirred at 55 °C for 1 h. The solution was diluted with EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography using a gradient of 0 to 25% EtOAc in hexanes to give 227 mg of the title compound (30%). ES-MS m / z 437 (M+H).

[0332] Preparation 65 2-(5 5 -chloro-3-oxa-2,5(2,6)-dipyridina-1(1,3)-benzenacyclononaphane-1 4 -yl)acetic acid

[0333] [ka]

[0334] 2-(5) in ACN (2.6 mL) and water (0.9 mL) 5-Chloro-3-oxa-2,5(2,6)-dipyridina-1(1,3)-benzenacyclonaphane-1 4 To a solution of ethyl (4-yl)acetate (226 mg, 0.517 mmol) was added 1,5,7-triazabicyclo[4.4.0]dec-5-ene (227 mg, 1.60 mmol). The mixture was stirred at 45° C. for 4 h. The reaction was quenched with aqueous citric acid (1 M, 5 mL). The solution was diluted with EtOAc (10 mL). The aqueous layer was removed and extracted with EtOAc (3×5 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 202 mg of the title compound (96%), which was carried forward without further purification. ES-MS m / z 409 (M+H).

[0335] Preparation 66 (S)-4-(2-(5 5 -chloro-3-oxa-2,5(2,6)-dipyridina-1(1,3)-benzenacyclononaphane-1 4 -yl)acetamido)-3-methoxy-5-((oxetan-2-ylmethyl)amino)benzoate methyl

[0336] [ka]

[0337] 2-(5 mL) in DMF (5 mL) 5 -chloro-3-oxa-2,5(2,6)-dipyridina-1(1,3)-benzenacyclononaphane-1 4To a solution of 4-amino-3-methoxy-5-[[(2S)-oxetan-2-yl]methylamino]benzoate (147 mg, 0.552 mmol) and methyl 4-amino-3-methoxy-5-[[(2S)-oxetan-2-yl]methylamino]benzoate (147 mg, 0.552 mmol), pyridine (0.40 mL, 4.9 mmol) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (1.7 M in EtOAc, 0.75 mL, 1.3 mmol) were added. The mixture was stirred at room temperature for 2 hours. The crude reaction mixture was diluted with water (20 mL). The resulting white solid was collected by vacuum filtration. The solid was washed with water and dried under vacuum to give 286 mg of the title compound (88%). ES-MS m / z 657 (M+H).

[0338] Preparation 67 (S)-2-((5 5 -chloro-3-oxa-2,5(2,6)-dipyridina-1(1,3)-benzenacyclononaphane-1 4 -yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester

[0339] [ka]

[0340] (S)-4-(2-(5)-(5-chloro-2-methyl-2-propanol) in 1,2-dichloroethane (2.5 mL) and acetic acid (2.5 mL) 5 -chloro-3-oxa-2,5(2,6)-dipyridina-1(1,3)-benzenacyclononaphane-1 4 A solution of methyl 5-((oxetan-2-ylmethyl)acetamido)-3-methoxy-5-((oxetan-2-ylmethyl)amino)benzoate (286 mg, 0.434 mmol) was stirred at 45° C. for 14 h. The solution was heated at 55° C. for an additional 1 h. The reaction mixture was loaded onto silica gel, concentrated, and purified by silica gel chromatography using a gradient of 0-100% EtOAc in hexanes to give 107 mg of the title compound (39%). ES-MS m / z 639 (M+H).

[0341] Preparation 68 3-Bromo-5-chloro-pyridine-2-carboxylic acid methyl ester

[0342] [ka]

[0343] To a solution of 3-bromo-5-chloro-pyridine-2-carboxylic acid (25.0 g, 100.4 mmol) in MeOH (200 mL) was added sulfuric acid (28.0 mL, 512 mmol) at 0 °C. The mixture was warmed to room temperature and then heated to 90 °C and stirred for 4 h. The mixture was concentrated under reduced pressure, and the residue was then diluted with a saturated solution of NaHCO (150 mL, 2N). The aqueous material was transferred to a separatory funnel and then extracted three times with EtOAc (100 mL). The combined organic extracts were washed with saturated aqueous NaCl (100 mL), dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to give 24.9 g of the title compound as a yellow solid (95%). ES-MS m / z 251.8 (M+1).

[0344] Preparation 69 (3-Bromo-5-chloro-2-pyridyl)methanol

[0345] [ka]

[0346] To a solution of methyl 3-bromo-5-chloro-pyridine-2-carboxylate (20.0 g, 76.7 mmol) in MeOH (50 mL) cooled to 0 °C was added NaBH (8.79 g, 230 mmol) predissolved in THF (10.0 mL). The solution was stirred at ambient temperature for 5 h and then quenched by the addition of a saturated solution of NH Cl (100 mL). The mixture was transferred to a separatory funnel, further diluted with water (100 mL), and then extracted twice with EtOAc (50 mL). The combined organics were washed with saturated aqueous NaCl (60 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0–26% EtOAc in petroleum ether to afford 17.0 g of the title compound as a pale yellow solid (98%). ES-MS m / z 224.1 (M+1).

[0347] Preparation 70 3-Bromo-5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]pyridine

[0348] [ka]

[0349] To a solution of (3-bromo-5-chloro-2-pyridyl)methanol (10.0 g, 44.1 mmol) and triphenylphosphine (14.0 g, 52.8 mmol) in THF (50 mL) was added 6-chloro-2-hydroxypyridine (6.40 g, 48.0 mmol) and diisopropyl azidodicarboxylate (10.6 mL, 52.8 mmol) under a nitrogen atmosphere at ambient temperature. The mixture was stirred overnight at ambient temperature and purified by silica gel chromatography using a gradient of 0-10% EtOAc in petroleum ether to afford 15.0 g of the title compound as a pale yellow solid (83%). ES-MS m / z 334.8 (M+1).

[0350] Preparation 71 3-Allyl-5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]pyridine

[0351] [ka]

[0352] To a solution of 3-bromo-5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]pyridine (12.5 g, 36.7 mmol), tetrakis(triphenylphosphine)palladium(0) (4.37 g, 3.67 mmol), and LiCl (4.66 g, 110 mmol) in 1,4-dioxane (60 mL) was added allyltributyltin (15.9 g, 46.4 mmol) at ambient temperature under a nitrogen atmosphere. The mixture was heated to 110 °C and stirred for 1 h. The reaction was quenched with a saturated solution of KF (50 mL), and then the mixture was transferred to a separatory funnel and extracted three times with EtOAc (50 mL). The combined organic extracts were washed with saturated aqueous NaCl, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-10% EtOAc in petroleum ether to give 11.6 g of the title compound as a pale yellow oil (95%). ES-MS m / z 295.2 (M+1).

[0353] Preparation 72 2-[4-bromo-2-[(E)-3-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]-3-pyridyl]prop-1-enyl]phenyl]acetic acid ethyl ester

[0354] [ka]

[0355] To a solution of 3-allyl-5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]pyridine (5.0 g, 16 mmol) and ethyl 2-(4-bromo-2-iodophenyl)acetate (9.0 g, 22 mmol) in DMF (160 mL) was added Pd(OAc), 2-(dicyclohexylphosphino)biphenyl (1.1 g, 3.0 mmol), and TEA (4.4 mL, 31 mmol) at ambient temperature under a nitrogen atmosphere. The mixture was heated to 90 °C and stirred overnight. The volatiles were removed under reduced pressure, and the residue was then diluted with water (60 mL), transferred to a separatory funnel, and extracted three times with EtOAc (20 mL). The combined organics were washed with saturated aqueous NaCl (60 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography using a gradient of 0-16% EtOAc in petroleum ether to give 7.6 g of the title compound as a brown oil (81%). ES-MS m / z 537 (M+1).

[0356] Preparation 73 2-[4-bromo-2-[3-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]-3-pyridyl]propyl]phenyl]acetic acid ethyl ester

[0357] [ka]

[0358] To a solution of ethyl 2-[4-bromo-2-[(E)-3-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]-3-pyridyl]prop-1-enyl]phenyl]acetate (5.0 g, 8.4 mmol) in MeOH (10.0 mL) was added chlorotris(triphenylphosphine)rhodium(I) (3.2 g, 3.4 mmol) at ambient temperature under a hydrogen atmosphere (15 PSI). The mixture was stirred overnight at ambient temperature and then concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted three times with EtOAc (10 mL). The combined organics were washed with saturated aqueous NaCl (60 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography using a gradient of 0–20% EtOAc in petroleum ether to afford 3.71 g of the title compound as a brown oil (72%). ES-MS m / z 539(M+1).

[0359] Preparation 74 2-(5 5 -chloro-3-oxa-2(2,6),5(2,3)-dipyridina-1(1,3)-benzenacyclooctaphane-1 4 -yl)acetic acid ethyl ester

[0360] [ka]

[0361] To a solution of ethyl 2-[4-bromo-2-[3-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]-3-pyridyl]propyl]phenyl]acetate (2.5 g, 4.1 mmol) and CsF (1.0 g, 6.5 mmol) in 1,4-dioxane (290 mL) was added (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (350 mg, 0.405 mmol) and hexamethylditin (1.76 g, 5.32 mmol) under a nitrogen atmosphere at ambient temperature. The mixture was heated to 110 °C and stirred overnight. The mixture was diluted with water (50 mL) and then extracted three times with EtOAc (100 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse-phase chromatography [Column: YMC-Triart Prep C18 250 mm × 50 mm, 10 μm; Mobile phase: 0.225% aqueous formic acid (A), ACN (B), Gradient: 55% to 95% solvent B in solvent A]. The combined aqueous fractions were lyophilized to afford 220 mg of the title compound as a yellow solid (11%). ES-MS m / z 423.2 (M+1).

