Compounds as GLP-1r agonists

Abstract

The present application provides compounds of Formula (I), or pharmaceutically acceptable salts thereof, that may be used as a glucagon-like peptide- 1 receptor (GLP-1R) agonist. Also provided are pharmaceutical compositions containing such compounds, or pharmaceutically acceptable salts thereof. Methods of preparing these compounds and compositions, and methods of using these compounds and compositions to treat or prevent a disease or a condition mediated by GLP-1R, are also provided.

Description

COMPOUNDS AS GLP-1R AGONISTS CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No.63 / 682,441, filed August 13, 2024, the contents of which are incorporated herein by reference in their entirety. BACKGROUND

[0002] Diabetes is a major public health concern because of its increasing prevalence and associated health risks. The disease is characterized by high levels of blood glucose resulting from defects in insulin production, insulin action, or both. Two major forms of diabetes are recognized, Type 1 and Type 2. Type 1 diabetes (T1D) develops when the body’s immune system destroys pancreatic beta cells, the only cells in the body that make the hormone insulin that regulates blood glucose. To survive, people with Type 1 diabetes must have insulin administered by injection or a pump. Type 2 diabetes mellitus (T2DM) usually begins with either insulin resistance or when there is insufficient production of insulin to maintain an acceptable glucose level.

[0003] Currently, various pharmacological approaches are available for treating hyperglycemia and subsequently, T2DM (Hampp, C. et al. Use of Antidiabetic Drugs in the U.S., 2003-2012, Diabetes Care 2014, 37, 1367-1374). One of them is glucagon-like peptide-1 receptor (GLP-1R) agonists (e.g., liraglutide, albiglutide, exenatide, lixisenatide, dulaglutide, semaglutide), which enhance secretion of insulin by acting on the pancreatic beta-cells. Marketed GLP-1R agonists are peptides administered by subcutaneous injection. Liraglutide is additionally approved for the treatment of obesity.

[0004] GLP-1 is a 30 amino acid long incretin hormone secreted by the L-cells in the intestine in response to ingestion of food. GLP-1 has been shown to stimulate insulin secretion in a physiological and glucose-dependent manner, decrease glucagon secretion, inhibit gastric emptying, decrease appetite, and stimulate proliferation of beta-cells. In non-clinical experiments GLP-1 promotes continued beta-cell competence by stimulating transcription of genes important for glucose-dependent insulin secretion and by promoting beta-cell neogenesis (Meier et al. Biodrugs.2003; 17 (2): 93-102).

[0005] In a healthy individual, GLP-1 plays an important role regulating post-prandial blood glucose levels by stimulating glucose-dependent insulin secretion by the pancreas resulting in increased glucose absorption in the periphery. GLP-1 also suppresses glucagon secretion, leadingto reduced hepatic glucose output. In addition, GLP-1 delays gastric emptying and slows small bowel motility delaying food absorption. In people with T2DM, the normal post-prandial rise in GLP-1 is absent or reduced (Vilsboll T, et al. Diabetes.2001.50; 609-613).

[0006] Holst (Physiol. Rev. 2007, 87, 1409) and Meier (Nat. Rev. Endocrinol. 2012, 8, 728) describe that GLP-1 receptor agonists, such as liraglutide and exendin-4, have 3 major pharmacological activities to improve glycemic control in patients with T2DM by reducing fasting and postprandial glucose (FPG and PPG): (i) increased glucose-dependent insulin secretion (improved first- and second-phase), (ii) glucagon suppressing activity under hyperglycemic conditions, (iii) delay of gastric emptying rate resulting in retarded absorption of meal-derived glucose.

[0007] There remains a need of developing GLP-1 receptor agonists for an easily-administered prevention and / or treatment for cardiometabolic and associated diseases. SUMMARY

[0008] Disclosed are compounds that can be used as glucagon-like peptide-1 receptor (GLP- 1R) agonists, compositions containing these compounds and methods for treating diseases and / or conditions mediated by GLP-1R.

[0009] In some embodiments, the present disclosure provides a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: R1is C1-6alkyl or C1-6haloalkyl, wherein the alkyl is optionally substituted with deuterium; R2is C1-6 alkyl; R6is H or halogen; R3is H or C1-6 alkyl; R4is halogen, C1-6alkyl, or C1-6haloalkyl;n is 0 to 5; each R5independently is halo or -CN; and R7is -C(O)OH or 5- to 10-membered heteroaryl.

[0010] In some embodiments, the present disclosure provides a pharmaceutical composition comprising the compound of any one of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0011] In some embodiments, the present disclosure provides a method of treating a disease mediated by glucagon-like peptide-1 receptor (GLP-1R) in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of any one of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, or any pharmaceutical composition disclosed herein.

[0012] In some embodiments, the disease is a liver disease. In some embodiments, the liver disease is primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), drug induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition associated cholestasis (PNAC), bacterial overgrowth or sepsis associated cholestasis, autoimmune hepatitis, viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), graft versus host disease, transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intra- or extrahepatic malignancy, Sjogren’s syndrome, sarcoidosis, Wilson’s disease, Gaucher’s disease, hemochromatosis, or alpha-1-antitrypsin deficiency.

[0013] In some embodiments, the disease is diabetes.

[0014] In some embodiments, the disease is cardiometabolic disease.

[0015] In some embodiments, the disease is obesity.

[0016] In some embodiments, the present disclosure provides the use any one of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease mediated by GLP-1R.

[0017] In some embodiments, the present disclosure provides a method of decreasing food intake in an individual in need thereof, comprising administering to the individual any one of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, or any pharmaceutical composition herein.

[0018] In some embodiments, the present disclosure provides a method of increasing glucose tolerance in an individual in need thereof, comprising administering to the individual any one of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, or any pharmaceutical composition herein.

[0019] In some embodiments, the present disclosure provides a compound obtainable by, or obtained by, a method for preparing a compound as described herein (e.g., a method comprising one or more steps described in Examples 1-17).

[0020] In some embodiments, the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein (e.g., the intermediate is selected from the intermediates described in Examples 1-17.

[0021] In some embodiments, the present disclosure provides a method of modulating GLP-1R activity (e.g., in vitro or in vivo), comprising contacting a cell with an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0022] In some embodiments, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0023] In some embodiments, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0024] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in modulating GLP-1R activity (e.g., in vitro or in vivo).

[0025] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease or disorder disclosed herein.

[0026] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder disclosed herein.

[0027] In some embodiments, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for modulating GLP-1R activity (e.g., in vitro or in vivo).

[0028] In some embodiments, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0029] In some embodiments, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or disorder disclosed herein.

[0030] In some embodiments, the present disclosure provides a method of preparing a compound of the present disclosure.

[0031] In some embodiments, the present disclosure provides a method of preparing a compound, comprising one or more steps described herein.

[0032] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting. In the case of conflict between the chemical structures and names of the compounds disclosed herein, the chemical structures will control.

[0033] Other features and advantages of the disclosure will be apparent from the following detailed description and claims. DETAILED DESCRIPTION

[0034] The present disclosure relates to compounds, prodrugs, and pharmaceutically acceptable salts thereof, which may modulate GLP-1R activity and are accordingly useful in methods of treatment of the human or animal body, e.g., in the treatment of a disease mediated by GLP-1R. The present disclosure also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them and to their use in the treatment of disorders inwhich GLP-1R is implicated, such as diabetes, non-alcoholic fatty liver disease (NASH), obesity, hyperglycemia, and / or insulinoma.

[0035] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0036] Without wishing to be limited by this statement, it is understood that, while various options for variables are described herein, the disclosure intends to encompass operable embodiments having combinations of the options. The disclosure may be interpreted as excluding the non-operable embodiments caused by certain combinations of the options.

[0037] As used herein, “alkyl”, “C1, C2, C3, C4, C5or C6alkyl” or “C1-C6alkyl” is intended to include C1, C2, C3, C4, C5 or C6 straight chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, C5 or C6 branched saturated aliphatic hydrocarbon groups. For example, C1-C6alkyl is intends to include C1, C2, C3, C4, C5and C6alkyl groups. Examples of alkyl include, moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, or n-hexyl. In some embodiments, a straight chain or branched alkyl has six or fewer carbon atoms (e.g., C1-C6for straight chain, C3-C6for branched chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms. A divalent alkyl group is referred to herein as “alkylene.”

[0038] As used herein, the term “optionally substituted alkyl” refers to unsubstituted alkyl or alkyl having designated substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0039] As used herein, the term “alkenyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond. For example, the term “alkenyl” includes straight chain alkenyl groups (e.g., ethenyl,propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), and branched alkenyl groups. In certain embodiments, a straight chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term “C2-C6” includes alkenyl groups containing two to six carbon atoms. The term “C3-C6” includes alkenyl groups containing three to six carbon atoms. A divalent alkenyl group is referred to herein as “alkenylene.”

[0040] As used herein, the term “optionally substituted alkenyl” refers to unsubstituted alkenyl or alkenyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0041] As used herein, the term “alkynyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, “alkynyl” includes straight chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), and branched alkynyl groups. In certain embodiments, a straight chain or branched alkynyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term “C2-C6” includes alkynyl groups containing two to six carbon atoms. The term “C3-C6” includes alkynyl groups containing three to six carbon atoms. As used herein, “C2-C6 alkenylene linker” or “C2-C6 alkynylene linker” is intended to include C2, C3, C4, C5 or C6 chain (linear or branched) divalent unsaturated aliphatic hydrocarbon groups. For example, C2-C6alkenylene linker is intended to include C2, C3, C4, C5and C6alkenylene linker groups. A divalent alkynyl group is referred to herein as “alkynylene.”

[0042] As used herein, the term “optionally substituted alkynyl” refers to unsubstituted alkynyl or alkynyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl,alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or Heteroaromatic moiety.

[0043] Other optionally substituted moieties (such as optionally substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl) include both the unsubstituted moieties and the moieties having one or more of the designated substituents. For example, substituted heterocyclyl includes those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6- tetramethyl-1,2,3,6-tetrahydropyridinyl.

[0044] As used herein, the term “cycloalkyl” refers to a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spiro rings) system having 3 to 30 carbon atoms (e.g., C3-C12, C3-C10, or C3-C8). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl. In the case of polycyclic cycloalkyl, only one of the rings in the cycloalkyl needs to be non-aromatic. A divalent cycloalkyl group is referred to herein as “cycloalkylene.”

[0045] As used herein, the term “heterocyclyl” refers to a saturated or partially unsaturated 3-8 membered monocyclic, 7-12 membered bicyclic (fused, bridged, or spiro rings), or 11-14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms (such as O, N, S, P, or Se), e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g.¸ 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur, unless specified otherwise. Examples of heterocyclyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5- azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6- diazaspiro[3.3]heptanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, 1,4-dioxaspiro[4.5]decanyl, 1-oxaspiro[4.5]decanyl, 1-azaspiro[4.5]decanyl, 3’H-spiro[cyclohexane-1,1’-isobenzofuran]-yl, 7’H-spiro[cyclohexane-1,5’-furo[3,4-b]pyridin]-yl, 3’H-spiro[cyclohexane-1,1’-furo[3,4- c]pyridin]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1,4,5,6- tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7- tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2- azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2- azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa- azaspiro[3.4]octanyl, 2-oxa-azaspiro[3.4]octan-6-yl, 5,6-dihydro-4H-cyclopenta[b]thiophenyl, and the like. In the case of multicyclic heterocyclyl, only one of the rings in the heterocyclyl needs to be non-aromatic (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl, benzo[d][1,3]dioxole, 2,3- dihydrobenzo[b][1,4]dioxine, and the like). A divalent heterocyclyl group is referred to herein as “heterocyclylene.”

[0046] It is understood that when a variable has two attachments to the rest of the formula of the compound, the two attachments could be at the same atom or different atoms of the variable, as allowed by valency. For example, when a variable (e.g., variable X) is cycloalkyl or heterocyclyl, and has two attachments to the rest of the formula of the compound, the two attachments could be at the same atom or different atoms of the cycloalkyl or heterocyclyl.

[0047] As used herein, the term “aryl” refers to groups monocyclic or multicyclic systems with one or more aromatic rings that do not contain any heteroatom in the ring structure(s). The term aryl includes both monovalent species and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like. For example, an aryl is phenyl. A divalent aryl group is referred to herein as “arylene.”

[0048] As used herein, the term “heteroaryl” refers to a stable 5-, 6-, or 7-membered monocyclic or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic aromatic heterocyclic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g.¸ 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or other substituents, as defined). The nitrogen and sulfur heteroatoms may optionally beoxidised (i.e., N O and S(O)p, where p = 1 or 2). It is to be noted that total number of S and Oatoms in the aromatic heterocycle is not more than 1. Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, isothiazole, pyridine, pyrazine, purine, pyridazine, pyrimidine, and the like. Heteroarylgroups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl, 2,3-dihydro-1H- pyrrolopyridine, 1,2,3,4-tetrahydronaphthyridine, 2,3-dihydro-pyridooxazine, 2,3-dihydro-1H- pyrrolopyridine, 2,3-dihydrooxazolopyridine, and the like). A bivalent heteroaryl group is referred to herein as “heteroarylene.”

[0049] Furthermore, the terms “aryl” and “heteroaryl” include multicyclic aryl and heteroaryl groups, respectively, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, quinoline, isoquinoline, naphthrydine, indole, benzofuran, purine, benzofuran, deazapurine, indolizine.

[0050] The cycloalkyl, heterocyclyl, aryl, or heteroaryl ring can be substituted at one or more ring positions (e.g., the ring-forming carbon or heteroatom such as N) with such substituents as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl and heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., tetralin, methylenedioxyphenyl such as benzo[d][1,3]dioxole-5-yl).

[0051] As used herein, the term “substituted,” means that any one or more hydrogen atoms on the designated atom is replaced with a selection from the indicated groups, provided that the designated atom’s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is oxo or keto (i.e., =O), then 2 hydrogen atoms on the atom are replaced. Keto substituents are not present on aromatic moieties. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N or N=N).

[0052] “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0053] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such formula. Combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0054] When any variable (e.g., R) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R moieties, then the group may optionally be substituted with up to two R moieties and R at each occurrence is selected independently from the definition of R. Also, combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0055] As used herein, the term “hydroxy” or “hydroxyl” includes groups with an -OH or -O-.

[0056] As used herein, the term “halo” or “halogen” refers to fluoro, chloro, bromo and iodo.

[0057] The term “haloalkyl” or “haloalkoxyl” refers to an alkyl or alkoxyl substituted with one or more halogen atoms.

[0058] The term “heteroalkyl” refers to an alkyl group, as defined herein, wherein at least one carbon atom has been replaced by a heteroatom selected from the group consisting of oxygen, nitrogen, or sulfur. The nitrogen atom may be substituted or unsubstituted (e.g., NR wherein R is H or other substituents, as defined). The nitrogen and sulfur heteroatoms may optionally beoxidised (i.e., N O and S(O)p, where p = 1 or 2). A divalent heteroalkyl is referred to herein as“heteroalkylene.”

[0059] As used herein, the term “optionally substituted haloalkyl” refers to unsubstituted haloalkyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino andalkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0060] As used herein, the term “alkoxy” or “alkoxyl” includes substituted and unsubstituted alkyl, alkenyl and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy and trichloromethoxy.

[0061] As used herein, the expressions “one or more of A, B, or C,” “one or more A, B, or C,” “one or more of A, B, and C,” “one or more A, B, and C,” “selected from the group consisting of A, B, and C”, “selected from A, B, and C”, and the like are used interchangeably and all refer to a selection from a group consisting of A, B, and / or C, i.e., one or more As, one or more Bs, one or more Cs, or any combination thereof, unless indicated otherwise.

[0062] It is to be understood that the present disclosure provides methods for the synthesis of the compounds of any of the Formulae described herein. The present disclosure also provides detailed methods for the synthesis of various disclosed compounds of the present disclosure according to the following schemes as well as those shown in the Examples.

[0063] It is to be understood that, throughout the description, where compositions are described as having, including, or comprising specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processesalso consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.

[0064] It is to be understood that the synthetic processes of the disclosure can tolerate a wide variety of functional groups, therefore various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt thereof.

[0065] It is to be understood that compounds of the present disclosure can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or which will be apparent to the skilled artisan in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as Smith, M. B., March, J., March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5thedition, John Wiley & Sons: New York, 2001; Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rdedition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for organic Synthesis, John Wiley and Sons (1995), incorporated by reference herein, are useful and recognised reference textbooks of organic synthesis known to those in the art

[0066] One of ordinary skill in the art will note that, during the reaction sequences and synthetic schemes described herein, the order of certain steps may be changed, such as the introduction and removal of protecting groups. One of ordinary skill in the art will recognise that certain groups may require protection from the reaction conditions via the use of protecting groups. Protecting groups may also be used to differentiate similar functional groups in molecules. A list of protecting groups and how to introduce and remove these groups can be found in Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rdedition, John Wiley & Sons: New York, 1999.

[0067] It is to be understood that, unless otherwise stated, any description of a method of treatment or prevention includes use of the compounds to provide such treatment or prevention as is described herein. It is to be further understood, unless otherwise stated, any description of a method of treatment or prevention includes use of the compounds to prepare a medicament to treat or prevent such condition. The treatment or prevention includes treatment or prevention of human or non-human animals including rodents and other disease models.

[0068] It is to be understood that, unless otherwise stated, any description of a method of treatment includes use of the compounds to provide such treatment as is described herein. It is to be further understood, unless otherwise stated, any description of a method of treatment includes use of the compounds to prepare a medicament to treat such condition. The treatment includes treatment of human or non-human animals including rodents and other disease models.

[0069] As used herein, the term “subject” includes human and non-human animals, as well as cell lines, cell cultures, tissues, and organs. In some embodiments, the subject is a mammal. The mammal can be e.g., a human or appropriate non-human mammal, such as primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or a pig. The subject can also be a bird or fowl. In some embodiments, the subject is a human.

[0070] As used herein, the term “subject in need thereof” refers to a subject having a disease or having an increased risk of developing the disease. A subject in need thereof can be one who has been previously diagnosed or identified as having a disease or disorder disclosed herein. A subject in need thereof can also be one who is suffering from a disease or disorder disclosed herein. Alternatively, a subject in need thereof can be one who has an increased risk of developing such disease or disorder relative to the population at large (i.e., a subject who is predisposed to developing such disorder relative to the population at large). A subject in need thereof can have a refractory or resistant a disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that does not respond or has not yet responded to treatment). The subject may be resistant at start of treatment or may become resistant during treatment. In some embodiments, the subject in need thereof received and failed all known effective therapies for a disease or disorder disclosed herein. In some embodiments, the subject in need thereof received at least one prior therapy.

[0071] As used herein, the term “treating” or “treat” describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, to alleviate the symptoms or complications of a disease, conditionor disorder, or to eliminate the disease, condition or disorder. The term “treat” can also include treatment of a cell in vitro or an animal model. It is to be appreciated that references to “treating” or “treatment” include the alleviation of established symptoms of a condition. “Treating” or “treatment” of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

[0072] It is to be understood that a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, can or may also be used to prevent a relevant disease, condition or disorder, or used to identify suitable candidates for such purposes.

[0073] As used herein, the term “preventing,” “prevent,” or “protecting against” describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder.

[0074] It is to be understood that one skilled in the art may refer to general reference texts for detailed descriptions of known techniques discussed herein or equivalent techniques. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3rdedition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, N.Y.; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, N.Y.; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18thedition (1990). These texts can, of course, also be referred to in making or using some embodiments of the disclosure.

[0075] It is to be understood that the present disclosure also provides pharmaceutical compositions comprising any compound described herein in combination with at least one pharmaceutically acceptable excipient or carrier.

[0076] As used herein, the term “pharmaceutical composition” is a formulation containing the compounds of the present disclosure in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosageform is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial. The quantity of active ingredient (e.g., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved. One skilled in the art will appreciate that it is sometimes necessary to make variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for the topical or transdermal administration of a compound of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.

[0077] As used herein, the term “pharmaceutically acceptable” refers to those compounds, anions, cations, materials, compositions, carriers, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0078] As used herein, the term “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use. A “pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient.

[0079] It is to be understood that a pharmaceutical composition of the disclosure is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents forthe adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

[0080] It is to be understood that a compound or pharmaceutical composition of the disclosure can be administered to a subject in many of the well-known methods currently used for chemotherapeutic treatment. For example, a compound of the disclosure may be injected into the blood stream or body cavities or taken orally or applied through the skin with patches. The dose chosen should be sufficient to constitute effective treatment but not so high as to cause unacceptable side effects. The state of the disease condition (e.g., a disease or disorder disclosed herein) and the health of the patient should preferably be closely monitored during and for a reasonable period after treatment.

[0081] As used herein, the term “therapeutically effective amount”, refers to an amount of a pharmaceutical agent to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Therapeutically effective amounts for a given situation can be determined by experimentation that is within the skill and judgment of the clinician.

[0082] It is to be understood that, for any compound, the therapeutically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic / prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50 % of the population) and LD50 (the dose lethal to 50 % of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50 / ED50. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.

[0083] Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance / response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.

[0084] The pharmaceutical compositions containing active compounds of the present disclosure may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilising processes. Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and / or auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Of course, the appropriate formulation is dependent upon the route of administration chosen.

[0085] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers includephysiological saline, bacteriostatic water, Cremophor EL (BASF, Parsippany, N.J.) orphosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), cyclodextrins and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectablecompositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[0086] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilisation. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0087] Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, capsules or sachets. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, orange flavoring.

[0088] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebuliser.

[0089] Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays, powders orsuppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.

[0090] The active compounds can be prepared with pharmaceutically acceptable carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No.4,522,811.

[0091] It may be advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the disclosure are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved.

[0092] In therapeutic applications, the dosages of the pharmaceutical compositions used in accordance with the disclosure vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage. Generally, the dose should be sufficient to result in slowing, and preferably regressing, the symptoms of the disease or disorder disclosed herein and also preferably causing complete regression of the disease or disorder. An effective amount of a pharmaceutical agent is that which provides an objectively identifiable improvement as noted by the clinician or other qualified observer. Improvement in survival and growth indicates regression. As used herein, the term “dosage effective manner” refers to amount of an active compound to produce the desired biological effect in a subject or cell.

[0093] It is to be understood that the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0094] It is to be understood that, for the compounds of the present disclosure being capable of further forming salts, all of these forms are also contemplated within the scope of the claimed disclosure.

[0095] As used herein, the term “pharmaceutically acceptable salts” refer to derivatives of the compounds of the present disclosure wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral organic acid salts of basic residues such as amines, alkali organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, 1,2-ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluene sulfonic, and the commonly occurring amine acids, e.g., glycine, alanine, phenylalanine, arginine, etc.

[0096] In some embodiments, the pharmaceutically acceptable salt is a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a diethylamine salt, a choline salt, a meglumine salt, a benzathine salt, a tromethamine salt, an ammonia salt, an arginine salt, or a lysine salt.

[0097] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like. The present disclosure also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. In the salt form, it is understood that the ratio ofthe compound to the cation or anion of the salt can be 1:1, or any ratio other than 1:1, e.g., 3:1, 2:1, 1:2, or 1:3.

[0098] It is to be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same salt.

[0099] The compounds, or pharmaceutically acceptable salts thereof, are administered orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, and parenterally. In one embodiment, the compound is administered orally. One skilled in the art will recognise the advantages of certain routes of administration.

[0100] The dosage regimen utilising the compounds is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed.

[0101] Techniques for formulation and administration of the disclosed compounds of the disclosure can be found in Remington: the Science and Practice of Pharmacy, 1edition, Mack Publishing Co., Easton, PA (1995). In an embodiment, the compounds described herein, and the pharmaceutically acceptable salts thereof, are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous organic solutions. The compounds will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein.

[0102] All percentages and ratios used herein, unless otherwise indicated, are by weight. Other features and advantages of the present disclosure are apparent from the different examples. The provided examples illustrate different components and methodology useful in practicing the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure the skilled artisan can identify and employ other components and methodology useful for practicing the present disclosure.

[0103] In the synthetic schemes described herein, compounds may be drawn with one particular configuration for simplicity. Such particular configurations are not to be construed as limiting the disclosure to one or another isomer, tautomer, regioisomer or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regioisomers or stereoisomers; however, it will be understood thata given isomer, tautomer, regioisomer or stereoisomer may have a higher level of activity than another isomer, tautomer, regioisomer or stereoisomer.

