Glucagon-like peptide 1 receptor agonists

Abstract

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

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, WO 2021 / 160127, WO 2021 / 187886, WO 2021 / 1974 64, Chinese Patent Application Publication Nos. 113480534, 113493447, International Publication Nos. 2021 / 219019, 2021 / 244645, 2021 / 249492, Chinese Patent Application Publication Nos. 113801136, 113816948, International Publication Nos. 2021 / 254470, 2021 / 259309, 2022 / 007979, 2022 / 031994, 2022 / 028572, 2022 / 040600, 2022 / 042691, and 2 022 / 068772, 2022 / 078407, 2022 / 078380, 2022 / 078152, Chinese Patent Application Publication No. 114478497, International Publication No. 2022 / 109182, 2022 / 111624, Chinese Patent Application Publication No. 114591296, International Publication No. 2022 / 116693, 2022 / 135572, Chinese Patent Application Publication No. 114634510, 114716423, 114763352, 114805336, International Publication No. These are disclosed in Chinese Patent Application Publication No. 022 / 165076, Chinese Patent Application Publication No. 114907351, International Publication Nos. 2022 / 184849, 2022 / 192428, 2022 / 192430, 2022 / 202864, 2022 / 199458, 2022 / 199661, 2022 / 216094, 2022 / 219495, 2022 / 225914, 2022 / 225941, 2022 / 228490, and International Publication No. 2022 / 235717.

[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. Furthermore, there is a need for more potent small molecule GLP-1R agonists. In particular, there is a need for GLP-1R agonists that are more potent and can be effective at lower doses. Summary of the Invention

[0006] The compounds disclosed herein have GLP-1R agonist activity. Certain compounds of the present invention have in vitro potency at the GLP-1 receptor comparable to that of native GLP-1(7-36)NH2.

[0007] Thus, the present invention provides a compound of formula:

[0008] [ka] During the ceremony,

[0009] [ka] is a phenyl, a 5- or 6-membered heteroaryl, or a pyridone, which phenyl, heteroaryl, or pyridone may optionally be joined by one or two R 1 is replaced by 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, -C(O)NH2,

[0010] [ka] [In the formula, each 9 are independently CH or N, and there is not more than one X in the ring 9 is N, and each R eis 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 d or C1-C3 alkyl optionally substituted with OH; -A- is -CH2O-, -OCH2-, or -CH2NH-, Y 1 , Y 2 , Y 7 , and Y 8 are independently N, CH, or CR 2 and Y 1 , Y 2 , Y 7 , and Y 8 At most one of the following is N and Y 1 , Y 2 , Y 7 , and Y 8 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 , Y5 , and Y 6 Two or fewer of the 2 and R 2 is independently at each occurrence halo or methyl; R 3 is C1-C2 alkoxy, C1-C4 alkoxy optionally substituted with hydroxy or C1-C3 haloalkyl; 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; The present invention provides a compound, or a pharmaceutically acceptable salt thereof.

[0013] Formula I includes all individual enantiomers 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] is one or two R 1 In certain embodiments,

[0020] [ka] is one or two R independently selected from CN, halo, C1-C3 alkyl, C1-C3 alkoxy, or 5-membered heteroaryl; 1 In certain embodiments,

[0021] [ka] is one or two R independently selected from CN, F, CH3, OCH3, or triazole; 1 In a further embodiment,

[0022] [ka] is one or two R independently selected from CN, F, or OCH 1 In yet another embodiment,

[0023] [ka] is phenyl substituted with CN and F, or phenyl substituted with CN and OCH3, preferably phenyl substituted with CN and F.

[0024] In an alternative embodiment,

[0025] [ka] is one or two R1 In certain embodiments,

[0026] [ka] is one or two R independently selected from CN, C1-C3 alkyl, halo, or —C(O)NH2 1 In certain embodiments,

[0027] [ka] is one or two R independently selected from CN, CH, or —C(O)NH 1 is a pyridine substituted with

[0028] In a further alternative embodiment,

[0029] [ka] is one or two R 1 In certain embodiments,

[0030] [ka] is one R that is C1-C3 alkyl 1 is a pyridone substituted with

[0031] In a further alternative embodiment,

[0032] [ka] is one or two R 1 In certain embodiments, the aryl is a 5-membered heteroaryl selected from pyrazole, isoxazole, tetrazole, triazole, or thiophene optionally substituted with

[0033] [ka] is one R selected from CN and C1-C3 alkyl 1 In certain embodiments, the aryl is a 5-membered heteroaryl selected from pyrazole, isoxazole, tetrazole, triazole, or thiophene optionally substituted with

[0034] [ka] is one R selected from CN and CH 1 is a 5-membered heteroaryl selected from pyrazole, isoxazole, tetrazole, triazole, or thiophene optionally substituted with

[0035] In one embodiment, -A- is -CH2O-.

[0036] In one embodiment, Y 3 is N.

[0037] In one embodiment, Y 4 is CH.

[0038] In one embodiment, Y 5 is CH.

[0039] In one embodiment, Y 6 is CH.

[0040] In one embodiment, Y 3 is N and Y 4 , Y 5 , and Y 6 is CH.

[0041] In one embodiment, Y 1 is CR 2 is.

[0042] In one embodiment, Y 2 is CH.

[0043] In one embodiment, Y 7 is CR 2 is.

[0044] In one embodiment, Y 8 is CH.

[0045] In one embodiment, R 2 is F or methyl.

[0046] In one embodiment, Y 1 and Y 7 is CR 2 and Y 2 and Y 8 is CH. In a further embodiment, Y 1 and Y 7 is CR 2 and Y 2 and Y 8 is CH and R 2 is independently F or methyl. In yet a further embodiment, Y 1 is C(CH3) or C(F), and Y 7 is C(F) and Y 2 and Y 8 is CH. Preferably, Y 1 is C(CH3).