[0362] Preparation 75 2-(5 5 -chloro-3-oxa-2(2,6),5(2,3)-dipyridina-1(1,3)-benzenacyclooctaphane-1 4 -yl)acetic acid

[0363] [ka]

[0364] 2-(5-Hydroxy-2-methyl-2-propanol) in ACN (4.0 mL), water (1.5 mL), and THF (1.5 mL) 5 -chloro-3-oxa-2(2,6),5(2,3)-dipyridina-1(1,3)-benzenacyclooctaphane-1 4A solution containing ethyl (4-yl)acetate (210 mg, 0.447 mmol) was sparged with nitrogen. The flask was then charged with 1,5,7-triazabicyclo[4.4.0]dec-5-ene (192 mg, 1.35 mmol), sealed with a septum, and flushed with nitrogen. The mixture was stirred at ambient temperature for 2 hours and then quenched with a 1 M aqueous solution of citric acid (5 mL, to pH = 4.5). The resulting colorless solid was filtered and dried under vacuum to give 187.7 mg of the title compound as a colorless solid (99%). ES-MS m / z 395.2 (M+1).

[0365] Preparation 76 (S)-4-(2-(5 5 -chloro-3-oxa-2(2,6),5(2,3)-dipyridina-1(1,3)-benzenacyclooctaphane-1 4 -yl)acetamido)-3-methoxy-5-((oxetan-2-ylmethyl)amino)benzoate methyl

[0366] [ka]

[0367] 2-(5 5 -chloro-3-oxa-2(2,6),5(2,3)-dipyridina-1(1,3)-benzenacyclooctaphane-1 4 To a solution of (2S)-oxetan-2-yl)acetic acid (180 mg, 0.429 mmol), methyl 4-amino-3-methoxy-5-[[(2S)-oxetan-2-yl]methylamino]benzoate (135 mg, 0.502 mmol), and HATU (250 mg, 0.644 mmol) at ambient temperature was added DIPEA (0.205 mL, 1.15 mmol). The mixture was stirred at ambient temperature for 2 hours, then diluted with water (15 mL) and extracted three times with EtOAc (15 mL). The combined organics were washed with saturated aqueous NaCl (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 380 mg of the crude title compound as a pale yellow solid (99%), which was used without purification. ES-MS m / z 643.3 (M+1).

[0368] Preparation 77 (S)-2-((5 5 -chloro-3-oxa-2(2,6),5(2,3)-dipyridina-1(1,3)-benzenacyclooctaphane-1 4 -yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester

[0369] [ka]

[0370] (S)-4-(2-(5)-(5-chloro-2-methyl-2-propanol) in 1,2-dichloroethane (4.14 mL) and acetic acid (4.14 mL) 5 -chloro-3-oxa-2(2,6),5(2,3)-dipyridina-1(1,3)-benzenacyclooctaphane-1 4 A solution of methyl 5-((oxetan-2-ylmethyl)acetamido)-3-methoxy-5-((oxetan-2-ylmethyl)amino)benzoate (370 mg, 0.414 mmol) under nitrogen was heated to 55° C. and stirred overnight. Volatiles were removed under reduced pressure, then the crude residue was dissolved in toluene (5 mL) and concentrated under reduced pressure (concentration with toluene was repeated two more times). The residue was purified by silica gel chromatography using a gradient of 0-7% MeOH in DCM to afford 281 mg of the title compound as a yellow solid (86%). ES-MS m / z 625.3 (M+1).

[0371] Preparation 78 (S)-2-((5 5 -cyano-3-oxa-2(2,6),5(2,3)-dipyridina-1(1,3)-benzenacyclooctaphane-1 4 -yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester

[0372] [ka]

[0373] In a dry round-bottom flask, add (S)-2-((5 5 -chloro-3-oxa-2(2,6),5(2,3)-dipyridina-1(1,3)-benzenacyclooctaphane-1 4 Methyl 4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (210 mg, 0.265 mmol), zinc cyanide (30.0 mg, 0.240 mmol), Pd(TFA) (9 mg, 0.03 mmol), rac-2-(di-tert-butylphosphino)-1,1′-binaphthyl (22 mg, 0.054 mmol), and zinc (0.1 g, 2 mmol) were charged under nitrogen. The flask was evacuated and refilled with nitrogen three times, then DMF (2.7 mL) was added via syringe. The mixture was heated to 80 °C and stirred overnight. The crude material was diluted with water (5 mL) and then extracted twice with EtOAc (10 mL). The combined organics were washed with saturated aqueous NaCl (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-4% MeOH in DCM to give 143 mg of the title compound as a brown solid (62%). ES-MS m / z 616.3 (M+1).

[0374] Preparation 79 2-[(6-chloro-2-pyridyl)oxymethyl]-5-cyanobenzoic acid methyl ester

[0375] [ka]

[0376] A mixture of 6-chloropyridin-2-ol (5.37 g, 41.5 mmol), potassium carbonate (10.87 g, 78.65 mmol), and methyl 2-(bromomethyl)-5-cyanobenzoate (10 g, 39 mmol) in ACN (130 mL) was stirred at room temperature under nitrogen for 4 hours. Additional ACN (50 mL) was added, and the mixture was stirred for an additional 15 minutes. The crude suspension was filtered through a pad of silica and rinsed with ACN. The filtrate was concentrated to give the title compound (10.77 g, 90%), which was used without further purification. ES-MS m / z 303 (M+1).

[0377] Preparation 80 4-[(6-chloro-2-pyridyl)oxymethyl]-3-(hydroxymethyl)benzonitrile

[0378] [ka]

[0379] At 0°C, sodium borohydride (4.08 g, 108 mmol) was added portionwise to a solution of methyl 2-[(6-chloro-2-pyridyl)oxymethyl]-5-cyanobenzoate (10.77 g, 35.58 mmol) in THF (90 mL) and MeOH (45 mL). The resulting solution was stirred at 0°C for 10 minutes, then warmed to room temperature and stirred for 3 hours. Additional sodium borohydride (2 g, 50 mmol) was added and stirring continued for 2 hours. The final amount of sodium borohydride (2 g, 50 mmol) was added and stirring continued for 30 minutes before quenching with water (50 mL). The quenched reaction was partitioned between EtOAc (100 mL) and saturated aqueous NaCl (50 mL). The saturated aqueous NaCl solution was separated and extracted with additional EtOAc (2 x 50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to give a crude white solid which was purified by silica gel chromatography to give the title compound (7.75 g, 79%). ES-MS m / z 275 (M+1).

[0380] Preparation 81 4-[(6-chloro-2-pyridyl)oxymethyl]-3-formyl-benzonitrile

[0381] [ka]

[0382] A suspension of manganese dioxide (33 g, 380 mmol) and 4-[(6-chloro-2-pyridyl)oxymethyl]-3-(hydroxymethyl)benzonitrile (10.3 g, 37.5 mmol) in DCM (150 mL) was stirred at room temperature. After 3 h, additional manganese dioxide (30 g, 350 mmol) was added and stirring was continued. After 1.5 h, more manganese dioxide (15 g, 170 mmol) was added and stirring was continued for 2 h. The reaction suspension was then filtered through diatomaceous earth and rinsed with EtOAc. The filtrate was concentrated to give the title compound, which was used without further purification (8.88 g, 87%). ES-MS m / z 273 (M+1).

[0383] Preparation 82 4-(((6-chloropyridin-2-yl)oxy)methyl)-3-(1-hydroxyallyl)benzonitrile (racemic mixture)

[0384] [ka]

[0385] Vinylmagnesium bromide (1.0 M in THF, 34 mL, 34 mmol) was added over 15 min to a stirred solution of 4-[(6-chloro-2-pyridyl)oxymethyl]-3-formyl-benzonitrile (8.88 g, 32.6 mmol) in THF (160 mL) at 0 °C. The reaction was stirred for 10 min before half-saturated aqueous NH4Cl was added. The mixture was diluted with EtOAc (100 mL), the aqueous phase was separated, and extracted with additional EtOAc (50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was purified using silica gel chromatography using a gradient of EtOAc and hexanes to give the title compound (5.4 g, 17 mmol). ES-MS m / z 283 (M-OH).

[0386] Preparation 83 2-[4-bromo-2-[3-[2-[(6-chloro-2-pyridyl)oxymethyl]-5-cyano-phenyl]-3-oxo-propyl]-5-methyl-phenyl]acetic acid ethyl ester

[0387] [ka]

[0388] A mixture of ethyl 2-(4-bromo-2-iodo-5-methylphenyl)acetate (4.5 g, 12 mmol), 4-(((6-chloropyridin-2-yl)oxy)methyl)-3-(1-hydroxyallyl)benzonitrile (racemic mixture, 3.2 g, 11 mmol), palladium(II) acetate (120 mg, 0.53 mmol), TEA (3.7 mL, 27 mmol), and ACN (20 mL) was sparged with nitrogen for 20 minutes and then heated at 80° C. for 20 hours. Additional palladium(II) acetate (120 mg, 0.53 mmol) was added, and heating was continued for 5 hours. Additional palladium(II) acetate (120 mg, 0.53 mmol) and TEA (2.2 mL, 16 mmol) were added, and heating was continued for 19 hours. The mixture was cooled to room temperature and filtered through a pad of diatomaceous earth, rinsing the pad with EtOAc. The filtrate was concentrated to give a residue that was purified using silica gel chromatography using a gradient of EtOAc and hexanes. The product obtained from flash chromatography was combined with the previously isolated gray solid to give the title compound as an overall off-white solid (3.8 g, 63%). ES-MS m / z 555 / 557 / 559 (M+H).