[0104] All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any is pertinent prior art, nor does it constitute any admission as to the contents or date of the same. The invention having now been described by way of written description, those of skill in the art will recognize that the invention can be practiced in a variety of embodiments and that the foregoing description and examples below are for purposes of illustration and not limitation of the claims that follow.

[0105] As use herein, the phrase “compound of the disclosure” refers to those compounds which are disclosed herein, both generically and specifically. Compounds of the Present Disclosure

[0106] In some embodiments, the present disclosure provides a compound of Formula (I)or a pharmaceutically acceptable salt thereof, wherein: R1is C1-6 alkyl or C1-6 haloalkyl, wherein the alkyl is optionally substituted with deuterium; R2is C1-6alkyl; R6is H or halogen; R3is H or C1-6 alkyl; R4is halogen, C1-6alkyl, or C1-6haloalkyl; n is 0 to 5; and each R5independently is halo or -CN; and R7is -C(O)OH or 5- to 10-membered heteroaryl.

[0107] In some embodiments, R1is C1-6alkyl. In some embodiments, R1is methyl, or ethyl. In some embodiments, R1comprises at least one deuterium. In some embodiments, R1is C1-6alkyl comprising at least one deuterium. In some embodiments, R1is -CD2CH3.

[0108] In some embodiments, R1is C1-6 haloalkyl. In some embodiments, R1is C1-6 fluoroalkyl.

[0109] In some embodiments, R1is -CHF2 or -CH2CH2F.

[0110] In some embodiments, R2is methyl.

[0111] In some embodiments, R6is H. In some embodiments, R6is F.

[0112] In some embodiments, R3is H. In some embodiments, R3is C1-6 alkyl. In some embodiments, R3is methyl.

[0113] In some embodiments, R4is halogen. In some embodiments, R4is chloro.

[0114] In some embodiments, R4is C1-6 alkyl. In some embodiments, R4is methyl.

[0115] In some embodiments, R4is C1-6haloalkyl. In some embodiments, R4is C1haloalkyl. In some embodiments, R4is C1-6fluoroalkyl. In some embodiments, R4is CF3.

[0116] In some embodiments, R3is methyl and R4is CF3.

[0117] In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2.

[0118] In some embodiments, at least one R5is halo. In some embodiments, at least one R5is fluoro. In some embodiments, at least one R5is chloro. In some embodiments, at least one R5is cyano.

[0119] In some embodiments, n is 1 and R5is chloro. In some embodiments, n is 2, one R5is fluoro, and the other R5is cyano. In some embodiments, n is 2, one R5is fluoro, and the other R5is chloro.

[0120] It is understood that, for a compound of the present disclosure, variables R1, R2, R6, R3, R4, n, R5, and R7, where applicable, selected from the groups described herein, and any group described herein for any of variables R1, R2, R6, R3, R4, n, R5and R7, can be combined, where applicable, with any group described herein for one or more of the remainder of variables R1, R2, R6, R3, R4, n, R5, and R7.

[0121] In some embodiments, the compound is selected from the compounds described in Table 1 and prodrugs and pharmaceutically acceptable salts thereof.

[0122] In some embodiments, the compound is selected from the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0123] In some embodiments, the compound is selected from the prodrugs of compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0124] In some embodiments, the compound is selected from the compounds described in Table 1. Table 1

[0125] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds described in Table 1.

[0126] In some embodiments, the present disclosure provides a compound being an isotopic derivative (e.g., isotopically labeled compound) of any one of the compounds of the Formulae disclosed herein.

[0127] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1 and prodrugs and pharmaceutically acceptable salts thereof.

[0128] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0129] In some embodiments, the compound is an isotopic derivative of any one of prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0130] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1.

[0131] It is understood that the isotopic derivative can be prepared using any of a variety of art- recognised techniques. For example, the isotopic derivative can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0132] In some embodiments, the isotopic derivative is a deuterium labeled compound.

[0133] In some embodiments, the isotopic derivative is a deuterium labeled compound of any one of the compounds of the Formulae disclosed herein.

[0134] The term “isotopic derivative”, as used herein, refers to a derivative of a compound in which one or more atoms are isotopically enriched or labelled. For example, an isotopic derivative of a compound of Formula (I) is isotopically enriched with regard to, or labelled with, one or more isotopes as compared to the corresponding compound of Formula (I). In some embodiments, the isotopic derivative is enriched with regard to, or labelled with, one or more atoms selected from2H,13C,14C,15N,18O,29Si,31P, and34S. In some embodiments, the isotopic derivative is a deuterium labeled compound (i.e., being enriched with2H with regard to one or more atoms thereof). In some embodiments, the compound is a18F labeled compound. In some embodiments, the compound is a123I labeled compound, a124I labeled compound, a125I labeled compound, a129I labeled compound, a131I labeled compound, a135I labeled compound, or any combination thereof. In some embodiments, the compound is a33S labeled compound, a34S labeled compound, a35S labeled compound, a36S labeled compound, or any combination thereof.

[0135] It is understood that the18F,123I,124I,125I,129I,131I,135I,32S,34S,35S, and / or36S labeled compound, can be prepared using any of a variety of art-recognised techniques. For example, the deuterium labeled compound can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples described herein, by substituting a18F,123I,124I,125I,129I,131I,135I,3S,34S,35S, and / or36S labeled reagent for a non-isotope labeled reagent.

[0136] A compound of the invention or a pharmaceutically acceptable salt or solvate thereof that contains one or more of the aforementioned18F,123I,124I,125I,129I,131I,135I,32S,34S,35S, and36S atom(s) is within the scope of the invention. Further, substitution with isotope (e.g,,18F,123I,124I,125I,129I,131I,135I,3S,34S,35S, and / or36S) may afford certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements.

[0137] For the avoidance of doubt it is to be understood that, where in this specification a group is qualified by “described herein”, the said group encompasses the first occurring and broadest definition as well as each and all of the particular definitions for that group.

[0138] A suitable pharmaceutically acceptable salt of a compound of the disclosure is, for example, an acid-addition salt of a compound of the disclosure which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic acid. In addition, a suitable pharmaceutically acceptable salt of a compound of the disclosure which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0139] It will be understood that the compounds of any one of the Formulae disclosed herein and any pharmaceutically acceptable salts thereof, comprise stereoisomers, mixtures of stereoisomers, polymorphs of all isomeric forms of said compounds.

[0140] It will be understood that while compounds disclosed herein may be presented in one particular configuration. Such particular configuration is not to be construed as limiting the disclosure to one or another isomer, tautomer, regioisomer or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regioisomers or stereoisomers. In some embodiments, the presentation of a compound herein in a particular configuration intends to encompass, and to refer to, each of the available isomers, tautomers, regioisomers, and stereoisomers of the compound, or any mixture thereof; while the presentation further intends to refer to the specific configuration of the compound.

[0141] It will be understood that while compounds disclosed herein may be presented without specified configuration (e.g., without specified stereochemistry). Such presentation intends to encompass all available isomers, tautomers, regioisomers, and stereoisomers of the compound. In some embodiments, the presentation of a compound herein without specified configuration intends to refer to each of the available isomers, tautomers, regioisomers, and stereoisomers of the compound, or any mixture thereof.

[0142] As used herein, the term “isomerism” means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereoisomers,” and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers”or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture.”

[0143] As used herein, the term “chiral centre” refers to a carbon atom bonded to four nonidentical substituents.

[0144] As used herein, the term “chiral isomer” means a compound with at least one chiral centre. Compounds with more than one chiral centre may exist either as an individual diastereomer or as a mixture of diastereomers, termed “diastereomeric mixture.” When one chiral centre is present, a stereoisomer may be characterised by the absolute configuration (R or S) of that chiral centre. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral centre. The substituents attached to the chiral centre under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc.1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ.1964, 41, 116).

[0145] As used herein, the term “geometric isomer” means the diastereomers that owe their existence to hindered rotation about double bonds or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.

[0146] It is to be understood that the compounds of the present disclosure may be depicted as different chiral isomers or geometric isomers. It is also to be understood that when compounds have chiral isomeric or geometric isomeric forms, all isomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any isomeric forms, it being understood that not all isomers may have the same level of activity.

[0147] It is to be understood that the structures and other compounds discussed in this disclosure include all atropic isomers thereof. It is also to be understood that not all atropic isomers may have the same level of activity.

[0148] As used herein, the term “atropic isomers” are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances inchromatography techniques, it has been possible to separate mixtures of two atropic isomers in select cases.

[0149] As used herein, the term “tautomer” is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solutions where tautomerisation is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertible by tautomerisations is called tautomerism. Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism arises as a result of the aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxy groups (-OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose.

[0150] It is to be understood that the compounds of the present disclosure may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any tautomer form. It will be understood that certain tautomers may have a higher level of activity than others.

[0151] An enantiomer can be characterised by the absolute configuration of its asymmetric centre and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarised light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0152] The compounds of this disclosure may possess one or more asymmetric centres; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example bysynthesis from optically active starting materials or by resolution of a racemic form. Some of the compounds of the disclosure may have geometric isomeric centres (E- and Z- isomers). It is to be understood that the present disclosure encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that possess GLP-1R agonist activity.

[0153] The present disclosure also encompasses compounds of the disclosure as defined herein which comprise one or more isotopic substitutions.

[0154] It is to be understood that the compounds of any Formula described herein include the compounds themselves, as well as their salts, and their solvates, if applicable. A salt, for example, can be formed between an anion and a positively charged group (e.g., amino) on a substituted compound disclosed herein. Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).

[0155] As used herein, the term “pharmaceutically acceptable anion” refers to an anion suitable for forming a pharmaceutically acceptable salt. Likewise, a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on a substituted compound disclosed herein. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion or diethylamine ion. The substituted compounds disclosed herein also include those salts containing quaternary nitrogen atoms.

[0156] It is to be understood that the compounds of the present disclosure, for example, the salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules. Nonlimiting examples of hydrates include monohydrates, dihydrates, etc. Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0157] As used herein, the term “solvate” means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H2O.

[0158] As used herein, the term “analog” refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacementof one functional group by another functional group). Thus, an analog is a compound that is similar or comparable in function and appearance, but not in structure origin to the reference compound.

[0159] As used herein, the term “derivative” refers to compounds that have a common core structure and are substituted with various groups as described herein.

[0160] As used herein, the term “bioisostere” refers to a compound resulting from the exchange of an atom or of a group of atoms with another, broadly similar, atom or group of atoms. The objective of a bioisosteric replacement is to create a new compound with similar biological properties to the parent compound. The bioisosteric replacement may be physicochemically or topologically based. Examples of carboxylic acid bioisosteres include, but are not limited to, acyl sulfonamides, tetrazoles, sulfonates and phosphonates. See, e.g., Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0161] It is also to be understood that certain compounds of any one of the Formulae disclosed herein may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. A suitable pharmaceutically acceptable solvate is, for example, a hydrate such as hemi-hydrate, a mono-hydrate, a di-hydrate or a tri-hydrate. It is to be understood that the disclosure encompasses all such solvated forms that possess GLP-1R agonist activity.

[0162] Compounds of any one of the Formulae disclosed herein may exist in a number of different tautomeric forms and references to compounds of Formula (I) include all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by Formula (I). Examples of tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci-nitro.

[0163] Compounds of any one of the Formulae disclosed herein containing an amine function may also form N-oxides. A reference herein to a compound of Formula (I) that contains an amine function also includes the N-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. N-oxides can be formed by treatment of the corresponding amine with an oxidising agent such as hydrogen peroxide or a peracid (e.g., a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm.1977, 7, 509-514) in which the amine compound is reacted with meta-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.

[0164] The compounds of any one of the Formulae disclosed herein may be administered in the form of a prodrug which is broken down in the human or animal body to release a compound of the disclosure. A prodrug may be used to alter the physical properties and / or the pharmacokinetic properties of a compound of the disclosure. A prodrug can be formed when the compound of the disclosure contains a suitable group or substituent to which a property-modifying group can be attached. Examples of prodrugs include derivatives containing in vivo cleavable alkyl or acyl substituents at the ester or amide group in any one of the Formulae disclosed herein.

[0165] Accordingly, the present disclosure includes those compounds of any one of the Formulae disclosed herein as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a prodrug thereof. Accordingly, the present disclosure includes those compounds of any one of the Formulae disclosed herein that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of any one of the Formulae disclosed herein may be a synthetically-produced compound or a metabolically-produced compound.

[0166] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein is one that is based on reasonable medical judgment as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity. Various forms of prodrug have been described, for example in the following documents: a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, A.C.S. SymposiumSeries, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0167] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof. An in vivo cleavable ester or ether of a compound of any one of the Formulae disclosed herein containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester forming groups for a hydroxy group include C1-C10 alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C1- C10alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(C1-C6alkyl)2carbamoyl, 2- dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C1-C4alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include -acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0168] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a C1-4alkylamine such as methylamine, a (C1-C4 alkyl)2amine such as dimethylamine, N-ethyl-N-methylamine or diethylamine, a C1-C4 alkoxy-C2-C4 alkylamine such as 2-methoxyethylamine, a phenyl-C1-C4 alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.

[0169] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with C1-C10 alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N- dialkylaminomethyl,morpholinomethyl,piperazin-1-ylmethyl and 4-(C1-C4alkyl)piperazin-1- ylmethyl.

[0170] The in vivo effects of a compound of any one of the Formulae disclosed herein may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of any one of the Formulae disclosed herein. As stated hereinbefore, the in vivo effects of a compound of any one of the Formulae disclosed herein may also be exerted by way of metabolism of a precursor compound (a prodrug).

[0171] Suitably, the present disclosure excludes any individual compounds not possessing the biological activity defined herein. Pharmaceutical Compositions

[0172] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as an active ingredient. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound of each of the formulae described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table 1.

[0173] As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0174] The compounds of present disclosure can be formulated for oral administration in forms such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. The compounds of present disclosure on can also be formulated for intravenous (bolus or in-fusion), intraperitoneal, topical, subcutaneous, intramuscular or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts.

[0175] The formulation of the present disclosure may be in the form of an aqueous solution comprising an aqueous vehicle. The aqueous vehicle component may comprise water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of a solubility enhancing agent, chelating agent, preservative, tonicity agent, viscosity / suspending agent, buffer, and pH modifying agent, and a mixture thereof.

[0176] Any suitable solubility enhancing agent can be used. Examples of a solubility enhancingagent include cyclodextrin, such as those selected from the group consisting of hydroxypropyl- -cyclodextrin, methyl- -cyclodextrin, randomly methylated- -cyclodextrin, ethylated- -cyclodextrin, triacetyl- -cyclodextrin, peracetylated- -cyclodextrin, carboxymethyl- -cyclodextrin, hydroxyethyl- -cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl- -cyclodextrin, glucosyl- -cyclodextrin, sulfated -cyclodextrin (S- -CD), maltosyl- -cyclodextrin, -cyclodextrin sulfobutyl ether, branched- -cyclodextrin, hydroxypropyl- -cyclodextrin, randomly methylated- -cyclodextrin, and trimethyl- -cyclodextrin, and mixturesthereof.

[0177] Any suitable chelating agent can be used. Examples of a suitable chelating agent include those selected from the group consisting of ethylenediaminetetraacetic acid and metal salts thereof, disodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof.

[0178] Any suitable preservative can be used. Examples of a preservative include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate, phenylmercury neodecanoate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl- p-hydroxybenzoate, and sorbic acid, and mixtures thereof.

[0179] The aqueous vehicle may also include a tonicity agent to adjust the tonicity (osmotic pressure). The tonicity agent can be selected from the group consisting of a glycol (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and a mixture thereof.

[0180] The aqueous vehicle may also contain a viscosity / suspending agent. Suitable viscosity / suspending agents include those selected from the group consisting of cellulose derivatives, such as methyl cellulose, ethyl cellulose, hydroxyethylcellulose, polyethylene glycols (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethyl cellulose, hydroxypropylmethyl cellulose, and cross-linked acrylic acid polymers (carbomers), such as polymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol (Carbopols - such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P), and a mixture thereof.

[0181] In order to adjust the formulation to an acceptable pH (typically a pH range of about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), theformulation may contain a pH modifying agent. The pH modifying agent is typically a mineral acid or metal hydroxide base, selected from the group of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, and preferably sodium hydroxide and / or hydrochloric acid. These acidic and / or basic pH modifying agents are added to adjust the formulation to the target acceptable pH range. Hence it may not be necessary to use both acid and base - depending on the formulation, the addition of one of the acid or base may be sufficient to bring the mixture to the desired pH range.

[0182] The aqueous vehicle may also contain a buffering agent to stabilise the pH. When used, the buffer is selected from the group consisting of a phosphate buffer (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), a borate buffer (such as boric acid, or salts thereof including disodium tetraborate), a citrate buffer (such as citric acid, or salts thereof including sodium citrate), and -aminocaproic acid, and mixtures thereof.

[0183] The formulation may further comprise a wetting agent. Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oils, polyoxyethylenated sorbitan esters (polysorbates), polymers of oxyethylated octyl phenol (Tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty esters, and polyoxyethylene fatty esters, and mixtures thereof.

[0184] Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavouring agent such as peppermint, methyl salicylate, orange flavoring.

[0185] According to a further aspect of the disclosure there is provided a pharmaceutical composition which comprises a compound of the disclosure as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.

[0186] The compositions of the disclosure may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).

[0187] The compositions of the disclosure may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and / or preservative agents.

[0188] An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent a GLP-1R related condition referred to herein, slow its progression and / or reduce the symptoms associated with the condition.

[0189] An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat a GLP-1R related condition referred to herein, slow its progression and / or reduce the symptoms associated with the condition.

[0190] The size of the dose for therapeutic or prophylactic purposes of a compound of Formula (I) will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine. Methods of Use

[0191] In some embodiments, the present disclosure provides a method of modulating GLP-1R activity (e.g., in vitro or in vivo), comprising contacting a cell with an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0192] In some embodiments, the present disclosure provides a method of modulating GLP-1R activity (e.g., in vitro or in vivo), comprising contacting a cell with a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0193] In some embodiments, the present disclosure provides a method of modulating GLP-1R activity (e.g., in vitro or in vivo), comprising contacting a cell with a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0194] In some embodiments, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0195] In some embodiments, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0196] In some embodiments, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0197] In some embodiments, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0198] In some embodiments, the disease or disorder is associated with an implicated GLP-1R activity. In some embodiments, the disease or disorder is a disease or disorder in which GLP-1R activity is implicated.

[0199] In some embodiments, the disease or disorder is diabetes, NASH, insulinoma, obesity, and / or hyperglycemia.

[0200] In some embodiments, the present disclosure provides a method of treating or preventing diabetes, NASH, insulinoma, obesity, and / or hyperglycemia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0201] In some embodiments, the present disclosure provides a method of treating diabetes, NASH, insulinoma, obesity, and / or hyperglycemia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0202] In some embodiments, the present disclosure provides a method of treating or preventing diabetes, NASH, insulinoma, obesity, and / or hyperglycemia in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0203] In some embodiments, the present disclosure provides a method of treating diabetes, NASH, insulinoma, obesity, and / or hyperglycemia in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0204] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in modulating GLP-1R activity (e.g., in vitro or in vivo).

[0205] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in modulating GLP-1R activity (e.g., in vitro or in vivo).

[0206] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease or disorder disclosed herein.

[0207] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder disclosed herein.

[0208] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing diabetes, NASH, insulinoma, obesity, and / or hyperglycemia in a subject in need thereof.

[0209] In some embodiments, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating diabetes, NASH, insulinoma, obesity, and / or hyperglycemia in a subject in need thereof.

[0210] In some embodiments, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for modulating GLP-1R activity (e.g., in vitro or in vivo).

[0211] In some embodiments, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0212] In some embodiments, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or disorder disclosed herein.

[0213] In some embodiments, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing diabetes, NASH, insulinoma, obesity, and / or hyperglycemia in a subject in need thereof.

[0214] In some embodiments, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer in a subject in need thereof.

[0215] The present disclosure provides compounds that function as modulators of GLP-1R activity.

[0216] In some embodiments, the compounds of the present disclosure are agonists of the GLP- 1 receptor.

[0217] In some embodiments, the modulation of the GLP-1R receptor is activation of the GLP- 1R receptor.

[0218] Effectiveness of compounds of the disclosure can be determined by industry-accepted assays / disease models according to standard practices of elucidating the same as described in the art and are found in the current general knowledge.

[0219] The present disclosure also provides a method of treating a disease or disorder in which GLP-1R activity is implicated in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0220] In accordance with the present application, a disease or condition to be treated and / or prevented is selected from the group consisting of cardiometabolic and associated diseases including diabetes (T1 D and / or T2DM, including pre-diabetes), idiopathic T1 D (Type 1 b), latentautoimmune diabetes in adults (LADA), early-onset T2DM (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease (e.g., acute kidney disorder, tubular dysfunction, proinflammatory changes to the proximal tubules), diabetic retinopathy, adipocyte dysfunction, visceral adipose deposition, sleep apnea, obesity (including hypothalamic obesity and monogenic obesity) and related comorbidities (e.g., osteoarthritis and urine incontinence), eating disorders (including binge eating syndrome, bulimia nervosa, and syndromic obesity such as Prader-Willi and Bardet-Biedl syndromes), weight gain from use of other agents (e.g., from use of steroids and antipsychotics), excessive sugar craving, dyslipidemia (including hyperlipidemia, hypertriglyceridemia, increased total cholesterol, high LDL cholesterol, and low HDL cholesterol), hyperinsulinemia, liver diseases such as NAFLD, steatosis, NASH, fibrosis, cirrhosis, and hepatocellular carcinoma, cardiovascular disease, atherosclerosis (including coronary artery disease), peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction (e.g. necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, post-prandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson’s Disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attacks, vascular restenosis, impaired glucose metabolism, conditions of impaired fasting plasma glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcerations, ulcerative colitis, hyper apo B lipoproteinemia, Alzheimer’s Disease, schizophrenia, impaired cognition, inflammatory bowel disease, short bowel syndrome, Crohn’s disease, colitis, irritable bowel syndrome, Polycystic Ovary Syndrome and addiction (e.g., alcohol and / or drug abuse), prevention or treatment of Polycystic Ovary Syndrome and treatment of addiction (e.g., alcohol and / or drug abuse).

[0221] In some embodiments, provided herein is a method of treating a cardiometabolic disease in a subject (e.g., a human patient) in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0222] In some embodiments, provided herein is a method of treating diabetes in a subject (e.g., a human patient) in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. Exemplary diabetes include, but are not limited to, T1 D, T2DM, pre-diabetes, idiopathic T1 D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, and gestational diabetes.

[0223] In some embodiments, provided herein is a method of treating a liver disorder in a subject (e.g., a human patient) in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. Exemplary liver disorders include, without limitation, liver inflammation, fibrosis, and steatohepatitis. In some embodiments, the liver disorder is selected from the list consisting of primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), drug induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition associated cholestasis (PNAC), bacterial overgrowth or sepsis associated cholestasis, autoimmune hepatitis, viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), graft versus host disease, transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intra- or extrahepatic malignancy, Sjogren’s syndrome, sarcoidosis, Wilson’s disease, Gaucher’s disease, hemochromatosis, and alpha-1- antitrypsin deficiency. In some embodiments, the liver disorder is selected from the list consisting of liver inflammation, liver fibrosis, alcohol induced fibrosis, steatosis, alcoholic steatosis, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), non-alcoholic fatty liver disease (NAFLD), and non-alcoholic steatohepatitis (NASH). In some embodiments, the liver disorder is selected from the group consisting of liver fibrosis, alcohol induced fibrosis, steatosis, alcoholic steatosis, NAFLD, and NASH. In one embodiment, the liver disorder is NASH. In another embodiment, the liver disorder is liver inflammation. In another embodiment, the liver disorder is liver fibrosis. In another embodiment, the liver disorder is alcohol induced fibrosis. In another embodiment, the liver disorder is steatosis. In another embodiment, the liver disorder is alcoholic steatosis. In another embodiment, the liver disorder is NAFLD. In one embodiment, the treatment methods provided herein impedes or slows the progression of NAFLD to NASH. In one embodiment, the treatment methods provided herein impedes or slows the progression of NASH. NASH can progress, e.g., to one or more of liver cirrhosis, hepatic cancer, etc. In some embodiments, the liver disorder is NASH. In some embodiments, the patient has had a liver biopsy. In some embodiments, the method further comprises obtaining the results of a liver biopsy.

