Glucagon-like peptide 1 receptor agonists

Abstract

In one embodiment, the present invention provides a compound of the formula: # imgabs0 # or a pharmaceutically acceptable salt thereof, as well as methods of using such compounds in the treatment of type 2 diabetes mellitus.

Description

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

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

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

[0004] WO2018 / 109607 discloses certain benzimidazole derivatives described as GLP-1R agonists. Additional GLP-1 agonist compounds are disclosed in WO2019 / 239371, WO2019 / 239319, WO2020 / 103815, WO2020 / 207474, WO2020 / 263695, WO2021 / 018023, WO2021 / 081207, WO2021 / 096284, WO2021 / 096304, WO2021 / 112538, WO2021 / 154796, WO2021 / 160127, WO2021 / 187886, WO2021 / 197464, CN113480534, CN113493447, WO2021 / 219019, WO2021 / 244645, WO2021 / 249492, CN113801136, CN113816948, WO2021 / 254470, WO2021 / 259309, WO2022 / 007979, WO2022 / 031994, WO2022 / 028572, WO2022 / 040600, WO2022 / 042691, WO2022 / 068772, WO2022 / 078407, WO2022 / 078380, WO2022 / 078152, CN114478497, WO2022 / 109182, WO2022 / 111624, CN114591296, WO2022 / 116693, WO2022 / 135572, CN114634510, CN114716423, CN114763352, CN114805336, WO2022 / 165076, CN114907351, WO2022 / 184849, WO2022 / 192428, WO2022 / 192430, WO2022 / 202864, WO2022 / 199458, WO2022 / 199661, WO2022 / 216094, WO2022 / 219495, WO2022 / 225914, WO2022 / 225941, WO2022 / 228490 and WO2022 / 235717.

[0005] However, alternative GLP-1R agonists are needed. In particular, GLP-1R agonists that can be administered orally are needed. There is also 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 effective at lower doses.

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

[0007] Accordingly, the present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0008]

[0009] wherein

[0010] is phenyl, a 5- or 6-membered heteroaryl or pyridone, which phenyl, heteroaryl or pyridone is optionally substituted by one or two R 1 substituents;

[0011] R 1 is independently CN; halogen; C1-C3 alkyl optionally substituted by OH; C1-C3 haloalkyl; C1-C3 alkoxy; C3-C5 cycloalkyl; -SO2C1-C3 alkyl; -C(O)NH2; wherein each X 9 is independently CH or N, and no more than one X 9 in the ring is N, each R e is independently selected from: H, C1-C3 haloalkyl, halogen, C3-C5 cycloalkyl and C1-C3 alkyl optionally substituted by OH, R h is H, C1-C3 haloalkyl, halogen, C3-C5 cycloalkyl, OH, -NR c R d or C1-C3 alkyl optionally substituted by OH;

[0012] a 5- or 6-membered heteroaryl or phenyl, wherein the heteroaryl or phenyl is optionally substituted by one or two substituents independently selected from: C1-C3 alkoxy, C3-C5 cycloalkyl, -CH2-C3-C5 cycloalkyl, -SO2C1-C3 alkyl, C4-C5 heterocyclic group, -CH2-C4-C5 heterocyclic group, halogen, C1-C3 haloalkyl, C1-C3 haloalkoxy, CN, -CONR c R d 、-NR c R d or C1-C3 alkyl optionally substituted by OH;

[0013] -A- is -CH2O-, -OCH2- or -CH2NH-;

[0014] Y 1 、Y 2 、Y 7 and Y 8 are independently N, CH or CR2 , wherein Y 1 , Y 2 , Y 7 and Y 8 of no more than one is N, and Y 1 , Y 2 , Y 7 and Y 8 of no more than two are CR 2 ;

[0015] Y 3 , Y 4 , Y 5 and Y 6 are independently N, CH or CR 2 , wherein Y 3 , Y 4 , Y 5 and Y 6 of no more than two are N, and Y 3 , Y 4 , Y 5 and Y 6 of no more than two are CR 2 ;

[0016] R 2 is independently halogen or methyl each time it appears;

[0017] R 3 is a C1-C4 alkoxy optionally substituted by C1-C2 alkoxy, hydroxy or C1-C3 haloalkyl;

[0018] R 4 is

[0019] R 5 is -CO2H,

[0020] R c and R d are each independently H or C1-C3 alkyl.

[0021] Formula I includes all individual enantiomers and their mixtures, as well as racemates.

[0022] In one embodiment, a compound of the following formula is provided:

[0023]

[0024] or a pharmaceutically acceptable salt thereof.

[0025] In one embodiment, a compound of the following formula is provided:

[0026]

[0027] or a pharmaceutically acceptable salt thereof.

[0028] In one embodiment, is a phenyl optionally substituted by one or two R 1 substituents. In a particular embodiment, is a phenyl substituted by one or two R independently selected from CN, halogen, C1-C3 alkyl, C1-C3 alkoxy or 5-membered heteroaryl 1 substituents. In a particular embodiment, is a phenyl substituted by one or two R independently selected from CN, F, CH3, OCH3 or triazole 1 substituents. In a further embodiment, is a phenyl substituted by one or two R independently selected from CN, F or OCH3 1 substituents. In a still further embodiment, is a phenyl substituted by CN and F or a phenyl substituted by CN and OCH3, preferably a phenyl substituted by CN and F.

[0029] In an alternative embodiment, is a pyridine optionally substituted by one or two R 1 substituents. In a particular embodiment, is a pyridine substituted by one or two R independently selected from CN, C1-C3 alkyl, halogen or -C(O)NH2 1 substituents. In a particular embodiment, is a pyridine substituted by one or two R independently selected from CN, CH3 or -C(O)NH2 1 substituents.

[0030] In a further alternative embodiment, is a pyridone optionally substituted by one or two R 1 substituents. In a particular embodiment, is a pyridone substituted by one R 1 substituent, said R 1 being C1-C3 alkyl.

[0031] In a further alternative embodiment, is a 5-membered heteroaryl selected from: pyrazole, isoxazole, tetrazole, triazole or thiophene, optionally substituted by one or two R 1 substituents. In a particular embodiment, is a 5-membered heteroaryl selected from: pyrazole, isoxazole, tetrazole, triazole or thiophene, optionally substituted by one R selected from CN and C1-C3 alkyl 1 substituent. In a particular embodiment, is a 5-membered heteroaryl selected from pyrazole, isoxazole, tetrazole, triazole or thiophene, optionally substituted with one R selected from CN and CH3 1 substituted.