[0389] Preparation 84 Ethyl 2-[4-bromo-2-[3-[2-[(6-chloro-2-pyridyl)oxymethyl]-5-cyano-phenyl]-3-hydroxy-propyl]-5-methyl-phenyl]acetate (racemic mixture)

[0390] [ka]

[0391] At room temperature, sodium borohydride (130 mg, 3.44 mmol) was added to a suspension of ethyl 2-[4-bromo-2-[3-[2-[(6-chloro-2-pyridyl)oxymethyl]-5-cyano-phenyl]-3-oxo-propyl]-5-methyl-phenyl]acetate (3.8 g, 6.8 mmol) in a mixture of EtOH (40 mL) and THF (20 mL). The mixture was stirred for 15 minutes and then quenched with saturated aqueous NaHCO (25 mL). The quenched mixture was partitioned between EtOAc (500 mL) and water (100 mL). The organic phase was separated, washed with saturated aqueous NaCl (75 mL), dried over MgSO, filtered, and concentrated to give the title compound (3.8 g, 100%), which was carried forward without further purification. ES-MS m / z 557 / 559 / 561 (M+H).

[0392] Preparation 85 2-(5 4 -cyano-6-hydroxy-1 6 -methyl-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 -yl) ethyl acetate (racemic mixture)

[0393] [ka]

[0394] A mixture of bis(tri-tert-butylphosphine)palladium(0) (420 mg, 0.805 mmol), cesium fluoride (2.50 g, 16.3 mmol), ethyl 2-[4-bromo-2-[3-[2-[(6-chloro-2-pyridyl)oxymethyl]-5-cyano-phenyl]-3-hydroxy-propyl]-5-methyl-phenyl]acetate (racemic mixture, 3.00 g, 5.38 mmol), and bis(pinacolato)diboron (2.09 g, 8.07 mmol) in 9:1 MeOH / water (100 mL) was sparged with nitrogen gas at room temperature for 20 minutes. The mixture was then warmed to 70 °C and stirred for 20 hours. After cooling to room temperature, the mixture was filtered through diatomaceous earth and washed with DCM (25 mL). The filtrate was concentrated, and the product was purified by silica gel chromatography using a gradient of EtOAc in DCM. The title compound was obtained as a white solid (408 mg, 17%). ES-MS m / z 443 (M+H).

[0395] Preparation 86 2-(5 4 -cyano-6-hydroxy-1 6 -methyl-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 -yl)acetic acid (racemic mixture)

[0396] [ka]

[0397] 2-(5-Hydroxyethyl 2-methyl-2-propanol) in water (2 mL), 1,4-dioxane (4 mL), and ACN (4 mL) 4 -cyano-6-hydroxy-1 6 -methyl-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4A solution of ethyl 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine (racemic mixture, 458 mg, 1.03 mmol) and 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine (400 mg, 2.82 mmol) was sparged with nitrogen for 10 minutes and stirred at room temperature for 16 hours. Citric acid (15% aqueous solution, 10 mL) was added dropwise, forming a white solid. The suspension was partitioned between DCM (200 mL) and water (50 mL). The aqueous layer was separated and extracted with DCM (5 × 100 mL). The combined organic layers were dried (MgSO), filtered, and concentrated to give the title compound (430 mg, 77% purity, 71% yield), which was used without further purification. ES-MS m / z 415 (M+H).

[0398] Preparation 87 4-(2-(5 4 -cyano-6-hydroxy-1 6 -methyl-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 -yl)acetamido)-3-fluoro-5-((((S)-oxetan-2-yl)methyl)amino)benzoate (mixture of diastereomers)

[0399] [ka]

[0400] 2-(5 4 -cyano-6-hydroxy-1 6 -methyl-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4(2S)-oxetan-2-ylmethyl)acetic acid (racemic mixture, 200 mg, 77% purity, 0.371 mmol), methyl 4-amino-3-fluoro-5-[[(2S)-oxetan-2-ylmethyl]amino]benzoate (104 mg, 0.409 mmol), pyridine (0.300 mL, 3.71 mmol), and 1-propanephosphonic anhydride (50% by weight in DMF, 0.550 mL, 0.933 mmol) were stirred in DMF (4 mL) at room temperature for 21 h. Water (8 mL) was added to give a white precipitate, and the entire mixture was partitioned between half-saturated aqueous NaHCO3 (75 mL) and methylene chloride (200 mL). The organic phase was separated, dried over magnesium sulfate, filtered, and concentrated to give the title compound (265 mg, 70% purity, 77% yield), which was carried forward without further purification. ES-MS m / z 651 (M+H).

[0401] Preparation 88 2-((5 4 -cyano-6-hydroxy-1 6 -methyl-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 -yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (mixture of diastereomers)

[0402] [ka]

[0403] 4-(2-(5 4 -cyano-6-hydroxy-1 6 -methyl-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4A solution of methyl 5-((((S)-oxetan-2-yl)methyl)acetamido)-3-fluoro-5-((((S)-oxetan-2-yl)methyl)amino)benzoate (mixture of diastereomers, 235 mg, 70% purity, 0.253 mmol) was heated at 55° C. for 18 hours. The mixture was warmed at 60° C. for 3 hours and at 65° C. for 48 hours. The mixture was cooled to room temperature, concentrated, and purified by silica gel chromatography using a gradient of EtOAc in hexanes to give the title compound as a brown oil (99 mg, 62%). ES-MS m / z 633 (M+H).

[0404] Preparation 89 4-(2-(5 4 -cyano-6-hydroxy-1 6 -methyl-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 -yl)acetamido)-3-((((S)-oxetan-2-yl)methyl)amino)benzoate (mixture of diastereomers)

[0405] [ka]

[0406] 2-(5 4 -cyano-6-hydroxy-1 6 -methyl-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4A mixture of (2S)-oxetan-2-yl)acetic acid (racemic mixture, 200 mg, 77% purity, 0.371 mmol), methyl 4-amino-3-[[(2S)-oxetan-2-yl]methylamino]benzoate (96 mg, 0.40 mmol), pyridine (0.300 mL, 3.71 mmol), and 1-propanephosphonic anhydride (50% by weight in DMF, 0.550 mL, 0.933 mmol) in DMF (4 mL) was stirred at room temperature for 21 hours. Addition of water (8 mL) gave a white precipitate, which was filtered, rinsed with additional water (10 mL), and dried under vacuum to give the title compound as a white solid (204 mg, 83% purity, 60% yield). ES-MS m / z 635 (M+H).

[0407] Preparation 90 2-((5 4 -cyano-6-hydroxy-1 6 -methyl-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 -yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (Isomer 1 and Isomer 2)

[0408] [ka]

[0409] 4-(2-(5 4 -cyano-6-hydroxy-1 6 -methyl-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4A solution of methyl 3-((((S)-oxetan-2-yl)methyl)acetamido)-3-((((S)-oxetan-2-yl)methyl)amino)benzoate (mixture of diastereomers, 204 mg, 83% purity, 0.267 mmol) was heated at 55° C. for 18 h. The mixture was cooled to RT, concentrated, and purified by silica gel chromatography using a gradient of EtOAc in hexanes to give the title compound as a white solid (mixture of diastereomers, 165 mg, 99%). ES-MS m / z 615 (M+H).

[0410] The diastereomeric mixture was dissolved in MeOH (3 mL) and DCM (3 mL), filtered, and eluted through a Chiralpak® AS-H column (30 × 250 mm) using 40% iPrOH (w / 0.2% IPAm):60% CO at 90 mL / min to give Isomer 1 (first-eluting isomer) as a white solid (48.9 mg, >99% de) and Isomer 2 (second-eluting isomer) as a white solid (46.5 mg, >99% de). Both isomers: ES-MS m / z 615.2.0 (M+1).

[0411] Preparation 91 2-((2-allyl-4-chlorobenzyl)oxy)-6-chloropyridine

[0412] [ka]

[0413] A mixture of 2-chloro-6-[(4-chloro-2-iodo-phenyl)methoxy]pyridine (25.2 g, 66.3 mmol), bis(triphenylphosphine)palladium(II) dichloride (2.4 g, 3.4 mmol), potassium carbonate (18.6 g, 135 mmol), and allylboronic acid pinacol ester (19 mL, 98.3 mmol) was stirred at 90 °C in a mixture of 1,4-dioxane (150 mL) and water (6 mL). After 5.5 h, the reaction mixture was cooled to room temperature and filtered through a pad of diatomaceous earth and magnesium sulfate. The filtrate was concentrated. The crude product was purified by silica gel chromatography using a gradient of EtOAc and hexane to give 16.75 g of the title compound (86%). ES-MS m / z 294 / 296 (M+H).

[0414] Preparation 92 E)-2-(4-bromo-2-(3-(5-chloro-2-(((6-chloropyridin-2-yl)oxy)methyl)phenyl)allyl)phenyl)acetic acid and 2-[4-Bromo-2-[(E)-3-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]phenyl]prop-1-enyl]phenyl]acetic acid (Mixture of olefin positional isomers)

[0415] [ka]

[0416] Stirring 2-(4-bromo-2-iodo-phenyl)acetic acid (15.73 g, 30.45 mmol), 2-((2-allyl-4-chlorobenzyl)oxy)-6-chloropyridine (8.35 g, 28.4 mmol), TEA (7.7 mL, 55 mmol), palladium(II) acetate (320 mg, 1.42 mmol), and 2-(dicyclohexylphosphino)biphenyl (975 mg, 2.78 mmol) in DMF (60 mL) was stirred at 90° C. under nitrogen for 16 h. The reaction mixture was cooled to room temperature, and 15% aqueous citric acid (200 mL) was added. The resulting yellow solution was separated from the brown oil in the flask by decanting. The yellow solution was extracted with EtOAc (100 mL) and diluted with additional EtOAc (400 mL), which was used to dissolve the brown oil in the reaction flask. The resulting solution was washed with water (200 mL), half-saturated aqueous NaHCO3 (3 x 100 mL), and saturated aqueous NaCl (200 mL), then dried over magnesium sulfate, filtered, and concentrated. The mixture of title compounds was obtained as a brown foam (15 g), which was carried forward without further purification. ES-MS m / z 508 (M+H).