[0224] In accordance with the present application, a compound described herein, or a pharmaceutically acceptable salt thereof, can be administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. In some embodiments, it is a compound of any embodiment of Formula (I) or a sub- formula thereof, or selected from the compounds of Table 1, or a pharmaceutically acceptable salt thereof. The compounds and / or compositions described herein may be administered orally, rectally, vaginally, parenterally, or topically.

[0225] In some embodiments, the compounds and / or compositions may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the bloodstream directly from the mouth.

[0226] In some embodiments, the compounds and / or compositions may be administered directly into the bloodstream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.

[0227] In some embodiments, the compounds and / or compositions may be administered topically to the skin or mucosa, that is, dermally or transdermally. In some embodiments, the compounds and / or compositions may be administered intranasally or by inhalation. In some embodiments, the compounds and / or compositions may be administered rectally or vaginally. In some embodiments, the compounds and / or compositions may be administered directly to the eye or ear.

[0228] The compounds and / or compositions described herein can be used alone, or in combination with other therapeutic agents. The administration of two or more agents “in combination” means that all of the agents are administered closely enough in time that each may generate a biological effect in the same time frame. The presence of one agent may alter the biological effects of the other agent(s). The two or more agents may be administered simultaneously, concurrently or sequentially. Additionally, simultaneous administration may be carried out by mixing the agents prior to administration or by administering the compounds at the same point in time but as separate dosage forms at the same or different site of administration.

[0229] In some embodiments, the one or more other therapeutic agent is an anti-diabetic agent including but not limited to a biguanide (e.g., metformin), a sulfonylurea (e.g., tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide.glyclopyramide, glimepiride, or glipizide), a thiazolidinedione (e.g., pioglitazone, rosiglitazone, or lobeglitazone), a glitazar (e.g., saroglitazar, aleglitazar, muraglitazar or tesaglitazar), a meglitinide (e.g., nateglinide, repaglinide), a dipeptidyl peptidase 4 (DPP-4) inhibitor (e.g., sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, dutogliptin, or omarigliptin), a glitazone (e.g., pioglitazone, rosiglitazone, balaglitazone, rivoglitazone, or lobeglitazone), a sodium-glucose linked transporter 2 (SGLT2) inhibitor (e.g., empagliflozin, canagliflozin, dapagliflozin, ipragliflozin, Ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, or ertugliflozin), an SGLTL1 inhibitor, a GPR40 agonist (FFAR1 / FFA1 agonist, e.g. fasiglifam), glucose-dependent insulinotropic peptide (GIP) and analogues thereof, an alpha glucosidase inhibitor (e.g. voglibose, acarbose, or miglitol), or an insulin or an insulin analogue, including the pharmaceutically acceptable salts of the specifically named agents and the pharmaceutically acceptable solvates of said agents and salts.

[0230] In some embodiments, the one or more other therapeutic agent is an antiobesity agent including but not limited to peptide YY or an analogue thereof, a neuropeptide Y receptor type 2 (NPYR2) agonist, a NPYR1 or NPYR5 antagonist, a cannabinoid receptor type 1 (CB1 R) antagonist, a lipase inhibitor (e.g., orlistat), a human proislet peptide (HIP), a melanocortin receptor 4 agonist (e.g., setmelanotide), a melanin concentrating hormone receptor 1 antagonist, a farnesoid X receptor (FXR) agonist (e.g. obeticholic acid), zonisamide, phentermine (alone or in combination with topiramate), a norepinephrine / dopamine reuptake inhibitor (e.g., buproprion), an opioid receptor antagonist (e.g., naltrexone), a combination of norepinephrine / dopamine reuptake inhibitor and opioid receptor antagonist (e.g., a combination of bupropion and naltrexone), a GDF-15 analog, sibutramine, a cholecystokinin agonist, amylin and analogues therof (e.g., pramlintide), leptin and analogues thereof (e.g., metroleptin), a serotonergic agent (e.g., lorcaserin), a methionine aminopeptidase 2 (MetAP2) inhibitor (e.g., beloranib or ZGN- 1061), phendimetrazine, diethylpropion, benzphetamine, an SGLT2 inhibitor (e.g., empagliflozin, canagliflozin, dapagliflozin, ipragliflozin, Ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, or ertugliflozin), an SGLTL1 inhibitor, a dual SGLT2 / SGLT1 inhibitor, a fibroblast growth factor receptor (FGFR) modulator, an AMP-activated protein kinase (AMPK) activator, biotin, a MAS receptor modulator, or a glucagon receptor agonist (alone or incombination with another GLP-1 R agonist, e.g., liraglutide, exenatide, dulaglutide, albiglutide, lixisenatide, or semaglutide), including the pharmaceutically acceptable salts of the specifically named agents and the pharmaceutically acceptable solvates of said agents and salts.

[0231] In some embodiments, the one or more other therapeutic agent is an agent to treat NASH including but not limited to PF-05221304, an FXR agonist (e.g., obeticholic acid), a PPAR a / d agonist (e.g., elafibranor), a synthetic fatty acid-bile acid conjugate (e.g., aramchol), a caspase inhibitor (e.g., emricasan), an anti-lysyl oxidase homologue 2 (LOXL2) monoclonal antibody (e.g., simtuzumab), a galectin 3 inhibitor (e.g., GR-MD-02), a MAPK5 inhibitor (e.g., GS- 4997), a dual antagonist of chemokine receptor 2 (CCR2) and CCR5 (e.g., cenicriviroc), a fibroblast growth factor21 (FGF21) agonist (e.g., BMS-986036), a leukotriene D4 (LTD4) receptor antagonist (e.g., tipelukast), a niacin analogue (e.g., ARI 3037MO), an ASBT inhibitor (e.g., volixibat), an acetyl-CoA carboxylase (ACC) inhibitor (e.g., NDI 010976), a ketohexokinase (KHK) inhibitor, a diacylglyceryl acyltransferase 2 (DGAT2) inhibitor, a CB1 receptor antagonist, an anti- CB1 R antibody, or an apoptosis signal-regulating kinase 1 (ASK1) inhibitor, including the pharmaceutically acceptable salts of the specifically named agents and the pharmaceutically acceptable solvates of said agents and salts. Articles of Manufacture and Kits

[0232] The present disclosure further provides articles of manufacture comprising a compound, or a pharmaceutically acceptable salt thereof in accordance with the present application, a composition described herein, or one or more unit dosages described herein in suitable packaging. In certain embodiments, the article of manufacture is for use in any of the methods described herein. Suitable packaging (e.g., containers) is known in the art and includes, for example, vials, vessels, ampules, bottles, jars, flexible packaging and the like. An article of manufacture may further be sterilized and / or sealed.

[0233] The kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub- unit doses. For example, kits may be provided that contain sufficient dosages of a compound, or a pharmaceutically acceptable salt thereof in accordance with the present application, a composition described herein, and / or one or more other therapeutic agent useful for a disease detailed herein to provide effective treatment of an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. Kits may also include multiple unit doses of thecompounds / compositions described herein and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies

[0234] The kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component(s) of the methods of the present disclosure. The instructions included with the kit generally include information as to the components and their administration to an individual. Routes of Administration

[0235] Compounds of the present disclosure, or pharmaceutically acceptable salts thereof, may be administered alone as a sole therapy or can be administered in addition with one or more other substances and / or treatments. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment.

[0236] For example, therapeutic effectiveness may be enhanced by administration of an adjuvant (i.e. by itself the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the individual is enhanced). Alternatively, by way of example only, the benefit experienced by an individual may be increased by administering the compound of Formula (I) with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit.

[0237] In the instances where the compound of the present disclosure is administered in combination with other therapeutic agents, the compound of the disclosure need not be administered via the same route as other therapeutic agents, and may, because of different physical and chemical characteristics, be administered by a different route. For example, the compound of the disclosure may be administered orally to generate and maintain good blood levels thereof, while the other therapeutic agent may be administered intravenously. The initial administration may be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician.

[0238] The particular choice of other therapeutic agent will depend upon the diagnosis of the attending physicians and their judgment of the condition of the individual and the appropriate treatment protocol. According to this aspect of the disclosure there is provided a combination foruse in the treatment of a disease in which GLP-1R activity is implicated comprising a compound of the disclosure as defined hereinbefore, or a pharmaceutically acceptable salt thereof, and another suitable agent.

[0239] According to a further aspect of the disclosure there is provided a pharmaceutical composition which comprises a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in combination with a suitable, in association with a pharmaceutically acceptable diluent or carrier.

[0240] In addition to its use in therapeutic medicine, compounds of Formula (I) and pharmaceutically acceptable salts thereof are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of modulators of GLP-1R activity in laboratory animals such as dogs, rabbits, monkeys, mini-pigs, rats and mice, as part of the search for new therapeutic agents.

[0241] In any of the above-mentioned pharmaceutical composition, process, method, use, medicament, and manufacturing features of the instant disclosure, any of the alternate embodiments of macromolecules of the present disclosure described herein also apply.

[0242] The compounds of the disclosure or pharmaceutical compositions comprising these compounds may be administered to a subject by any route of administration, whether systemically / peripherally or topically (i.e., at the site of desired action).

[0243] Routes of administration include, but are not limited to, oral (e.g. by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray or powder); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra- arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly. Methods of Synthesis

[0244] In some embodiments, the present disclosure provides a method of preparing a compound of the present disclosure.

[0245] In some embodiments, the present disclosure provides a method of a compound, comprising one or more steps as described herein.

[0246] In some embodiments, the present disclosure provides a compound obtainable by, or obtained by, or directly obtained by a method for preparing a compound as described herein.

[0247] In some embodiments, the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein.

[0248] The compounds of the present disclosure can be prepared by any suitable technique known in the art. Particular processes for the preparation of these compounds are described further in the accompanying examples.

[0249] In the description of the synthetic methods described herein and in any referenced synthetic methods that are used to prepare the starting materials, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be selected by a person skilled in the art.

[0250] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions utilised.

[0251] It will be appreciated that during the synthesis of the compounds of the disclosure in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituent groups to prevent their undesired reaction. The skilled chemist will appreciate when such protection is required, and how such protecting groups may be put in place, and later removed. For examples of protecting groups, see one of the many general texts on the subject, for example, ‘Protective Groups in Organic Synthesis’ by Theodora Green (publisher: John Wiley & Sons). Protecting groups may be removed by any method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with the minimum disturbance of groups elsewhere in the molecule. Thus, if reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.

[0252] By way of example, a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl group, anarylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

[0253] A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia. Alternatively, an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.

[0254] A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a tert-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.

[0255] Once a compound of Formula (I) has been synthesised by any one of the processes defined herein, the processes may then further comprise the additional steps of: (i) removing any protecting groups present; (ii) converting the compound Formula (I) into another compound of Formula (I); (iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and / or (iv) forming a prodrug thereof.

[0256] The resultant compounds of Formula (I) can be isolated and purified using techniques well known in the art.

[0257] In some embodiments, the reaction of the compounds is carried out in the presence of a suitable solvent, which is preferably inert under the respective reaction conditions. Examples of suitable solvents comprise but are not limited to hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichlorethylene, 1,2- dichloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentylmethyl ether (CPME), methyl tert-butyl ether (MTBE) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone, methylisobutylketone (MIBK) or butanone; amides, such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N-methylpyrrolidinone (NMP); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate or methyl acetate, or mixtures of the said solvents or mixtures with water.

[0258] The reaction temperature is suitably between about -100 °C and 300 °C, depending on the reaction step and the conditions used.

[0259] Reaction times are generally in the range between a fraction of a minute and several days, depending on the reactivity of the respective compounds and the respective reaction conditions. Suitable reaction times are readily determinable by methods known in the art, for example reaction monitoring. Based on the reaction temperatures given above, suitable reaction times generally lie in the range between 10 minutes and 48 hours.

[0260] Moreover, by utilising the procedures described herein, in conjunction with ordinary skills in the art, additional compounds of the present disclosure can be readily prepared. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.

[0261] As will be understood by the person skilled in the art of organic synthesis, compounds of the present disclosure are readily accessible by various synthetic routes, some of which are exemplified in the accompanying examples. The skilled person will easily recognise which kind of reagents and reactions conditions are to be used and how they are to be applied and adapted in any particular instance – wherever necessary or useful – in order to obtain the compounds of thepresent disclosure. Furthermore, some of the compounds of the present disclosure can readily be synthesised by reacting other compounds of the present disclosure under suitable conditions, for instance, by converting one particular functional group being present in a compound of the present disclosure, or a suitable precursor molecule thereof, into another one by applying standard synthetic methods, like reduction, oxidation, addition or substitution reactions; those methods are well known to the skilled person. Likewise, the skilled person will apply – whenever necessary or useful – synthetic protecting (or protective) groups; suitable protecting groups as well as methods for introducing and removing them are well-known to the person skilled in the art of chemical synthesis and are described, in more detail, in, e.g., P.G.M. Wuts, T.W. Greene, “Greene’s Protective Groups in Organic Synthesis”, 4th edition (2006) (John Wiley & Sons).

[0262] General routes for the preparation of a compound of the application are described in Schemes A to W herein. EXEMPLARY EMBODIMENTS

[0263] Embodiment I-1. A compound of Formula (I)or a pharmaceutically acceptable salt thereof, wherein: R1is C1-6 alkyl or C1-6 haloalkyl, wherein the alkyl is optionally substituted with deuterium; R2is C1-6alkyl; R6is H or halogen; R3is H or C1-6 alkyl; R4is halogen, C1-6alkyl, or C1-6haloalkyl; n is 0 to 5; each R5independently is halo or -CN; and R7is -C(O)OH or 5- to 10-membered heteroaryl.

[0264] Embodiment I-2. The compound of embodiment I-1, wherein R1is C1-6alkyl.

[0265] Embodiment I-3. The compound of embodiment I-1 or I-2, wherein R1is methyl.

[0266] Embodiment I-4. The compound of any one of the preceding embodiments, wherein R1is ethyl.

[0267] Embodiment I-5. The compound of any one of the preceding embodiments, wherein R1is CD2CH3.

[0268] Embodiment I-6. The compound of any one of the preceding embodiments, wherein R1 is C1-6 haloalkyl.

[0269] Embodiment I-7. The compound of any one of the preceding embodiments, wherein R1 is C1-6 fluoroalkyl.

[0270] Embodiment I-8. The compound of any one of the preceding embodiments, wherein R1 is -CHF2.

[0271] Embodiment I-9. The compound of any one of the preceding embodiments, wherein R1 is -CH2CH2F.

[0272] Embodiment I-10. The compound of any one of the preceding embodiments, wherein R2 is methyl.

[0273] Embodiment I-11. The compound of any one of the preceding embodiments, wherein R6 is H.

[0274] Embodiment I-12. The compound of any one of the preceding embodiments, wherein R6 is F.

[0275] Embodiment I-13. The compound of any one of the preceding embodiments, wherein R3is H.

[0276] Embodiment I-14. The compound of any one of the preceding embodiments, wherein R3is C1-6 alkyl.

[0277] Embodiment I-15. The compound of any one of the preceding embodiments, wherein R3is methyl.

[0278] Embodiment I-16. The compound of any one of the preceding embodiments, wherein R4is halogen.

[0279] Embodiment I-17. The compound of any one of the preceding embodiments, wherein R4is chloro.

[0280] Embodiment I-18. The compound of any one of the preceding embodiments, wherein R4is C1-6alkyl.

[0281] Embodiment I-19. The compound of any one of the preceding embodiments, wherein R4is methyl.

[0282] Embodiment I-20. The compound of any one of the preceding embodiments, wherein R4is C1-6 haloalkyl.

[0283] Embodiment I-21. The compound of any one of the preceding embodiments, wherein R4is C1-6 fluoroalkyl.

[0284] Embodiment I-22. The compound of any one of the preceding embodiments, wherein R4is CF3.

[0285] Embodiment I-23. The compound of any one of the preceding embodiments, wherein R3is methyl and R4is CF3.

[0286] Embodiment I-24. The compound of any one of the preceding embodiments, wherein n is 1.

[0287] Embodiment I-25. The compound of any one of the preceding embodiments, wherein n is 2.

[0288] Embodiment I-26. The compound of any one of the preceding embodiments, wherein at least one R5is halo.

[0289] Embodiment I-27. The compound of any one of the preceding embodiments, wherein at least one R5is fluoro.

[0290] Embodiment I-28. The compound of any one of the preceding embodiments, wherein at least one R5is chloro.

[0291] Embodiment I-29. The compound of any one of the preceding embodiments, wherein at least one R5is cyano.

[0292] Embodiment I-30. The compound of any one of the preceding embodiments, wherein n is 1, and R5is chloro.

[0293] Embodiment I-31. The compound of any one of the preceding embodiments, wherein n is 2, one R5is fluoro, and the other R5is cyano.

[0294] Embodiment I-32. The compound of any one of the preceding embodiments, wherein R7is -COOH.

[0295] Embodiment I-33. The compound of any one of the preceding embodiments, wherein R7is 5- membered heteroaryl.

[0296] Embodiment I-34. The compound of any one of the preceding embodiments, wherein R7is tetrazole.

[0297] Embodiment I-35. The compound of any one of the preceding embodiments, wherein n is 2, one R5is fluoro, and the other R5is chloro.

[0298] Embodiment I-36. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from any one of the compounds in Table 1.

[0299] Embodiment I-37. A pharmaceutical composition comprising the compound of any one of the previous embodiments, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0300] Embodiment I-38. A method of treating a disease mediated by glucagon-like peptide-1 receptor (GLP-1R) in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of the compound of any one of embodiments I-1 to I-36, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment I-37.

[0301] Embodiment I-39. The method of embodiment I-38, wherein the disease is a liver disease.

[0302] Embodiment I-40. The method of embodiment I-39, wherein the liver disease is primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), drug induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition associated cholestasis (PNAC), bacterial overgrowth or sepsis associated cholestasis, autoimmune hepatitis, viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), graft versus host disease, transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intra- or extrahepatic malignancy, Sjogren’s syndrome, sarcoidosis, Wilson’s disease, Gaucher’s disease, hemochromatosis, or alpha-1- antitrypsin deficiency.

[0303] Embodiment I-41. The method of embodiment I-38, wherein the disease is diabetes.

[0304] Embodiment I-42. The method of embodiment I-38, wherein the disease is a cardiometabolic disease.

[0305] Embodiment I-43. The method of embodiment I-38, wherein the disease is obesity.

[0306] Embodiment I-44. A method of decreasing food intake in an individual in need thereof, comprising administering to the individual a compound, or a pharmaceutically acceptable salt thereof, of any one of embodiments I-1 to I-36 or the pharmaceutical composition of embodiment I-37.

[0307] Embodiment I-45. A method of increasing glucose tolerance in an individual in need thereof, comprising administering to the individual a compound, or a pharmaceutically acceptablesalt thereof, of any one of embodiments I-1 to I-36 or the pharmaceutical composition of embodiment I-37.

[0308] Embodiment I-46. Use of the compound of any one of embodiments I-1 to I-36, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment I-37, in the preparation of a medicament for the treatment of a disease mediated by glucagon-like peptide-1 receptor (GLP-1R).

[0309] Embodiment I-47. The use of embodiment I-46, wherein the disease is a liver disease.

[0310] Embodiment I-48. The use of embodiment I-47, wherein the liver disease is primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), drug induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition associated cholestasis (PNAC), bacterial overgrowth or sepsis associated cholestasis, autoimmune hepatitis, viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), graft versus host disease, transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intra- or extrahepatic malignancy, Sjogren’s syndrome, sarcoidosis, Wilson’s disease, Gaucher’s disease, hemochromatosis, or alpha-1- antitrypsin deficiency.

[0311] Embodiment I-49. The use of embodiment I-46, wherein the disease is diabetes.

[0312] Embodiment I-50. The use of embodiment I-46, wherein the disease is a cardiometabolic disease.

[0313] Embodiment I-51. The use of embodiment I-46, wherein the disease is obesity.

[0314] Embodiment I-52. Use of the compound, or a pharmaceutically acceptable salt thereof, of any one of embodiments I-1 to I-36 or the pharmaceutical composition of embodiment I-37 for use in the manufacture of a medicament for decreasing food intake.

[0315] Embodiment I-53. Use of the compound, or a pharmaceutically acceptable salt thereof, of any one of embodiments I-1 to I-36 or the pharmaceutical composition of embodiment I-37 for use in the manufacture of a medicament for increasing glucose tolerance.

[0316] Embodiment I-54. The compound of any one of embodiments I-1 to I-36, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment I-37, for use in treating a disease mediated by glucagon-like peptide-1 receptor (GLP-1R).

[0317] Embodiment I-55. The compound, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to embodiment I-54, wherein the disease is a liver disease.

[0318] Embodiment I-56. The compound, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to embodiment I-55, wherein the liver disease is primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), drug induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition associated cholestasis (PNAC), bacterial overgrowth or sepsis associated cholestasis, autoimmune hepatitis, viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), graft versus host disease, transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intra- or extrahepatic malignancy, Sjogren’s syndrome, sarcoidosis, Wilson’s disease, Gaucher’s disease, hemochromatosis, or alpha-1- antitrypsin deficiency.

[0319] Embodiment I-57. The compound, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to embodiment I-54, wherein the disease is diabetes.

[0320] Embodiment I-58. The compound, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to embodiment I-54, wherein the disease is a cardiometabolic disease.

[0321] Embodiment I-59. The compound, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to embodiment I-54, wherein the disease is obesity.

[0322] Embodiment I-60. The compound, or a pharmaceutically acceptable salt thereof, of any one of embodiments I-1 to I-36 or the pharmaceutical composition of embodiment I-37 for use in decreasing food intake.

[0323] Embodiment I-61. The compound, or a pharmaceutically acceptable salt thereof, of any one of embodiments I-1 to I-36 or the pharmaceutical composition of embodiment I-37 for use in increasing glucose tolerance.EXAMPLES Example A. Synthesis Example A1. (S)-2-((2-((4-Chloro-2-fluorobenzyl)oxy)-8-methyl-3-(trifluoromethyl)-5,8- dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-4-(2-hydroxyethoxy)-1-methyl-1H- benzo[d]imidazole-6-carboxylic acid (Compound 15)General procedure for preparation of Intermediate 2:

[0324] To a solution of Intermediate 1 (500 mg, 1.70 mmol, 1.2 eq), Intermediate 1A (530 mg, 1.41 mmol, 1 eq) in ACN (12 mL) was added K2CO3 (586 mg, 4.24 mmol, 3 eq). The mixture was stirred at 60°C for 2 hr. LC-MS showed ~11% of Intermediate 1 remained. Several new peaks were shown on LC-MS and ~83% of desired Compound was detected. The mixture was diluted with H2O (15 mL), extracted with EtOAc (15 mL * 3). The combined organic layer was washed with 10 mL brine, dried over Na2SO4, filtered and the filtrate was concentrated to give a crude product. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18250 * 50 mm * 10 um; mobile phase: [H2O (10 mM NH4HCO3) - ACN]; gradient: 65% - 95% B over 10.0 min). Intermediate 2 (680 mg, 1.07 mmol, 76% yield) was obtained as a white solid.

[0325] LCMS: RT = 1.812 min, MS cal.: 632.2, 633.2, [M+H]+= 633.1, 634.1

[0326] 1H NMR (400 MHz, CHLOROFORM-d) = 7.76 (s, 1 H), 7.59 (s, 1 H), 7.45 (t, J = 8.0 Hz, 1 H), 7.42 (s, 1 H), 7.14 (d, J = 8.4 Hz, 1 H), 7.10 (dd, J = 9.6, 1.6 Hz, 1 H), 6.25 - 6.13 (m, 1 H), 5.56 - 5.40 (m, 3 H), 5.37 - 5.25 (m, 1 H), 4.88 (d, J = 5.6 Hz, 2 H), 4.25 (d, J = 13.6 Hz, 1 H), 4.01 (d, J = 13.6 Hz, 1 H), 3.96 (s, 3 H), 3.92 (s, 3 H), 3.85 (d, J = 6.4 Hz, 1 H), 3.07 – 2.96 (m, 1 H), 2.83 - 2.59 (m, 3 H), 1.50 (d, J = 6.4 Hz, 3 H) General procedure for preparation of Intermediate 3:

[0327] To a solution of Intermediate 2 (600 mg, 948 mol, 1 eq) in DMF (6 mL) was added Intermediate 2A (683 mg, 4.74 mmol, 5 eq), Pd(PPh3)4 (110 mg, 94.8 mol, 0.1 eq). The mixture was stirred at 50°C for 12 hr. LC-MS showed Intermediate 2 was consumed completely and onemain peak with desired mass was detected. The reaction mixture was added a.q. NaHCO310 mL, then filtered and the filter cake was washed with 15 mL of H2O, dissolved in DCM 15 mL, brine 15 mL, dried over Na2SO4, filtered and the filtrate was concentrated to give a crude product. The residue was triturated with PE 5 mL and filtered to afford a white solid. Intermediate 3 (530 mg, 894 mol, 94% yield) was obtained as a white solid.