[0047] In one embodiment, R 3 is C1-C4 alkoxy optionally substituted with C1-C2 alkoxy. In a further embodiment, R 3 is -OCH3 or -OCH2CH2OCH3. Preferably, R 3 is -OCH3.

[0048] In one embodiment, R 5 is CO2H.

[0049] In one embodiment, the formula:

[0050] [ka] A compound of the formula:

[0051] [ka] is a phenyl, a 5- or 6-membered heteroaryl, or a pyridone, which phenyl, heteroaryl, or pyridone may optionally be joined by one or two R 1 is replaced by R 1 is CN, halo, C1-C3 alkyl, C1-C3 alkoxy, —C(O)NH2, or 5-membered heteroaryl; R 2 is independently at each occurrence halo or methyl; R 3 is C1-C4 alkoxy optionally substituted with C1-C2 alkoxy; A compound, or a pharmaceutically acceptable salt thereof, is provided.

[0052] In one embodiment, the formula:

[0053] [ka] wherein R 1 is F or OCH3, R 2 is F or CH3, R 3 is -OCH3 or -OCH2CH2OCH3, A compound, or a pharmaceutically acceptable salt thereof, is provided.

[0054] In one embodiment, in the compound of formula IV, R 3 is -OCH3.

[0055] In one embodiment, a compound selected from: 2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-5-methyl-phenyl]methyl]-7-methoxy-3-[[oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid, 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, 2-(4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, 2-(4-(6-((6-cyanopyridin-3-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, 2-[[4-[6-[(6-cyano-2-methyl-3-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-7-methoxy-3-[[oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid, 2-[[4-[6-[(6-carbamoyl-2-methyl-3-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-7-methoxy-3-[[oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid, 2-[[2,5-difluoro-4-[6-[(1-methyl-6-oxo-3-pyridyl)methoxy]-2-pyridyl]phenyl]methyl]-7-(2-methoxyethoxy)-3-[[oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid, 2-(4-(6-((5-cyanothiophen-2-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, 2-(4-(6-((4-cyano-2-methylbenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, 2-(2,5-difluoro-4-(6-((2-methyl-2H-1,2,3-triazol-4-yl)methoxy)pyridin-2-yl)benzyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, 2-(4-(6-((4-(1H-1,2,4-triazol-1-yl)benzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, 2-(2,5-difluoro-4-(6-(isoxazol-3-ylmethoxy)pyridin-2-yl)benzyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, 2-(4-(6-((4-cyano-2-methoxybenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, 2-(2,5-difluoro-4-(6-((1-methyl-1H-pyrazol-3-yl)methoxy)pyridin-2-yl)benzyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, 2-(2,5-difluoro-4-(6-((2-methyl-2H-tetrazol-5-yl)methoxy)pyridin-2-yl)benzyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, or a pharmaceutically acceptable salt thereof.

[0056] In a further embodiment, a compound selected from: 2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-5-methyl-phenyl]methyl]-7-methoxy-3-[[oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid, 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, 2-(4-(6-((4-cyano-2-methoxybenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, or a pharmaceutically acceptable salt thereof.

[0057] In linker A, the left end group is attached to the X ring and the right end group is attached to the Y ring. 3 It is attached to the containing ring.

[0058] The term "halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0059] "C1~C n The 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.

[0060] "C1~C nThe 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.

[0061] "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., -O(alkyl). Examples of C1-C4 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, and butoxy.

[0062] "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.

[0063] The term "C3-C5 cycloalkyl" refers to a monocyclic saturated carbocyclic ring containing from 3 to 5 carbon atoms, specifically cyclopropyl, cyclobutyl, or cyclopentyl.

[0064] 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.

[0065] The term "C4-C5 heterocyclyl" refers to a 4- or 5-membered monocyclic saturated ring containing one or more heteroatoms, for example, oxetane.

[0066] Formula I encompasses Formulas II, IIa, IIb, III, IIIa, IIIb, IV, IVa, and IVb, 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.

[0067] 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.

[0068] 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.

[0069] 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.

[0070] 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.

[0071] 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.

[0072] 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.

[0073] 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.

[0074] In one embodiment, there is provided a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in therapy.

[0075] 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.

[0076] In another embodiment, there is provided a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in lowering blood glucose levels.

[0077] 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.

[0078] In another embodiment, there is provided a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of obesity.

[0079] 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.

[0080] 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.

[0081] 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.

[0082] 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.

[0083] 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.

[0084] 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.

[0085] In another embodiment, there is provided a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of type II diabetes.

[0086] In another embodiment, there is provided a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in lowering blood glucose levels.

[0087] In another embodiment, there is also provided a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of hyperglycemia.

[0088] In another embodiment, there is provided a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of obesity.

[0089] In another embodiment, there is also provided a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of NASH.

[0090] 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.

[0091] 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.

[0092] 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.

[0093] 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.

[0094] 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.

[0095] As used herein, the term "patient" includes mammals. The patient is preferably human.

[0096] 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).

[0097] Compounds of Formula I and their pharmaceutically acceptable salts are useful in the therapeutic applications of the present invention, with certain stereoconfigurations being preferred.

[0098] The compounds of the present invention include

[0099] [ka] or a pharmaceutically acceptable salt thereof.

[0100] While the present invention contemplates all individual enantiomers, mixtures thereof, and racemates, the compounds of Formulas Ia, IIa, IIIa, Va, and VIIa, and pharmaceutically acceptable salts thereof, are especially preferred.

[0101] 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)).

[0102] 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).

[0103] 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, "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, "HATU" refers to 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, "HEK" refers to human embryonic kidney, "HEPES" refers to 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, "h" refers to hour, "IPA" refers to isopropanol, "MeOH" refers to methanol or methyl alcohol, "min" refers to minute, "RT" refers to room temperature, and "S N "Ar" refers to a nucleophilic aromatic substituent, "T3P" refers to 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide, "TEA" refers to triethylamine, and "THF" refers to tetrahydrofuran.

[0104] 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. Certain 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.