[0032] In one embodiment, -A- is -CH2O-.

[0033] In one embodiment, Y 3 is N.

[0034] In one embodiment, Y 4 is CH.

[0035] In one embodiment, Y 5 is CH.

[0036] In one embodiment, Y 6 is CH.

[0037] In one embodiment, Y 3 is N; and Y 4 , Y 5 and Y 6 is CH.

[0038] In one embodiment, Y 1 is CR 2 .

[0039] In one embodiment, Y 2 is CH.

[0040] In one embodiment, Y 7 is CR 2 .

[0041] In one embodiment, Y 8 is CH.

[0042] In one embodiment, R 2 is F or methyl.

[0043] 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 ; Y 2 and Y 8 is CH; and R 2 is independently F or methyl. In a still further embodiment, Y 1 is C(CH3) or C(F); Y 7 is C(F); Y2 and Y 8 is CH. Preferably, Y 1 is C(CH3).

[0044] In one embodiment, R 3 is a C1-C4 alkoxy optionally substituted with a C1-C2 alkoxy. In a further embodiment, R 3 is -OCH3 or -OCH2CH2OCH3. Preferably, R 3 is -OCH3.

[0045] In one embodiment, R 5 is -CO2H.

[0046] In one embodiment, there is provided a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0047]

[0048] wherein is phenyl, a 5- or 6-membered heteroaryl or pyridone, said phenyl, heteroaryl or pyridone being optionally substituted with one or two Rs 1 substituents;

[0049] R 1 is CN, halogen, C1-C3 alkyl, C1-C3 alkoxy, -C(O)NH2 or a 5-membered heteroaryl;

[0050] R 2 is independently halogen or methyl each time it appears;

[0051] R 3 is a C1-C4 alkoxy optionally substituted with a C1-C2 alkoxy.

[0052] In one embodiment, there is provided a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0053]

[0054] wherein R 1 is F or OCH3;

[0055] R 2 is F or CH3; and

[0056] R 3 is -OCH3 or -OCH2CH2OCH3.

[0057] In one embodiment, in the compound of formula IV, R 3 is -OCH3.

[0058] In one embodiment, a compound is provided, which is selected from:

[0059] 2-[[4-[6-[(4-Cyano-2-fluorophenyl)methoxy]-2-pyridinyl]-2-fluoro-5-methyl-phenyl]methyl]-7-methoxy-3-[[oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid;

[0060] 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;

[0061] 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;

[0062] 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;

[0063] 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;

[0064] 2-[[4-[6-[(6-Cyano-2-methyl-3-pyridinyl)methoxy]-2-pyridinyl]-2,5-difluorophenyl]methyl]-7-methoxy-3-[[oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid;

[0065] 2-[[4-[6-[(6-Carbamoyl-2-methyl-3-pyridinyl)methoxy]-2-pyridinyl]-2,5-difluorophenyl]methyl]-7-methoxy-3-[[oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid;

[0066] 2-[[2,5-Difluoro-4-[6-[(1-methyl-6-oxo-3-pyridinyl)methoxy]-2-pyridinyl]phenyl]methyl]-7-(2-methoxyethoxy)-3-[[oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid;

[0067] 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;

[0068] 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;

[0069] 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;

[0070] 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;

[0071] 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;

[0072] 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;

[0073] 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;

[0074] 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;

[0075] or a pharmaceutically acceptable salt thereof.

[0076] In a further embodiment, there is provided a compound selected from:

[0077] 2-(4-[6-[(4-cyano-2-fluorophenyl)methoxy]-2-pyridinyl]-2-fluoro-5-methyl-phenyl]methyl]-7-methoxy-3-[[oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid;

[0078] 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;

[0079] 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;

[0080] 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;

[0081] or a pharmaceutically acceptable salt thereof.

[0082] In linker A, the left-hand terminal group as written is attached to the X ring and the right-hand terminal group is attached to the ring containing Y 3 ring.

[0083] The term "halogen" or "halo" means fluorine, chlorine, bromine or iodine.

[0084] The term "C1-C n alkyl" means a straight or branched chain saturated hydrocarbon containing from 1 to n carbon atoms. Examples of C1-C4 alkyl include, but are not limited to, methyl, ethyl, propyl, butyl and tert-butyl. Examples of C1-C3 alkyl include, but are not limited to, methyl, ethyl and propyl. C1-C2 alkyl is methyl or ethyl.

[0085] The term "C1-C n haloalkyl" means a C1-C n alkyl as defined herein which is substituted with one or more halogens. Examples of C1-C3 haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl and pentafluoroethyl.

[0086] The term "C1-C n alkoxy" means a straight or branched chain saturated hydrocarbon containing from 1 to n carbon atoms attached via an oxygen atom, i.e. -O(alkyl). Examples of C1-C4 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy and butoxy.

[0087] The term "C1-C n"Haloalkoxy" means a C1-C alkoxy as defined herein which is substituted by one or more halogens. n Examples of C1-C3 haloalkoxy include, but are not limited to, trifluoromethoxy, difluoromethoxy, and pentafluoroethoxy.

[0088] The term "C3-C5 cycloalkyl" means a monocyclic saturated carbocyclic ring containing 3 to 5 carbon atoms. Specifically, it refers to cyclopropyl, cyclobutyl, or cyclopentyl.

[0089] The term "heteroaryl" means a monocyclic aromatic ring containing one or more heteroatoms preferably selected from N, S, and O. Examples of 5-membered heteroaryl include, but are not limited to, pyrazole, triazole, and thiazole. Examples of 6-membered heteroaryl include, but are not limited to, pyridine and pyridazine.

[0090] The term "C4-C5 heterocyclic group" means a 4- or 5-membered monocyclic saturated ring containing one or more heteroatoms, such as oxetane.

[0091] Formula I includes Formulas II, IIa, IIb, III, IIIa, IIIb, IV, IVa, and IVb. Hereinafter, for example, when referring to Formula I in a method of treatment and therapeutic use, it is also considered as referring to each and all of these sub-formulas.

[0092] In another embodiment, there is provided a pharmaceutically acceptable composition which comprises 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.