[0328] LCMS: RT = 0.515 min, MS cal.: 592.2, 594.1, [M+H]+= 593.3, 595.2

[0329] 1H NMR (400 MHz, CHLOROFORM-d) = 10.92 (br d, J = 2.0 Hz, 1 H), 7.68 (s, 1 H), 7.53 (s, 1 H), 7.48 - 7.41 (m, 2 H), 7.16 - 7.06 (m, 2 H), 5.53 - 5.44 (m, 1 H), 5.43 - 5.33 (m, 1 H), 4.28 - 4.18 (m, 1 H), 4.09 (d, J = 13.6 Hz, 1 H), 3.95 (s, 3 H), 3.91 (s, 3 H), 3.89 - 3.79 (m, 1 H), 3.04 – 2.93 (m, 1 H), 2.83 - 2.74 (m, 1 H), 2.72 - 2.62 (m, 1 H), 2.61 - 2.49 (m, 1 H), 1.50 - 1.41 (m, 3 H) General procedure for preparation of Intermediate 4:

[0330] To a solution of Intermediate 3 (530 mg, 894 mol, 1 eq) Intermediate 3A (2.05 g, 7.15 mmol, 8 eq) in ACN (5 mL) was added K2CO3 (371 mg, 2.68 mmol, 3 eq). The mixture was stirred at 60°C for 24 hr. LC-MS showed ~11% of Intermediate 3 remained. Several new peaks were shown on LC-MS and ~70% of desired Compound was detected. The mixture was diluted with H2O (15 mL), extracted with EtOAc (15 mL * 3). The combined organic layer was washed with 10 mL brine, dried over Na2SO4, filtered and the filtrate was concentrated to give a crude product. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 1). Intermediate 4 (340 mg, 453 mol, 51% yield) was obtained as a yellow oil.

[0331] LCMS: RT = 0.658 min, MS cal.: 750.3, 751.3, [M+H]+= 751.4, 752.4

[0332] 1H NMR (400 MHz, CHLOROFORM-d) = 7.77 (s, 1 H), 7.60 (s, 1 H), 7.47 (s, 1 H), 7.46 - 7.43 (m, 1 H), 7.18 - 7.07 (m, 2 H), 5.55 - 5.50 (m, 1 H), 5.407- 5.40 (m, 1 H), 4.38 (t, J = 6.4 Hz, 2 H), 4.28 - 4.20 (m, 1 H), 4.13 (d, J = 6.4 Hz, 2 H), 3.99 - 4.06 (m, 1 H), 3.96 (s, 3 H), 3.92 (s, 3 H), 3.89 - 3.80 (m, 1 H), 3.02 (s, 1 H), 2.86 - 2.57 (m, 3 H), 1.50 (s, 3 H), 0.90 (s, 9 H), 0.10 (s, 6 H)General procedure for preparation of Intermediate 5:

[0333] To a solution of Intermediate 4 (340 mg, 453 mol, 1 eq) in THF (3.4 mL) was added TBAF (1 M, 453 L, 1 eq). The mixture was stirred at 20°C for 12 hr. LC-MS showed Intermediate 4 was consumed completely and one main peak with desired mass was detected. The mixture was diluted with H2O (15 mL), extracted with EtOAc (15 mL * 3). The combined organic layer was washed with 10 mL brine, dried over Na2SO4, filtered and the filtrate was concentrated to give a crude product. Intermediate 5 (230 mg, 36 mol, 80% yield) was obtained as a white solid.

[0334] LCMS: RT = 1.655 min, MS cal.: 636.2, 637.2, [M+H]+= 637.0, 638.0 General procedure for preparation of Final Compound 15 (6):

[0335] To a solution of Intermediate 5 (100 mg, 157 mol, 1 eq) in THF (1 mL) was added LiOH.H2O (9.88 mg, 235 mol, 1.5 eq) in H2O (0.2 mL). The mixture was stirred at 25°C for 12 hr. LC-MS showed Intermediate 5 was consumed completely and one main peak with desired mass was detected. The mixture was purified by prep-HPLC (column: WePure Biotech XP tC18 150 * 40 * 7 um; mobile phase: [H2O (10mM NH4HCO3) - ACN]; gradient: 25%-70% B over 8.0 min). (S)-2-((2-((4-Chloro-2-fluorobenzyl)oxy)-8-methyl-3-(trifluoromethyl)-5,8-dihydro-1,7- naphthyridin-7(6H)-yl)methyl)-4-(2-hydroxyethoxy)-1-methyl-1H-benzo[d]imidazole-6- carboxylic acid (26.13 mg, 41.94 mol, 26.72% yield) was obtained as a white solid.

[0336] LCMS: RT = 2.819 min, MS cal.: 622.2, 624.2, [M+H]+= 623.1, 625.1

[0337] HPLC: RT = 12.728 min, purity: 97.69%

[0338] SFC: ee% = 100.00%

[0339] 1H NMR (400 MHz, METHANOL-d4) = 7.89 (s, 1 H), 7.75 (s, 1 H), 7.49 - 7.45 (m, 1 H), 7.54 - 7.45 (m, 1 H), 7.32 (dd, J = 8.4, 1.6 Hz, 1 H), 7.28 (s, 1 H), 5.55 - 5.49 (m, 1 H), 5.45 - 5.39 (m, 1 H), 4.94 (d, J = 0.8 Hz, 1 H), 4.23 (t, J = 4.8 Hz, 2 H), 4.14 (d, J = 13.6 Hz, 1 H), 3.99 (d, J = 13.6 Hz, 1 H), 3.86 (s, 3 H), 3.84 - 3.77 (m, 3 H), 3.02 - 2.91 (m, 1 H), 2.87 - 2.74 (m, 1 H), 2.74 - 2.62 (m, 2 H), 1.40 (d, J = 6.8 Hz, 3 H) Example A2. (S)-2-((4-Chloro-2-fluorobenzyl)oxy)-7-((4-ethoxy-1-methyl-6-(1H-tetrazol-5- yl)-1H-benzo[d]imidazol-2-yl)methyl)-8-methyl-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7- naphthyridine (Compound 16)General procedure for preparation of Intermediate 2:

[0340] To a solution of Intermediate 1 (3.0 g, 10.9 mmol, 1 eq) in dioxane (30 mL) and KOAc (0.05M, 30 mL) was added K4[Fe(CN)6] (2.01 g, 5.45 mmol, 0.5 eq), XPhos (1.04 g, 2.18 mmol,0.2 eq), XPhos-Pd-G2 (1.72 g, 2.18 mmol, 0.2 eq) at 20°C under N2atmosphere. The suspension was degassed and purged with N2for 3 times. The mixture was stirred under N2atmosphere at 100°C for 12 hr. LC-MS showed Intermediate 1 was consumed completely and desired mass was detected. The reaction mixture was filtered, and then the filtrate was diluted with H2O (30 mL) and extracted with EtOAc (30 mL * 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=20 / 1, to 3 / 1). Intermediate 2 (1.8 g, 8.14 mmol, 75% yield) was obtained as a yellow solid.

[0341] 1H NMR (400 MHz, DMSO-d6) = 6.95 - 6.81 (m, 2H), 6.46 (br d, J = 4.4 Hz, 1H), 4.18 - 4.11 (m, 2H), 2.73 (d, J = 4.4 Hz, 3H), 1.26 (t, J = 7.2 Hz, 3H) General procedure for preparation of Intermediate 3:

[0342] To a solution of Intermediate 2 (1.3 g, 5.88 mmol, 1 eq) and TEA.HCl (1.62 g, 11.8 mmol, 2 eq) in Tol. (13 mL) was added NaN3(764 mg, 11.8 mmol, 2 eq) in portions. The suspension was degassed and purged with N2for 3 times. The mixture was stirred at 80 °C for 12 hr. LC-MS showed Intermediate 2 was consumed completely and desired mass was detected. The reaction mixture was cooled to 20°C, then TEA was added to the mixture until pH>12. The residue was purified directly by column chromatography (SiO2, EtOAc / MeOH=1 / 0 to 1 / 1). Intermediate 3 (1.05 g, 3.97 mmol, 68% yield) was obtained as a yellow oil.

[0343] 1H NMR (400 MHz, CHLOROFORM-d) = 7.24 (d, J = 1.2 Hz, 1H), 7.16 (d, J = 1.6 Hz, 1H), 6.45 - 6.33 (m, 1H), 4.25 - 4.16 (m, 2H), 3.04 - 2.96 (m, 3H), 1.48 - 1.41 (m, 3H)General procedure for preparation of Intermediate 4:

[0344] To a solution of Pd / C (800 mg) in MeOH (10.5 mL) was added Intermediate 3 (1.05 g, 3.97 mmol, 1 eq) in MeOH (10.5 mL) and THF (5.3 mL) at 20°C under N2 atmosphere. The mixture was degassed and purged with H2 for three times. The mixture was stirred under H2 (15 Psi) at 20°C for 2 hr. LC-MS showed Intermediate 4 was detected. The mixture was filtered through a Celite pad and washed by MeOH (15 mL * 3). The combined filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 1 to 0 / 1) and then (SiO2, DCM / MeOH = 10 / 1). Intermediate 4 (0.7 g, 2.99 mmol, 75% yield) was obtained as a yellow oil.

[0345] 1H NMR (400 MHz, DMSO-d6) = 7.03 (d, J = 1.6 Hz, 1H), 6.86 (d, J = 1.2 Hz, 1H), 4.09 - 4.03 (m, 2H), 2.79 (m, 3H), 1.41 - 1.34 (m, 3H) General procedure for preparation of Intermediate 5:

[0346] To a solution of Intermediate 4 (500 mg, 2.13 mmol, 1 eq) in MeCN (5 mL) was added Intermediate 4A (660 mg, 4.27 mmol, 575 L, 2.0 eq) and p-TsOH (73.5 mg, 427 mol, 0.2 eq) at 20°C , the mixture was stirred at 60°C for 2 hr. LC-MS showed Intermediate 4 was consumed completely and desired mass was detected. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give a residue. Intermediate 5 (0.42 g, 1.43 mmol, 67% yield) was obtained as a yellow solid.

[0347] 1H NMR (400 MHz, DMSO-d6), 7.92 (d, J = 1.2 Hz, 1H), 7.44 (d, J = 1.2 Hz, 1H), 5.11 (s, 2H), 4.40 - 4.29 (m, 2H), 3.91 (s, 3H), 1.45 (t, J = 6.8 Hz, 3H)General procedure for preparation of Final Compound 16 (6):

[0348] To a solution of Intermediate 5 (140 mg, 478 mol, 1 eq) and Intermediate 5A (197.16 mg, 526.09 mol, 1.1 eq) in DMF (2.8 mL) was added K2CO3 (198.30 mg, 1.43 mmol, 3 eq) at 20°C. The mixture was stirred at 20°C for 24 hr. LC-MS showed product was detected. The reaction mixture was filtered. The mixture was purified by prep-HPLC (acidic condition; column: Phenomenex Luna C18 100 * 30mm * 3um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 35%-65% B over 8.0 min). (S)-2-((4-Chloro-2-fluorobenzyl)oxy)-7-((4-ethoxy-1-methyl-6-(1H- tetrazol-5-yl)-1H-benzo[d]imidazol-2-yl)methyl)-8-methyl-3-(trifluoromethyl)-5,6,7,8- tetrahydro-1,7-naphthyridine (28.89 mg, 44.47 mol, 9.30% yield, 97.14% purity) was obtained as a white solid.

[0349] LCMS: RT = 2.523 min, MS cal.: 630.2, [M+H]+= 631.2

[0350] HPLC: RT = 13.583 min, purity: 97.14%

[0351] 1H NMR (400 MHz, DMSO-d6) = 7.89 (s, 1H), 7.81 (s, 1H), 7.55 - 7.44 (m, 2H), 7.41 - 7.36 (m, 1H), 7.35 - 7.29 (m, 1H), 5.58 - 5.48 (m, 1H), 5.47 - 5.38 (m, 1H), 4.37 - 4.29 (m, 2H), 4.19 - 4.10 (m, 1H), 4.03 - 3.97 (m, 1H), 3.88 (s, 3H), 3.86 - 3.80 (m, 1H), 3.04 - 2.93 (m, 1H), 2.90 - 2.77 (m, 1H), 2.76 - 2.62 (m, 2H), 1.45 (t, J = 6.8 Hz, 3H), 1.43 - 1.37 (m, 3H)Example A3. (S)-2-((4-chloro-2-fluorobenzyl)oxy)-7-((4-methoxy-1-methyl-6-(2H-tetrazol- 5-yl)-1H-benzo[d]imidazol-2-yl)methyl)-8-methyl-3-(trifluoromethyl)-5,6,7,8-tetrahydro- 1,7-naphthyridine (Compound 17)General procedure for preparation of Intermediate 2:

[0352] To a solution of Intermediate 1 (9 g, 45.9 mmol, 1 eq) in THF (90 mL) was added CH3NH2(12.39 g, 184 mmol, 4 eq, HCl salt) and K2CO3(38.1 g, 275 mmol, 6 eq). The mixture was stirred at 20 °C for 2hr. TLC indicated Intermediate 1 was consumed completely and one new spot formed. The reaction was clean according to TLC (Petroleum ether / Ethyl acetate =5 / 1, product Rf= 0.52). The reaction mixture was added with H2O 10 mL and extracted withEtOAc (10mL * 3). The combined organic layers were washed with brine (10 mL *3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. Intermediate 2 (9.5 g, 45.9 mmol, 99% yield) was obtained as a yellow solid.

[0353] 1H NMR (400 MHz, CHLOROFORM-d) = 6.66 (d, J = 1.6 Hz, 1H), 6.53 (d, J = 1.6 Hz, 1H), 5.96 (s, 1H), 3.92 (s, 3H), 2.94 (d, J = 5.2 Hz, 3H) General procedure for preparation of Intermediate 3:

[0354] MeOH (160 mL) was charged to the 250 mL three-necked round bottom flask, then Intermediate 2 (8.3 g, 40.1 mmol, 1 eq) and NH4Cl (10.7 g, 200 mmol, 5 eq) in H2O (80 mL) was added to the mixture at 20°C. At 20 °C (inner temperature), Fe (11.19 g, 200 mmol, 5 eq) was added in portions to the reaction mixture. After the addition, the mixture was stirred at 70°C for 2 hr. LC-MS showed Intermediate 2 was consumed completely and one main peak with desired mass was detected. The mixture was filtered, the filter cake was washed with EtOAc (100 mL*3). The combined organic phase was washed with brine (100 mL*2), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. Intermediate 3 (7 g, 39.5 mmol, 99% yield) was obtained as a green solid.

[0355] LCMS: RT = 0.949 min, MS cal.: 177.1, [M+1]+=178.0

[0356] 1H NMR (400 MHz, CHLOROFORM-d) = 6.70 (d, J = 1.6 Hz, 1H), 6.65 (d, J = 1.6 Hz, 1H), 3.87 (s, 3H), 3.80 - 3.54 (m, 3H), 2.87 (s, 3H) General procedure for preparation of Intermediate 4:

[0357] To a solution of Intermediate 3 (2 g, 11.3 mmol, 1 eq), Intermediate 3A (2.62 g, 16.9 mmol, 2.28 mL, 1.5 eq) in CH3CN (20 mL) was added p-TsOH (194 mg, 1.13 mmol, 0.1 eq). The mixture was stirred at 60°C for 2 hr. LC-MS showed Intermediate 3 was consumed completely and one main peak with desired mass was detected. The residue was poured into water 50 mL. The aqueous phase was extracted with EtOAc (50 mL*3). The combined organic phase was washed with brine (50 mL*2), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. Intermediate 4 (2.48 g, 10.5 mmol, 93% yield) was obtained as a green solid.

[0358] LCMS: RT = 1.002 min, MS cal.: 235.0, [M+H]+= 235.8

[0359] 1H NMR (400 MHz, CHLOROFORM-d) = 7.36 (s, 1H), 6.92 (s, 1H), 4.86 (s, 2H), 4.05 (s, 3H), 3.91 (s, 3H) General procedure for preparation of Intermediate 5:

[0360] A mixture of Intermediate 4 (100 mg, 424 mol, 1 eq), Intermediate 4A (175 mg, 467 mol, 1.1 eq), K2CO3(176 mg, 1.27 mmol, 3 eq) in ACN (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 60°C for 12 hrs under N2 atmosphere. LC-MS showed Intermediate 4 was consumed completely and one main peak with desired mass was detected. The residue mixture was diluted with H2O 5 mL and extracted with EtOAc (5 mL*3). The combined organic layers were washed with brine 5 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / 1 to 0 / 1). Intermediate 5 (180 mg, 314 mol, 74% yield) was obtained as a white solid.

[0361] LCMS: RT = 1.577 min, MS cal.: 573.16, [M+H]+= 574.2

[0362] 1H NMR (400 MHz, CHLOROFORM –d) = 7.60 (s, 1H), 7.45 (t, J = 8.0 Hz, 1H), 7.36 (d, J = 1.2 Hz, 1H), 7.15 (dd, J = 1.6, 8.4 Hz, 1H), 7.11 (dd, J = 2.0, 9.6 Hz, 1H), 6.92 (d, J = 1.2 Hz, 1H), 5.58 - 5.41 (m, 2H), 4.23 (d, J = 13.6 Hz, 1H), 4.06 (s, 3H), 4.02 (d, J = 13.6 Hz,1H), 3.92 (s, 3H), 3.83 (d, J = 6.8 Hz, 1H), 3.07 - 2.98 (m, 1H), 2.84 - 2.75 (m, 1H), 2.74 - 2.58 (m, 2H), 1.50 (d, J = 6.8 Hz, 3H) General procedure for preparation of Final Compound 17 (6):

[0363] A mixture of Intermediate 5 (100 mg, 174 mol, 1 eq), TMSN3(161 mg, 1.39 mmol, 183 L, 8 eq) in Tol. (1 mL) was degassed and purged with N2 for 3 times, and then n-Bu2SnO (130 mg, 523 mol, 3 eq) was added to the reaction mixture at 20°C. The mixture was stirred at 130°C for 4 hrs under N2 atmosphere. LC-MS showed Intermediate 5 was consumed completely and one main peak with desired mass was detected. The reaction mixture was cooled to room temperature and a.q. KF was added to the reaction mixture. The residue mixture was diluted with H2O 2 mL and extracted with EtOAc (5 mL*3). The combined organic layers were washed with brine 5 mL, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (column: Phenomenex luna C18100*40mm*5 um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 25%-60% B over 8.0 min). (S)-2-((4-chloro- 2-fluorobenzyl)oxy)-7-((4-methoxy-1-methyl-6-(2H-tetrazol-5-yl)-1H-benzo[d]imidazol-2- yl)methyl)-8-methyl-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine (15.1 mg, 24.5 mol, 14% yield, 100% purity) was obtained as a white solid.

[0364] LCMS: RT = 1.265 min, MS cal.:616.17, [M+H]+= 617.1

[0365] 1H NMR (400 MHz, METHANOL -d4) = 7.90 (s, 1H), 7.87 (d, J = 1.2 Hz, 1H), 7.55 - 7.45 (m, 2H), 7.40 (d, J = 0.8 Hz, 1H), 7.32 (dd, J = 1.6, 8.2 Hz, 1H), 5.56 - 5.40 (m, 2H), 4.22 - 4.12 (m, 1H), 4.03 (s, 4H), 3.90 (s, 3H), 3.88 - 3.80 (m, 1H), 3.06 - 2.94 (m, 1H), 2.89 - 2.63 (m, 3H), 1.41 (d, J = 6.8 Hz, 3H)Example A4. (S)-2-((2-((4-chloro-2-fluorobenzyl)oxy)-8-methyl-3-(trifluoromethyl)-5,8- dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-4-(ethoxy-1,1-d2)-1-methyl-1H- benzo[d]imidazole-6-carboxylic acid (Compound 12)General procedure for preparation of Intermediate 2:

[0366] The reactions were set up in 2 batches. To the round bottom flask was added Et2O (150 mL) and then the flask was degassed and purged with N25 times. The mixture was cooled to 0°C under N2atmosphere. The mixture was added LiAlD4(3.72 g, 98 mmol, 1 eq) in portions at - 10°C (inner temperature) over 5 minutes under N2atmosphere. After addition, the mixture was stirred at -10°C (inner temperature) for 10 min and a solution of Intermediate 1 (10 g, 98 mmol, 9.20 mL, 1 eq) in Et2O (25 mL) was added dropwise via constant pressure dropping funnel to maintain the reaction temperature at -10°C under N2atmosphere. After the addition, the mixture was stirred under N2 atmosphere at -10°C for 1 hr.1HNMR showed the Intermediate 1 was consumed. The reaction mixture was quenched by NaOD (4 mL, 15% w / w) dropwise and followed by D2O (4 mL) at -10°C under N2 atmosphere. The mixture was stirred at -10°C for 0.5 hr, then the mixture was combined and filtered under slight N2 streem atmosphere. The filter cake was washed by Et2O (150 mL) and THF (200 mL). The filtrate was combined, and Intermediate 2 was obtained as a THF / Et2O=1 / 1 solution (440 g, ~3% w / w). General procedure for preparation of Intermediate 3:

[0367] A mixture of Intermediate 2A (14.7 g, 62.4 mmol, 1 eq), Intermediate 2 (100 g, 62.4 mmol, 1 eq) (solution of Et2O / THF = 1 / 1 ~3% w / w), PPh3(24.6 g, 93.6 mmol, 1.5 eq) was degassed and purged with N2 for 3 times, and then the mixture was added DIAD (18.9 g, 93.6 mmol, 18.1 mL, 1.5 eq) at 0°C , and then the mixture was stirred at 25°C for 12 hr under N2 atmosphere. TLC (Petroleum ether / Ethyl acetate = 5 / 1, Rf = 0.41) indicated 50% of Intermediate2A was remained, and one major new spot with lower polarity was detected. The reaction mixture was diluted with H2O 100 mL and extracted with DCM (100 mL*4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 100 / 1 to 0 / 1). Intermediate 3 (6.8 g, 25.6 mmol, 40% yield) was obtained as an orange solid.

[0368] 1H NMR (400 MHz, CHLOROFORM-d) = 7.03 (dd, J = 1.6, 8.8 Hz, 1H), 6.98 (d, J = 1.6 Hz 1H), 1.43 (s, 3H) General procedure for preparation of Intermediate 4:

[0369] A mixture of Intermediate 3 (6.8 g, 25.6 mmol, 1 eq), CH3NH2•HCl (3.45 g, 51.1 mmol, 2 eq), K2CO3 (14.1 g, 102 mmol, 4 eq) in THF (68 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25°C for 12 hr under N2 atmosphere. LCMS (RT = 1.335 min) showed Intermediate 3 was consumed completely and one main peak with desired mass was detected. The reaction mixture was diluted with H2O 50 mL and extracted with DCM (50 mL*3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 100 / 1 to 0 / 1). Intermediate 4 (6.9 g, 24.9 mmol, 97% yield) was obtained as an orange solid.

[0370] 1H NMR (400 MHz, CHLOROFORM-d) = 6.51 (d, J = 1.6 Hz, 1H), 6.45 - 6.29 (m, 2H), 2.90 (s, 3H), 1.42 (s, 3H)General procedure for preparation of Intermediate 5:

[0371] A mixture of Intermediate 4 (200 mg, 722 mol, 1 eq), TEA (365 mg, 3.61 mmol, 502 L, 5 eq) in MeOH (2 mL) was degassed and purged with Ar for 3 times, then the mixture was added Pd(dppf)Cl2•CH2Cl2 (58.9 mg, 72.2 mol, 0.1 eq) at 20°C and then the mixture was stirred at 80°C for 12 hr under CO (50 psi) atmosphere. TLC (Petroleum ether / Ethyl acetate = 3 / 1, Rf = 0.24) indicated Intermediate 4 was consumed completely and one new spot formed. The reaction mixture was filtered, the filter cake was washed by EtOAc 20 mL. The filtrate was added FA (1 M) until pH = 6-7 and extracted with EA (10 mL*3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 100 / 1 to 0 / 1). Intermediate 5 (100 mg, 442 mol, 61% yield) was obtained as a gray oil.