[0105] Scheme 1

[0106] [ka] Scheme 1 shows two routes used to prepare intermediate 7, which is used to prepare compounds of the present invention. In the first route, aryl difluoride 1 is reacted with amine 2 using a carbonate base at elevated temperature in a S-coupling step. N Ar affords intermediate 3, followed by a second S reaction with the sodium alkoxide of alcohol 4. N Ar to give intermediate 5. In a second route, these two steps are carried out in reverse order to give intermediate 5. The nitro group of intermediate 5 is then reduced to diamine intermediate 7 using a palladium catalyst and hydrogen gas.

[0107] Scheme 2

[0108] [ka] Scheme 2 illustrates the preparation of compound 14, starting with the coupling of acid intermediate 8 and amino intermediate 7 using T3P and an organic base to give amide intermediate 9. Intermediate 9 is cyclized with acetic acid at elevated temperature to give benzimidazole intermediate 10, which then undergoes Suzuki coupling with boronic ester 11 using a palladium catalyst and a carbonate base at elevated temperature to give intermediate 12. Subsequent alkylation with alkyl bromide 13 and a carbonate base at elevated temperature gives compound 14. Alternatively, reaction of intermediate 12 with alcohol 16 under Mitsunobu conditions (diisopropyl azodicarboxylate and triphenylphosphine) gives compound 14 (a compound of Formula I where A is -CHO-).

[0109] Scheme 3

[0110] [ka] Scheme 3 shows the preparation of compound 19, starting with the conversion of aryl bromide 10 to boronic ester 15 using bis(pinacolato)diboron, potassium acetate, and a palladium catalyst at elevated temperature. Alternatively, alcohol 16 can undergo nucleophilic aromatic substitution (S) with 2-bromo-6-fluoropyridine 17 using an alkoxide base at elevated temperature. N Ar) reaction to give intermediate 18. Intermediates 15 and 18 are then coupled using a palladium catalyst, potassium acetate, and elevated temperature to give compound 19 (where A is —CHO—, Y 3 N, Y 4 , Y 5 and Y 6 is CH) to obtain a compound of formula I.

[0111] Scheme 4

[0112] [ka] Scheme 4 illustrates the preparation of compounds of formula I starting from acid intermediate 20, which is coupled with aniline intermediate 7 using amide coupling conditions, such as HATU and an amine base, to give amide 21. Amide 21 is then cyclized with acetic acid at elevated temperature to give compounds of formula I.

[0113] In each of Schemes 1-4, R as defined in Formula I 5 To prepare compounds of the invention where R is —COH, the synthetic steps described in Schemes 1-4 can be carried out using R protected as a methyl or ethyl ester (—COCH or —COCHCH). 5 As a final step, this ester is hydrolyzed with guanidine base at elevated temperature to give R 5 =-CO2H to obtain a compound.

[0114] Preparation 1 3,5-Difluoro-4-nitro-benzoic acid methyl ester

[0115] [ka] A solution of thionyl chloride (37 mL, 74 mmol) in MeOH (110 mL) is cooled to -10 °C and 3,5-difluoro-4-nitro-benzonitrile (2.8 g, 15 mmol) is added. The reaction mixture is stirred at room temperature for 3 h, then the temperature is gradually increased to 65 °C over 2 h. The mixture is filtered and concentrated under reduced pressure. The residue is dissolved in EtOAc (150 mL) and the organics are washed with saturated aqueous sodium bicarbonate (50 mL) and saturated aqueous NaCl (50 mL). The organic phase is dried over NaSO, filtered, and concentrated under reduced pressure. The residue is purified by silica gel chromatography using 10% EtOAc in petroleum ether to give 2.24 g of the title compound (66%). 1 H-NMR (400MHz, CDCl3) δ7.78(d,2H),4.0(s,3H).

[0116] Preparation 2 3-Fluoro-5-methoxy-4-nitro-benzoic acid methyl ester

[0117] [ka] To a solution of methyl 3,5-difluoro-4-nitrobenzoate (0.3 g, 1.38 mmol) in MeOH (4 mL) is added a solution of sodium methylbenzoate (25% by weight in MeOH, 0.33 mL, 1.44 mmol), and the reaction mixture is heated at 65 °C for 2.5 h. The reaction mixture is cooled to room temperature, then water is added, and the mixture is extracted with EtOAc (3 × 5 mL). The combined organics are washed with saturated aqueous NaCl, dried over MgSO4, then filtered and concentrated in vacuo. The residue is 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).

[0118] Preparation 3 (S)-3-Methoxy-4-nitro-5-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester

[0119] [ka] To a solution of methyl 3-fluoro-5-methoxy-4-nitrobenzoate (1.0 g, 4.4 mmol) in THF (20 mL) and DMF (10 mL) was added TEA (1.5 mL, 1.09 g, 11 mmol) at room temperature. To the slightly yellow solution was added [(2S)-oxetan-2-yl]methanamine (0.42 g, 4.8 mmol, 100% by weight), and the rust-colored solution was stirred under nitrogen at room temperature overnight and then heated at 35° C. for 72 h. The reaction mixture was partially concentrated and then diluted with EtOAc (100 mL) and water (50 mL). The organic layer was separated, and the aqueous layer was back-extracted with EtOAc (2×50 mL). The combined organics were washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated to dryness under high vacuum. The residue was purified by flash chromatography using a gradient of 5-30% EtOAc in DCM to give the title compound (0.99 g, 73%) as a yellow oil. The sample was analyzed by H NMR and LC / MS. ES / MS m / z 296 (M+H).