[0093] In another embodiment, there is provided a method of treating type II diabetes in a patient, the method comprising administering to a patient in need of treatment a pharmaceutically acceptable composition which comprises an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient. In one embodiment, the pharmaceutically acceptable composition is formulated for oral administration. Preferably, the patient is human.

[0094] In another embodiment, there is provided a method of treating type II diabetes 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.

[0095] In another embodiment, there is provided a method of reducing the blood glucose level 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.

[0096] In another embodiment, there is provided a method of treating hyperglycemia 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.

[0097] 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.

[0098] In another embodiment, there is provided a method of treating non-alcoholic steatohepatitis (NASH) 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.

[0099] In one embodiment, there is provided a compound of formula I or a pharmaceutically acceptable salt thereof for use in therapy.

[0100] In another embodiment, there is provided a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of type II diabetes.

[0101] In another embodiment, there is provided a compound of formula I or a pharmaceutically acceptable salt thereof for reducing blood glucose levels.

[0102] In another embodiment, there is further provided a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of hyperglycemia.

[0103] In another embodiment, there is provided a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of obesity.

[0104] In another embodiment, there is further provided a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of NASH.

[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 type II diabetes.

[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 reducing blood glucose levels.

[0107] 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.

[0108] 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.

[0109] 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.

[0110] In another embodiment, there is provided a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of type II diabetes.

[0111] In another embodiment, there is provided a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof for reducing blood glucose levels.

[0112] In another embodiment, there is further provided a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of hyperglycemia.

[0113] In another embodiment, there is provided a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of obesity.

[0114] In another embodiment, there is further provided a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of NASH.

[0115] The compound of formula I can be used in combination with one or more therapeutic agents simultaneously, separately or sequentially. Examples of additional therapeutic agents include, but are not limited to, metformin, thiazolidinedione, sulfonylurea, dipeptidyl peptidase 4 inhibitor, sodium-glucose cotransporter and ketohexokinase inhibitor.

[0116] 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 for humans.

[0117] As used herein, the term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention that are considered acceptable for clinical use and / or veterinary use. Examples of pharmaceutically acceptable salts and common methods for their preparation can be found in "Handbook of Pharmaceutical Salts: Properties, Selection and Use" P. Stahl et al., Second Revised Edition, Wiley-VCH, 2011 and S.M. Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Sciences, 1977, 66(1), 1-19.

[0118] The term "effective amount" means the amount or dose of a compound of formula I or a pharmaceutically acceptable salt thereof that provides the desired effect in a patient being diagnosed or treated after administration in a single dose or multiple doses to the patient. A attending physician, being a person skilled in the art, can readily determine the effective amount by using conventional techniques and by observing the results obtained in similar circumstances. Factors considered in determining the effective amount or dose of a compound include: whether the compound or its salt is administered; co-administration of other agents, if used; the body size, age and general health of the patient; the extent or severity of the disorder involved; the response of the individual patient; the mode of administration; the bioavailability characteristics of the formulation administered; the selected dosage regimen; and other relevant circumstances. The compounds of the present invention are effective at daily doses falling within the range of about 0.01 to about 15 mg / kg body weight.

[0119] As used herein, the terms "treating / to treat / treatment" mean reducing, alleviating or reversing the progression or severity of an existing symptom, disorder or condition, such as hyperglycemia, which may include increasing insulin secretion.

[0120] As used herein, the term "patient" includes mammals. The patient is preferably human.

[0121] The compounds of formula I can be formulated into pharmaceutical compositions for administration by any route that renders the compound bioavailable. Preferably, such compositions are for oral administration. Preferably, the pharmaceutical composition is formulated as a tablet, capsule or solution. The tablet, capsule or solution may include an amount of the compound of formula I effective for treating a patient in need of treatment. Such pharmaceutical compositions and methods for their preparation are well known in the art (see, for example, "Remington: The Science and Practice of Pharmacy", edited by A. Adejare, 23rd Edition, 2020, Elsevier Science).

[0122] The compounds of formula I and their pharmaceutically acceptable salts can be used for the therapeutic uses of the present invention, and certain configurations are preferred.

[0123] The compounds of the present invention include:

[0124]

[0125]

[0126] or a pharmaceutically acceptable salt thereof.

[0127] Although the present invention contemplates all individual enantiomers, mixtures thereof and racemates, the compounds of formula IIa, IIIa and IVa and their pharmaceutically acceptable salts are particularly preferred.

[0128] One of ordinary skill in the art can separate or resolve individual enantiomers at any convenient point in the synthesis of the compounds of the present invention by methods such as selective crystallization techniques, 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).

[0129] Pharmaceutically acceptable salts of the compounds of the present invention can be formed, for example, by reacting a compound of Formula I with a suitable pharmaceutically acceptable base under standard conditions known in the art in a suitable solvent (see, e.g., Bastin, R. J. et al.; Org. Process Res. Dev., 4, 427 - 435, 2000; and Berge, S. M. et al., J. Pharm. Sci., 66, 1 - 19, 1977).

[0130] Certain abbreviations used herein are defined according to Daub G. H. et al., "The Use of Acronyms in Organic Chemistry" Aldrichimica Acta, 1984, 17(1), 6 - 23. 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; "EC 50 " refers to the reagent concentration that produces a 50% response of the target activity compared to a predetermined 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; "S N Ar" refers to nucleophilic aromatic substitution; "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.

[0131] The compounds of the present invention can be prepared by various procedures, some of which are illustrated in the following preparations and examples. The specific synthetic steps of the various routes can be combined in different ways to prepare the compounds of the present invention or their salts. The products of the following steps can be recovered by conventional methods, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization. The reagents and starting materials are readily available to those of ordinary skill in the art. The individual isomers, enantiomers, and diastereoisomers 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 invention without limiting the scope of the invention.

[0132] Scheme 1

[0133]

[0134] Scheme 1 shows two routes for preparing Intermediate 7, which is used for preparing the compounds of the present invention. In the first route, an aryl difluoride 1 is subjected to S N Ar with an amine 2 using a carbonate base at an elevated temperature to obtain Intermediate 3, which is then subjected to a second S NAr to obtain intermediate 5. In the second route, these two steps are carried out in the reverse order to obtain intermediate 5. Then, the nitro group of intermediate 5 is reduced to diamine intermediate 7 using a palladium catalyst and hydrogen.