[0372] 1H NMR (400 MHz, CHLOROFORM-d) = 7.17 (d, J = 1.2 Hz, 1H), 7.14 (d, J = 1.2 Hz, 1H), 3.88 (s, 3H), 2.93 (s, 3H), 1.43 (s, 3H) General procedure for preparation of Intermediate 6:

[0373] A mixture of Intermediate 5 (100 mg, 442 mol, 1 eq), Intermediate 5A (137 mg, 884 mol, 119 L, 2 eq), TosOH (15.2 mg, 88.4 mol, 0.2 eq) in ACN (1 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 60°C for 2 hr under N2atmosphere. LCMS (RT = 1.081 min) showed Intermediate 5 was consumed completely and one main peak with desired mass was detected. The reaction mixture was diluted with H2O 5 mL and extractedwith DCM (5 mL*3). The combined organic layers were washed with brine (5 mL*2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. Intermediate 6 (100 mg, crude) was obtained as a white solid.

[0374] 1H NMR (400 MHz, CHLOROFORM-d) = 7.86 - 7.67 (m, 1H), 7.42 (d, J = 0.8 Hz, 1H), 4.94 (s, 2H), 3.97 (s, 3H), 3.93 (s, 3H), 1.55 (s, 3H) General procedure for preparation of Compound 7:

[0375] A mixture of Intermediate 6 (90 mg, 316 mol, 1 eq), Intermediate 6A (130 mg, 348 mol, 1.1 eq), K2CO3 (131 mg, 948 mol, 3 eq) in ACN (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 60°C for 2 hr under N2atmosphere. LCMS (RT = 1.793 min) showed Intermediate 6 was consumed completely and one main peak with desired mass was detected. The reaction mixture was diluted with H2O 10 mL and extracted with DCM (10 mL*3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 100 / 1 to 0 / 1). Intermediate 7 (130 mg, 209 mol, 66% yield) was obtained as a yellow solid.

[0376] 1H NMR (400 MHz, CHLOROFORM-d) = 7.75 (d, J = 1.2 Hz, 1H), 7.59 (s, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.40 (d, J = 1.2 Hz, 1H), 7.19 - 7.07 (m, 2H), 5.59 - 5.39 (m, 2H), 4.26 (d, J = 13.6 Hz, 1H), 4.02 (d, J = 13.6 Hz, 1H), 3.96 (s, 3H), 3.92 (s, 3H), 3.85 (q, J = 6.4 Hz, 1H), 3.02 (ddd, J = 4.4, 7.6, 11.6 Hz, 1H), 2.84 - 2.56 (m, 3H), 1.56 (s, 3H), 1.50 (d, J = 6.8 Hz, 3H)General procedure for preparation of Final Compound 12 (8):

[0377] A mixture of Compound 7 (120 mg, 193 mol, 1 eq), LiOH H2O (12.1 mg, 289 mol,1.5 eq) in THF (0.7 mL) and H2O (0.3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25°C for 12 hr under N2 atmosphere. LCMS (RT = 1.246 min) showed Compound 7 was consumed completely and one main peak with desired mass was detected. The reaction mixture was filtered. The filtrate was purified by prep-HPLC (column: Waters Xbridge BEH C18100*30 mm*10 um; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 40%- 70% B over 8.0 min). (S)-2-((2-((4-chloro-2-fluorobenzyl)oxy)-8-methyl-3-(trifluoromethyl)- 5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-4-(ethoxy-1,1-d2)-1-methyl-1H- benzo[d]imidazole-6-carboxylic acid (25.6 mg, 42.1 mol, 21% yield) was obtained as a white solid.

[0378] LCMS: RT = 2.962 min, MS cal.: 608.2, [M+H]+= 609.2

[0379] HPLC: RT = 13.191 min, purity: 100.00%

[0380] 1H NMR (400 MHz, METHANOL-d4) = 7.76 - 7.70 (m, 2H), 7.54 - 7.40 (m, 2H), 7.29 - 7.15 (m, 2H), 5.59 - 5.38 (m, 2H), 4.21 (d, J = 13.6 Hz, 1H), 4.01 (d, J = 13.6 Hz, 1H), 3.93 (s, 3H), 3.85 (d, J = 6.8 Hz, 1H), 3.12 - 2.99 (m, 1H), 2.94 - 2.81 (m, 1H), 2.77 - 2.62 (m, 2H), 1.55 - 1.45 (m, 6H)Example A5. (S)-2-((2-((2-Chlorobenzyl)oxy)-8-methyl-3-(trifluoromethyl)-5,8-dihydro-1,7- naphthyridin-7(6H)-yl)methyl)-4-(difluoromethoxy)-7-fluoro-1-methyl-1H- benzo[d]imidazole-6-carboxylic acid (Compound 13)General procedure for preparation of Intermediate 2:

[0381] To a solution of Intermediate 1 (58 mg, 180 mol, 1 eq) and Intermediate 1A (64.1 mg, 180 mol, 1 eq) in ACN (0.6 mL) was added K2CO3(49.7 mg, 360 mol, 2 eq) at 20°C. The mixture was stirred at 60°C for 2 hr. LC-MS (Rt =0.593) showed Intermediate 1 was consumed completely and desired mass was detected. The reaction mixture was diluted with H2O (3 mL) and extracted with EtOAc (1 mL * 3). The combined organic layers were washed with brine (3 mL*2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=10 / 1 to 1 / 1). Intermediate 2 (60 mg, 93.3 mol, 52% yield) was obtained as a white solid.

[0382] LCMS: RT =0.593 min, MS cal.: 642.1, [M+H]+= 643.3General procedure for preparation of Final Compound 13 (3):

[0383] To a solution of Intermediate 2 (60 mg, 93.3 mol, 1 eq) in THF (0.45 mL) was added LiOH.H2O (5.87 mg, 140 mol, 1.5 eq) in H2O (0.15 mL) at 25°C. The mixture was stirred at 25°C for 12 hr. LC-MS (Rt =1.298) showed Compound 2 was consumed completely and desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient: 45%-75% B over 8.0 min). (S)-2-((2-((2-Chlorobenzyl)oxy)-8-methyl-3-(trifluoromethyl)-5,8-dihydro-1,7- naphthyridin-7(6H)-yl)methyl)-4-(difluoromethoxy)-7-fluoro-1-methyl-1H-benzo[d]imidazole- 6-carboxylic acid (20.1 mg, 32 mol, 34% yield) was obtained as a white solid.

[0384] LCMS: RT =1.298 min, MS cal.: 628.1, [M+H]+= 629.1

[0385] HPLC: RT =13.961, purity: 98.50%

[0386] NMR (400 MHz, DMSO-d6) = 7.90 (s, 1H), 7.55 - 7.48 (m, 2H), 7.47 (t, J =74.4, 1H), 7.39 - 7.34 (m, 2H), 7.32 (d, J = 4.8 Hz, 1H), 5.62 - 5.54 (m, 1H), 5.52 - 5.43 (m, 1H), 4.16 (d, J = 13.6 Hz, 1H), 4.07 - 3.98 (m, 4H), 3.86 (q, J = 6.4 Hz, 1H), 3.02 - 2.90 (m, 1H), 2.88 - 2.77 (m, 1H), 2.76 - 2.61 (m, 2H), 1.39 (d, J = 6.8 Hz, 3H)Example A6. (S)-2-((2-((4-Cyano-2-fluorobenzyl)oxy)-8-methyl-3-(trifluoromethyl)-5,8- dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-4-ethoxy-1-methyl-1H-benzo[d]imidazole-6- carboxylic acid (Compound 14)General procedure for preparation of Intermediate 2:

[0387] To a solution of Intermediate 1 (50 mg, 145 mol, 1 eq) in ACN (0.5 mL) was added K2CO3(60.1 mg, 435 mol, 3 eq) and Intermediate 1A (63.6 mg, 174 mol, 1.2 eq). The mixture was stirred at 60°C for 12 hr. Several new peaks were shown on LC-MS (product Rt = 1.744 min) and ~78% of desired Compound was detected. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (5 mL * 3). The combined organic layers were washed with brine (5 mL * 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 1 to 0 / 1). Intermediate 2 (90 mg, 134 mol, 92% yield) was obtained as a white solid.

[0388] LCMS: RT = 1.758 min, MS cal.: 673.2, [M+H]+= 674.1

[0389] 1H NMR (400 MHz, DMSO-d6) = 8.02 (d, J = 1.2 Hz, 1H), 7.95 - 7.87 (m, 2H), 7.74 (dd, J = 1.2, 8.0 Hz, 1H), 7.69 - 7.61 (m, 1H), 7.53 - 7.45 (m, 2H), 7.39 (d, J = 1.2 Hz, 1H), 7.36 - 7.24 (m, 3H), 5.67 - 5.51 (m, 2H), 4.32 (q, J = 7.2 Hz, 2H), 4.17 (d, J = 13.6 Hz, 1H), 4.03 (d, J = 13.6 Hz, 1H), 3.92 (s, 3H), 3.83 (d, J = 6.8 Hz, 1H), 3.05 - 2.92 (m, 1H), 2.88 - 2.78 (m, 1H), 2.76 - 2.64 (m, 2H), 1.44 (t, J = 6.8 Hz, 3H), 1.36 (d, J = 6.8 Hz, 3H) General procedure for preparation of Final Compound 14 (3):

[0390] To a solution of Intermediate 2 (90 mg, 134 mol, 1 eq) in THF (0.63 mL) was added LiOH•H2O (8.41 mg, 200 mol, 1.5 eq) and H2O (0.27 mL). The mixture was stirred at 25°C for 12 hr. LC-MS (product, Rt = 1.130 min) showed ~27% of Intermediate 2 remained. Several new peaks were shown on LC-MS and ~64% of desired Compound was detected. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150*40mm*10um; mobile phase: [H2O (10 mM NH4HCO3) - ACN]; gradient: 20%-80% B over 8.0 min). (S)-2-((2-((4- Cyano-2-fluorobenzyl)oxy)-8-methyl-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)- yl)methyl)-4-ethoxy-1-methyl-1H-benzo[d]imidazole-6-carboxylic acid (28.7 mg, 48.1 mol, 36% yield, 96.5 % purity) was obtained as a white solid.

[0391] LCMS: RT = 2.491 min, MS cal.: 597.2, [M+H]+= 598.2

[0392] HPLC: RT = 12.103 min, purity: 96.52%

[0393] 1H NMR (400 MHz, DMSO-d6) = 7.95 - 7.86 (m, 2H), 7.79 - 7.71 (m, 2H), 7.69 - 7.61 (m, 1H), 7.26 (d, J = 0.8 Hz, 1H), 5.67 - 5.49 (m, 2H), 4.26 (q, J = 6.8 Hz, 2H), 4.13 (d, J = 13.6 Hz, 1H), 3.98 (d, J = 13.6 Hz, 1H), 3.86 (s, 3H), 3.81 (d, J = 6.8 Hz, 1H), 3.02 - 2.91 (m, 1H), 2.87 - 2.76 (m, 1H), 2.75 - 2.60 (m, 2H), 1.42 (t, J = 7.2 Hz, 3H), 1.35 (d, J = 6.8 Hz, 3H)Example A7. (S)-2-((2-((4-Cyano-2-fluorobenzyl)oxy)-8-methyl-3-(trifluoromethyl)-5,8- dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-4-methoxy-1-methyl-1H-benzo[d]imidazole-6- carboxylic acid (Compound 1)General procedure for preparation of Intermediate 2:

[0394] A mixture of Intermediate 1 (200 mg, 609 mol, 1 eq), Intermediate 1A (130 mg, 609 mol, 1 eq), Ag2CO3 (202 mg, 731 mol, 1.2 eq) in Tol. (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 110°C for 2 hr under N2 atmosphere. LCMS (product: RT = 1.492 min) showed the starting material was consumed completely. The resulting product was diluted in Tol. (5 mL) and filtered to remove the insoluble. The filter liquor was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 100 / 1 to 5 / 1). Intermediate 2 (210 mg, 455 mol, 75% yield) was obtained as a white solid.

[0395] LCMS: RT = 1.502 min, MS cal.: 461.3, [M+H]+= 462.1

[0396] NMR (400 MHz, CHLOROFORM-d) = 7.75 - 7.68 (m, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.53 - 7.47 (m, 1H), 7.41 (d, J = 9.2 Hz, 1H), 5.70 - 5.52 (m, 2H), 5.46 (q, J = 6.8 Hz, 1H), 5.09 - 4.98 (m, 1H), 4.75 (br dd, J = 5.2, 13.2 Hz, 1H), 4.24 - 4.12 (m, 1H), 3.48 (br t, J = 11.6 Hz, 1H), 3.23 - 3.13 (m, 1H), 3.07 - 2.93 (m, 1H), 2.88 - 2.70 (m, 1H), 1.62 (br d, J = 6.4 Hz, 1H), 1.58 - 1.49 (m, 4H) General procedure for preparation of Intermediate 3:

[0397] To a solution of Intermediate 2 (100 mg, 217 mol, 1 eq) in ACN (1 mL) was added K2CO3(240 mg, 1.73 mmol, 8 eq) and H2O (0.5 mL). The mixture was stirred at 90°C for 12 hr. LCMS (product: RT = 1.286 min) showed the starting material was consumed completely. Thereaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL * 3). The combined organic layers were washed with brine (10 mL * 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product Intermediate 3 (75 mg, crude) was used into the next step without further purification.

[0398] LCMS: RT = 1.286 min, MS cal.: 365.3, [M+H]+= 366.1 General procedure for preparation of Intermediate 4:

[0399] A mixture of Intermediate 3 (75 mg, 205 mol, 1 eq), Intermediate 3A (55.2 mg, 205 mol, 1 eq), K2CO3 (85.1 mg, 616 mol, 3 eq) in ACN (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 60°C for 12 hr under N2 atmosphere. LCMS (product: RT = 1.541 min) showed the starting material was consumed completely. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL * 3). The combined organic layers were washed with brine (20 mL * 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 100 / 1 to 0 / 1). Intermediate 4 (90 mg, 151 mol, 73% yield) was obtained as a yellow solid.

[0400] LCMS: RT = 1.546 min, MS cal.: 597.6, [M+H]+= 598.2

[0401] 1H NMR (400 MHz, CHLOROFORM-d) = 7.79 - 7.76 (m, 1H), 7.68 - 7.63 (m, 1H), 7.62 (s, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.41 (s, 1H), 7.38 (d, J = 9.2 Hz, 1H), 5.69 - 5.49 (m, 2H), 4.26 - 4.19 (m, 1H), 4.08 (s, 3H), 4.00 (br d, J = 13.6 Hz, 1H), 3.98 - 3.95 (m, 3H), 3.92 (s, 3H), 3.89 - 3.76 (m, 1H), 3.03 (br d, J = 5.6 Hz, 1H), 2.89 - 2.56 (m, 3H), 1.46 (br d, J = 6.4 Hz, 3H)General procedure for preparation of Final Compound 1 (5):

[0402] To a solution of Intermediate 4 (70 mg, 117 mol, 1 eq) in THF (0.7 mL) was added LiOH.H2O (7.37 mg, 176 mol, 1.5 eq) in H2O (0.3 mL). The mixture was stirred at 25°C for 12 hr. LCMS (product: RT = 1.103 min) showed the starting material was consumed completely. The crude product was purified by reversed-phase HPL C (column: Waters Xbridge BEH C18 100*30 mm*10 um; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 30% - 60% B over 8.0 min). (S)-2-((2-((4-Cyano-2-fluorobenzyl)oxy)-8-methyl-3-(trifluoromethyl)-5,8-dihydro- 1,7-naphthyridin-7(6H)-yl)methyl)-4-methoxy-1-methyl-1H-benzo[d]imidazole-6-carboxylic (27.5 mg, 46.6 mol, 40% yield, 98.7% purity) was obtained as a white solid.

[0403] LCMS: RT = 2.674 min, MS cal.: 583.5, [M+H]+= 584.2

[0404] HPLC: RT = 11.543 min, purity = 98.663 %

[0405] 1H NMR (400 MHz, DMSO-d6) = 7.91 (br t, J = 4.4 Hz, 2H), 7.80 - 7.72 (m, 2H), 7.70 - 7.61 (m, 1H), 7.28 (s, 1H), 5.68 - 5.47 (m, 2H), 4.13 (br d, J = 13.6 Hz, 1H), 4.02 - 3.93 (m, 4H), 3.88 - 3.78 (m, 4H), 3.01 - 2.91 (m, 1H), 2.88 - 2.77 (m, 1H), 2.76 - 2.61 (m, 2H), 1.35 (br d, J = 6.4 Hz, 3H)Example A8. (S)-2-((2-((4-Chloro-2-fluorobenzyl)oxy)-8-methyl-3-(trifluoromethyl)-5,8- dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-4-ethoxy-1-methyl-1H-benzo[d]imidazole-6- carboxylic acid (Compound 2)General procedure for preparation of Intermediate 2:

[0406] To a solution of Intermediate 1 (3 g, 12.7 mmol, 1 eq) in DMF (30 mL) was added K2CO3 (5.27 g, 38.1 mmol, 3 eq) and Intermediate 1A (2.63 g, 24.2 mmol, 1.80 mL, 1.9 eq). The mixture was stirred at 25°C for 12 hr. TLC (Petroleum ether: Ethyl acetate = 6:1, Rf = 0.46) indicated Intermediate 1 was consumed completely and one new spot formed. The reaction wasclean according to TLC. The reaction mixture was added to ice H2O (30 mL). The aqueous layer was extracted with EtOAc (30 mL * 3). The combined organic phase was washed with brine (20 mL * 3), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum. Intermediate 2 (3.6 g, crude) was obtained as a white solid.

[0407] 1H NMR (400 MHz, CHLOROFORM-d) = 7.06 - 6.96 (m, 2H), 4.16 (q, J = 7.1 Hz, 2H), 1.45 (t, J = 7.0 Hz, 3H) General procedure for preparation of Intermediate 3:

[0408] To a solution of Intermediate 2 (3.3 g, 12.5 mmol, 1 eq) in THF (33 mL) was added K2CO3(8.64 g, 62.5 mmol, 5 eq) and CH3NH2•HCl (2.53 g, 37.5 mmol, 3 eq). The mixture was stirred at 20°C for 12 hr. HNMR showed Intermediate 2 was consumed completely and desired compound was detected. The reaction mixture was diluted with H2O 30 mL and extracted with EtOAc (25 mL * 3). The combined organic layers were washed with brine 30 mL, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. Intermediate 3 (3.6 g, crude) was obtained as a yellow solid.

[0409] 1H NMR (400 MHz, CHLOROFORM-d) = 6.52 (d, J = 1.6 Hz, 1H), 6.41 (d, J = 1.6 Hz, 1H), 6.39 - 6.14 (m, 1H), 4.10 (q, J = 7.2 Hz, 2H), 2.91 (s, 3H), 1.44 (t, J = 7.2 Hz, 3H) General procedure for preparation of Intermediate 4:

[0410] The reactions were carried out in parallel as 4 batches. To a solution of Intermediate 3 (500 mg, 1.82 mmol, 1 eq) and Intermediate 3A (1.33 g, 10.9 mmol, 1.19 mL, 6 eq) in DMF (5mL) was added TEA (1.10 g, 10.9 mmol, 1.52 mL, 6 eq) and Pd(dppf)Cl2•CH2Cl2(148 mg, 182 mol, 0.1 eq) at 20°C under N2. The mixture was stirred at 120°C for 2 h. Several new peaks were shown on LC-MS and ~31% of desired Compound was detected. The four reactions were combined for workup. The reaction mixture was filtered, and 30 mL H2O was added to the filtrate, the mixture was extraced with EA (15 mL × 3), the combined organic phase was washed with brine 30 mL, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The four reactions were combined for purification. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 0 / 1). Intermediate 4 (5.15 g, crude) was obtained as a yellow solid.

[0411] LCMS: RT = 1.511 min, MS cal: 316.1, [M+H]+= 317.1

[0412] 1H NMR (400 MHz, DMSO-d6) = 9.33 (br s, 7H), 7.58 - 7.41 (m, 2H), 7.38 - 7.24 (m, 3H), 7.15 (br t, J = 7.2 Hz, 14H), 7.06 (br d, J = 13.6 Hz, 2H), 6.75 (br d, J = 7.2 Hz, 20H), 6.39 (br d, J = 5.2 Hz, 1H), 4.19 (br d, J = 7.2 Hz, 2H), 4.02 (q, J = 6.4 Hz, 3H), 2.79 (br d, J = 4.4 Hz, 3H), 1.99 (d, J = 0.8 Hz, 3H), 1.36 (br t, J = 6.8 Hz, 1H), 1.29 (br t, J = 6.8 Hz, 3H), 1.23 - 1.11 (m, 4H) General procedure for preparation of Intermediate 5:

[0413] The reactions were carried out in parallel as 2 batches. Equip a 250 mL round bottom flask, addition H2balloon. Pd / C (695 mg) was charged to the round bottom flask, then THF (83 mL) was added to the mixture. Intermediate 4 (4.15 g, 4.40 mmol, 1 eq) was added to the reaction mixture at 20°C. After the addition, the mixture was stirred at 20°C for 16 hr. The reaction was monitored by LCMS. Several new peaks were shown on LC-MS and ~83.8% of desired Compound was detected. The reaction mixture was filtered, and the filter cake was washed with THF (100 mL × 3), the combined filtrate was concentrated under reduced pressure to give a residue. Crude product from repeated reactions (1 g) and (4.15 g) were combined for further purification. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethylacetate=10 / 1 to 1 / 0). Intermediate 5 (1.26 g, 4.40 mmol, 100% yield) was obtained as a yellow solid.

[0414] LCMS: RT = 1.282 min, MS cal.: 286.1, [M+H]+= 287.1

[0415] 1H NMR (400 MHz, METHANOL-d4) = 7.49 - 7.37 (m, 2H), 7.31 - 7.21 (m, 2H), 7.19 - 7.12 (m, 3H), 6.86 - 6.70 (m, 1H), 4.12 (q, J = 7.2 Hz, 2H), 2.88 (s, 3H), 1.44 (t, J = 6.8 Hz, 3H) General procedure for preparation of Intermediate 6:

[0416] To a solution of Intermediate 5 (345 mg, 1.20 mmol, 1 eq) in ACN (3.45 mL) was added TosOH (41.5 mg, 241 mol, 0.2 eq) and Intermediate 5A (559 mg, 3.61 mmol, 487 L, 3 eq). The mixture was stirred at 60°C for 1 hr. LC-MS showed Intermediate 5 was consumed completely and desired mass was detected. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (5 mL *3). The combined organic layers were washed with brine (4 mL * 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. Intermediate 6 (550 mg, crude) was obtained as a white solid.

[0417] LCMS: RT = 1.291 min, MS cal.: 344.1, [M+H]+= 344.9

[0418] 1H NMR (400 MHz, DMSO-d6) = 8.06 (d, J = 1.2 Hz, 1H), 7.53 - 7.45 (m, 2H), 7.41 (d, J = 0.8 Hz, 1H), 7.38 - 7.26 (m, 3H), 5.13 (s, 2H), 4.32 (q, J = 6.8 Hz, 2H), 3.94 (s, 3H), 1.43 (t, J = 6.8 Hz, 3H) General procedure for preparation of Intermediate 7:

[0419] To a solution of Intermediate 6 (35 mg, 102 mol, 1 eq) in ACN (0.35 mL) was added K2CO3(42.1 mg, 305 mol, 3 eq) and Intermediate 6A (45.7 mg, 122 mol, 1.2 eq). The mixture was stirred at 60°C for 12 hr. LC-MS showed Intermediate 6 was consumed completely and desired mass was detected. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (5mL *3). The combined organic layers were washed with brine (3 mL * 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=0 / 1 to 1 / 0). Intermediate 7 (45 mg, 65.9 mol, 65% yield) was obtained as a white solid.