[0120] Preparation 4 Methyl 4-amino-3-methoxy-5-[[(2S)-oxetan-2-ylmethyl]amino]benzoate

[0121] [ka] To a slurry of 5% sulfided platinum on carbon (211 mg, 1.08 mmol) in EtOAc (25 mL) in a 250 mL Parr bottle was added a solution of methyl (S)-3-methoxy-4-nitro-5-((oxetan-2-ylmethyl)amino)benzoate (0.98 g, 3.3 mmol) in EtOAc (25 mL). The reaction vessel was sealed, purged with nitrogen, purged with hydrogen, and then pressurized to 60 psig with hydrogen. The reaction was sealed at this pressure and shaken at room temperature for 4 hours. The suspension was filtered through a pad of diatomaceous earth, and the filtrate was concentrated under reduced pressure to give the title compound (0.90 g, quantitative yield) as an oil that crystallized on standing. ES / MS m / z 267 (M+H).

[0122] Preparation 5 3-Fluoro-5-(2-methoxyethoxy)-4-nitro-benzoic acid methyl ester

[0123] [ka] To a suspension of sodium hydride (60% in mineral oil, 92 mg, 2.30 mmol) in THF (10 mL) was added 2-methoxyethanol (0.18 mL, 2.31 mmol), and the mixture was stirred at room temperature for 30 minutes. Next, methyl 3,5-difluoro-4-nitrobenzoate (0.5 g, 2.30 mmol) was added, and the mixture was stirred at 60 °C for 16 hours. The reaction was diluted with water (100 mL) and extracted with EtOAc (3 × 50 mL). The organics were dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography using a gradient of 0–20% EtOAc in heptane to afford the title compound (225 mg, 40%) as a yellow oil. ES / MS m / z 274 (M+H).

[0124] Preparation 6 Methyl 3-(2-methoxyethoxy)-4-nitro-5-[[[(2S)-oxetan-2-yl]methyl]amino]benzoate

[0125] [ka] To a solution of methyl 3-fluoro-5-(2-methoxyethoxy)-4-nitrobenzoate (0.34 g, 1.23 mmol) in dry DMF (4 mL) was added TEA (428 μL, 3.07 mmol) and (S)-oxetan-2-ylmethanamine (109.3 mg, 1.229 mmol), and the reaction mixture was stirred at 35° C. overnight. Additional TEA (100 μL, 0.717 mmol) and (S)-oxetan-2-ylmethanamine (32.8 mg, 0.369 mmol) were added, and the reaction mixture was stirred at 35° C. for 1 h. The reaction was diluted with water and extracted four times with EtOAc. The combined organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of 0-30% EtOAc in heptane to give the title compound (228 mg, 55%) as an orange oil. ES / MS m / z 341 (M+H).

[0126] Preparation 7 Methyl 4-amino-3-(2-methoxyethoxy)-5-[[[(2S)-oxetan-2-yl]methyl]amino]benzoate

[0127] [ka] To a reaction vessel containing iron (0.325 g, 5.82 mmol) and ammonium chloride (0.015 g, 0.28 mmol) suspended in water (4.36 mL) was added acetic acid (0.073 mL, 1.3 mmol), and the reaction mixture was stirred at 50° C. for 15 minutes. Subsequently, a solution of methyl 3-(2-methoxyethoxy)-4-nitro-5-[[(2S)-oxetan-2-yl]methylamino]benzoate (0.198 g, 0.582 mmol) in DMF (1.45 mL) was added, and the reaction mixture was stirred at 50° C. for 20 minutes. The mixture was filtered through a pad of diatomaceous earth and washed with EtOAc. Saturated aqueous NaHCO was added to the filtrate, and the organic layer was dried over MgSO, filtered, and concentrated under reduced pressure to afford the title compound (0.181 g, quantitative yield) as a yellow oil, which was carried forward without further purification of the reaction. ES / MS m / z 311(M+H)

[0128] Preparation 8 Methyl 2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-5-methyl-phenyl]methyl]-7-methoxy-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate

[0129] [ka] To a mixture of 2-[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-phenyl]acetic acid (prepared essentially as described in WO 2020 / 263695, 500 mg, 1.3 mmol) and methyl 4-amino-3-methoxy-5-[[(2S)-oxetan-2-yl]methylamino]benzoate (375 mg, 1.4 mmol) in DIPEA (0.73 mL, 4.2 mmol) and DMF (5 mL), HATU (800 mg, 2.1 mmol) was added at room temperature. After stirring at room temperature for 3.5 hours, the reaction mixture was diluted with EtOAc (30 mL), washed with water and saturated aqueous NaCl, dried over NaSO, filtered, and concentrated. The residue was dissolved in acetic acid (5 mL), and the mixture was stirred at 35° C. for 48 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in EtOAc (25 mL). The organic mixture was washed with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel chromatography using a gradient of 20-100% EtOAc in hexanes to give the title compound (500 mg, 57% yield). ES / MS (m / z): 625 (M+H).

[0130] Preparation 9 Methyl (S)-4-(2-(4-bromo-2,5-difluorophenyl)acetamido)-3-methoxy-5-((oxetan-2-ylmethyl)amino)benzoate

[0131] [ka] A mixture of 2-(4-bromo-2,5-difluorophenyl)acetic acid (5.0 g, 20 mmol), methyl 4-amino-3-methoxy-5-[[(2S)-oxetan-2-yl]methylamino]benzoate (5.8 g, 22 mmol), DMF (40 mL), pyridine (8.0 mL, 99 mol), and T3P (50% in THF, 30 mL, 50 mmol) was stirred at room temperature for 1 hour. The mixture was diluted with 100 mL of water, and the resulting solid was collected by vacuum filtration to give 9.9 g of the title compound (100%). ES / MS m / z 499 and 501 (M+H).

[0132] Preparation 10 Methyl (S)-2-(4-bromo-2,5-difluorobenzyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0133] [ka] A solution of methyl (S)-4-(2-(4-bromo-2,5-difluorophenyl)acetamido)-3-methoxy-5-((oxetan-2-ylmethyl)amino)benzoate (9.9 g, 20 mmol) in acetic acid (100 mL) was stirred at 55° C. for 18 h. The solution was concentrated and the residue was purified by silica gel chromatography using a gradient of 10 to 100% EtOAc in hexanes followed by 5% MeOH in DCM to give 8.3 g of the title compound (87%). ES / MS m / z 481 and 483 (M+H).