[0135] Scheme 2

[0136]

[0137] Scheme 2 shows the preparation of compound 14, which begins with coupling acid intermediate 8 and amino intermediate 7 using T3P and an organic base to obtain amide intermediate 9. Intermediate 9 is cyclized using acetic acid at an elevated temperature to obtain benzimidazole intermediate 10, which then undergoes Suzuki coupling with boronic ester 11 using a palladium catalyst and a carbonate base at an elevated temperature to obtain intermediate 12. Alkylation with alkyl bromide 13 and a carbonate base at an elevated temperature subsequently gives compound 14. Alternatively, reaction of intermediate 12 and alcohol 16 under Mitsunobu conditions (diisopropyl azodicarboxylate and triphenylphosphine) gives compound 14 (a compound of formula I where A is -CH2O-).

[0138] Scheme 3

[0139]

[0140] Scheme 3 shows the preparation of compound 19, which begins with converting aryl bromide 10 to boronic ester 15 using bis(pinacolato)diboron, potassium acetate, and a palladium catalyst at an elevated temperature. Separately, alcohol 16 undergoes a nucleophilic aromatic substitution (S N Ar) reaction with 2-bromo-6-fluoropyridine 17 using an alcohol base at an elevated temperature to obtain intermediate 18. Then, intermediate 15 and 18 are coupled using a palladium catalyst, potassium acetate, and an elevated temperature to obtain compound 19 (a compound of formula I where A is -CH2O-; Y 3 is N, and Y 4 , Y 5 and Y 6 are CH).

[0141] Scheme 4

[0142]

[0143] Y 1 ,Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8, R 3 , R 4 , and R 5 as defined in Formula I

[0144] Scheme 4 shows the preparation of a compound of Formula I starting from acid intermediate 20, using amide coupling conditions such as HATU and an amine base to couple acid intermediate 20 with aniline intermediate 7 to give amide 21. Amide 21 is then cyclized using acetic acid at an elevated temperature to give the compound of Formula I.

[0145] In each of Schemes 1 - 4, in order to prepare a compound of the present invention in which R 5 is -CO2H as defined in Formula I, the synthetic steps described in Schemes 1 - 4 are carried out with R 5 protected as a methyl or ethyl ester (-CO2CH3 or -CO2CH2CH3). As a final step, the ester is hydrolyzed with a guanidine base at an elevated temperature to give a compound in which R 5 = -CO2H.

[0146] Preparation 1

[0147] Methyl 3,5-difluoro-4-nitrobenzoate

[0148]

[0149] A solution of thionyl chloride (37 mL, 74 mmol) in MeOH (110 mL) was cooled to -10 °C and 3,5-difluoro-4-nitrobenzonitrile (2.8 g, 15 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours and then the temperature was gradually raised to 65 °C over 2 hours. The mixture was filtered and concentrated under reduced pressure. The residue was dissolved in EtOAc (150 mL) and the organic matter was washed with saturated aqueous sodium bicarbonate (50 mL) and saturated aqueous NaCl (50 mL). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 10% EtOAc / petroleum ether to give 2.24 g of the title compound (66%). 1 1H-NMR (400 MHz, CDCl3) δ 7.78 (d, 2H), 4.0 (s, 3H).

[0150] Preparation 2

[0151] Methyl 3-fluoro-5-methoxy-4-nitrobenzoate

[0152]

[0153] 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 methoxide (25 wt% 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 organic layers 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 / heptane (0 to 10%) to afford 245 mg (76%) of the title compound as a yellow oil. ES / MS m / z 230 (M+H).

[0154] Preparation 3

[0155] (S)-Methyl 3-methoxy-4-nitro-5-((oxetan-2-ylmethyl)amino)benzoate

[0156]

[0157] 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) at room temperature was added TEA (1.5 mL, 1.09 g, 11 mmol). To this pale yellow solution was added [(2S)-oxetan-2-yl]methanamine (0.42 g, 4.8 mmol, 100 wt%), and the rust-colored solution was stirred overnight at room temperature under nitrogen, then heated at 35 °C for 72 h. The reaction mixture was partially concentrated; then it was 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 organic layers were washed with saturated aqueous NaCl and dried over Na2SO4, filtered, concentrated, and dried under high vacuum. The residue was purified by flash chromatography using a gradient of 5 to 30% EtOAc / DCM to afford the title compound as a yellow oil (0.99 g, 73%). The sample was analyzed by 1H NMR and LC / MS. ES / MS m / z 296 (M+H).

[0158] Preparation 4

[0159] Methyl 4-amino-3-methoxy-5-[[(2S)-oxetan-2-ylmethyl]amino]benzoate

[0160]

[0161] To a slurry of 5% platinum sulfide-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 with hydrogen to 60 psig. The reaction was sealed at this pressure and shaken at room temperature for 4 h. The suspension was filtered through a Celite pad and the filtrate was concentrated under reduced pressure to afford the title compound as an oil (0.90 g, quantitative yield), which crystallized on standing. ES / MS m / z 267 (M+H).

[0162] Preparation 5

[0163] Methyl 3-fluoro-5-(2-methoxyethoxy)-4-nitro-benzoate

[0164]

[0165] 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 min. Next, methyl 3,5-difluoro-4-nitro-benzoate (0.5 g, 2.30 mmol) was added and the mixture was stirred at 60 °C for 16 h. The reaction was diluted with water (100 mL) and extracted with EtOAc (3 × 50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography using a gradient of 0 to 20% EtOAc / heptane to afford the title compound as a yellow oil (225 mg, 40%). ES / MS m / z 274 (M+H).

[0166] Preparation 6

[0167] Methyl 3-(2-methoxyethoxy)-4-nitro-5-[[[(2S)-oxetan-2-yl]methyl]amino]benzoate

[0168]

[0169] To a solution of methyl 3-fluoro-5-(2-methoxyethoxy)-4-nitrobenzoate (0.34 g, 1.23 mmol) in anhydrous 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 overnight at 35 °C. 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 for 1 h at 35 °C. The reaction was diluted with water and extracted four times with EtOAc. The combined organic phases were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 0 to 30% EtOAc / heptane to afford the title compound as an orange oil (228 mg, 55%). ES / MS m / z 341 (M+H).