[0420] LCMS: RT = 1.907 min, MS cal.: 682.2, [M+H]+= 683.1

[0421] 1H NMR (400 MHz, DMSO-d6) = 8.02 (d, J = 1.2 Hz, 1H), 7.89 (s, 1H), 7.56 - 7.45 (m, 4H), 7.39 (d, J = 1.2 Hz, 1H), 7.36 - 7.25 (m, 4H), 5.58 - 5.38 (m, 2H), 4.32 (q, J = 6.8 Hz, 2H), 4.18 (d, J = 13.6 Hz, 1H), 4.04 (d, J = 13.6 Hz, 1H), 3.93 (s, 3H), 3.84 (q, J = 6.4 Hz, 1H), 2.98 (ddd, J = 4.0, 7.8, 11.9 Hz, 1H), 2.68 (br s, 3H), 1.50 - 1.36 (m, 6H) General procedure for preparation of Final Compound 28:

[0422] To a solution of Intermediate 7 (65 mg, 95.2 mol, 1 eq) in THF (0.7 mL) was added LiOH•H2O (5.99 mg, 143 mol, 1.5 eq) in H2O (0.3 mL). The mixture was stirred at 25°C for 12 hr. LC-MS showed ~10% of Intermediate 7 remained. Several new peaks were shown on LC- MS and ~80% of desired Compound was detected. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient: 35%-75% B over 8.0 min). (S)-2-((2-((4-Chloro-2- fluorobenzyl)oxy)-8-methyl-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)- 4-ethoxy-1-methyl-1H-benzo[d]imidazole-6-carboxylic acid (28.8 mg, 47.4 mol, 50% yield, 100% purity) was obtained as a white solid.

[0423] LCMS: RT = 2.690 min, MS cal.: 606.2, [M+H]+= 607.1

[0424] HPLC: RT = 13.836 min, purity: 100%

[0425] 1H NMR (400 MHz, DMSO-d6) = 7.89 (s, 1H), 7.75 (d, J = 1.2 Hz, 1H), 7.55 - 7.45 (m, 2H), 7.32 (dd, J = 2.0, 8.2 Hz, 1H), 7.26 (d, J = 1.2 Hz, 1H), 5.57 - 5.49 (m, 1H), 5.47 - 5.38 (m, 1H), 4.26 (q, J = 7.2 Hz, 2H), 4.14 (d, J = 13.6 Hz, 1H), 3.99 (d, J = 13.6 Hz, 1H), 3.86 (s, 3H), 3.83 - 3.76 (m, 1H), 3.01 - 2.93 (m, 1H), 2.85 - 2.77 (m, 1H), 2.75 - 2.65 (m, 2H), 1.47 - 1.35 (m, 6H) Example A9. (S)-2-((2-((4-Cyano-2-fluorobenzyl)oxy)-8-methyl-3-(trifluoromethyl)-5,8- dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-7-fluoro-4-methoxy-1-methyl-1H- benzo[d]imidazole-6-carboxylic acid (Compound 3)General procedure for preparation of Intermediate 2:

[0426] To a solution of Intermediate 1 (94.5 mg, 271 mol, 1.1 eq) in ACN (2 mL) was added K2CO3 (102 mg, 739 mol, 3 eq) and Intermediate 1A (90 mg, 246 mol, 1 eq). The mixture was stirred at 60°C for 2 hr. LCMS showed Intermediate 1 was consumed completely and onemain peak with desired mass was detected. The reaction mixture was diluted with H2O 5 mL and extracted with EtOAc mL (20 mL * 2). The combined organic layers were washed with brine 10 mL, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc=1 / 0 to 1 / 1). Intermediate 2 (100 mg, 137 mol, 56% yield) was obtained as a white solid.

[0427] LCMS: RT = 1.716 min, MS cal.: 677.2 / 678.2, [M+1]+=678.2 / 679.1

[0428] 1HNMR (400 MHz, DMSO-d6) = 7.94 - 7.89 (m, 2H), 7.76 - 7.72 (m, 1H), 7.68 - 7.62 (m, 1H), 7.52 - 7.46 (m, 2H), 7.36 - 7.27 (m, 3H), 7.18 (d, J = 4.4 Hz, 1H), 5.67 - 5.60 (m, 1H), 5.56 - 5.48 (m, 1H), 4.18 - 4.12 (m, 1H), 4.04 (s, 4H), 3.97 (s, 3H), 3.88 - 3.81 (m, 1H), 3.02 - 2.93 (m, 1H), 2.89 - 2.79 (m, 1H), 2.79 - 2.63 (m, 2H), 1.36 (br d, J = 6.8 Hz, 3H) General procedure for preparation of Final Compound 3 (3):

[0429] To a solution of Intermediate 2 (80 mg, 118 mol, 1 eq) in THF (0.7 mL) and H2O (0.3 mL) was added LiOH•H2O (7.43 mg, 177 mol, 1.5 eq). The mixture was stirred at 25°C for 12 hr. After monitoring, the mixture was added LiOH•H2O (991 g, 23.6 mol, 0.2 eq). The mixture was stirred at 25°C for 4 hr. LCMS showed 18% of Intermediate 2 remained. Two new peaks were shown on LCMS and 70% of desired compound was detected. The mixture was added THF 0.1 mL. The residue was purified by prep-HPLC (neutral condition:column: Waters Xbridge Prep OBD C18150*40mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:20%-70% B over 8.0 min). (S)-2-((2-((4-Cyano-2-fluorobenzyl)oxy)-8-methyl-3-(trifluoromethyl)-5,8- dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-7-fluoro-4-methoxy-1-methyl-1H- benzo[d]imidazole-6-carboxylic acid (23.5 mg, 38.6 mol, 33% yield) was obtained as a white solid.

[0430] LCMS: RT = 2.700 min, MS cal.: 601.2 / 602.2, [M+H]+=602.2 / 603.2

[0431] HPLC: RT = 11.620 min

[0432] 1HNMR (400 MHz, DMSO-d6) =7.93 - 7.89 (m, 2H), 7.74 (dd, J = 1.2, 8 Hz, 1H), 7.68 - 7.63 (m, 1H), 6.93 (d, J = 4.8 Hz, 1H), 5.65 - 5.59 (m, 1H), 5.55 - 5.50 (m, 1H), 4.08 (d, J = 14.2 Hz, 1H), 3.99 - 3.92 (m, 4H), 3.87 (s, 3H), 3.83 - 3.78 (m, 1H), 3.01 - 2.91 (m, 1H), 2.88 - 2.78 (m, 1H), 2.75 - 2.65 (m, 2H), 1.34 (d, J = 6.8 Hz, 3H) Example A10. (S)-2-((2-((4-Chloro-2-fluorobenzyl)oxy)-8-methyl-3-(trifluoromethyl)-5,8- dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-4-methoxy-1-methyl-1H-benzo[d]imidazole-6- carboxylic acid (CompoundGeneral procedure for preparation of Intermediate 2:

[0433] A mixture of Intermediate 1 (230 mg, 489 mol, 1 eq), K2CO3 (270 mg, 1.95 mmol, 4 eq) in MeOH (2 mL) and H2O (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 35°C for 12hr under N2atmosphere. LCMS showed Intermediate 1 was consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H2O(15 mL) and extracted with EtOAc (15 mL * 3). The combined organic layers were washed with brine (15 mL * 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. Intermediate 2 (173 mg, 462 mol, 94% yield) was a white solid.

[0434] 1H NMR (400 MHz, DMSO-d6) = 7.80 (s, 1H), 7.54 - 7.42 (m, 2H), 7.31 (d, J = 8.8 Hz, 1H), 5.48 (q, J = 12.8 Hz, 2H), 3.84 (br t, J = 6.0 Hz, 1H), 3.14 - 2.97 (m, 1H), 2.83 - 2.59 (m, 3H), 2.56 - 2.52 (m, 1H), 1.34 (d, J = 6.4 Hz, 3H). General procedure for preparation of Intermediate 3:

[0435] To a solution of Intermediate 2(60 mg, 160 mol, 1 eq) and Intermediate 13A (47.3 mg, 176 mol, 1.1 eq) in ACN (0.6 mL) was added K2CO3 (66.4 mg, 480 mol, 3 eq) at 25°C. The mixture was stirred at 60°C for 12hr. LCMS showed Intermediate 2 was consumed and desired mass was detected. The reaction mixture was partitioned between EtOAc and water. The mixture was poured into separatory funnel and separated. The aqueous layer was extracted with EtOAc (3 mL*3). The combined organic layer was washed with brine 4 mL (2 mL * 2), dried over Na2SO4, filtered and the filtrate was concentrated to give a crude product. The crude product was triturated with MBTE (2mL) at 25 °C for 10 min. Intermediate 3 (80 mg, 132 mol, 82% yield) was obtained as a yellow solid.

[0436] LCMS: RT = 0.537 min, MS cal.:606.2 / 608.2, [M+ H] + = 607.2 / 609.1

[0437] 1H NMR (400 MHz, DMSO-d6) = 7.88 (s, 1H), 7.82 (d, J = 1.2 Hz, 1H), 7.54 - 7.44 (m, 2H), 7.35 - 7.26 (m, 2H), 5.55 - 5.39 (m, 2H), 4.17 - 3.98 (m, 2H), 3.97 (s, 3H), 3.88 (s, 6H), 3.86 - 3.80 (m, 1H), 2.97 (dt, J = 7.6, 4.4 Hz, 1H), 2.87 - 2.76 (m, 1H), 2.76 - 2.60 (m, 2H), 1.39 (d, J = 6.4 Hz, 3H)General procedure for preparation of Final Compound 4(4):

[0438] To a solution of Intermediate 3 (70 mg, 115 mol, 1 eq) in H2O (0.3 mL) and THF (0.7 mL) was added LiOH.H2O (7.26 mg, 173 mol, 1.5 eq) at 25°C. The mixture was stirred at 25°C for 12 hr. LCMS showed Intermediate 3 was consumed and desired mass was detected.

[0439] The reaction was used directly for purification. The residue was purified by Prep-HPLC (column: Waters xbridge 150*25mm 10um; mobile phase: [H2O (10mM NH4HCO3) -ACN]; gradient: 26%-66% B over 8.0 min). (S)-2-((2-((4-Chloro-2-fluorobenzyl)oxy)-8-methyl-3- (trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-4-methoxy-1-methyl-1H- benzo[d]imidazole-6-carboxylic acid (28.6 mg, 47.8 mol, 42% yield, 99% purity) was obtained as a white solid.

[0440] LCMS: RT =2.903 min, MS cal.: 592.2 / 594.2, [M+H] + = 593.2 / 595.2

[0441] HPLC: RT =13.312 purity: 99.01%

[0442] 1H NMR (400 MHz, DMSO-d6) = 7.88 (s, 1H), 7.77 (d, J = 0.8 Hz, 1H), 7.55 - 7.45 (m, 2H), 7.32 (dd, J = 8.2, 1.6 Hz, 1H), 7.28 (d, J = 0.8 Hz, 1H), 5.56 - 5.39 (m, 2H), 4.13 (d, J = 13.6 Hz, 1H), 3.99 (d, J = 13.8 Hz, 1H), 3.96 (s, 3H), 3.86 (s, 3H), 3.83 (br d, J = 7.2 Hz, 1H), 3.02 - 2.93 (m, 1H), 2.86 - 2.77 (m, 1H), 2.76 - 2.63 (m, 2H), 1.39 (d, J = 6.8 Hz, 3H)Example A11. (S)-2-((2-((4-Chloro-2-fluorobenzyl)oxy)-8-methyl-3-(trifluoromethyl)-5,8- dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-7-fluoro-4-methoxy-1-methyl-1H- benzo[d]imidazole-6-carboxylic acid (Compound 5)General procedure for preparation of Intermediate 2:

[0443] To a solution of Intermediate 1 (60 mg, 160 mol, 1 eq) and Intermediate 1A (55.8 mg, 160 mol, 1 eq) in ACN (2 mL) was added K2CO3(66.4 mg, 480 mol, 3 eq) at 15°C, the mixture was stirred at 60°C for 12hr. LCMS showed Intermediate 1 was consumed completely and one main peak with desired m / z was detected. The reaction mixture was diluted with H2O (2 mL) and extracted with DCM (2 mL * 3). The combined organic layers were washed with brine (2 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=1 / 0 to 1 / 1) to obtained Intermediate 2 (90 mg, 131 mol, 82% yield) as a white solid.

[0444] LCMS: RT = 1.879 min, MS cal.: 686.1, [M +H] + = 687.1

[0445] 1H NMR (400 MHz, DMSO-d6) = 7.90 (s, 1H), 7.55 - 7.45 (m, 4H), 7.36 - 7.27 (m, 4H), 7.19 (d, J = 4.6 Hz, 1H), 5.57 - 5.49 (m, 1H), 5.47 - 5.40 (m, 1H), 4.21 - 4.12 (m, 1H), 4.05 (s, 3H), 3.97 (s, 3H), 3.90 - 3.79 (m, 1H), 2.99 (ddd, J = 4.2, 7.9, 11.9 Hz, 1H), 2.90 - 2.79 (m, 1H), 2.78 - 2.63 (m, 3H), 1.40 (d, J = 6.8 Hz, 3H) General procedure for preparation of Final Compound 5(3):

[0446] To a solution of Intermediate 2 (80 mg, 116 mol, 1 eq) in THF (0.7 mL) and H2O (0.3 mL) was added LiOH.H2O (7.33 mg, 175 mol, 1.5 eq) at 15°C, the mixture was stirred at 25°C for 12hr. LCMS showed Intermediate 2 was consumed completely and one main peak with desired m / z was detected. The mixture was filtered and purified by prep-HPLC (neutral condition; column: Waters Xbridge Prep OBD C18150*40mm*10um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient: 25%-75% B over 8.0 min) to obtained (S)-2-((2-((4- Chloro-2-fluorobenzyl)oxy)-8-methyl-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)- yl)methyl)-7-fluoro-4-methoxy-1-methyl-1H-benzo[d]imidazole-6-carboxylic acid (28.6 mg, 46.8 mol, 40% yield) as a white solid.

[0447] LCMS: RT = 1.232 min, MS cal.: 610.1, [M +H] + = 611.1

[0448] 1H NMR (400 MHz, METHANOL-d4) = 7.74 (s, 1H), 7.49 (t, J = 8.2 Hz, 1H), 7.28 - 7.16 (m, 2H), 7.07 (d, J = 4.8 Hz, 1H), 5.59 - 5.40 (m, 2H), 4.18 (d, J = 13.6 Hz, 1H), 4.10 (s, 3H), 4.02 (s, 1H), 3.98 (s, 3H), 3.84 (q, J = 6.8 Hz, 1H), 3.11 - 3.02 (m, 1H), 2.93 - 2.83 (m, 1H), 2.77 - 2.63 (m, 2H), 1.48 (d, J = 6.8 Hz, 3H)Example A12. (S)-2-((2-((4-Chloro-2-fluorobenzyl)oxy)-8-methyl-3-(trifluoromethyl)-5,8- dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-4-(difluoromethoxy)-1-methyl-1H- benzo[d]imidazole-6-carboxylic acid (Compound 6)General procedure for preparation of Intermediate 2:

[0449] A mixture of Intermediate 1 (0.44 g, 1.34 mmol, 1 eq) in toluene (5 mL), then Ag2CO3(555 mg, 2.01 mmol, 91.3 L, 1.5 eq) and Intermediate 1A (330 mg, 1.47 mmol, 1.1 eq) was added to the mixture. The mixture was stirred at 100°C for 2hr under N2 atmosphere. TLC showed Intermediate 1 was consumed completely and one main peak with desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE:EA = 10:1 to 3:1). Intermediate 2 (0.62 g, 1.24 mmol, 92% yield, 94% purity) was obtained as a faint yellow oil.

[0450] LCMS: RT = 2.561 min, MS cal.: 470.1, [M+H]+= 471.1

[0451] NMR (400 MHz, CHLOROFORM-d) = 7.68 (s, 1H), 7.66 (s, 1H), 7.48 - 7.45 (m, 1H), 7.45 - 7.41 (m, 1H), 7.16 (br d, J = 2.0 Hz, 1H), 7.15 - 7.10 (m, 2H), 5.57 - 5.51 (m, 2H), 5.50 - 5.42 (m, 3H), 5.05 (q, J = 6.4 Hz, 1H), 4.74 (dd, J = 5.2, 13.2 Hz, 1H), 4.17 (br dd, J = 3.6, 14.1 Hz, 1H), 3.54 - 3.41 (m, 1H), 3.18 (dt, J = 4.0, 12.8 Hz, 1H), 3.05 - 2.91 (m, 2H), 2.83 - 2.71 (m, 2H), 1.65 (s, 1H), 1.63 (s, 1H), 1.58 (s, 2H), 1.56 (s, 3H) General procedure for preparation of Intermediate 3:

[0452] A mixture of Intermediate 2 (200 mg, 425 mol, 1 eq), K2CO3(235 mg, 1.70 mmol, 4 eq) in MeOH (2 mL) and H2O (1 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 35°C for 12hr under N2atmosphere. LCMS showed Intermediate 2 was consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H2O (15 mL) and extracted with EtOAc (15 mL * 3). The combined organic layers were washed with brine (15 mL * 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. Intermediate 3 (100 mg, 267 mol, 63% yield) was obtained as a white solid.

[0453] LCMS: RT = 0.453 min, MS cal.: 374.08, [M+H]+= 375.0General procedure for preparation of Intermediate 4:

[0454] A mixture of Intermediate 3 (100 mg, 267 mol, 1 eq), Intermediate 4A (81.30 mg, 267 mol, 1 eq), K2CO3(111 mg, 801 mol, 3 eq) in ACN (2 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 60°C for 2hr under N2atmosphere. LCMS showed Intermediate 3 was consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove ACN. The residue was diluted with H2O (10 mL) and extracted with EtOAc (10 mL *3). The combined organic layers were washed with brine (10 mL *3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 0 / 1). Intermediate 4 (90 mg, 140 mol, 52% yield) was obtained as a yellow solid.

[0455] LCMS: RT = 2.120 min, MS cal.: 642.15, [M+H]+= 643.2 General procedure for preparation of Final Compound 6 (5):

[0456] A mixture of Intermediate 4 (90 mg, 140 mol, 1 eq), LiOH.H2O (8.81 mg, 210 mol, 1.5 eq) in THF (0.7 mL) and H2O (0.3 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 25°C for 12hr under N2atmosphere. LCMS showed Intermediate 4 was consumed completely and one main peak with desired mass was detected. The reaction mixture was diluted with H2O (5 mL) and extracted with DCM (5 mL *3). The combined organiclayers were washed with brine (3 mL *3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150*40 mm*10 um; mobile phase: [H2O (10 mM NH4HCO3) - ACN]; gradient:15%-65% B over 8.0 min). (S)-2-((2-((4-Chloro-2-fluorobenzyl)oxy)-8-methyl-3- (trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-4-(difluoromethoxy)-1- methyl-1H-benzo[d]imidazole-6-carboxylic acid (27.32 mg, 43.44 mol, 31.03% yield, 100% purity) was obtained as a white solid.

[0457] LCMS: RT = 2.988 min, MS cal.: 628.1, [M+H]+= 629.2

[0458] HPLC: RT = 14.170 min, purity:100%

[0459] 1H NMR (400 MHz, DMSO-d6) = 8.03 (s, 1H), 7.89 (s, 1H), 7.62 (t, J = 74.4 Hz, 2H), 7.54 - 7.45 (m, 3H), 7.32 (dd, J = 2.0, 8.4 Hz, 1H), 5.56 - 5.40 (m, 2H), 4.11 (dd, J = 14.0, 61.2 Hz, 2H), 3.91 (s, 3H), 3.85 (br d, J = 6.8 Hz, 1H), 3.02 - 2.93 (m, 1H), 2.86 - 2.77 (m, 1H), 2.67 (br d, J = 2.0 Hz, 2H), 1.41 (d, J = 6.8 Hz, 3H)Example A13. 2-((2-((4-Chloro-2-fluorobenzyl)oxy)-3-methyl-5,8-dihydro-1,7- naphthyridin-7(6H)-yl)methyl)-4-(difluoromethoxy)-1-methyl-1H-benzo[d]imidazole-6- carboxylic acid (Compound 7)7 General procedure for preparation of Intermediate 2:

[0460] To a mixture of Intermediate 1 (500 mg, 2.00 mmol, 1 eq) in THF (10 mL) was added NBS (391 mg, 2.20 mmol, 1.1 eq) in one portion at 20°C under N2. The mixture was de-gassed under reduced pressure and recharged with N2. The mixture was stirred at 20°C for 4 hours. The color of the solution changed black. LC-MS showed Compound 1 was consumed completely and one main peak with desired mass was detected. The mixture was concentrated in vacuum. The residue was poured into water (10 mL). The aqueous phase was extracted with ethyl acetate 10 mL*3). The combined organic phase was washed with brine (20 mL*2), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum. The crude product was used to next step without purification. Intermediate 2 (500 mg, 1.52 mmol, 76% yield) as a white solid.

[0461] LCMS: RT = 0.410 min, MS cal.:328.0, [M-(t-Bu) + H]+= 275.0

[0462] 1H NMR (400 MHz, METHANOL-d4) = 12.02 (br s, 1H), 7.75 (s, 1H), 4.24 (br s, 2H), 3.49 (br t, J = 5.2 Hz, 2H), 2.47 (br t, J = 6.0 Hz, 2H), 1.41 (s, 9H) General procedure for preparation of Compound 3:

[0463] To a mixture of Intermediate 2 (100 mg, 304 mol, 1 eq) and Intermediate 2A (102 mg, 456 mol, 1.5 eq) in DMF (1 mL) was added Ag2CO3 (168 mg, 608 mol, 27.6 L, 2 eq) in one portion at 20°C under N2. The mixture was stirred at 100 °C for 2 hours. LC-MS showed Intermediate 2 was consumed completely and one main peak with desired mass was detected. Filtrated, the mixtrue was concentrated in vacuum. The crude product was purifid by prep-TLC (Petroleum ether: Ethyl acetate = 10:1, Rf=0.4). Intermediate 3 (110 mg, 233 mol, 77% yield) as a white solid.

[0464] LCMS: RT = 0.745 min, MS cal.:470.0, [M+H-(t-Bu)]+=417.1

[0465] 1H NMR (400 MHz, METHANOL-d4) = 7.90 (s, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.49 (dd, J = 2.0, 10.0 Hz, 1H), 7.34 (dd, J = 1.6, 8.0 Hz, 1H), 5.39 (s, 2H), 4.40 (s, 2H), 3.56 (br t, J = 5.6 Hz, 2H), 2.71 (br t, J = 5.6 Hz, 2H), 1.43 (s, 9H)General procedure for preparation of Intermediate 4:

[0466] To a mixture of Intermediate 3 (100 mg, 212 mol, 1 eq) and methylboronic acid (63.5 mg, 1.06 mmol, 5 eq) in Tol. (0.8 mL) and H2O (0.2 mL) was added PCy3 (5.94 mg, 21.2 mol, 6.87 L, 0.1 eq), K3PO4.H2O (146 mg, 636 mol, 3 eq), Pd(OAc)2 (4.76 mg, 21.2 mol, 0.1 eq) in one portion at 20°C. The mixture was de-gassed under reduced pressure and recharged with N2. The mixture was stirred at 80°C for 2 hours. LC-MS showed Compound 3 was consumed completely and one main peak with desired mass was detected. Filtrate, the mixtrue was concentrated in vacuum. The crdue prodcut was purfied by prep-TLC (Petroleum ether: Ethyl acetate = 10:1, Rf = 0.4). Intermediate 4 (60 mg, 147 mol, 70% yield) as a white solid.

[0467] LCMS: RT = 0.730 min, MS cal.:406.1, [M+H]+=407.1

[0468] 1H NMR (400 MHz, METHANOL-d4) = 7.60 - 7.55 (m, 1H), 7.47 (dd, J = 2.0, 10.0 Hz, 1H), 7.36 (s, 1H), 7.31 (dd, J = 2.0, 8.4 Hz, 1H), 5.34 (s, 2H), 4.38 (br s, 2H), 3.55 (br t, J = 5.6 Hz, 2H), 2.65 (br t, J = 5.6 Hz, 2H), 2.11 (s, 3H), 1.43 (s, 9H) General procedure for preparation of Intermediate 5:

[0469] To a mixture of Intermediate 4 (80 mg, 197 mol, 1 eq) in EtOAc (1 mL) was added HCl / EtOAc (4 M, 983 L, 20 eq) in one portion at 20°C under N2. The mixture was stirred at 60°C for 2 hours. The color of the solution changed to white. LC-MS showed Intermediate 4 was consumed completely and one main peak with desired mass was detected. To a mixture was added Saturated sodium carbonate solution to PH=9~10. The aqueous phase was extracted with EtOAc (2 mL*3). The combined organic phase was washed with brine (3 mL*2), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum. The crude prodcut was used to next step without purification. Compound 5 (60 mg, 196 mol, 99% yield) as a white solid.