[0134] Preparation 11 Methyl (S)-2-(2,5-difluoro-4-(6-hydroxypyridin-2-yl)benzyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0135] [ka] A mixture of methyl (S)-2-(4-bromo-2,5-difluorobenzyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (4.3 g, 8.9 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ol (2.7 g, 12 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.37 g, 0.50 mmol), and potassium carbonate (4.0 g, 29 mmol) in 1,4-dioxane (45 mL) and water (11 mL) was stirred at 70° C. for 6.5 hours. The mixture was diluted with 100 mL of water and stirred vigorously at room temperature for 5 minutes. The solid was collected by vacuum filtration and washed with EtOAc (6×50 mL) to give 3.0 g of the title compound (68%). ES / MS m / z 496 (M+H).

[0136] Preparation 12 Methyl (S)-4-(2-(4-bromo-2,5-difluorophenyl)acetamido)-3-(2-methoxyethoxy)-5-((oxetan-2-ylmethyl)amino)benzoate

[0137] [ka] A mixture of 2-(4-bromo-2,5-difluorophenyl)acetic acid (2.1 g, 8.3 mmol), methyl 4-amino-3-(2-methoxyethoxy)-5-[[(2S)-oxetan-2-yl]methylamino]benzoate (2.3 g, 7.4 mmol), DMF (15 mL), pyridine (3.2 mL, 40 mol), and T3P (50% in THF, 12 mL, 20 mmol) was stirred at room temperature for 1 hour. The mixture was diluted with 100 mL of water, and the resulting solid was collected by vacuum filtration to give 4.3 g of the title compound (95%). ES / MS m / z 543 and 545 (M+H).

[0138] Preparation 13 Methyl (S)-2-(4-bromo-2,5-difluorobenzyl)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0139] [ka] A solution of methyl (S)-4-(2-(4-bromo-2,5-difluorophenyl)acetamido)-3-(2-methoxyethoxy)-5-((oxetan-2-ylmethyl)amino)benzoate (4.3 g, 7.9 mmol) in acetic acid (40 mL) was stirred at 55° C. for 18 h. The solution was concentrated and the residue was purified by silica gel chromatography using a gradient of 20 to 100% EtOAc in hexanes to give 3.2 g of the title compound (78%). ES / MS m / z 525 and 527 (M+H).

[0140] Preparation 14 Methyl (S)-2-(2,5-difluoro-4-(6-hydroxypyridin-2-yl)benzyl)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0141] [ka] A mixture of methyl (S)-2-(4-bromo-2,5-difluorobenzyl)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (975 mg, 1.86 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ol (632 mg, 2.86 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.098 g, 0.13 mmol), and potassium carbonate (826 mg, 5.98 mmol) in 1,4-dioxane (9.3 mL) and water (2.3 mL) was stirred at 70° C. for 3 hours. The mixture was diluted with 50 mL of water and stirred vigorously at room temperature for 5 minutes. The solid was collected by vacuum filtration and washed with EtOAc (5 x 20 mL) to give 885 mg of the title compound (88%). ES / MS m / z 540 (M+H).

[0142] Preparation 15 Methyl 2-[[4-[6-[(6-cyano-2-methyl-3-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-7-methoxy-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate

[0143] [ka] To a stirred solution of 5-(hydroxymethyl)-6-methyl-pyridine-2-carbonitrile (112 mg, 0.718 mmol) in anhydrous THF (3.5 mL) at 0 °C, triphenylphosphine (245 mg, 0.934 mmol), methyl (S)-2-(2,5-difluoro-4-(6-hydroxypyridin-2-yl)benzyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (300 mg, 0.605 mmol), and finally diisopropyl azodicarboxylate (0.19 mL, 0.96 mmol) were added dropwise. The reaction was allowed to warm to room temperature and stirred overnight. After 16 h, the reaction was diluted with EtOAc and deionized water, the layers were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with saturated aqueous NaCl, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0-20% MeOH in EtOAc and concentrated under reduced pressure to give 82 mg of the title compound (22%). ES / MS m / z 626 (M+H).

[0144] Preparation 16 Methyl 2-[[2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-7-(2-methoxyethoxy)-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate

[0145] [ka] To a stirred solution of methyl (S)-2-(4-bromo-2,5-difluorobenzyl)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (150 mg, 0.286 mmol) in 1,4-dioxane (2 mL) was added bis(pinacolato)diboron (148 mg, 0.577 mmol) and potassium acetate (86 mg, 0.88 mmol). The resulting mixture was degassed and purged with nitrogen three times. 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride in DCM complex (24 mg, 0.03 mmol) was then added, and the mixture was stirred at 80 °C for 16 h. The reaction was cooled to room temperature, diluted with EtOAc and deionized water, the layers were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with saturated aqueous NaCl, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using a gradient of 0-10% MeOH in EtOAc and concentrated under reduced pressure to give 168 mg of the title compound (72%). ES / MS m / z 491 (M+H with boronic acid).

[0146] Preparation 17 5-[(6-bromo-2-pyridyl)oxymethyl]-1-methyl-pyridin-2-one

[0147] [ka] To a stirred solution of 5-(hydroxymethyl)-1-methyl-pyridin-2-one (367 mg, 2.64 mmol) and 2-bromo-6-fluoropyridine (565 mg, 3.15 mmol) in anhydrous THF (4 mL) at room temperature was added potassium tert-butoxide (358 mg, 3.16 mmol). The reaction was stirred at 55 °C for 16 h. The reaction mixture was quenched with saturated aqueous ammonium chloride, warmed to room temperature, diluted with EtOAc and deionized water, the layers were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with saturated aqueous NaCl, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using a gradient of 0-10% MeOH in EtOAc and concentrated under reduced pressure to give 213 mg of the title compound (26%). ES / MS m / z 294 & 296 (M+H).