[0417] Preparation 93 (S,E)-4-(2-(4-bromo-2-(3-(5-chloro-2-(((6-chloropyridin-2-yl)oxy)methyl)phenyl)allyl)phenyl)acetamido)-3-methoxy-5-((oxetan-2-ylmethyl)amino)benzoate methyl and Methyl 4-[[2-[4-bromo-2-[(E)-3-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]phenyl]prop-1-enyl]phenyl]acetyl]amino]-3-methoxy-5-[[[(2S)-oxetan-2-yl]methyl]amino]benzoate (mixture of olefin positional isomers)

[0418] [ka]

[0419] (E)-2-(4-bromo-2-(3-(5-chloro-2-(((6-chloropyridin-2-yl)oxy)methyl)phenyl)allyl)phenyl)acetic acid and 2-[4-bromo-2-[(E)-3-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]phenyl]prop-1-enyl]phenyl]acetic acid (mixture of olefin positional isomers, 7.15 g, 14.1 mmol), 4-amino-3-methoxy- A solution of methyl 5-[[(2S)-oxetan-2-yl]methylamino]benzoate (4.03 g, 15.1 mmol), pyridine (5.6 mL, 69 mmol), and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (50% in DMF, 21 mL, 35 mmol) in DMF (28 mL) was stirred at room temperature for 5.25 h, and water (150 mL) was added. The resulting paste was dissolved in EtOAc. The aqueous layer was separated and extracted with additional EtOAc (100 mL). The organic layers were combined, washed with water (100 mL), dried over MgSO4, filtered, and concentrated to give the title product (13 g), which was carried forward without purification. ES-MS m / z 756.2 (M+H).

[0420] Preparation 94 (S,E)-2-(4-bromo-2-(3-(5-chloro-2-(((6-chloropyridin-2-yl)oxy)methyl)phenyl)allyl)benzyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate and Methyl 2-[[4-bromo-2-[(E)-3-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]phenyl]prop-1-enyl]phenyl]methyl]-7-methoxy-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (mixture of olefin positional isomers)

[0421] [ka]

[0422] A solution of methyl (S,E)-4-(2-(4-bromo-2-(3-(5-chloro-2-(((6-chloropyridin-2-yl)oxy)methyl)phenyl)allyl)phenyl)acetamido)-3-methoxy-5-((oxetan-2-ylmethyl)amino)benzoate and methyl 4-[[2-[4-bromo-2-[(E)-3-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]phenyl]prop-1-enyl]phenyl]acetyl]amino]-3-methoxy-5-[[[(2S)-oxetan-2-yl]methyl]amino]benzoate (mixture of olefin regioisomers, 13 g, 14 mmol) in a mixture of 1,2-dichloroethane (32 mL) and acetic acid (32 mL) was heated at 50° C. for 18 hours. The temperature was increased to 60° C. for 1 hour and then cooled to room temperature. The mixture was concentrated and the product was purified by silica gel chromatography using a gradient of EtOAc and hexanes to give the title compound (7.1 g, 73%, mixture of olefin regioisomers). ES-MS m / z 738 (M+H).

[0423] Preparation 95 (S,E)-2-((5 4 -chloro-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphan-6-ene-1 4 -yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester and (S,E)-2-((5 4 -chloro-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphan-7-ene-1 4 -yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (mixture of olefin positional isomers)

[0424] [ka]

[0425] [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (627 mg, 0.848 mmol), bis(pinacolato)diboron (2.48 g, 9.77 mmol), potassium acetate (2.21 g, 22.5 mmol), and (S,E)-2-(4-bromo-2-(3-(5-chloro-2-(((6-chloropyridin-2-yl)oxy)methyl)phenyl)allyl)benzyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate and 2-[[4-bromo-2-[(E A mixture of methyl 3-[5-chloro-2-[(6-chloro-2-pyridyl)oxymethyl]phenyl]prop-1-enyl]phenyl]methyl]-7-methoxy-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (6.0 g, 8.1 mmol, mixture of olefin regioisomers) was heated at 90° C. for 3.5 h, after which additional bis(pinacolato)diboron (440 mg, 1.7 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (160 mg, 0.22 mmol) were added and heated for an additional 3.5 h. The mixture was cooled to room temperature and filtered through a pad of silica gel. The silica gel and reaction flask were washed with dioxane (160 mL), and the filtrate was treated with chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (1.0 g, 1.2 mmol), water (40 mL), and tribasic potassium phosphate (5.4 g, 25 mmol). The solution was heated at 55 °C for 1 h 20 min. After cooling to room temperature, the reaction mixture was partitioned between EtOAc (200 mL) and half-saturated aqueous NaCl (100 mL). The organic layer was separated, dried over MgSO4, filtered, and concentrated. The product was purified by silica gel chromatography using a gradient of EtOAc and hexane to give the title compound as an orange-white solid (1.8 g, 36%, mixture of olefin regioisomers). ES-MS m / z 622 (M+H).

[0426] Preparation 96 2-((54 -Chloro-6-hydroxy-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 -yl)methyl)-4-methoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate and (S)-2-((5 4 -chloro-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 -yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester

[0427] [ka]

[0428] At room temperature, a solution of borane dimethyl-sulfide complex in THF (1 M, 0.700 mL, 7.52 mmol) was added to (S,E)-2-((5 4 -chloro-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphan-6-ene-1 4To a solution of methyl (S,E)-2-((54-chloro-3-oxa-2(2,6)-pyridin-1(1,3),5(1,2)-dibenzenacyclooctaphan-7-en-14-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate and methyl (S,E)-2-((54-chloro-3-oxa-2(2,6)-pyridin-1(1,3),5(1,2)-dibenzenacyclooctaphan-7-en-14-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (mixture of olefin isomers, 1.55 g, 2.49 mmol) was added over 5 minutes. The reaction was stirred at room temperature for 4 hours, then water (10 mL) and sodium perborate tetrahydrate (4.0 g, 26 mmol) were carefully added. After 2.5 hours, the reaction mixture was filtered through diatomaceous earth and concentrated. The crude residue was partitioned between EtOAc (200 mL) and saturated aqueous NaHCO3 (100 mL). The EtOAc was separated, washed with saturated aqueous NaCl (2 x 75 mL), dried over MgSO4, filtered, and concentrated to give the crude product as a yellow powder (1.55 g). The product mixture contained a 1:3 ratio of des-hydroxy and hydroxy products and was used in the next step without further purification. Hydroxy product ES-MS m / z 640.0 (M+1). Des-hydroxy product: ES-MS m / z 624.0 (M+1).

[0429] Preparation 97 4-[(6-chloro-2-pyridyl)oxymethyl]-3-iodobenzonitrile

[0430] [ka]

[0431] A mixture of 4-(bromomethyl)-3-iodo-benzonitrile (20 g, 62 mmol), 6-chloropyridin-2-ol (8.5 g, 65 mmol), and silver carbonate (17.1 g, 62.0 mmol) in 1,4-dioxane (600 mL) was stirred at 70° C. for 24 h. The mixture was recharged with 6-chloropyridin-2-ol (1.6 g, 12 mmol) and silver carbonate (3.5 g, 13 mmol) and stirred at 70° C. for 5 h and at room temperature for 18 h. The mixture was filtered through a pad of silica, rinsed with DCM, and concentrated to give 24.5 g of the title compound (107%). ES-MS m / z 371 (M+H) + .

[0432] Preparation 98 4-[(6-chloro-2-pyridyl)oxymethyl]-3-[(E)-2-ethoxyvinyl]benzonitrile

[0433] [ka]

[0434] A solution of 4-[(6-chloro-2-pyridyl)oxymethyl]-3-iodo-benzonitrile (9.2 g, 25 mmol), 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.5 mL, 31 mmol), bis(triphenylphosphine)palladium(II) dichloride (900 mg, 1.27 mmol), and potassium phosphate (2.0 M in water, 40 mL, 80 mmol) in THF (140 mL) was stirred under reflux for 4 h. The solution was diluted with water (150 mL) and EtOAc (200 mL). The aqueous layer was extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with water (100 mL) and saturated aqueous NaCl (100 mL) and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 5-50% EtOAc in cyclohexane to give 5.9 g of the title compound (75%). ES-MS m / z 315 (M+H) + .

[0435] Preparation 99 4-[(6-chloro-2-pyridyl)oxymethyl]-3-(2-oxoethyl)benzonitrile

[0436] [ka]

[0437] A mixture of 4-[(6-chloro-2-pyridyl)oxymethyl]-3-[(E)-2-ethoxyvinyl]benzonitrile (3.84 g, 12.0 mmol) and hydrochloric acid (4 M in 1,4-dioxane) (18.0 mL, 72.0 mmol) in THF (40 mL) was stirred at room temperature for 2 hours. Additional hydrochloric acid (4 M in 1,4-dioxane, 40 mL, 40 mmol) was then added, and the mixture was stirred at room temperature for 2 hours and then at 40° C. for an additional 2 hours. After cooling to room temperature, the solvent was removed under reduced pressure to give a residue, which was dissolved in MTBE (100 mL). Water (100 mL) was added, and the mixture was stirred at room temperature for 5 minutes. The organic layer was separated, and the aqueous layer was extracted with MTBE (3×100 mL). The combined organic layers were washed with 2 M aqueous sodium carbonate (2 x 100 mL), water (100 mL), saturated aqueous NaCl (100 mL), and dried over sodium sulfate. The organic mixture was filtered through a pad of silica gel and the solvent was removed under reduced pressure to give the title compound as a brown solid (5.46 g, 80%). ES-MS m / z 287 (M+H). + .