[0470] LCMS: RT = 0.406 min, MS cal.: 306.1, [M+H]+= 307.1

[0471] 1H NMR (400 MHz, CHLOROFORM-d) = 7.51 (t, J = 8.0 Hz, 1H), 7.40 (s, 1H), 7.25 - 7.19 (m, 2H), 5.41 (s, 2H), 4.23 (s, 2H), 3.49 (t, J = 6.4 Hz, 2H), 3.00 (t, J = 6.4 Hz, 2H), 2.20 (s, 3H) General procedure for preparation of Intermediate 6:5 6

[0472] To a mixture of Intermediate 5 (60 mg, 196 mol, 1 eq) and Intermediate 5A (53.6 mg, 176 mol, 0.9 eq) in ACN (1 mL) was added K2CO3 (81.1 mg, 587 mol, 3 eq) in one portion at 20°C under N2. The mixture was stirred at 60°C for 2 hours. The color of the solution changed to black. LC-MS showed Intermediate 5 was consumed completely and one main peak with desired mass was detected. Filtrate was concentrated in vacuum. The crude product was purified by prep-TLC (Petroleum ether: Ethyl acetate=1:1, Rf = 0.2). Intermediate 6 (80 mg, 139 mol, 71% yield) as a white solid.

[0473] LCMS: RT = 0.518 min, MS cal.:574.2, [M+H]+= 575.3

[0474] NMR (400 MHz, CHLOROFORM-d) = 8.10 (d, J = 1.2 Hz, 1H), 7.66 (t, J = 74 Hz, 1H), 7.56 - 7.51 (m, 2H), 7.43 (dd, J = 2.0, 9.6 Hz, 1H), 7.31 (s, 1H), 7.28 (dd, J = 2.0, 8.4 Hz, 1H), 5.29 (s, 2H), 4.04 (s, 2H), 3.94 (s, 3H), 3.90 (s, 3H), 3.59 (s, 2H), 2.80 - 2.75 (m, 2H), 2.72 - 2.66 (m, 2H), 2.09 (s, 3H) General procedure for preparation of Final Compound 7(7):

[0475] To a mixture of Intermediate 6 (70 mg, 122 mol, 1 eq) in THF (0.7 mL) and H2O (0.3 mL) was added LiOH.H2O (7.66 mg, 183 mol, 1.5 eq) in one portion at 20°C under N2. The mixture was stirred at 20°C for 10 hours. The color of the solution changed yellow. LC-MS showed Intermediate 6 was consumed completely and one main peak with desired mass was detected. The mixture was filtered and concentrated in vacuum. The crude product was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150*40mm*10um; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 15%-65% B over 8.0 min). 2-((2-((4-Chloro-2- fluorobenzyl)oxy)-3-methyl-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-4- (difluoromethoxy)-1-methyl-1H-benzo[d]imidazole-6-carboxylic acid (26.8 mg, 47.7 mol, 39% yield) as a white solid.

[0476] LCMS: RT = 2.825 min, MS cal.:560.1, [M+H]+= 561.2

[0477] HPLC: RT = 12.837 min, purity: 94.33%

[0478] 1H NMR (400 MHz, METHANOL-d4) = 8.06 (d, J = 1.2 Hz, 1H), 7.65 (t, J = 74.4 Hz, 1H), 7.56 - 7.51 (m, 2H), 7.44 (dd, J = 2.0, 10.0 Hz, 1H), 7.31 (s, 1H), 7.28 (dd, J = 1.6, 8.4 Hz, 1H), 5.29 (s, 2H), 4.04 (s, 2H), 3.93 (s, 3H), 3.58 (s, 2H), 2.80 - 2.74 (m, 2H), 2.69 (br d, J = 4.8 Hz, 2H), 2.09 (s, 3H)Example A14. 2-((2-((4-Chloro-2-fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7- naphthyridin-7(6H)-yl)methyl)-4-(difluoromethoxy)-1-methyl-1H-benzo[d]imidazole-6- carboxylic acid (Compound 8)7 General procedure for preparation of Intermediate 2:

[0479] To a mixture of Intermediate 1 (500 mg, 2.00 mmol, 1 eq) in ACN (10 mL) was added NIS (494 mg, 2.20 mmol, 1.1 eq) in one portion at 25°C under N2. The mixture was de-gassedunder reduced pressure and recharged with N2. The mixture was stirred at 80°C for 4 hours. The color of the solution changed to black. LC-MS showed Intermediate 1 was consumed completely and one main peak with desired mass was detected. The mixture was concentrated in vacuum. The residue was poured into water (10 mL). The aqueous phase was extracted with ethyl acetate 10 mL*3). The combined organic phase was washed with brine (20 mL*2), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum. The product was used to next step without purification. Intermediate 2 (550 mg, 1.46 mmol, 73% yield) as a yellow solid.

[0480] LCMS: RT = 0.422 min, MS cal.:376.1, [M-(t-Bu)+H]+= 321.0

[0481] 1H NMR (400 MHz, METHANOL-d4) = 11.99 - 11.76 (m, 1H), 7.93 (s, 1H), 4.23 (s, 2H), 3.47 (br t, J = 5.6 Hz, 2H), 2.46 (t, J = 5.6 Hz, 2H), 1.41 (s, 9H) General procedure for preparation of Intermediate 3:23

[0482] To a mixture of t Intermediate 2 (400 mg, 1.06 mmol, 1 eq) and Intermediate 2A (356 mg, 1.59 mmol, 1.5 eq) in DMF (4.5 mL) was added Ag2CO3 (586 mg, 2.13 mmol, 96.5 L, 2 eq) in one portion at 20°C under N2. The mixture was stirred at 100 °C for 2 hours. LC-MS showed Intermediate 2 was consumed completely and one main peak with desired mass was detected. Filtrate was concentrated in vacuum. The crude product was purified by prep-TLC (Petroleum ether: Ethyl acetate=10:1, Rf=0.4). Intermediate 3 (330 mg, 636 mol, 60% yield) as a white solid.

[0483] LCMS: RT = 0.761 min, MS cal.:518.0, [M+H-(t-Bu)]+= 463.1

[0484] 1H NMR (400 MHz, METHANOL-d4) = 8.03 (s, 1H), 7.59 (t, J = 8.4 Hz, 1H), 7.49 (dd, J = 10.0, 2.0 Hz, 1H), 7.35 (dd, J = 8.0, 1.6 Hz, 1H), 5.36 (s, 2H), 4.39 (s, 2H), 3.54 (t, J = 5.6 Hz, 2H), 2.68 (t, J = 5.2 Hz, 2H), 1.42 (s, 9H)General procedure for preparation of Intermediate 4:

[0485] To a mixture of Intermediate 3 (330 mg, 636 mol, 1 eq) in DMF (6 mL) was added CuI (121 mg, 636 mol, 1 eq) and methyl 2,2-difluoro-2-fluorosulfonyl-acetate (367 mg, 1.91 mmol, 243 L, 3 eq) in one portion at 25°C under N2. The mixture was de-gassed under reduced pressure and recharged with N2. The mixture was stirred at 80°C for 2 hours. LC-MS showed Compound 3 was consumed completely and one main peak with desired mass was detected. The mixture was concentrated in vacuum. The crude product was purified by prep-TLC (Petroleum ether: Ethyl acetate=10:1, Rf=0.4). Intermediate 4 (160 mg, 347 mol, 55% yield) as a white solid.

[0486] LCMS: RT = 0.711 min, MS cal.:460.1, [M-(t-Bu)+H]+=405.1

[0487] 1H NMR (400 MHz, METHANOL-d4) = 7.95 (s, 1H), 7.55 (t, J = 8.4 Hz, 1H), 7.49 (dd, J = 10.0, 2.0 Hz, 1H), 7.34 (dd, J = 8.4, 2.0 Hz, 1H), 5.47 (s, 2H), 4.49 (s, 2H), 3.59 (t, J = 5.6 Hz, 2H), 2.77 (t, J = 5.6 Hz, 2H), 1.43 (s, 9H) General procedure for preparation of Intermediate 5:

[0488] To a mixture of Intermediate 4 (140 mg, 304 mol, 1 eq) in EtOAc (1 mL) was added HCl / EtOAc (4 M, 1.52 mL, 20 eq) in one portion at 20°C. The mixture was stirred at 20°C for 1 hours. LC-MS showed Intermediate 4 was consumed completely and one main peak with desired mass was detected. To the mixture was added saturated sodium carbonate solution to PH=9~10. The aqueous phase was extracted with EtOAc (2 mL*3). The combined organic phase was washed with brine (3 mL*2), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum. Thecrude product was used to next step without purification. Intermediate 5 (100 mg, 277 mol, 91% yield) as a white solid.

[0489] LCMS: RT = 0.424 min, MS cal.: 360.1, [M+H]+= 361.1

[0490] 1H NMR (400 MHz, CHLOROFORM-d) = 7.97 (s, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.27 - 7.21 (m, 2H), 5.53 (s, 2H), 4.35 (s, 2H), 3.54 (t, J = 6.4 Hz, 2H), 3.09 (t, J = 6.4 Hz, 2H) General procedure for preparation of Intermediate 6:

[0491] To a mixture of Intermediate 5 (100 mg, 277 mol, 1 eq) and Intermediate 5A (84.5 mg, 277 mol, 1 eq) in ACN (3 mL) was added K2CO3(115 mg, 832 mol, 3 eq) in one portion at 20°C under N2. The mixture was stirred at 60°C for 2 hours. The color of the solution changed to black. LC-MS showed Intermediate 5 was consumed completely and one main peak with desired mass was detected. Filtrate was concentrated in vacuum. The crude product was purified by prep-TLC (Petroleum ether: Ethyl acetate=1:1,Rf=0.2). Intermediate 6 (110 mg, 175 mol, 63% yield) as a white solid.

[0492] LCMS: RT = 0.581 min, MS cal.:628.1, [M+H]+= 629.3

[0493] 1H NMR (400 MHz, CHLOROFORM-d) = 8.11 (s, 1H), 7.92 (s, 1H), 7.67 (t, J = 74.0 Hz, 1H), 7.58 - 7.43 (m, 3H), 7.31 (dd, J = 8.0, 1.6 Hz, 1H), 5.43 (s, 2H), 4.11 ( s, 2H), 3.96 - 3.92 (m, 3H), 3.91 - 3.87 (m, 3H), 3.74 ( s, 2H), 2.82 (s, 4H) General procedure for preparation of Final Compound 8 (7):

[0494] To a mixture of Compound 6 (110 mg, 175 mol, 1 eq) in THF (0.7 mL) and H2O (0.3 mL) was added LiOH.H2O (7.34 mg, 175 mol, 1 eq) in one portion at 20°C under N2. The mixture was stirred at 20°C for 10 hours. The color of the solution changed yellow. LC-MS showed Compound 6 was consumed completely and one main peak with desired mass was detected. The mixture was filtered and concentrated in vacuum. The crude product was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150*40mm*10um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient:15%-65% B over 8.0 min). 2-((2-((4-Chloro-2- fluorobenzyl)oxy)-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-4- (difluoromethoxy)-1-methyl-1H-benzo[d]imidazole-6-carboxylic acid (29.2 mg, 47.4 mol, 27% yield) as a white solid.

[0495] LCMS: RT = 2.864 min, MS cal.:614.1, [M+H]+= 615.1

[0496] HPLC: RT = 13.873 min, purity: 96.94%

[0497] 1H NMR (400 MHz, METHANOL-d4) = 8.06 (d, J = 1.2 Hz, 1H), 7.91 (d, J = 1.2 Hz,1H), 7.65 (t, J=74.4 Hz, 1H), 7.54 - 7.49 (m, 2H), 7.47 - 7.43 (m, 1H), 7.31 (dd, J = 8.0, 1.6 Hz, 1H), 5.42 (s, 2H), 4.08 (s, 2H), 3.93 (s, 3H), 3.72 (s, 2H), 2.85 - 2.78 (m, 4H)Example A15. (S)-2-((2-((2-Chlorobenzyl)oxy)-8-methyl-3-(trifluoromethyl)-5,8-dihydro- 1,7-naphthyridin-7(6H)-yl)methyl)-4-(2-fluoroethoxy)-1-methyl-1H-benzo[d]imidazole-6- carboxylic acid (Compound 9)56General procedure for preparation of Intermediate 4A:

[0498] A mixture of Intermediate 6 (100 mg, 413 mol, 1 eq), Intermediate 1A (191 mg, 1.24 mmol, 167 L, 3 eq), TosOH (14.2 mg, 82.6 mol, 0.2 eq) in ACN (0.5 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 60 °C for 2 hr under N2atmosphere.LC-MS product, RT = 1.047min showed Intermediate 6 was consumed completely anddesired mass was detected. The reaction mixture concentrated under reduced pressure to give a residue. Intermediate 4A (120 mg, 399 mol, 97% yield) was obtained as a yellow solid.

[0499] LCMS: RT = 1.047 min, MS cal.: 300.07, [M+H]+= 300.9

[0500] 1H NMR (400 MHz, CHLOROFORM-d) = 7.82 (d, J = 1.2 Hz, 1H), 7.47 (d, J = 1.2 Hz, 1H), 4.99 (s, 2H), 4.95-4.82 (dt, J = 47.2, 4.0 Hz, 2H), 4.57-4.48 (dt, J = 26.8, 4.4 HZ,2H), 3.98 - 3.93 (m, 6H), 3.81 (s, 3H) General procedure for preparation of Intermediate 2:

[0501] A mixture of Intermediate 1 (1 g, 2.92 mmol, 1 eq), TMSI (1.46 g, 7.30 mmol, 994 L, 2.5 eq) in MeCN (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 45°C for 2 hr under N2 atmosphere. TLC (Petroleum ether: Ethyl acetate = 1:1, Rf = 0.51) indicated Intermediate 1 was consumed completely and one new spot formed. The reaction was clean according to TLC. The reaction mixture was diluted with H2O 40 mL and extracted with EtOAc 60 mL (20 mL * 3). The combined organic layers were washed with brine 20 mL, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. Intermediate 2 (940 mg, 2.86 mmol, 98% yield) was obtained as a yellow solid.

[0502] LCMS: RT = 1.015 min, MS cal.: 328.06, [M+H]+= 328.9.

[0503] 1H NMR (400 MHz, DMSO) = 12.58 - 12.06 (m, 1H), 7.85 - 7.81 (m, 1H), 7.66 - 7.58 (m, 1H), 7.56 (br dd, J = 2.8, 6.8 Hz, 1H), 5.22 (q, J = 6.6 Hz, 1H), 5.00 - 4.83 (m, 1H), 4.45 - 4.36 (m, 1H), 4.50 - 4.31 (m, 1H), 3.99 - 3.91 (m, 1H), 3.96 (br d, J = 14.2 Hz, 1H), 3.71 - 3.49 (m, 1H), 2.75 - 2.58 (m, 2H), 1.58 (d, J = 6.6 Hz, 1H), 1.54 - 1.46 (m, 1H), 1.49 (d, J = 6.8 Hz, 1H)General procedure for preparation of Intermediate 3:

[0504] A mixture of Intermediate 2 (940 mg, 2.86 mmol, 1 eq), Intermediate 2A (589 mg, 2.86 mmol, 372 L, 1 eq), Ag2CO3 (948 mg, 3.44 mmol, 156 L, 1.2 eq) in Tol. (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 110°C for 2 hr under N2 atmosphere. LC-MS (Rt = 1.649min) showed Intermediate 2 was consumed completely and one main peak with desired mass was detected. The suspension was filtered through a pad of Celite and filter cake was washed with EtOAc(10 mL*3). The reaction mixture was diluted with H2O 40 mL and extracted with EtOAc 60 (20 mL * 3). The combined organic layers were washed with brine 30 mL, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 100 / 1 to 10 / 1). Intermediate 3 (1.03 g, 2.27 mmol, 79% yield) was obtained as a colorless oil.

[0505] LCMS: RT = 1.649 min MS cal:452.07 [M+H]+= 453.0

[0506] 1H NMR (400 MHz, DMSO) = 8.03 (s, 1H), 7.58 - 7.47 (m, 2H), 7.37 (br dd, J = 4.0, 5.2 Hz, 2H), 5.75 (s, 1H), 5.73 - 5.72 (m, 1H), 5.66 - 5.46 (m, 2H), 5.23 (q, J = 6.4 Hz, 1H), 4.94 - 4.83 (m, 1H), 4.94 - 4.83 (m, 1H), 4.83 - 4.80 (m, 1H), 4.53 - 4.43 (m, 1H), 4.42 - 4.41 (m, 1H), 4.02 (br d, J = 13.2 Hz, 1H), 3.67 - 3.54 (m, 1H), 2.95 - 2.80 (m, 2H), 1.59 (d, J = 6.4 Hz, 1H), 1.48 (d, J = 6.8 Hz, 2H) General procedure for preparation of Intermediate 4:

[0507] A mixture of Intermediate 3 (800 mg, 1.77 mmol, 1 eq), K2CO3(977 mg, 7.07 mmol, 4 eq) in H2O (3 mL), MeOH (6 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 35°C for 12 hr under N2 atmosphere. LC-MS product, Rt = 1.424min showed Intermediate 3 was consumed completely and desired mass was detected.

[0508] The reaction mixture was diluted with H2O 20 mL brine 10mL and extracted withEtOAc 60 mL (20 mL * 3). The combined organic layers were washed with Brine 15 mL, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. Intermediate 4 (600 mg, 1.68 mmol, 95% yield) was obtained as a white solid.

[0509] LCMS: RT = 1.424 min, MS cal.: 356.09, [M+H]+= 357.9

[0510] 1H NMR (400 MHz, DMSO) = 7.81 (s, 1H), 7.55 - 7.46 (m, 2H), 7.39 - 7.33 (m, 2H), 5.59 - 5.46 (m, 2H), 3.84 (q, J = 6.4 Hz, 1H), 3.12 - 3.01 (m, 1H), 2.84 - 2.60 (m, 4H), 1.32 (d, J = 6.8 Hz, 3H) General procedure for preparation of Intermediate 5:

[0511] A mixture of Intermediate 4 (142 mg, 399 mol, 1 eq), Intermediate 4A (120 mg, 399 mol, 1 eq), K2CO3 (165 mg, 1.20 mmol, 3 eq) in ACN (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 60°C for 2 hr under N2atmosphere. LC-MSproduct, Rt = 1.725min showed Intermediate 4 was consumed completely and desired masswas detected. The reaction mixture was diluted with H2O 15mL and extracted with EtOAc 30 mL (10 mL * 3). The combined organic layers were washed with brine 15 mL, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 1 / 1). Intermediate 5 (230 mg, 370 mol, 93% yield) was obtained as a yellow solid.

[0512] LCMS: RT = 1.725 min, MS cal.: 620.18, [M+H]+=621.1

[0513] 1H NMR (400 MHz, CDCl3) = 7.80 (d, J = 1.2 Hz, 1H), 7.61 (s, 1H), 7.58 - 7.55 (m, 1H), 7.44 (d, J = 0.8 Hz, 1H), 7.39 (dd, J = 1.6, 7.6 Hz, 1H), 7.32 - 7.20 (m, 3H), 5.64 - 5.49 (m, 2H), 4.98-4.84 (dt, J = 47.2, 4.0 Hz, 2H), 4.62-4.53(dt, J = 26.8 Hz, 4.4 Hz, 2H), 4.27 (br d, J = 13.2 Hz, 1H), 4.06 - 3.84 (m, 8H), 3.13 - 2.56 (m, 4H), 1.50 (br d, J = 4.4 Hz, 3H) General procedure for preparation of Final Compound 9 (6):

[0514] A mixture of Intermediate 5 (100 mg, 161 mol, 1 eq), LiOH.H2O (10.1 mg, 242 mol, 1.5 eq) in THF (0.7 mL) and H2O (0.3 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 25°C for 12 hr under N2atmosphere. LC-MS (product, RT = 1.234min) showed Intermediate 5 was consumed completely and desired mass was detected. The reaction was purified directly. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150*40mm*10um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient:15%-65% B over 8.0 min). (S)-2-((2-((2-Chlorobenzyl)oxy)-8-methyl-3-(trifluoromethyl)-5,8-dihydro-1,7- naphthyridin-7(6H)-yl)methyl)-4-(2-fluoroethoxy)-1-methyl-1H-benzo[d]imidazole-6- carboxylic acid (29.7 mg, 48.6 mol, 30% yield, 99.6% purity) was obtained as a white solid.

[0515] LCMS: RT = 2.566 min, MS cal.: 606.17, [M+H]+= 607.2

[0516] HPLC: RT = 13.17 min, purity: 99.57%

[0517] 1H NMR (400 MHz, MEDO) = 7.90 (s, 1H), 7.80 (s, 1H), 7.56 - 7.46 (m, 2H), 7.39 - 7.34 (m, 2H), 7.30 (s, 1H), 5.62 - 5.43 (m, 2H), 4.90-4.76 (dt, J=47.6, 2.8 HZ, 2H), 4.55-4.46 (dt, J = 30.4, 3.6 Hz, 2H), 4.15 (d, J = 13.2 Hz, 1H), 4.00 (d, J = 13.8 Hz, 1H), 3.87 (s, 3H), 3.84 (br d, J = 6.8 Hz, 1H), 3.04 - 2.88 (m, 1H), 2.87 - 2.76 (m, 1H), 2.75 - 2.59 (m, 2H), 1.39 (d, J = 6.8 Hz, 3H)Example A16.2-((3-Chloro-2-((4-chloro-2-fluorobenzyl)oxy)-5,8-dihydro-1,7-naphthyridin- 7(6H)-yl)methyl)-4-(difluoromethoxy)-1-methyl-1H-benzo[d]imidazole-6-carboxylic acid (Compound 10)General procedure for preparation of Intermediate 2:

[0518] To a mixture of Intermediate 1 (300 mg, 1.12 mmol, 1 eq) and phenylmethanol (362 mg, 3.35 mmol, 347 L, 3 eq) in dioxane (3 mL) was added Cs2CO3 (727 mg, 2.23 mmol, 2 eq), Brettphos Pd G4 (103 mg, 112 mol, 0.1 eq) in one portion at 25°C. The mixture was de-gassed under reduced pressure and recharged with N2. The mixture was stirred at 90°C for 12 hours. Thecolor of the solution changed to black. LC-MS showed Intermediate 1 was consumed completely and one main peak with desired mass was detected. The reaction mixture was quenched by addition H2O (5 mL). The aqueous phase was extracted with ethyl acetate (5 mL*3). The combined organic phase was washed with saturated brine (10 mL*1), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum. The crude product was purified by prep-TLC (Petroleum ether: Ethyl acetate=10:1, Rf=0.4). Intermediate 2 (300 mg, 881 mol, 79% yield) as a white solid.

[0519] LCMS: RT = 0.637 min, MS cal.:340.2, [M+H]+= 341.2

[0520] 7.47 - 7.41 (m, 3H), 7.37 - 7.32 (m, 2H), 7.31 - 7.26 (m, 1H), 6.66 (d, J = 8.4 Hz, 1H), 5.32 (s, 2H), 4.49 (s, 2H), 3.65 (br t, J = 5.2 Hz, 2H), 2.74 (t, J = 5.6 Hz, 2H), 1.50 (s, 9H) General procedure for preparation of Intermediate 3:

[0521] To a mixture of Intermediate 2 (300 mg, 881 mol, 1 eq) in MeOH (6 mL) was added Pd / C (93.8 mg, 88.1 mol, 10% purity, 0.1 eq) in one portion at 25°C under N2. The mixture was de-gassed under reduced pressure and recharged with H2. Then, the mixture was de-gassed under reduced pressure and recharged with H2(15Psi). The mixture was stirred at 25°C for 2 hours under H2(15 Psi). The solution changed to cloudy. LC-MS showed Intermediate 2 was consumed completely and one main peak with desired mass was detected. The suspension was filtered, and the filter cake was washed with MeOH (10 mL*3). The combined filtrates were concentrated to dryness to give product. Intermediate 3 (200 mg, 799 mol, 91% yield) as a white solid.

[0522] LCMS: RT = 0.367 min, MS cal.:250.1, [M+H-t-Bu]+= 195.1

[0523] 1H NMR (400 MHz, METHANOL-d4) = 7.40 (d, J = 9.2 Hz, 1H), 6.39 (d, J = 9.2 Hz, 1H), 4.40 (br s, 2H), 3.63 (br t, J = 5.6 Hz, 2H), 2.58 (t, J = 5.6 Hz, 2H), 1.49 (s, 9H)General procedure for preparation of Intermediate 4:

[0524] To a mixture of Intermediate 3 (600 mg, 2.40 mmol, 1 eq), Intermediate 3A (804 mg, 3.60 mmol, 1.5 eq) and Ag2CO3 (1.32 g, 4.79 mmol, 218 L, 2 eq) in toluene (10 mL) was degassed and purged with N2 for 3 times. The mixture was stirred 100°C for 12 hours. The color changes to brown. LC-MS showed Intermediate 3 was consumed completely and one main peak with desired mass was detected. The suspension was filtered, the mixture was concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether / Ethyl acetate=100 / 0, 4 / 96). Intermediate 4 (700 mg, 1.78 mmol, 74% yield) as a white solid.