[0148] Preparation 18 Methyl 2-[[2,5-difluoro-4-[6-[(1-methyl-6-oxo-3-pyridyl)methoxy]-2-pyridyl]phenyl]methyl]-7-(2-methoxyethoxy)-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate

[0149] [ka] To a stirred solution of 5-[(6-bromo-2-pyridyloxymethyl-1-methyl-pyridin-2-one (108 mg, 0.366 mmol) and methyl 2-[[2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-7-(2-methoxyethoxy)-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (168 mg, 0.293 mmol) and potassium acetate (91 mg, 0.93 mmol) in 1,4-dioxane (1.5 mL) and water (0.3 mL) was added 1,1'-bis(di (Phenylphosphino)ferrocene-palladium(II) dichloride DCM complex (25 mg, 0.030 mmol) was added. The reaction mixture was stirred under nitrogen at 90 °C for 2 h. After 2 h, the reaction was cooled to room temperature, diluted with EtOAc and deionized water, the layers were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with saturated aqueous NaCl, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using a gradient of 0-10% MeOH in EtOAc and concentrated under reduced pressure to give 81 mg of the title compound (42%). ES / MS m / z 661 (M+H).

[0150] Example 1 2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-5-methyl-phenyl]methyl]-7-methoxy-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid

[0151] [ka] To a mixture of methyl 2-[[4-[6-[(4-cyano-2-fluorophenyl)methoxy]-2-pyridyl]-2-fluoro-5-methyl-phenyl]methyl]-7-methoxy-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (500 mg, 0.80 mmol), THF (5 mL), ACN (10 mL), and water (1 mL) was added 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine (340 mg, 2.4 mmol). The mixture was heated at 60°C for 1 hour and then stirred at room temperature overnight. The mixture was neutralized with aqueous citric acid and concentrated. The residue was purified by reverse-phase flash chromatography on a C18 column using a gradient of 10-100% ACN in 10 mM aqueous ammonium bicarbonate (pH 10) to give the title compound (398 mg, 81%). ES / MS (m / z): 611 (M+H).

[0152] Example 2 (S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0153] [ka] A mixture of methyl (S)-2-(2,5-difluoro-4-(6-hydroxypyridin-2-yl)benzyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (0.15 g, 0.30 mmol), potassium carbonate (0.18 g, 1.3 mmol), and 4-(bromomethyl)-3-fluoro-benzonitrile (80 mg, 0.37 mmol) in ACN (3.0 mL) was stirred at 45° C. for 4.5 hours. To the mixture was added 1,5,7-triazabicyclo[4.4.0]dec-5-ene (215 mg, 1.51 mmol) in water (0.5 mL), and the mixture was stirred at 55° C. for 2 hours. The reaction mixture was concentrated onto diatomaceous earth and purified by reverse-phase chromatography on a C18 column using a gradient of 0-100% ACN in 10 mM aqueous ammonium bicarbonate containing 5% MeOH to give 27 mg of the title compound (15%). ES / MS m / z 615 (M+H).

[0154] Example 3 (S)-2-(4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0155] [ka] A mixture of methyl (S)-2-(2,5-difluoro-4-(6-hydroxypyridin-2-yl)benzyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (0.20 g, 0.40 mmol), potassium carbonate (0.17 g, 1.3 mmol), and 6-(bromomethyl)pyridine-3-carbonitrile (99 mg, 0.50 mmol) in ACN (4.0 mL) was stirred at 45 °C for 5 hours and at 50 °C for 2 hours. The suspension was filtered through a pad of diatomaceous earth, and to the filtrate was added 1,5,7-triazabicyclo[4.4.0]dec-5-ene (300 mg, 2.11 mmol) in water (0.7 mL). The mixture was stirred at 55 °C for 35 minutes and then quenched with 1 M aqueous citric acid (2 mL). The mixture was extracted with EtOAc (2 x 5 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography on a C18 column using a gradient of 14-48% ACN in 10 mM aqueous ammonium bicarbonate containing 5% MeOH to afford 23 mg of the title compound (10%). ES / MS m / z 598 (M+H).

[0156] Example 4 (S)-2-(4-(6-((6-cyanopyridin-3-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0157] [ka] The title compound was prepared essentially as described in Example 3, purified by reverse-phase chromatography on a C18 column using 5-(bromomethyl)pyridine-2-carbonitrile with a gradient of 23% to 58% ACN in 10 mM aqueous ammonium bicarbonate containing 5% MeOH, followed by SFC purification on a Chiralpak® AS-H column with 40% IPA in CO2. ES / MS m / z 598 (M+H).

[0158] Example 5 (S)-2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0159] [ka] The title compound was prepared essentially as described in Example 3 using 4-(bromomethyl)-3-fluoro-benzonitrile and methyl (S)-2-(2,5-difluoro-4-(6-hydroxypyridin-2-yl)benzyl)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate and purified by reverse-phase chromatography on a C18 column using a gradient of 23 to 58% ACN in 10 mM aqueous ammonium bicarbonate containing 5% MeOH. ES / MS m / z 659 (M+H).