[0170] Preparation 7

[0171] Methyl 4-amino-3-(2-methoxyethoxy)-5-[[[(2S)-oxetan-2-yl]methyl]amino]benzoate

[0172]

[0173] To a reaction vessel containing iron (0.325 g, 5.82 mmol), 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 min. Then, 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 min. The mixture was filtered through a Celite pad and washed with EtOAc. Saturated aqueous NaHCO3 was added to the filtrate, the organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to afford the title compound as a yellow oil (0.181 g, quantitative yield), which was used without further purification of the unreacted. ES / MS m / z 311 (M+H)

[0174] Preparation 8

[0175] Methyl 2-[[4-[6-[(4-cyano-2-fluorophenyl)methoxy]-2-pyridinyl]-2-fluoro-5-methylphenyl]methyl]-7-methoxy-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate

[0176]

[0177] At room temperature, HATU (800 mg, 2.1 mmol) was added to a mixture of 2-[4-[6-[(4-cyano-2-fluorophenyl)methoxy]-2-pyridinyl]-2-fluorophenyl]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). After stirring at room temperature for 3.5 h, the reaction mixture was diluted with EtOAc (30 mL), washed with water and saturated aqueous NaCl solution, dried over Na2SO4, filtered and concentrated. The residue was dissolved in acetic acid (5 mL), and the mixture was stirred at 35 °C for 48 h. 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 solution and saturated aqueous NaCl solution, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by silica gel chromatography using a gradient of 20 - 100% EtOAc / hexane to give the title compound (500 mg, 57% yield). ES / MS (m / z): 625 (M+H).

[0178] Preparation 9

[0179] (S)-Methyl 4-(2-(4-bromo-2,5-difluorophenyl)acetamido)-3-methoxy-5-((oxetan-2-ylmethyl)amino)benzoate

[0180]

[0181] 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 h. 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).

[0182] Preparation 10

[0183] (S)-Methyl 2-(4-bromo-2,5-difluorobenzyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0184]

[0185] 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 / hexanes, followed by 5% MeOH / DCM to afford 8.3 g of the title compound (87%). ES / MS m / z 481 and 483 (M+H).

[0186] Preparation 11

[0187] (S)-Methyl 2-(2,5-difluoro-4-(6-hydroxypyridin-2-yl)benzyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0188]

[0189] 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 h. The mixture was diluted with 100 mL of water and stirred vigorously at room temperature for 5 min. The solid was collected by vacuum filtration and washed with EtOAc (6 × 50 mL) to afford 3.0 g of the title compound (68%). ES / MS m / z 496 (M+H).

[0190] Preparation 12

[0191] (S)-Methyl 4-(2-(4-bromo-2,5-difluorophenyl)acetamido)-3-(2-methoxyethoxy)-5-((oxetan-2-ylmethyl)amino)benzoate

[0192]

[0193] 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 mmol) and T3P (50% in THF, 12 mL, 20 mmol) was stirred at room temperature for 1 h. The mixture was diluted with 100 mL of water and the resulting solid was collected by vacuum filtration to afford 4.3 g of the title compound (95%). ES / MS m / z 543 and 545 (M+H).

[0194] Preparation 13

[0195] (S)-Methyl 2-(4-bromo-2,5-difluorobenzyl)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0196]

[0197] 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 / hexane to afford 3.2 g of the title compound (78%). ES / MS m / z 525 and 527 (M+H).

[0198] Preparation 14

[0199] (S)-Methyl 2-(2,5-difluoro-4-(6-hydroxypyridin-2-yl)benzyl)-4-(2-methoxyethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0200]

[0201] 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 a mixture of 1,4-dioxane (9.3 mL) and water (2.3 mL) were stirred at 70 °C for 3 h. The mixture was diluted with 50 mL of water and stirred vigorously for 5 min at room temperature. The solid was collected by vacuum filtration and washed with EtOAc (5 × 20 mL) to afford 885 mg of the title compound (88%). ES / MS m / z 540 (M+H).

[0202] Preparation 15

[0203] Methyl 2-[[4-[6-[(6-cyano-2-methylpyridin-3-yl)methoxy]-2-pyridinyl]-2,5-difluorophenyl]methyl]-7-methoxy-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylate

[0204]

[0205] To a stirred solution of 5-(hydroxymethyl)-6-methylpyridine-2-carbonitrile (112 mg, 0.718 mmol) in anhydrous THF (3.5 mL) at 0 °C was added 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) dropwise. The reaction was warmed 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 / EtOAc and concentrated under reduced pressure to afford 82 mg of the title compound (22%). ES / MS m / z 626 (M+H).

[0206] Preparation 16

[0207] 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]-1H-benzo[d]imidazole-5-carboxylate

[0208]

[0209] 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), potassium acetate (86 mg, 0.88 mmol), and the resulting mixture was degassed and purged with nitrogen three times. Then 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) DCM complex (24 mg, 0.03 mmol) was 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 with EtOAc twice. 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 - 10% MeOH / EtOAc and concentrated under reduced pressure to afford 168 mg of the title compound (72%). ES / MS m / z 491 (M+H of the boronic acid).

[0210] Preparation 17

[0211] 5-[(6-Bromo-2-pyridinyl)oxymethyl]-1-methyl-2(1H)-pyridinone

[0212]

[0213] At room temperature, potassium tert-butoxide (358 mg, 3.16 mmol) was added to a stirred solution of 5-(hydroxymethyl)-1-methylpyridin-2-one (367 mg, 2.64 mmol) and 2-bromo-6-fluoropyridine (565 mg, 3.15 mmol) in anhydrous THF (4 mL). 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 silica gel chromatography using a gradient of 0-10% MeOH / EtOAc and concentrated under reduced pressure to afford 213 mg of the title compound (26%). ES / MS m / z 294&296 (M+H).

[0214] Preparation 18

[0215] Methyl 2-[[2,5-difluoro-4-[6-[(1-methyl-6-oxo-3-pyridinyl)methoxy]-2-pyridinyl]phenyl]methyl]-7-(2-methoxyethoxy)-3-[[(2S)-oxetan-2-yl]methyl]-1H-benzo[d]imidazole-5-carboxylate

[0216]

[0217] To a stirred solution of 5-[(6-bromo-2-pyridinyl)oxymethyl]-1-methylpyridin-2-one (108 mg, 0.366 mmol), 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]-1H-benzo[d]imidazole-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(diphenylphosphino)ferrocene-palladium(II) dichloride DCM complex (25 mg, 0.030 mmol). 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 silica gel chromatography using a gradient of 0-10% MeOH / EtOAc and concentrated under reduced pressure to afford 81 mg of the title compound (42%). ES / MS m / z 661 (M+H).