[0438] Preparation 100 4-[(6-chloro-2-pyridyl)oxymethyl]-3-(2-hydroxybut-3-enyl)benzonitrile (racemic mixture)

[0439] [ka]

[0440] A mixture of 4-[(6-chloro-2-pyridyl)oxymethyl]-3-(2-oxoethyl)benzonitrile (5.45 g, 19.0 mmol) in dry THF (100 mL) was cooled to −20° C. Then, vinylmagnesium bromide solution (1.0 M in THF, 57 mL, 57 mmol) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. The mixture was cooled to −10° C., and additional vinylmagnesium bromide solution (1.0 M in THF, 20 mL, 20 mmol) was added, and the mixture was stirred at room temperature for another 30 minutes. After cooling to −10° C., the reaction was quenched with 5% aqueous citric acid (100 mL), and EtOAc (100 mL) was added. The mixture was stirred at room temperature for 10 minutes, the organic phase was separated, and the aqueous phase was extracted with EtOAc (3×100 mL). The combined organic layers were washed with water (100 mL), saturated aqueous NaCl (100 mL), dried over sodium sulfate, and the solvent was removed under reduced pressure to give a residue that was purified by column chromatography (5% to 50% EtOAc in cyclohexane) to give the title compound as a colorless oil that solidified on standing (1.85 g, 31%). ES-MS m / z 315 (M+H). + .

[0441] Preparation 101 2-[4-bromo-2-[4-[2-[(6-chloro-2-pyridyl)oxymethyl]-5-cyano-phenyl]-3-oxo-butyl]phenyl]acetic acid ethyl ester

[0442] [ka]

[0443] A mixture of 4-[(6-chloro-2-pyridyl)oxymethyl]-3-(2-hydroxybut-3-enyl)benzonitrile (racemic mixture, 1.8 g, 5.7 mmol), ethyl 2-(4-bromo-2-iodo-phenyl)acetate (2.50 g, 6.78 mmol), and triethyl acetonitrile (2.0 mL, 14 mmol) in ACN (20 mL) was degassed (N bubbling) at room temperature for 10 min. Palladium(II) acetate (0.134 g, 0.597 mmol) was then added portionwise, and the mixture was heated at 85 °C for 3 h. After cooling to room temperature, the solvent was removed under reduced pressure to give a brown residue, which was purified by column chromatography (5%-70% mixture of cyclohexane / EtOAc as eluent) to give the title compound as a white solid (1.51 g, 47%). ES-MS m / z 555, 557 and 558 (M+H) + .

[0444] Preparation 102 Ethyl 2-[4-bromo-2-[4-[2-[(6-chloro-2-pyridyl)oxymethyl]-5-cyano-phenyl]-3-hydroxy-butyl]phenyl]acetate (racemic mixture)

[0445] [ka]

[0446] A solution of ethyl 2-[4-bromo-2-[4-[2-[(6-chloro-2-pyridyl)oxymethyl]-5-cyano-phenyl]-3-oxo-butyl]phenyl]acetate (1.0 g, 1.8 mmol) in EtOH (8.0 mL) and THF (BHT stabilized) (4.5 mL) was cooled to 0 °C. Sodium borohydride (100 mg, 2.64 mmol) was then added portionwise, and the mixture was stirred at room temperature for 30 minutes. After cooling to 0 °C, the reaction was quenched with saturated aqueous sodium bicarbonate (10.0 mL), and EtOAc (20.0 mL) was added. The organic layer was separated, and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water (25 mL), saturated aqueous NaCl (25 mL), and the solvent was removed under reduced pressure to give a residue that was purified by silica gel chromatography (5-75% EtOAc in cyclohexane) to give the title compound (0.99 g, 99%) as a colorless oil that solidified on standing. ES-MS m / z 557, 559, and 561 (M+H). + .

[0447] Preparation 103 Ethyl 2-[2-[(4-[2-[(6-chloro-2-pyridyl)oxymethyl]-5-cyano-phenyl]-3-hydroxy-butyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate (racemic mixture)

[0448] [ka]

[0449] A mixture of ethyl 2-[4-bromo-2-[4-[2-[(6-chloro-2-pyridyl)oxymethyl]-5-cyanophenyl]-3-hydroxybutyl]phenyl]acetate (racemic mixture, 940 mg, 1.68 mmol), bis(pinacolato)diboron (1.31 g, 5.06 mmol), and potassium 2-ethylhexanoate (1.29 g, 6.72 mmol) in 1,4-dioxane (25 mL) was degassed by argon bubbling at room temperature for 15 minutes. Then, bis(triphenylphosphine)palladium(II) dichloride (120 mg, 0.167 mmol) was added, and the mixture was stirred at 60° C. for 18 hours. After cooling to room temperature, the solvent was removed under reduced pressure to give a black residue, which was purified by filtration through a pad of silica gel using DCM as eluent to give the title compound as a light brown solid (1.21 g, 1.845 mmol, 100%). ES-MS m / z 605 and 607 (M+H). + .

[0450] Preparation 104 2-(5 4 -cyano-7-hydroxy-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane-1 4 -yl) ethyl acetate (racemic mixture)

[0451] [ka]

[0452] A mixture of ethyl 2-[2-[(4-[2-[(6-chloro-2-pyridyl)oxymethyl]-5-cyano-phenyl]-3-hydroxy-butyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate (racemic mixture, 1.175 g, 1.942 mmol) in THF (BHT stabilized) (200 mL) was degassed by bubbling nitrogen through at room temperature for 15 min. Then, degassed (N bubbling for 10 min) 1 M aqueous potassium phosphate tribasic solution (20 mL) was added, and the mixture was degassed (N bubbling) for another 10 min at room temperature. Finally, X-Phos-Pd-G2-[chloro(2-dicyclohexylphosphino-2' ,4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)] (160 mg, 0.1993 mmol) was added portionwise, and the mixture was stirred at 70 °C for 45 min. After cooling to room temperature, EtOAc (100 mL) was added. The organic phase was separated, and the aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with water (50 mL), saturated aqueous NaCl (50 mL), and the solvent was removed under reduced pressure to give a brown oil, which was purified by silica gel chromatography (10 to 100% EtOAc in cyclohexane) to give the title compound as a white solid (243 mg, 28%). ES-MS m / z 443 and 444 (M+H). + .

[0453] Preparation 105 2-(5 4 -cyano-7-hydroxy-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane-1 4 -yl)acetic acid (racemic mixture)

[0454] [ka]

[0455] 2-(5-Hydroxy-2-methyl-2-methyl-1,2-diol) in ACN (5.0 mL), THF (1.7 mL) and water (1.7 mL) 4-cyano-7-hydroxy-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane-1 4 A mixture of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (racemic mixture, 225 mg, 0.493 mmol) and ethyl 2-methyl-2-benzoate (225 mg, 0.493 mmol) was degassed (N bubbling) at room temperature for 10 minutes. Then, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (210 mg, 1.47 mmol) was added portionwise, and the resulting mixture was stirred at 50° C. for 1.0 hour. After cooling to room temperature, water (5 mL) was added, and 5% aqueous citric acid was added dropwise to a pH of approximately 5, and the mixture was stirred at room temperature for 15 minutes. Then, additional water (10 mL) was added, and the mixture was stirred for an additional 30 minutes. The resulting solid was filtered, washed with water (5 mL), and dried under reduced pressure at room temperature to give the title compound (154 mg, 75.4%) as a white solid. ES-MS m / z 415 and 416 (M+H) + .

[0456] Preparation 106 2-((5 4 -cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclonaphane-1 4 Methyl-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (mixture of diastereomers)

[0457] [ka]

[0458] 2-(5) in pyridine (0.4 mL) and anhydrous DMF (2 mL) 4 -cyano-7-hydroxy-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane-1 4A mixture of (2S)-oxetan-2-yl)acetic acid (150 mg, 0.3620 mmol) and methyl 4-amino-3-[[(2S)-oxetan-2-yl]methylamino]benzoate (121 mg, 0.51213 mmol) was stirred at room temperature. Then, 1.68 M of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide in EtOAc (0.67 mL, 1.1 mmol) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction was quenched with 2 M aqueous sodium carbonate (10 mL), and EtOAc (10 mL) was added. The organic layer was separated, and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with water (10 mL), saturated aqueous NaCl (10 mL), dried over sodium sulfate, and the solvent was removed under reduced pressure to give a brown oil, which was dissolved in acetic acid (7.5 mL) and 2-chlorotoluene (7.5 mL). The mixture was stirred at 60° C. for 18 hours. After cooling to room temperature, the solvent was removed under reduced pressure to give a residue, which was purified by column chromatography (0-50% EtOAc in DCM) to give the title compound as a colorless glassy solid (101 mg, 45%). ES-MS m / z 615 and 616 (M+H). + .

[0459] Example 1 (S)-2-((5 6 -Cyano-1 6 -methyl-3-oxa-2(2,6),5(3,2)-dipyridina-1(1,3)-benzenacyclooctaphane-1 4 -yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0460] [ka]

[0461] (S)-2-((5 6 -Cyano-1 6-methyl-3-oxa-2(2,6),5(3,2)-dipyridina-1(1,3)-benzenacyclooctaphane-1 4 To a solution of methyl 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (95 mg, 0.16 mmol) was added 1,5,7-triazabicyclo[4.4.0]dec-5-ene (85 mg, 0.60 mmol). The mixture was stirred at 30 °C for 5 h. An additional portion of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (10 mg, 0.07 mmol) was added, and the mixture was stirred at 35 °C for 2 h. The crude reaction solution was loaded onto silica, and the residue was purified by silica gel chromatography using a gradient of 0 to 10% MeOH in DCM to give 57 mg of the title compound (59%). ES-MS m / z 586 (M+H).