[0160] Example 6 2-[[4-[6-[(6-cyano-2-methyl-3-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-7-methoxy-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid (Example 6a)

[0161] [ka] and 2-[[4-[6-[(6-carbamoyl-2-methyl-3-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-7-methoxy-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid (Example 6b)

[0162] [ka] A mixture of ACN (0.6 mL), 1,4-dioxane (0.6 mL), water (0.2 mL), and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (65 mg, 0.46 mmol) was sparged for 10 minutes and transferred to a reaction vessel containing methyl 2-[[4-[6-[(6-cyano-2-methyl-3-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-7-methoxy-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (47 mg, 0.08 mmol). The reaction mixture was stirred at 55 °C for 2 hours. After 2 hours, the reaction mixture was transferred to a separatory funnel containing EtOAc, washed with 10% aqueous citric acid, saturated aqueous NaCl, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography on a C18 column using a gradient of 0-100% ACN:10 mM aqueous formic acid. Fractions containing the title compound were concentrated under reduced pressure to remove volatile organic solvents, and the remaining aqueous layer was then acidified with 0.1 N aqueous hydrochloric acid and extracted three times with EtOAc. The combined organic layers were washed with saturated aqueous NaCl, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was repurified by reverse-phase chromatography on a C18 column using a gradient of 0-100% ACN:0.1% formic acid in water containing 0.1% formic acid to separate the two title compounds: the nitrile compound (Example 6a, 15 mg, 33%), ES / MS m / z 612 (M+H), and the amide compound (Example 6b, 11 mg, 23%), ES / MS m / z 630 (M+H).

[0163] Example 7 2-[[2,5-Difluoro-4-[6-[(1-methyl-6-oxo-3-pyridyl)methoxy]-2-pyridyl]phenyl]methyl]-7-(2-methoxyethoxy)-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid

[0164] [ka] A mixture of ACN (0.8 mL), 1,4-dioxane (0.8 mL), water (0.3 mL), and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (49 mg, 0.34 mmol) was sparged for 10 minutes and then added to a reaction vessel containing methyl 2-[[2,5-difluoro-4-[6-[(1-methyl-6-oxo-3-pyridyl)methoxy]-2-pyridyl]phenyl]methyl]-7-(2-methoxyethoxy)-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate (75 mg, 0.11 mmol). The reaction was stirred at room temperature for 16 hours and then diluted with EtOAc and 0.1 M aqueous hydrochloric acid. The layers were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography on a C18 column using a gradient of 0% to 100% ACN with 0.1% formic acid:0.1% aqueous formic acid. Fractions containing the desired product were concentrated under reduced pressure to remove the volatile organic solvents. The remaining aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was repurified by reverse-phase chromatography on a C18 column using a gradient of 0% to 100% ACN with 0.1% formic acid:0.1% aqueous formic acid to give 18.7 mg of the title compound (26%). ES / MS m / z 647 (M+H).

[0165] General procedure: O-Alkylation and subsequent ester hydrolysis: A mixture of methyl (S)-2-(2,5-difluoro-4-(6-hydroxypyridin-2-yl)benzyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (75 mg, 0.15 mmol), halide (1.2 equiv., 0.18 mmol), and potassium carbonate (62 mg, 0.45 mmol) in ACN (1.5 mL) is stirred at 50° C. for 5 h. Water (1 mL) is added, and the mixture is extracted with DCM (1 mL). The organic layer is filtered through diatomaceous earth and washed with DCM. The organic layer is concentrated, and the residue is added with 3,4,6,7,8,9-hexahydro-2H-pyrimido[1,2-a]pyrimidine (0.11 g, 0.76 mmol), ACN (1.5 mL), and water (0.25 mL). The mixture is stirred at 50° C. for 1 hour, and then water (1 mL) is added and the mixture is extracted with DCM (1 mL). The organic layer is filtered through diatomaceous earth, washed with DCM, concentrated, and then subjected to the specified chromatographic conditions.

[0166] The following examples were prepared following the general procedure above for O-alkylation and subsequent ester hydrolysis, using the listed halides as starting materials and using the specified chromatographic conditions.

[0167] [Table 1-1]

[0168] [Table 1-2]

[0169] [Table 1-3]

[0170] 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 * 10,000) are inversely proportional to the amount of cAMP present and are 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 maximum response observed for human GLP-1(7-36)NH2. Relative EC 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 1-14 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 1-14 are agonists of the human GLP-1 receptor. The compounds of Examples 1, 2, 5, and 13 exhibit potencies comparable to the native GLP-1(7-36)NH2 peptide in the 104 fmol / mg assay.

[0171] [Table 2]

[0172] [Table 3] EC 50 , nM = geometric mean of the concentration producing half-maximal stimulation (E max half of the mean mean), followed by the SEM (delta method) and the number of observations in parentheses. Stim Max% = arithmetic mean of percent stimulation by the point giving maximum stimulation on the concentration response curve relative to the maximum response produced by GLP-1(7-36)NH2, followed by SEM and number of observations in parentheses. E max , % = arithmetic mean ± SEM of the fitted apex of the concentration-response curve for percent of the maximal response to GLP-1(7-36)NH2.

[0173] In vivo intraperitoneal glucose tolerance test in human GLP-1R knock-in mice The efficacy of exemplary compounds in reducing blood glucose concentrations in vivo is determined using mice expressing human GLP-1R from the mouse Glp-1r locus (NCBI accession number NP_002053) (Jun, LS, et al., PLoS One. 2014 9:e93746). Mice fasted overnight are orally administered a test compound solubilized in 10% Kolliphor® (HS15) in polyethylene glycol 400 (PEG400). One hour after administration, the animals are administered glucose (2 g / kg) via intraperitoneal injection, and blood glucose levels are measured intermittently over the next two hours using a glucometer. A range of doses of the test compound are delivered, and the area under the curve calculations for each dose group are determined, which are expressed as ED1s with a 95% confidence interval. 50 When tested in the in vivo intraperitoneal glucose tolerance test described above, the compound of Example 1 exhibited the ED500 shown in Table 3. 50 (and 95% confidence interval) values ​​show efficacy in lowering blood glucose concentrations in mice expressing the human GLP-1R, indicating that this compound is an orally available and potent GLP-1R agonist in mice.