[0218] Example 1

[0219] 2-[[4-[6-[(4-Cyano-2-fluorophenyl)methoxy]-2-pyridinyl]-2-fluoro-5-methylphenyl]methyl]-7-methoxy-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid

[0220]

[0221] To a mixture of methyl 2-[[4-[6-[(4-cyano-2-fluorophenyl)methoxy]-2-pyridinyl]-2-fluoro-5-methylphenyl]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 h and then stirred overnight at room temperature. The mixture was neutralized with aqueous citric acid and concentrated. The residue was purified by reverse-phase flash chromatography using a gradient of 10 to 100% ACN / 10 mM aqueous ammonium bicarbonate (pH 10) on a C18 column to afford the title compound (398 mg, 81%). ES / MS (m / z): 611 (M+H).

[0222] Example 2

[0223] (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

[0224]

[0225] 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-fluorobenzonitrile (80 mg, 0.37 mmol) in ACN (3.0 mL) was stirred at 45 °C for 4.5 h. 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 h. The reaction mixture was concentrated onto silica gel and purified by reverse-phase chromatography using a gradient of 0 to 100% ACN / water containing 5% MeOH and 10 mM ammonium bicarbonate to afford 27 mg of the title compound (15%). ES / MS m / z 615 (M+H).

[0226] Example 3

[0227] (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

[0228]

[0229] 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 h and then at 50 °C for 2 h. The suspension was filtered through a pad of silica gel, and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (300 mg, 2.11 mmol) in water (0.7 mL) was added to the filtrate. The mixture was stirred at 55 °C for 35 min and then quenched with 1 M aqueous citric acid (2 mL). The mixture was extracted with EtOAc (2 × 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 using a gradient of 14 to 48% ACN / water containing 5% MeOH and 10 mM ammonium bicarbonate to afford 23 mg of the title compound (10%). ES / MS m / z 598 (M+H).

[0230] Example 4

[0231] (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

[0232]

[0233] The title compound was prepared substantially as described in Example 3 using 5-(bromomethyl)pyridine-2-carbonitrile and purified by reverse phase chromatography using a gradient of 23 to 58% ACN / 10 mM aqueous ammonium bicarbonate solution containing 5% MeOH on a C18 column, and then purified by SFC on an AS-H column with 40% IPA / CO2. ES / MS m / z 598 (M+H).

[0234] Example 5

[0235] (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

[0236]

[0237] The title compound was prepared substantially 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 using a gradient of 23 to 58% ACN / 10 mM aqueous ammonium bicarbonate solution containing 5% MeOH on a C18 column. ES / MS m / z 659 (M+H).

[0238] Example 6

[0239] 2-[[4-[6-[(6-Cyano-2-methyl-3-pyridinyl)methoxy]-2-pyridinyl]-2,5-difluorophenyl]methyl]-7-methoxy-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid (Example 6a)

[0240]

[0241] and

[0242] 2-[[4-[6-[(6-carbamoyl-2-methyl-3-pyridinyl)methoxy]-2-pyridinyl]-2,5-difluorophenyl]methyl]-7-methoxy-3-[[(2S)-oxetan-2-yl]methyl]-1H-benzo[d]imidazole-5-carboxylic acid (Example 6b)

[0243]

[0244] Bubble 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) for 10 minutes and transfer it to a reaction vessel containing methyl 2-[[4-[6-[(6-cyano-2-methyl-3-pyridinyl)methoxy]-2-pyridinyl]-2,5-difluorophenyl]methyl]-7-methoxy-3-[[(2S)-oxetan-2-yl]methyl]-1H-benzo[d]imidazole-5-carboxylate (47 mg, 0.08 mmol). Stir the reaction mixture at 55 °C for 2 hours. After 2 hours, transfer the reaction mixture to a separatory funnel containing EtOAc, wash with 10% aqueous citric acid solution and saturated NaCl aqueous solution, dry over magnesium sulfate, filter, and concentrate 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 solution. The fractions containing the title compound were concentrated under reduced pressure to remove the volatile organic solvents, then the remaining aqueous layer was acidified with 0.1 N aqueous hydrochloric acid solution and extracted three times with EtOAc. The combined organic layers were washed with saturated NaCl aqueous solution, 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 (containing 0.1% formic acid): 0.1% aqueous formic acid solution to separate two title compounds: the nitrile compound (Example 6a, 15 mg, 33%); and the amide compound (Example 6b, 11 mg, 23%), ES / MS m / z 630 (M + H).

[0245] Example 7

[0246] 2-[[2,5-difluoro-4-[6-[(1-methyl-6-oxo-3-pyridinyl)methoxy]-2-pyridinyl]phenyl]methyl]-7-(2-methoxyethoxy)-3-[[(2S)-oxetan-2-yl]methyl]-1H-benzo[d]imidazole-5-carboxylic acid

[0247]

[0248] 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 bubbled for 10 minutes and then added to a reaction vessel containing methyl 2-[[2,5-difluoro-4-[6-[(1-methyl-6-oxo-3-pyridinyl)methoxy]-2-pyridinyl]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 h 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 0-100% ACN (containing 0.1% formic acid):aqueous 0.1% formic acid. The 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 0-100% ACN (containing 0.1% formic acid):aqueous 0.1% formic acid to afford 18.7 mg of the title compound (26%). ES / MS m / z 647 (M+H).

[0249] General Procedure: O-alkylation followed by 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 eq, 0.18 mmol) and potassium carbonate (62 mg, 0.45 mmol) in ACN (1.5 mL) was stirred at 50 °C for 5 h. Water (1 mL) was added and the mixture was extracted with DCM (1 mL). The organic layer was filtered through diatomaceous earth and washed with DCM. The organic layer was concentrated and 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) were added to the residue. The mixture was stirred at 50 °C for 1 h, then water (1 mL) was added and the mixture was extracted with DCM (1 mL). The organic layer was filtered through diatomaceous earth, washed with DCM, concentrated and then subjected to the specified chromatographic conditions.

[0250] According to the general procedure for O-alkylation followed by ester hydrolysis described above, the following examples were prepared using the listed halides as starting materials and the specified chromatographic conditions.