[0462] Example 2 (S)-2-((5 4 -cyano-3-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

[0463] [ka]

[0464] (S)-2-((5 4 -cyano-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4To a solution of methyl 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (85 mg, 0.15 mmol), 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine (81 mg, 0.6 mmol) was added. The mixture was stirred at 45 °C for 2 h. The reaction was quenched with formic acid to pH 6-7 and extracted with chloroform / isopropanol (3:1). The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The solid was purified by C18 reverse-phase chromatography using a gradient of 55-80% ACN in aqueous ammonium acetate to give 29 mg of the title compound (35%). ES-MS m / z 571 (M+H).

[0465] Example 3 (S)-2-((5 6 -Cyano-1 6 -methyl-3-oxa-2(2,6),5(3,4)-dipyridina-1(1,3)-benzenacyclooctaphane-1 4 -yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0466] [ka]

[0467] (S)-2-((5 6 -Cyano-1 6 -methyl-3-oxa-2(2,6),5(3,4)-dipyridina-1(1,3)-benzenacyclooctaphane-1 4A solution of methyl 1-(oxetan-2-ylmethyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (105 mg, 0.148 mmol) and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (60 mg, 0.42 mmol) was stirred at room temperature overnight. The pH was adjusted to pH = 5 with formic acid and then concentrated under reduced pressure. The residue was purified by C18 reverse-phase chromatography using a gradient of 28-68% ACN in water containing 0.225% formic acid to give 30 mg of the title compound (32%). ES-MS m / z 616 (M+H).

[0468] Example 4 2-((5 4 -cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 -yl)methyl)-4-methoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (isomer 1)

[0469] [ka]

[0470] 2-((5 4 -Chloro-6-hydroxy-3-oxa-2(2,6)-pyridino-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4A mixture of ((S)-oxetan-2-yl)methyl)-4-methoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (isomer 1, see Example 21; 35 mg, 0.056 mmol), potassium ferrocyanide trihydrate (40 mg, 0.11 mmol), chloro(crotyl)(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)palladium(II) (9 mg, 0.01 mmol), potassium carbonate (8 mg, 0.06 mmol), water (0.75 mL), and 1,4-dioxane (2 mL) was heated at 75°C for 1 hour. The mixture was cooled to room temperature, adsorbed onto diatomaceous earth (approximately 10 g), and dried in a vacuum oven at 30°C for 16 hours. The product was purified by reverse-phase flash chromatography on a C18 column eluted with a gradient of 10-90% ACN in an aqueous mobile phase containing ammonium bicarbonate. The appropriate fractions were lyophilized to give the title compound as a white solid (10.5 mg, 31%). ES-MS m / z 617.4 (M+1).

[0471] Example 5 2-((5 4 -cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 -yl)methyl)-4-methoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (isomer 2)

[0472] [ka]

[0473] 2-((5 4 -Chloro-6-hydroxy-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4A mixture of ((S)-oxetan-2-yl)methyl)-4-methoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (isomer 2, see Example 21; 15 mg, 0.024 mmol), potassium ferrocyanide trihydrate (18 mg, 0.049 mmol), chloro(crotyl)(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)palladium(II) (4 mg, 0.006 mmol), potassium carbonate (4 mg, 0.029 mmol), water (0.5 mL), and 1,4-dioxane (1 mL) was heated at 90°C for 1.25 hours. The mixture was cooled to room temperature, adsorbed onto diatomaceous earth (approximately 10 g), and dried in a vacuum oven at 45°C for 2 hours. The product was first purified by reverse-phase flash chromatography using a C18 column, eluted with a gradient of ACN in an aqueous mobile phase containing ammonium bicarbonate, followed by SCF chromatography on a Chiralpak® AD-H column (4.6 × 150 mm), eluted with 40% isopropanol in CO at a flow rate of 5 mL / min to give the title compound as a white solid (7.8 mg, 54%). ES-MS m / z 617.2 (M+1).

[0474] Example 6 2-((5 4 -cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 -yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (isomer 1)

[0475] [ka]

[0476] 2-((5 4-cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 A solution of methyl 1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (isomer 1, 102 mg, 0.170 mmol) was purged with nitrogen for 5 minutes, and then 1,5,7-triazabicyclo[4.4.0]dec-5-ene (74 mg, 0.52 mmol) was added. The mixture was stirred at 60° C. for 70 minutes and then cooled to ambient temperature. Aqueous citric acid (5% w / v) was added and the organic solvent was removed under a stream of nitrogen. The resulting solid was collected by filtration and washed with water. The filter cake was dried in a vacuum oven at 40° C. overnight to give the title compound (84 mg, 81%) as a white solid. ES-MS m / z 587 (M+H) + .

[0477] Example 7 2-((5 4 -cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 -yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (isomer 2)

[0478] [ka]

[0479] 2-((5 4 -cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 The title compound was prepared essentially as described in Example 6 using methyl 1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (isomer 2). ES-MS m / z 587 (M+H) + .

[0480] Example 8 2-((5 4 -cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 -yl)methyl)-4-ethoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (isomer 1)

[0481] [ka]

[0482] 2-((5 4 -cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 The title compound was prepared essentially as described in Example 6 using methyl 4-ethoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (isomer 1). ES-MS m / z 631 (M+H) + .

[0483] Example 9 2-((5 4 -cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 -yl)methyl)-4-ethoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (isomer 2)

[0484] [ka]

[0485] 2-((5 4 -cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4The title compound was prepared essentially as described in Example 6 using methyl 4-ethoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (isomer 2). ES-MS m / z 631 (M+H) + .

[0486] Example 10 2-((5 4 -cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 -yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (isomer 1)

[0487] [ka]

[0488] 2-((5 4 -cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 The title compound was prepared essentially as described in Example 6 using methyl 4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (isomer 1). ES-MS m / z 605 (M+H) + .

[0489] Example 11 2-((5 4 -cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 -yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (isomer 2)

[0490] [ka]

[0491] 2-((5 4 -cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 The title compound was prepared essentially as described in Example 6 using methyl 4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (isomer 2). ES-MS m / z 605 (M+H) + .

[0492] Example 12 2-((5 4 -cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 -yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid (mixture of diastereomers)

[0493] [ka]

[0494] In a reaction vessel, 4 -((6-bromo-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-6-hydroxy-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-5 4A mixture of 1,2-diphenylphosphino-9,9-dimethylxanthene (8 mg, 0.013 mmol), benzonitrile (81 mg, 0.13 mmol), bis(benzonitrile)palladium chloride (5.4 mg, 0.013 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (8 mg, 0.013 mmol) was charged into the vessel. The vessel was purged with nitrogen, and anhydrous DMF (2.5 mL) was added. The mixture was stirred at ambient temperature for 5 minutes while purging with nitrogen, then phenyl formate (75 μL, 0.64 mmol) and TEA (110 μL, 0.78 mmol) were added, and the vessel was sealed. The mixture was stirred at ambient temperature for 10 minutes, then at 60° C. in a preheated bath for 7 hours. The mixture was cooled to ambient temperature, and aqueous citric acid (5% w / v) was added. The solid was collected by vacuum filtration and washed with water. The filter cake was stirred in THF (1.3 mL) and treated with 1 M aqueous lithium hydroxide (0.30 mL, 0.30 mmol, added in six portions over 2 h). After 2.5 h, aqueous citric acid (5% w / v) was added. The crude solid was collected by filtration, washed with water, and dried under reduced pressure. The dried solid was dissolved in DMSO and purified by reverse-phase flash chromatography (C18 column, gradient 10-100% ACN in aqueous NH4CO3) to afford the title compound (15 mg, 19%) as a light brown solid. ES-MS m / z 588 (M+H) + .

[0495] Example 13 (S)-2-((5 5 -chloro-3-oxa-2,5(2,6)-dipyridina-1(1,3)-benzenacyclononaphane-1 4 -yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0496] [ka]

[0497] Methyl (S)-2-((5 5-chloro-3-oxa-2,5(2,6)-dipyridina-1(1,3)-benzenacyclononaphane-1 4 To a solution of methyl 4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (107 mg, 0.167 mmol) was added 1,5,7-triazabicyclo[4.4.0]dec-5-ene (75 mg, 0.53 mmol). The mixture was stirred at 55 °C for 3.5 h. The crude reaction solution was loaded onto diatomaceous earth, and the residue was purified by C18 reverse-phase flash chromatography using a gradient of 0 to 100% ACN in 10 mM aqueous ammonium bicarbonate containing 5% MeOH to give 85 mg of the title compound (81%). ES-MS m / z 626 (M+H).

[0498] Example 14 (S)-2-((5 5 -cyano-3-oxa-2,5(2,6)-dipyridina-1(1,3)-benzenacyclononaphane-1 4 -yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0499] [ka]

[0500] (S)-2-((5 5 -chloro-3-oxa-2,5(2,6)-dipyridina-1(1,3)-benzenacyclononaphane-1 4A mixture of methyl 4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (30 mg, 0.047 mmol), palladium(II) trifluoroacetate (11 mg, 0.031 mmol), zinc (2 mg, 0.03 mmol), zinc cyanide (15 mg, 0.13 mmol), and rac-2-(di-t-butylphosphino-1,1'-binaphthyl) (22 mg, 0.054 mmol) was stirred at 80 °C for 16.5 h. The crude reaction mixture was loaded onto diatomaceous earth, and the residue was purified by C18 reverse-phase chromatography using a gradient of 0 to 60% ACN in 0.1% formic acid in water to give 8.5 mg of the title compound (29%). ES-MS m / z 616 (M+H).