[0174] [Table 4]

Claims

1. formula: 【Chemistry 1】 or a pharmaceutically acceptable salt thereof: [In the formula, 【Chemistry 2】 is phenyl, a 5- or 6-membered heteroaryl, or a pyridone, said phenyl, heteroaryl, or pyridone optionally containing one or two R １ is replaced by 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, —C(O)NH ２ , 【Transformation 3】 (In the formula, each 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; -A- is -CH ２ O-, -OCH ２ - or -CH ２ NH-, Y １ , Y ２ , Y ７ , and Y ８ are independently N, CH, or CR ２ and Y １ , Y ２ , Y ７ , and Y ８ At most one of １ , Y ２ , Y ７ , and Y ８ 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; R ３ But C １ ~C ２ Alkoxy, hydroxy or C １ ~C ３ C optionally substituted with haloalkyl １ ~C ４ is an alkoxy; R ４ but, 【Chemistry 4】 and R ５ が、-CO ２ H、 【Transformation 5】 and R ｃ and R ｄ are each independently H or C １ ~C ３ alkyl].

2. The compound has the formula: 【Transformation 6】 2. The compound of claim 1, wherein:

3. The compound has the formula: 【Transformation 7】 3. The compound of claim 2, wherein: 【Request Item 4】 【Chemistry 8】 optionally one or two R １ 4. The compound according to claim 1, wherein R is phenyl substituted with R, or a pharmaceutically acceptable salt thereof.

5. The phenyl may be selected from CN, halo, C １ ~C ３ Alkyl, C １ ~C ３ one or two R independently selected from alkoxy or 5-membered heteroaryl; １ 5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, substituted with:

6. The one or two R １ But CN, F, CH ３ , OCH ３ or a triazole, or a pharmaceutically acceptable salt thereof.

7. The one or two R １ is CN, F, or OCH ３ 7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, independently selected from:

8. -A- is -CH ２ The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R is O-.

9. Y １ and Y ７ is CR ２ and Y ２ and Y ８ The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein is CH.

10. R ２ 10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein is F or methyl.

11. Y ３ is N and Y ４ , Y ５ , and Y ６ The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein is CH.

12. R ３ However, optionally C １ ~C ２ Alkoxy-substituted C １ ~C ４ 12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, which is alkoxy.

13. R ３ But, -OCH ３ , or -OCH ２ CH ２ OCH ３ 13. The compound of claim 12, wherein:

14. R ５ But -CO ２ 14. The compound of any one of claims 1 to 13, wherein R is H, or a pharmaceutically acceptable salt thereof.

15. 2-[[4-[6-[(4-cyano-2-fluoro-phenyl)methoxy]-2-pyridyl]-2-fluoro-5-methyl-phenyl]methyl]-7-methoxy-3-[[oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid, 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, 2-(4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, 2-(4-(6-((6-cyanopyridin-3-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, 2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, 2-[[4-[6-[(6-cyano-2-methyl-3-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-7-methoxy-3-[[oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid, 2-[[4-[6-[(6-carbamoyl-2-methyl-3-pyridyl)methoxy]-2-pyridyl]-2,5-difluoro-phenyl]methyl]-7-methoxy-3-[[oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid, 2-[[2,5-difluoro-4-[6-[(1-methyl-6-oxo-3-pyridyl)methoxy]-2-pyridyl]phenyl]methyl]-7-(2-methoxyethoxy)-3-[[oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid; 2-(4-(6-((5-cyanothiophen-2-yl)methoxy)pyridin-2-yl)-2,5-difluorobenzyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, 2-(4-(6-((4-cyano-2-methylbenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, 2-(2,5-difluoro-4-(6-((2-methyl-2H-1,2,3-triazol-4-yl)methoxy)pyridin-2-yl)benzyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, 2-(4-(6-((4-(1H-1,2,4-triazol-1-yl)benzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, 2-(2,5-difluoro-4-(6-(isoxazol-3-ylmethoxy)pyridin-2-yl)benzyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, 2-(4-(6-((4-cyano-2-methoxybenzyl)oxy)pyridin-2-yl)-2,5-difluorobenzyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, 2-(2,5-difluoro-4-(6-((1-methyl-1H-pyrazol-3-yl)methoxy)pyridin-2-yl)benzyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, 2-(2,5-difluoro-4-(6-((2-methyl-2H-tetrazol-5-yl)methoxy)pyridin-2-yl)benzyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, 2. The compound of claim 1, selected from:

16. formula: 【Chemistry 9】 2. The compound of claim 1, wherein the compound is: [In the formula, 【Chemistry 10】 is phenyl, a 5- or 6-membered heteroaryl, or a pyridone, said phenyl, heteroaryl, or pyridone optionally containing one or two R １ is replaced by R １ But CN, Halo, C １ ~C ３ Alkyl, C １ ~C ３ Alkoxy, —C(O)NH ２ or a 5-membered heteroaryl; R ２ is independently at each occurrence halo or methyl; R ３ But C １ ~C ２ C optionally substituted with alkoxy １ ~C ４ is an alkoxy.

17. formula: 【Chemistry 11】 2. The compound of claim 1, wherein the compound is: [In the formula, R １ But F or OCH ３ and R ２ is F or CH ３ and R ３ But, -OCH ３ , or -OCH ２ CH ２ OCH ３ is.

18. 18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.

19. 20. A method of treating type II diabetes in a patient, comprising administering to said patient an effective amount of a compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof.

20. 20. 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 17, or a pharmaceutically acceptable salt thereof.

21. 20. 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 17, or a pharmaceutically acceptable salt thereof.

22. 20. 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 17, or a pharmaceutically acceptable salt thereof.

23. 23. The method of any one of claims 19 to 22, wherein the compound is administered orally.

24. 18. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, for use in therapy.

25. 20. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, for use in the treatment of type II diabetes.

26. 20. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, for use in lowering blood glucose levels.

27. 20. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, for use in the treatment of hyperglycemia.

28. 18. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, for use in the treatment of obesity.

29. 29. The compound for use according to any one of claims 24 to 28, or a pharmaceutically acceptable salt thereof, wherein the compound is administered orally.

30. 20. Use of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of type II diabetes.

31. 20. Use of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for lowering blood glucose levels.

32. 20. Use of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of hyperglycemia.

33. 20. Use of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of obesity.

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