[0251]

[0252]

[0253]

[0254] Biological assay

[0255] Human GLP-1 Receptor HEK293 Cell cAMP Assay

[0256] The functional activity of the GLP-1 receptor was assayed using cAMP formation in a HEK293 clonal cell line expressing human GLP-1R (NCBI accession number NP_002053) at expression densities of 581 ± 94 (n = 6) and 104 ± 12 (n = 5) fmol / mg protein (using 125 I] GLP-1(7-36)NH2 homologous competition binding assay). In a 20 μl assay volume (final DMSO concentration of 0.5%), hGLP-1R receptor-expressing cells were treated with the compound (20-point concentration-response curve in DMSO, 2.75-fold Labcyte Echo direct dilution, 384-well plate Corning Cat#3570) in DMEM (Gibco Cat#31053) supplemented with 1X GlutaMAX TM (Gibco Cat#35050), 0.1% bovine casein (Sigma C4765-10ML), 250 μM IBMX (3-isobutyl-1-methylxanthine, Acros Cat#228420010), and 20 mM HEPES (Gibco Cat#15630). After incubation at 37 °C for 30 minutes, the resulting increase in intracellular cAMP was quantified using the CisBio cAMP Dynamic 2HTRF detection kit (62AM4PEJ). Briefly, intracellular cAMP levels were detected by adding the cAMP-d2 conjugate (10 μL) in cell lysis buffer, followed by the addition of the antibody anti-cAMP-Eu 3+ -Cryptate (10 μL), also in cell lysis buffer. The resulting competitive assay was incubated at room temperature for at least 60 minutes and then measured using a PerkinElmer with excitation at 320 nm and emission at 665 nm and 620 nm Instrumental assay. The 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 (nM) generated in each well is converted to a percentage of the maximum response observed with human GLP-1(7-36)NH2. The relative EC 50 values and percent top (E max ) are derived by non-linear regression analysis of maximum response percentage vs. added compound concentration and fitted to a four-parameter logistic equation. The EC 50 and E max data when testing the compounds of Examples 1 to 14 in the above cAMP assay using HEK293 cells expressing 581 and 104 fmol / mg GLP-1R are shown in Tables 1 and 2, respectively. These data indicate that the compounds of Examples 1 to 14 are agonists of the human GLP-1 receptor. The compounds of Examples 1, 2, 5, and 13 showed potency comparable to that of native GLP-1(7-36)NH2 peptide in the 104 fmol / mg assay.

[0257] Table 1. HEK293 cell line with a GLP-1R expression density of 581 fmol / mg, intracellular cAMP response, relative EC 50 and %Stim Max

[0258] Example <![CDATA[EC 50 nM(SEM,n)]]> % Stim Max (SEM, n) 1 0.291(0.0681,n＝4) 125(3.95,n＝4) 2 0.221(0.0317,n＝5) 120(3.39,n＝5) 3 2.16(0.346,n＝4) 123(2.13,n＝4) 4 1.91(0.124,n＝5) 118(2.96,n＝5) 5 0.297(0.0315,n＝4) 123(3.72,n＝4) 6a 3.18(0.982,n＝4) 121(4.77,n＝4) 6b 35.2(8.11,n＝4) 104(6.13,n＝4) 7 113(24.6,n＝4) 105(4.63,n＝4) 8 0.785(0.132,n＝3) 116(3.39,n＝3) 9 0.3(0.025,n＝3) 117(6.8,n＝3) 10 37.5(1.26,n＝3) 126(4.66,n＝3) 11 0.402(0.0499,n＝3) 117(3.04,n＝3) 12 52.4(6.96,n＝4) 110(2.04,n＝4) 13 0.167(0.0191,n＝5) 125(5.29,n＝5) 14 25.7(4.76,n＝4) 118(4.46,n＝4)

[0259] Table 2. HEK293 cell line with a GLP-1R expression density of 104 fmol / mg, intracellular cAMP response, relative EC 50 , %Stim Max and E max

[0260] Example <![CDATA[EC 50 nM(SEM,n)]]> % Stim Max (SEM, n) <![CDATA[E max % ± SEM]]> 1 0.499(0.104,n＝4) 82.7(3.85,n＝4) 74±3 2 0.682(0.12,n＝5) 90.9(2.98,n＝5) 80±2 3 6.96(2.6,n＝4) 89.2(2.36,n＝4) 80±1 4 4.45(1.34,n＝5) 87.5(1.54,n＝5) 81±3 5 0.724(0.173,n＝4) 91.6(6.35,n＝4) 79±3 6a 10.6(1.94,n＝4) 87.9(3.76,n＝4) 70±5 6b 131(8.87,n＝4) 77.4(4.52,n＝4) 66±3 7 495(72.7,n＝4) 74.7(5.06,n＝4) 70±5 8 3.37(0.51,n＝4) 75.6(1.62,n＝4) 68±2 9 1.37(0.17,n＝5) 82.9(3.52,n＝5) 75±3 10 147(11.4,n＝3) 84.3(2.62,n＝3) 71±3 11 1.44(0.26,n＝5) 84.4(5.15,n＝5) 75±4 12 220(11.6,n＝4) 76(1.83,n＝4) 68±2 13 0.480(0.065,n＝6) 87.6(3.51,n＝6) 78±4 14 125(15.2,n＝4) 81.9(2.95,n＝4) 72±3 <![CDATA[GLP-1(7-36)NH2]]> 0.652(0.039,n＝48) 101±2

[0261] EC 50 , nM = geometric mean of the concentration that produces half of the maximum stimulation (half of E max ), followed by SEM (delta method) and number of observations in parentheses

[0262] %Stim Max = arithmetic mean of the percentage of stimulation at the point on the concentration-response curve that gives the maximum stimulation relative to the maximum response produced by GLP-1(7-36)NH2, followed by SEM and number of observations in parentheses

[0263] E max, % = the arithmetic mean at the top of the fitted concentration-response curve, as the percentage relative to the maximum response to GLP-1(7-36)NH2 ± SEM

[0264] In Vivo Intraperitoneal Glucose Tolerance Test in Human GLP-1R Knock-in Mice

[0265] The in vivo hypoglycemic potency of the exemplified compounds was determined using mice expressing human GLP-1R (NCBI accession number NP_002053) from the mouse Glp-1r locus (Jun, L.S. et al., PLoS One. 2014 9: e93746). The test compound dissolved in 10% (HS15) / polyethylene glycol 400 (PEG400) was orally administered to mice fasted overnight. One hour after dosing, glucose was administered to the animals by intraperitoneal injection (2 g / kg), and blood glucose levels were intermittently measured using a blood glucose meter over the next two hours. A range of doses of the test compound was delivered, the area under the curve was calculated for each dose group, and fitted to a four-parameter logistic model to serve as the ED 50 The in vivo potency was calculated. When tested in the above in vivo intraperitoneal glucose tolerance test, the compound of Example 1 exhibited hypoglycemic potency in mice expressing human GLP-1R, with ED 50 (and 95% confidence interval) values as shown in Table 3, indicating that this compound is a potent orally available GLP-1R agonist in mice.