[0501] Example 15 (S)-2-((5 5 -cyano-3-oxa-2(2,6),5(2,3)-dipyridina-1(1,3)-benzenacyclooctaphane-1 4 -yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0502] [ka]

[0503] (S)-2-((5 5 -cyano-3-oxa-2(2,6),5(2,3)-dipyridina-1(1,3)-benzenacyclooctaphane-1 4A solution of methyl 4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (137 mg, 0.158 mmol) was sparged with nitrogen. The flask was then charged with 1,5,7-triazabicyclo[4.4.0]dec-5-ene (67 mg, 0.47 mmol), sealed with a septum, and then flushed with nitrogen. The mixture was stirred overnight at ambient temperature and then quenched with aqueous formic acid (0.5 mL) until pH = 4.5. The resulting solid was filtered and dried under vacuum. The residue was purified by reverse-phase chromatography using a C18 column (100 mm × 30 mm × 10 μm) and a mobile phase gradient of 40% to 70% solvent A in solvent B, where solvent A was water containing 0.225% formic acid and solvent B was ACN. The combined fractions were concentrated under reduced pressure to remove organic volatiles, and then the residual aqueous solvent was removed by lyophilization to give 50.2 mg of the title compound as a colorless solid (52%). ES-MS m / z 602.5 (M+1).

[0504] Example 16 (S)-2-((5 5 -chloro-3-oxa-2(2,6),5(2,3)-dipyridina-1(1,3)-benzenacyclooctaphane-1 4 -yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0505] [ka]

[0506] (S)-2-((5 5 -chloro-3-oxa-2(2,6),5(2,3)-dipyridina-1(1,3)-benzenacyclooctaphane-1 4The title compound was prepared essentially as described in Example 15 using methyl 4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate to afford the title compound as a colorless solid. ES-MS m / z 611.5 (M+1).

[0507] Example 17 (S,E)-2-((5 4 -chloro-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphan-6-ene-1 4 -yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0508] [ka]

[0509] (S,E)-2-((5 4 -chloro-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphan-6-ene-1 4 -yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate and methyl (S,E)-2-((5 4 -chloro-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphan-7-ene-1 4A solution of methyl 4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (mixture of olefin regioisomers, 20 mg, 0.032 mmol) and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (10 mg, 0.070 mmol) was sparged with nitrogen. The mixture was then stirred at 45°C (16 h), 50°C (7 h), and 55°C (14 h). After cooling to room temperature, the product was adsorbed onto diatomaceous earth (10 g) and dried under reduced pressure at 50°C for 1 h. The product was loaded onto a C18 column using diatomaceous earth, which was purified using a gradient of 10–90% ACN in an aqueous mobile phase containing 10 mM ammonium bicarbonate to give the title compound (12.5 mg, quantitative yield, single olefin regioisomer) as a white solid. ES-MS m / z 608.0(M+1).

[0510] Example 18 2-((5 4 -cyano-6-hydroxy-1 6 -methyl-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 -yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Isomer 1 - Example 18a and Isomer 2 - Example 18b)

[0511] [ka]

[0512] 2-((5 mL) in water (0.5 mL), 1,4-dioxane (1 mL), and ACN (1 mL) 4 -cyano-6-hydroxy-1 6 -methyl-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4A solution of methyl 4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (99 mg, 0.16 mmol) was sparged with nitrogen for 10 minutes and stirred at 50° C. for 2 hours. The reaction solution was adsorbed onto C18 (25 g), dried in a vacuum oven at 50° C. for 1 hour, and then purified by reverse-phase flash chromatography on a C18 column using a gradient of 5-80% ACN in 10 mM aqueous ammonium carbonate to give the title compound as a white solid (mixture of diastereomers, 93 mg, 95%). The mixture of diastereomers was dissolved in MeOH (6 mL), filtered, and eluted through a Chiralpak® AS-H column (20 × 150 mm) using 35% EtOH:65% CO at a flow rate of 80 mL / min to give Isomer 1 (first eluting isomer, 43 mg, >98% de) and Isomer 2 (second eluting isomer, 41 mg, 91% de). Both Isomer 1 and Isomer 2: ES-MS m / z 619.0 (M+1).

[0513] Example 19 2-((5 4 -cyano-6-hydroxy-1 6 -methyl-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 -yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (isomer 1)

[0514] [ka]

[0515] 2-((5 mL) in water (0.5 mL), 1,4-dioxane (1 mL), and ACN (1 mL) 4 -cyano-6-hydroxy-1 6 -methyl-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4A solution of methyl 1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (isomer 1, 48.9 mg, 0.0796 mmol) was sparged with nitrogen for 10 minutes. 1,5,7-Triazabicyclo[4.4.0]dec-5-ene (30 mg, 0.21 mmol) was added, and the mixture was stirred at 50°C for 2 hours. The reaction solution was adsorbed onto C18 (25 g), dried in a vacuum oven at 50°C for 1 hour, and then purified by reverse-phase flash chromatography on a C18 column using a gradient of 5-80% ACN in 10 mM aqueous ammonium carbonate to give the title compound as a white solid (30 mg, 63%). ES-MS m / z 601.0 (M+H).

[0516] Example 20 2-((5 4 -cyano-6-hydroxy-1 6 -methyl-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 -yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (isomer 2)

[0517] [ka]

[0518] 2-((5 4 -cyano-6-hydroxy-1 6 -methyl-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 The title compound was prepared essentially as described in Example 19 using methyl 1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (isomer 2). ES-MS m / z 601.0 (M+H).

[0519] Example 21 (S)-2-((5 4-chloro-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 -yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 21a)

[0520] [ka] and 2-((5 4 -Chloro-6-hydroxy-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 -yl)methyl)-4-methoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Isomer 1 - Example 21b; Isomer 2 - Example 21c)

[0521] [ka]

[0522] 2-((5 4 -Chloro-6-hydroxy-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 -yl)methyl)-4-methoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate and methyl (S)-2-((5 4 -chloro-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4A mixture of methyl 4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (1.35 g, 2.11 mmol) was stirred in a degassed solution of 1,3,4,6,7,8-hexahydro-2h-pyrimido[1,2-a]pyrimidine (1 g, 7 mmol) in 1:1:1 ACN, THF, and water (10 mL). The mixture was stirred at 40 °C for 18 h, then cooled to room temperature and adsorbed onto diatomaceous earth (20 g). The diatomaceous earth was dried in a vacuum oven at 50 °C for 2 h and then loaded directly onto a silica gel chromatography column for purification. The product mixture was coeluted using a gradient of 0 to 10% MeOH in DCM containing acetic acid (1%) to give the product mixture as a yellow solid (1.35 g).

[0523] After subsequent purification by HPLC using a gradient of 25-40% ACN in 10 mM aqueous ammonium carbonate containing 5% MeOH, the des-hydroxy product (Example 21a) was obtained as a white solid (39 mg, 3%). ES-MS m / z 610.0 (M+1).

[0524] After further purification of the mixture by preparative HPLC using a gradient of 5 to 100% ACN in 0.1% aqueous formic acid, the hydroxy product diastereomeric mixture was obtained as a white solid (190 mg, 14%). ES-MS m / z 626.0 (M+1). A 150 mg portion of the diastereomeric mixture was dissolved in a mixture of DCM (1.5 mL) and MeOH (8 mL). The resulting solution was filtered and eluted through a Chiralpak® AS-H column (21 × 150 mm) using 20% ​​MeOH (w / 0.5% DMEA):80% CO at a flow rate of 80 mL / min to afford Isomer 1 (first-eluting isomer—Example 21b) as a white solid (66.2 mg, >99% de) and Isomer 2 (second-eluting isomer—Example 21c) as a white solid (71.9 mg, 94.2% de). Both Isomer 1 and Isomer 2: ES-MS m / z 626.0 (M+1).

[0525] Example 22 (S)-2-((5 4 -chloro-6-oxo-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 -yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0526] [ka]

[0527] 2-((5 4 -Chloro-6-hydroxy-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclooctaphane-1 4 A solution of ((S)-oxetan-2-yl)methyl)-4-methoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (25 mg, 1:1 diastereomeric mixture, 0.040 mmol) and Dess-Martin periodinane (18 mg, 0.042 mmol) was stirred at room temperature for 2.5 h. The reaction mixture was adsorbed onto diatomaceous earth (10 g), dried in a vacuum oven at 50 °C for 1.5 h, and purified by reverse-phase flash chromatography on a C18 column using a gradient of 10 to 80% ACN in 10 mM aqueous ammonium bicarbonate to give the title compound as a white solid (21 mg, 84%). ES-MS m / z 624.0 (M+1).

[0528] Example 23 2-((5 4 -cyano-7-hydroxy-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclononaphane-1 4 -yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Isomer 1 - Example 23a, and Isomer 2 - Example 23b)

[0529] [ka]

[0530] 2-((5 4 -cyano-6-hydroxy-3-oxa-2(2,6)-pyridina-1(1,3),5(1,2)-dibenzenacyclonaphane-1 4 A mixture of methyl 1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (mixture of diastereomers, 96 mg, 0.1562 mmol) and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (67 mg, 0.47 mmol) was degassed for 15 minutes by gently bubbling argon through the mixture at room temperature. Then, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (67 mg, 0.47 mmol) was added portionwise, and the mixture was heated at 65°C for 3 hours. After cooling to 0°C, 5% aqueous citric acid was added until pH = 5, followed by careful addition of water (5.0 mL), and the mixture was stirred at room temperature for an additional 30 minutes. The resulting solid was filtered, washed with water (10 mL), and dried under vacuum at 40°C for 72 hours to give a mixture of diastereomers of the title compound as a pale pink solid (82 mg, 87%).

[0531] A portion of the diastereomeric mixture (65 mg, 0.108 mmol) was purified by supercritical fluid chromatography [Column: Chiralpack® IH (20 × 250 mm; 5 μm); Mobile phase: Solvent A - CO2, Solvent B - MeOH + 0.5% DMEA, isocratic 30% Solvent B in Solvent A; Column temperature 40 °C; Flow rate: 80 mL / min] to give Isomer 1 (Example 23a, first-eluting isomer, 18.7 mg, 39%) and Isomer 2 (Example 23b, second-eluting isomer, 18.7 mg, 39%). Both Isomer 1 and Isomer 2: ES-MS m / z 601 and 602 (M+H). + .