[0266] Table 3. Hypoglycemic potency in mice expressing human GLP-1R

[0267] Example <![CDATA[Blood glucose reduction ED 50 (mg / kg)]]> 95% Confidence Interval 1 0.008 0.0045-0.0155

Claims

1. A compound of the following formula or a pharmaceutically acceptable salt thereof: wherein is phenyl, a 5- or 6-membered heteroaryl or pyridone, and the phenyl, heteroaryl or pyridone is optionally substituted by one or two Rs 1 substituted; R 1 independently at each occurrence is CN; halogen; C1-C3 alkyl optionally substituted with OH; C1-C3 haloalkyl; C1-C3 alkoxy; C3-C5 cycloalkyl; -SO2C1-C3 alkyl; -C(O)NH2; wherein each X 9 is independently CH or N, and no more than one X in the ring 9 is N, each R e is independently selected from: H, C1-C3 haloalkyl, halogen, C3-C5 cycloalkyl and C1-C3 alkyl optionally substituted with OH, R h is H, C1-C3 haloalkyl, halogen, C3-C5 cycloalkyl, OH, -NR c R d or C1-C3 alkyl optionally substituted with OH; 5- or 6-membered heteroaryl or phenyl, wherein said heteroaryl or phenyl is optionally substituted by one or two substituents independently selected from the following: C1-C3 alkoxy, C3-C5 cycloalkyl, -CH2-C3-C5 cycloalkyl, -SO2C1-C3 alkyl, C4-C5 heterocyclic group, -CH2-C4-C5 heterocyclic group, halogen, C1-C3 haloalkyl, C1-C3 haloalkoxy, CN, -CONR c R d 、-NR c R d or C1-C3 alkyl optionally substituted by OH; -A- is -CH2O-, -OCH2- or -CH2NH-; Y 1 , Y 2 , Y 7 and Y 8 are independently N, CH or CR 2 , where Y 1 , Y 2 , Y 7 and Y 8 No more than one of them is N, and Y 1 , Y 2 , Y 7 and Y 8 No more than two are CR 2 ; Y 3 、Y 4 、Y 5 and Y 6 are independently N, CH or CR 2 wherein no more than two of Y 3 、Y 4 、Y 5 and Y 6 are N, and no more than two of Y 3 、Y 4 、Y 5 and Y 6 are CR 2 ; R 2 independently at each occurrence is halogen or methyl; R 3 is a C1-C4 alkoxy group optionally substituted by a C1-C2 alkoxy group, a hydroxyl group or a C1-C3 haloalkyl group; R 4 is R 5 is -CO2H, R c and R d each independently is H or a C1-C3 alkyl group.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound has the following formula:

3. The compound or a pharmaceutically acceptable salt thereof according to claim 2, wherein the compound has the following formula:

4. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein is a phenyl group optionally substituted by one or two R 1 substituents.

5. The compound or a pharmaceutically acceptable salt thereof according to claim 4, wherein the phenyl group is substituted by one or two Rs independently selected from CN, halogen, C1-C3 alkyl, C1-C3 alkoxy or 5-membered heteroaryl 1 substituted.

6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein said one or two Rs 1 are independently selected from CN, F, CH3, OCH3 or triazole.

7. The compound or a pharmaceutically acceptable salt thereof according to claim 6, wherein said one or two Rs 1 are independently selected from CN, F or OCH3.

8. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein -A- is -CH2O-.

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

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

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

12. The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, wherein R 3 is a C1-C4 alkoxy group optionally substituted with a C1-C2 alkoxy group.

13. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein R 3 is -OCH3 or -OCH2CH2OCH3.

14. A compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, wherein R 5 is -CO2H.

15. The compound according to claim 1, selected from: 2-[[4-[6-[(4-cyano-2-fluorophenyl)methoxy]-2-pyridinyl]-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-pyridinyl)methoxy]-2-pyridinyl]-2,5-difluorophenyl]methyl]-7-methoxy-3-[[oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid; 2-[[4-[6-[(6-carbamoyl-2-methyl-3-pyridinyl)methoxy]-2-pyridinyl]-2,5-difluorophenyl]methyl]-7-methoxy-3-[[oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid; 2-[[2,5-difluoro-4-[6-[(1-methyl-6-oxo-3-pyridinyl)methoxy]-2-pyridinyl]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.

16. The compound or a pharmaceutically acceptable salt thereof according to claim 1, which has the following formula: wherein is phenyl, 5- or 6-membered heteroaryl or pyridone, said phenyl, heteroaryl or pyridone being optionally substituted by one or two R 1 substituents; R 1 is CN, halogen, C1-C3 alkyl, C1-C3 alkoxy, -C(O)NH2 or a 5-membered heteroaryl; R 2 each occurrence is independently a halogen or a methyl group; R 3 is a C1-C4 alkoxy group optionally substituted by a C1-C2 alkoxy group.

17. The compound or a pharmaceutically acceptable salt thereof according to claim 1, which has the following formula: wherein R 1 is F or OCH3; R 2 is F or CH3; and R 3 is -OCH3 or -OCH2CH2OCH3.

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

19. A method for treating type II diabetes in a patient, which comprises administering to the patient an effective amount of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17.

20. A method for reducing the blood glucose level in a patient, which comprises administering to the patient an effective amount of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17.

21. A method for treating hyperglycemia in a patient, which comprises administering to the patient an effective amount of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17.

22. A method for treating obesity in a patient, which comprises administering to the patient an effective amount of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17.

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

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

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

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

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

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

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

30. 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. 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 reducing blood glucose levels.

32. 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. 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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