[0532] Biological assays Human GLP-1 receptor HEK293 cell cAMP assay GLP-1 receptor functional activity was evaluated at expression densities of 581±94 (n=6) and 104±12 (n=5) fmol / mg protein ([ 125 [I] cAMP formation in a HEK293 clonal cell line expressing the human GLP-1R (NCBI accession number NP_002053) with GLP-1(7-36)NH2 (determined using a homologous competitive binding assay). hGLP-1R receptor-expressing cells are treated with compounds (20-point concentration-response curve in DMSO, 2.75x LabcyteEcho direct dilution, 384-well plate Corning Catalog No. 3570) in DMEM (Gibco Catalog No. 31053) supplemented with 1x GlutaMAX™ (Gibco Catalog No. 35050), 0.1% bovine casein (Sigma C4765-10ML), 250 μM IBMX (3-isobutyl-1-methylxanthine, Acros Catalog No. 228420010), and 20 mM HEPES (Gibco Catalog No. 15630) in an assay volume of 20 μL (final DMSO concentration 0.5%). After 30 minutes of incubation at 37°C, the resulting increase in intracellular cAMP is quantitatively determined using the CisBio cAMP Dynamic 2 HTRF Assay Kit (62AM4PEJ). Briefly, cAMP-d2 conjugate in cell lysis buffer (10 μL) was added, followed by antibody, anti-cAMP-Eu, also in cell lysis buffer (10 μL). 3+ -cryptate to detect intracellular cAMP levels. The resulting competitive assay is incubated at room temperature 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 665 nm / 620 nm) * The relative EC (10,000) is inversely proportional to the amount of cAMP present and is converted to nM cAMP per well using a cAMP standard curve. The amount of cAMP produced (nM) in each well is converted to a percentage of the maximal response observed for human GLP-1(7-36)NH2. 50 Value and maximum percentage (%) (E max) is derived by nonlinear regression analysis using percent maximum response versus added compound concentration fitted to a four-parameter logistic equation. The EC values ​​for the compounds of Examples 1-23 when tested in the above cAMP assay using HEK293 cells expressing GLP-1R at 581 and 104 fmol / mg were 50 and E max The data are shown in Tables 1 and 2, respectively. These data demonstrate that the compounds of Examples 1 to 23 are agonists of the human GLP-1 receptor.

[0533] [Table 1]

[0534] [Table 2] EC 50 , nM = geometric mean followed by SEM (delta method), number of observations in parentheses. E max , % = arithmetic mean followed by ± SEM, number of observations in parentheses for percent of maximal response to GLP-1(7-36)NH2 at hGLP-1R

Claims

1. formula: 【Chemistry 1】 or a pharmaceutically acceptable salt thereof: wherein -A- is C optionally substituted with OH, halo, or oxo. ３ ~C ４ Alkylene, or C ３ ~C ４ is alkenylene, 【Chemistry 2】 but, 【Transformation 3】 wherein a is the point of attachment to linker A and 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 and X １ , X ２ , X ３ , and X ４ At most two of １ , X ２ , X ３ , and X ４ Two or fewer of these are CR １ and X ５ is N, CH, or CR １ａ and X ６ , X ７ , and X ８ are independently N, CH, or CR １ and X ５ , X ６ , X ７ , and X ８ At most two of ５ , X ６ , X ７ , and X ８ Two or fewer of these are CR １ａ or CR １ and R １ independently at each occurrence, CN, halo, C optionally substituted with OH; １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, C ３ ~C ５ Cycloalkyl, —SO ２ C １ ~C ３ Alkyl, 【Chemistry 4】 wherein each X ９ are independently CH or N, and there is no more than one X in the ring ９ is N, and each R ｅ But H, C １ ~C ３ Haloalkyl, Halo, C ３ ~C ５ Cycloalkyl and optionally OH-substituted C １ ~C ３ alkyl; R ｈ But H, C １ ~C ３ Haloalkyl, Halo, C ３ ~C ５ Cycloalkyl, OH, —NR ｃ R ｄ or C optionally substituted with OH １ ~C ３ Alkyl, 5- or 6-membered heteroaryl or phenyl, wherein the 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 ｄ , -NR ｃ R ｄ or C optionally substituted with OH １ ~C ３ optionally substituted with one or two substituents independently selected from alkyl; R １ａ is CN, halo, C optionally substituted with OH １ ~C ３ Alkyl, C １ ~C ３ haloalkyl, or C １ ~C ３ is an 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 and Y １ , Y ２ , and Y ７ At most one of １ , Y ２ , and Y ７ Two or fewer of these are CR ２ and Y ３ , Y ４ , Y ５ , and Y ６ are independently N, CH, or CR ２ and Y ３ , Y ４ , Y ５ , and Y ６ At most two of ３ , Y ４ , Y ５ , and Y ６ Two or fewer of these are CR ２ and R ２ is independently at each occurrence halo or methyl; Z １ , Z ２ , and Z ３ are independently N, CH, or CR ３ and Z １ , Z ２ , and Z ３ At most two of １ , Z ２ , and Z ３ Two or fewer of these are CR ３ and R ３ But each occurrence is independent, halo; C １ ~C ４ Alkyl; C １ ~C ２ Alkoxy, OH, C １ ~C ３ Alkyl or C １ ~C ３ -OC optionally substituted with haloalkyl ４ ~C ６ Cycloalkyl; C １ ~C ２ Alkoxy, OH, C １ ~C ３ Alkyl or C １ ~C ３ -OC optionally substituted with haloalkyl ４ ~C ６ heterocyclyl; or C １ ~C ２ Alkoxy, OH, —NR ｆ R ｇ , -CONR ｃ R ｄ , CN, halo, or optionally C １ ~C ３ C optionally substituted with one or two substituents selected from 5- or 6-membered heteroaryl substituted with alkyl １ ~C ４ is an alkoxy, R ４ but, 【Transformation 5】 and R ５ が、-CO ２ H、 【Transformation 6】 and R ｃ and R ｄ are each independently H or C １ ~C ３ is alkyl, R ｆ is H or C １ ~C ３ is alkyl, R ｇ But H, C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, C ３ ~C ５ Cycloalkyl, C(O)C １ ~C ３ Alkyl, or C １ ~C ３ Alkyl C ３ ~C ５ a compound which is cycloalkyl.

2. The compound has the formula: 【Transformation 7】 The compound according to claim 1, wherein the compound is represented by the formula: or a pharmaceutically acceptable salt thereof.

3. The compound has the formula: 【Transformation 8】 The compound according to claim 2, wherein the compound is represented by the formula: or a pharmaceutically acceptable salt thereof. 【Request Item 4】 【Chemistry 9】 but, 【Chemistry 10】 The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein:

5. X １ , X ３ , and X ４ is CH, and X ２ But, CR １ and R １ The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein is CN or Cl.

6. X １ is N and X ２ But, CR １ and X ３ and X ４ is CH and R １ The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein is CN.

7. X １ and X ４ is CH, and X ２ But, CR １ and X ３ is N and R １ The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein is CN.

8. X １ and X ３ is CH, and X ２ But, CR １ and X ４ is N and R １ The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein is Cl. 【Request Item 9】 【Chemistry 11】 but, 【Chemistry 12】 The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein:

10. X ５ is N and X ６ But, CR １ and X ７ and X ８ is CH and R １ 10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein is CN or Cl.

11. -A- is -CH ２ CH(OH)CH ２ CH ２ -, -CH(OH)CH ２ CH ２ -, -CH ２ CH ２ CH ２ -, -CH ２ CH ２ CH ２ CH ２ -, -C(O)CH ２ CH ２ -, or -CH=CHCH ２ The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein

12. -B- is -CH ２ The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R is O-.

13. Y １ , Y ２ , and Y ７ The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein all of are CH.

14. Y １ But, CR ２ and Y ２ is CH and Y ７ is CH and R ２ The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein is methyl.

15. Y ３ is N and Y ４ , Y ５ , and Y ６ The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein is CH.

16. Z １ But, CR ３ and R ３ But F, -OCH ３ , or -OCH ２ CH ３ 16. The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein:

17. Z ２ The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein is CH.

18. Z ３ The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein is CH.

19. R ５ But -CO ２ The compound according to any one of claims 1 to 18, wherein R is H, or a pharmaceutically acceptable salt thereof.

20. formula: 【Chemistry 13】 The compound of claim 1, represented by the formula: or a pharmaceutically acceptable salt thereof: wherein X is 【Chemistry 14】 and X １ , X ３ , and X ４ are independently N or CH, and X １ , X ３ , and X ４ is N; R １ is CN or halo, Y １ but CH or CR ２ and R ２ is methyl, Z １ is N, CH, or CR ３ and R ３ But halo or C １ ~C ４ is an alkoxy.

21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.

22. 21. A method of treating type II diabetes in a patient, comprising administering to the patient an effective amount of a compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof.

23. 21. A method of lowering blood glucose levels in a patient, comprising administering to said patient an effective amount of a compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof.

24. 21. A method of treating hyperglycemia in a patient, comprising administering to said patient an effective amount of a compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof.

25. 21. A method of treating obesity in a patient, comprising administering to said patient an effective amount of a compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof.

26. The method of any one of claims 22 to 25, wherein the compound is administered orally.

27. 21. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, for use in therapy.

28. 21. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, for use in the treatment of type II diabetes.

29. 21. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, for use in lowering blood glucose levels.

30. 21. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, for use in the treatment of hyperglycemia.

31. 21. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, for use in the treatment of obesity.

32. 32. The compound or a pharmaceutically acceptable salt thereof for use according to any one of claims 27 to 31, wherein the compound is administered orally.

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