[0525] LCMS: RT = 0.695 min, MS cal.:392.1, [M+H]+= 393.2

[0526] 7.50 (t, J = 8.4 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.23 - 7.17 (m, 2H), 6.65 (d, J = 8.4 Hz, 1H), 5.35 (s, 2H), 4.48 (s, 2H), 3.65 (br t, J = 5.2 Hz, 2H), 2.74 (t, J = 5.6 Hz, 2H), 1.50 (s, 9H) General procedure for preparation of Intermediate 5:

[0527] To a mixture of Intermediate 4 (200 mg, 509 mol, 1 eq) in DMF (4 mL) was added NCS (136 mg, 1.02 mmol, 2 eq) in one portion at 25°C under N2. The mixture was de-gassed under reduced pressure and recharged with N2. The mixture was stirred at 40°C for 4 hours. The color of the solution changed to black. LC-MS showed Intermediate 4 was consumed completely and one main peak with desired mass was detected. The mixture was concentrated in vacuum.The crude product was purified by prep-TLC (Petroleum ether: Ethyl acetate=5:1, Rf=0.4). Intermediate 5 (90 mg, 210.63 mol, 41.37% yield) as a white solid.

[0528] LCMS: RT = 0.736 min, MS cal.:426.1, [M+H-t-Bu]+= 371.1

[0529] 1H NMR (400 MHz, CHLOROFORM-d) = 7.57 (s, 1H), 7.54 (t, J = 8.4 Hz, 1H), 7.25 - 7.19 (m, 2H), 5.43 (s, 2H), 4.48 (s, 2H), 3.67 - 3.61 (m, 2H), 2.74 (t, J = 5.6 Hz, 2H), 1.49 (s, 9H) General procedure for preparation of Intermediate 6:

[0530] To a mixture of Intermediate 5 (90 mg, 211 mol, 1 eq) in EtOAc (1 mL) was added HCl / EtOAc (4 M, 1.05 mL, 20 eq) in one portion at 20°C under N2. The mixture was stirred at 20°C for 1 hours. The color of the solution changed to yellow. LC-MS showed Intermediate 5 was consumed completely and one main peak with desired mass was detected. To a mixture was added saturated sodium carbonate solution to pH=9~10. The aqueous phase was extracted with DCM (2 mL*3). The combined organic phase was washed with brine (3 mL*2), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum. The crude product was used to next step without purification. Intermediate 6 (60 mg, 183 mol, 87% yield) as a white solid.

[0531] LCMS: RT = 0.416 min, MS cal.:326.1, [M+H]+= 327.2

[0532] 1H NMR (400 MHz, CHLOROFORM-d) = 7.73 (s, 1H), 7.54 (t, J = 8.4 Hz, 1H), 7.26 - 7.21 (m, 2H), 5.46 (s, 2H), 4.28 (s, 2H), 3.51 (t, J = 6.4 Hz, 2H), 3.04 (t, J = 6.4 Hz, 2H)General procedure for preparation of Intermediate 7:

[0533] To a mixture of Intermediate 6 (60 mg, 183 mol, 1 eq) and Intermediate 6A (55.9 mg, 183 mol, 1 eq) in ACN (1 mL) was added K2CO3(76.0 mg, 550 mol, 3 eq) in one portion at 20°C under N2. The mixture was stirred at 60 °C for 2 hours. The color of the solution changed to yellow. LC-MS showed Intermediate 6 was consumed completely and one main peak with desired mass was detected. Filtrated, the filtrate was concentrated in vacuum. The crude product was purified by prep-TLC (Petroleum ether: Ethyl acetate=1:1, Rf=0.3). Intermediate 7(62 mg, 104 mol, 57% yield) as a white solid.

[0534] LCMS: RT = 0.416 min, MS cal.:594.1, [M+H]+= 595.3

[0535] NMR (400 MHz, CHLOROFORM-d) = 8.11 (d, J = 1.2 Hz, 1H), 7.71 (s, 1H), 7.67 (t, J = 74.0 Hz, 1H), 7.57 - 7.53 (m, 2H), 7.46 (dd, J = 2.0, 10.0 Hz, 1H), 7.30 (dd, J = 2.0, 8.3 Hz, 1H), 5.35 (s, 2H), 4.06 (s, 2H), 3.94 (s, 3H), 3.90 (s, 3H), 3.64 (s, 2H), 2.79 (br d, J = 4.8 Hz, 2H), 2.75 (br d, J = 5.2 Hz, 2H) General procedure for preparation of Final Compound 10 (8):7 8

[0536] To a mixture of Intermediate 7 (60 mg, 101 mol, 1 eq) in THF (0.7 mL) and H2O (0.3 mL) was added LiOH.H2O (6.34 mg, 151 mol, 1.5 eq) in one portion at 20°C under N2. The mixture was stirred at 20 °C for 10 hours. LC-MS showed Intermediate 7 was consumed completely and one main peak with desired mass was detected. The mixture was filtered and concentrated in vacuum. The crude product was purified by prep-HPLC (column: Waters XbridgePrep OBD C18150*40mm*10um; mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:30%- 60% B over 8.0 min). 2-((3-Chloro-2-((4-chloro-2-fluorobenzyl)oxy)-5,8-dihydro-1,7- naphthyridin-7(6H)-yl)methyl)-4-(difluoromethoxy)-1-methyl-1H-benzo[d]imidazole-6- carboxylic acid (28.1 mg, 48.4 mol, 48% yield, 100% purity) as a colorless white solid

[0537] LCMS: RT = 2.812 min, MS cal.:580.1, [M+H]+= 581.1

[0538] HPLC: RT = 12.910 min, purity: 100%

[0539] 8.06 (s, 1H), 7.71 (s, 1H), 7.65 (t, J = 74 Hz, 1H), 7.58 - 7.52 (m, 2H), 7.48 - 7.43 (m, 1H), 7.31 (br d, J = 8.4 Hz, 1H), 5.36 (s, 2H), 4.06 (s, 2H), 3.92 (s, 3H), 3.63 (s, 2H), 2.78 (br d, J = 4.8 Hz, 2H), 2.75 (br d, J = 4.8 Hz, 2H)Example A17. (S)-2-((2-((2-Chlorobenzyl)oxy)-8-methyl-3-(trifluoromethyl)-5,8-dihydro- 1,7-naphthyridin-7(6H)-yl)methyl)-4-(difluoromethoxy)-1-methyl-1H-benzo[d]imidazole-6- carboxylic acid (Compound 11)General procedure for preparation of Intermediate 2:

[0540] THF (400 mL) was charged to the 2000 mL three-necked round bottom flask, then Intermediate 1 (35 g, 137 mmol, 1 eq) TMEDA (43.7 g, 376 mmol, 56.7 mL, 2.75 eq) was added at -25°C. At -25°C, TMPMgCl.LiCl(1 M, 376 mL, 2.75 eq) was added dropwise to the reaction mixture at -25°C within 0.5 hr. After the addition, the mixture was stirred at -25°C for 1 hr. CO2 gas was carefully bubbled into the reactor and the temperature of the exothermic reaction did not exceed -20°C. LCMS showed the starting material was consumed completely. The reaction mixture was added to TBME (1000 mL) and 10% aq. H2SO4 (500 mL) at 0°C within 30 min. The aqueous phase was acidified to pH 1 -2 with 5% aq. H2SO4. The mixture was extracted by TBME (500 mL*3). Then organic phase was combined and washed by H2O (500 mL), aq. NaCl (500 mL), dried with Na2SO4, filtered. The organic phase was concentrated under reduced pressure at 40°C to give a residue. Intermediate 2 (70 g, 233 mmol, 85% yield) was obtained as a white solid.

[0541] LCMS: RT = 0.736 min, MS cal.: 298.9, [M+H]+= 299.7

[0542] 1H NMR (400 MHz, DMSO-d6) = 8.24 (s, 1H), 4.13 (s, 3H) General procedure for preparation of Intermediate 3:

[0543] To a solution of Intermediate 2 (50 g, 167 mmol, 1 eq) in DCM (500 mL) was added HATU (69.7 g, 183 mmol, 1.1 eq) and DIEA (108 g, 833 mmol, 145 mL, 5 eq) at 0°C for 0.5 hr. The mixture was added with MeONHMe.HCl (24.4 g, 250 mmol, 1.5 eq). The mixture was stirred at 20 °C for 2hr. TLC (Petroleum ether: Ethyl acetate = 5:1 Rf=0.36) indicated Intermediate 2 was consumed completely. The reaction was then quenched with H2O (400 mL). The solution was extracted with DCM (2x300 mL) and the organic layers combined. The resulting mixture was washed with brine (200 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 100 / 1 to 0 / 1). Intermediate 3 (48 g, 140 mmol, 84% yield) was obtained as a white solid.

[0544] LCMS: RT = 1.801 min, MS cal.: 341.9, [M+H]+= 342.9

[0545] 1H NMR (400 MHz, CHLOROFORM-d) = 8.02 (s, 1H), 4.04 (s, 3H), 3.63 (s, 3H), 3.41 (s, 3H) General procedure for preparation of Intermediate 4:

[0546] THF (300 mL) was charged to the 1000 mL three-necked round bottom flask, then Intermediate 3 (30 g, 87.4 mmol, 1 eq) was added at -0°C. At 0oC (inner temperature), CH3MgBr (3 M, 58.3 mL, 2 eq) was added dropwise to the reaction mixture at 0oC. After the addition, the mixture was stirred at 0-25°C for 1 hr. TLC (Petroleum ether: Ethyl acetate = 5:1 Rf=0.67) indicated Intermediate 3 was consumed completely and one new spot formed. The reaction mixture was added to 100 mL (sat. NH4Cl) at 0 °C within 2 min. The mixture was extracted by EtOAc (300 mL*3). Then organic phase was combined and washed by H2O (100 mL), aq. brine (100 mL), dried with Na2SO4, filtered. The organic phase was concentrated under reduced pressure at 40°C to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 100 / 1 to 95 / 5). Intermediate 4 (30 g, crude) was obtained as a white solid.

[0547] LCMS: RT = 1.314 min, MS cal.: 296.9, [M+H]+= 297.7

[0548] 1H NMR (400 MHz, DMSO-d6) = 8.45 (s, 1H), 4.04 (s, 3H), 2.63 (s, 3H) General procedure for preparation of Intermediate 5:

[0549] A mixture of Intermediate 4 (25 g, 83.9 mmol, 1 eq), Noyori’s catalyst (1.07 g, 1.68 mmol, 0.02 eq), HCOOH (8.06 g, 168 mmol, 2 eq) and TEA (8.49 g, 83.9 mmol, 11.7 mL, 1 eq) in ACN (50 mL) was degassed and purged with N2for 3 times, and then the mixture was stirredat 20 °C for 2hr under N2atmosphere. TLC (Petroleum ether: Ethyl acetate = 5:1 Rf=0.5) indicated Intermediate 4 was consumed completely and one new spot formed. The reaction was then quenched with H2O (100 mL). The solution was extracted with ethyl acetate (2x100 mL) and the organic layers combined. The resulting mixture was washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 100 / 1 to 9 / 1). Compound 5 (25.4 g, 84.7 mmol, 64% yield) was obtained as a white solid.

[0550] LCMS: RT = 1.219 min, MS cal.: 298.9, [M+H]+= 298.8

[0551] SFC: RT = 2.562, ee% = 95.52%

[0552] 1H NMR (400 MHz, DMSO-d6) = 8.25 (s, 1H), 5.26 (d, J = 6.6 Hz, 1H), 5.05 (quin, J = 6.4 Hz, 1H), 4.03 (s, 3H), 1.38 (d, J = 6.4 Hz, 3H) General procedure for preparation of Intermediate 6:

[0553] A mixture of Intermediate 5 (14 g, 46.7 mmol, 1 eq), Intermediate 5A (8.08 g, 46.7 mmol, 1 eq), t-Bu3P Pd G2 (820 mg, 1.40 mmol, 0.03 eq), Cy2NMe (10.9 g, 56 mmol, 11.9 mL, 1.2 eq) in dioxane (150 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90°C for 120 hrs under N2 atmosphere. TLC indicated Intermediate 5 was consumed completely and two new spots formed (TLC- Ethyl acetate / Methanol =5 / 1, Product Rf=0.15). The reaction was clean according to TLC. The residue mixture was diluted with H2O (150 mL) and extracted with EtOAc (150 mL*3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was dissolved with EtOAc / PE=1 / 1(300 mL) and filtered by celite. The filtrate was concentrated under reduced pressure to give a residue. The crude product was triturated with MeOH (300 mL) at 25oC for 1 hr and filtered. The cake was dried under reduced pressure to give a residue. Compound 6 (13.2 g, 33.4 mmol, 71% yield, 99.3% purity) was obtained as a yellow solid.

[0554] LCMS: RT = 1.348min, MS cal.: 392.10, [M+H]+= 393.0

[0555] SFC: RT = 1.446min, ee% = 98.34

[0556] NMR (400 MHz, DMSO-d6) = 8.24 - 8.20 (m, 1H), 7.99 - 7.85 (m, 5H), 7.26 (d, J = 15.2 Hz, 1H), 5.32 (d, J = 5.6 Hz, 1H), 4.98 (t, J = 6.0 Hz, 1H), 4.03 (s, 3H), 1.45 (d, J = 6.4 Hz, 3H) General procedure for preparation of Intermediate 7:

[0557] Pd / C (6.50 g, 6.11 mmol, 10% purity) was charged to the 75 mL Hydrogenated bottle, then MeOH (130 mL) was added at 20°C. Intermediate 6 (13 g, 33.1 mmol, 1 eq) in THF (130 mL) was added to the reaction mixture at 20°C. The reaction mixture was degassed and purged with H23 times. The mixture was stirred under H2(50 Psi) at 25°C for 4hr. LC-MS showed Intermediate 6 was consumed completely and one main peak with desired mass was detected. The reaction mixture was filtered with celatom and filtrate was concentrated under reduced pressure to give a residue. Intermediate 7 (12.4 g, 30.2 mmol, 91% yield, 95.9% purity) was obtained as a white solid.

[0558] LCMS: RT = 1.258min, MS cal.: 394.11, [M+H]+= 395.0

[0559] SFC: RT = 2.155min, ee% = 98.12

[0560] 1H NMR (400 MHz, DMSO-d6) = 7.87 - 7.79 (m, 5H), 5.09 (d, J = 6.4 Hz, 1H), 5.01 - 4.91 (m, 1H), 3.96 (s, 3H), 3.86 - 3.75 (m, 2H), 3.17 - 2.96 (m, 2H), 1.36 (d, J = 6.4 Hz, 3H) General procedure for preparation of Intermediate 8:

[0561] A mixture of Intermediate 7 (9 g, 22.8 mmol, 1 eq) in EtOH (200 mL) was degassed and purged with N2for 3 times, and then N2H4•H2O (4.57 g, 91.3 mmol, 4.43 mL, 4 eq) was added to the reaction mixture. The mixture was stirred at 90°C for 2 hrs under N2 atmosphere. TLC indicated Intermediate 7 was consumed completely and one new spot formed (TLC- Ethyl acetate / Methanol =10 / 1, Product Rf=0.11). The reaction was clean according to TLC. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The crude product was triturated with DCM (400 mL) at 25oC for 10 mins and filtered. The filtrate was concentrated under reduced pressure to give a residue. Intermediate 8 (11 g, 38.2 mmol, 84% yield, 91.8% purity) was obtained as a white solid.

[0562] LCMS: RT = 0.831min, MS cal.: 264.11, [M+H]+= 265.0

[0563] SFC: RT = 1.176min, ee% = 100

[0564] 1H NMR (400 MHz, DMSO-d6) = 7.90 - 7.83 (m, 1H), 4.98 (q, J = 6.4 Hz, 1H), 3.97 (s, 3H), 2.83 - 2.63 (m, 4H), 1.41 (d, J = 6.4 Hz, 3H) General procedure for preparation of Intermediate 9:

[0565] DCM (110 mL) as charged to the three-necked round bottom flask, then Intermediate 8 (11 g, 41.6 mmol, 1 eq) and TEA (25.3 g, 250 mmol, 34.8 mL, 6 eq) was added to the mixture at 25°C. The mixture was degassed and purged with N2for 3 times, and then Cooled to 0°C. TFAA (21.9 g, 104 mmol, 14.5 mL, 2.5 eq) was added to the reaction mixture at 0°C and stirred at 25°C for 1 hr. TLC indicated Intermediate 8 was consumed completely and one new spot formed (TLC- Petroleum ether: Ethyl acetate =2 / 1, Product Rf=0.54). The reaction was clean according to TLC. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The reaction mixture was adjusted to pH=6-7 with FA(1M) and diluted with H2O (150 mL). The mixture was extracted with EtOAc (150 mL*3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / 1 to 5 / 1, TLC- Petroleum ether / Ethyl acetate =2 / 1, ProductRf=0.54). Intermediate 9 (13 g, 35.2 mmol, 85% yield, 98% purity) was obtained as a white solid.

[0566] LCMS: RT = 1.157min, MS cal.: 360.09, [M+H]+= 360.9

[0567] SFC: RT = 1.002min, ee% = 100

[0568] 1H NMR (400 MHz, DMSO-d6) = 9.48 (br t, J = 5.2 Hz, 1H), 7.81 (s, 1H), 5.18 (br d, J = 4.0 Hz, 1H), 4.97 (br s, 1H), 3.98 (s, 3H), 3.49 - 3.38 (m, 2H), 3.05 - 2.82 (m, 2H), 1.42 (d, J = 6.4 Hz, 3H) General procedure for preparation of Intermediate 10:

[0569] A mixture of Intermediate 9 (3 g, 8.33 mmol, 1), PPh3 (3.28 g, 12.5 mmol, 1.5 eq), DIAD (3.37 g, 16.7 mmol, 3.23 mL, 2 eq) in THF (30 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25°C for 12 hrs under N2 atmosphere. LC-MS showed Intermediate 9 was consumed completely and one main peak with desired mass was detected. The residue mixture was diluted with H2O (100 mL) and extracted with EtOAc (100 mL*3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / 1 to 5 / 1, TLC- Petroleum ether / Ethyl acetate =2 / 1, Product Rf=0.65). Intermediate 10 (1.9 g, 5.10 mmol, 61% yield, 91.9% purity) was obtained as a white solid.

[0570] LCMS: RT = 1.419min, MS cal.: 342.08, [M+H]+= 547.1

[0571] LCMS: RT = 1.423min, MS cal.: 342.08, [M+H]+= 342.9

[0572] SFC: RT = 0.677min, ee% = 95.74

[0573] 7.99 (s, 1H), 5.25 (q, J = 6.8 Hz, 1H), 4.89 (br d, J = 6.8 Hz, 1H), 4.53 - 4.43 (m, 1H), 4.08 - 4.00 (m, 1H), 3.96 (s, 3H), 3.67 - 3.54 (m, 1H), 2.96 - 2.80 (m, 2H), 1.64 (d, J = 6.8 Hz, 1H), 1.54 (d, J = 6.8 Hz, 2H)General procedure for preparation of Intermediate 11:

[0574] A mixture of Intermediate 10 (500 mg, 1.46 mmol, 1 eq) and TMSI (731 mg, 3.65 mmol, 497 L, 2.5 eq) in ACN (5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 45°C for 2 hrs under N2 atmosphere. LC-MS showed Intermediate 10 was consumed completely and one main peak with desired mass was detected. The reaction mixture was adjusted to pH=5-6 with a.q. NaHCO3and diluted with H2O (30 mL). The mixture was extracted with EtOAc (30 mL*3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. Intermediate 11 (470 mg, 1.24 mmol, 85% yield, 86.4% purity) was obtained as a brown solid.

[0575] LCMS: RT = 1.322min, MS cal.: 328.06, [M+H]+= 329.0

[0576] SFC: RT = 2.295min, ee% = 98.86

[0577] NMR (400 MHz, DMSO-d6) = 12.30 (br s, 1H), 7.83 (s, 1H), 5.22 (q, J = 6.8 Hz, 1H), 4.98 - 4.83 (m, 1H), 4.48 - 4.32 (m, 1H), 3.96 (br d, J = 14.4 Hz, 1H), 3.65 - 3.55 (m, 1H), 2.67 (br d, J = 4.8 Hz, 2H), 1.58 (d, J = 6.8 Hz, 1H), 1.49 (d, J = 6.8 Hz, 3H) General procedure for preparation of Intermediate 12:

[0578] A mixture of Intermediate 11 (470 mg, 1.43 mmol, 1 eq), Intermediate 11A (294 mg, 1.43 mmol, 186 L, 1 eq), Ag2CO3(474 mg, 1.72 mmol, 78 L, 1.2 eq) in Tol. (10 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 110°C for 2 hrs under N2atmosphere. LC-MS showed Intermediate 11 was consumed completely and one main peak with desired mass was detected. The reaction mixture was filtered and concentrated under reducedpressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / 1 to 5 / 1, TLC- Petroleum ether / Ethyl acetate =5 / 1, Product Rf=0.53). Intermediate 8 (490 mg, 1.06 mmol, 74% yield, 98.1% purity) was obtained as a white solid.

[0579] LCMS: RT = 2.452min, MS cal.: 452.07, [M+H]+= 453.1

[0580] SFC: RT = 1.081min, ee% = 98.12

[0581] NMR (400 MHz, CHLOROFORM –d) = 7.70 - 7.65 (m, 1H), 7.54 (dd, J = 2.0, 7.2 Hz, 1H), 7.42 - 7.37 (m, 1H), 7.31 - 7.22 (m, 2H), 5.67 - 5.52 (m, 2H), 5.47 (q, J = 6.8 Hz, 1H), 5.06 (br d, J = 6.8 Hz, 1H), 4.74 (dd, J = 5.6, 13.3 Hz, 1H), 4.21 - 4.14 (m, 1H), 3.53 - 3.42 (m, 1H), 3.18 (br d, J = 3.6 Hz, 1H), 3.05 - 2.91 (m, 1H), 2.79 (td, J = 1.6, 14.5 Hz, 1H), 2.05 (s, 1H), 1.63 (d, J = 6.8 Hz, 1H), 1.60 (s, 1H), 1.56 (d, J = 6.8 Hz, 2H) General procedure for preparation of Intermediate 13:

[0582] A mixture of Intermediate 12 (100 mg, 221 mol, 1 eq), K2CO3(122 mg, 883 mol, 4 eq) in MeOH (1 mL) and H2O (0.5 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 35°C for 12 hrs under N2atmosphere. LC-MS showed Intermediate 12 was consumed completely and one main peak with desired mass was detected. The residue mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL*3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. Intermediate 13 (73 mg, 199 mol, 90% yield, 97.5% purity) was obtained as a white solid.

[0583] LCMS: RT = 1.449min, MS cal.: 356.09, [M+H]+= 357.2

[0584] SFC: RT = 1.395min, ee% = 100

[0585] 1H NMR (400 MHz, METHANOL-d4) = 7.77 - 7.71 (m, 1H), 7.51 (dd, J = 3.6, 5.6 Hz, 1H), 7.44 - 7.38 (m, 1H), 7.34 - 7.25 (m, 2H), 5.57 (q, J = 13.6 Hz, 2H), 3.95 (q, J = 6.4 Hz,1H), 3.22 (td, J = 4.4, 12.3 Hz, 1H), 3.01 - 2.82 (m, 2H), 2.79 - 2.69 (m, 1H), 1.45 (d, J = 6.8 Hz, 3H) General procedure for preparation of Intermediate 14:

[0586] A mixture of Intermediate 13 (230 mg, 645 mol, 1 eq), Intermediate 13A (118 mg, 387 mol, 0.6 eq), K2CO3(267 mg, 1.93 mmol, 3 eq) in ACN (2.3 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 60°C for 2 hrs under N2atmosphere. TLC indicated Reactant 1 was consumed completely and one new spot formed. The reaction was clean according to TLC.(Petroleum ether : Ethyl acetate=1:1, product Rf=0.74) The residue mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL*3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=100 / 1 to 7 / 3, TLC- Petroleum ether / Ethyl acetate =2 / 1, Product Rf=0.74). Intermediate 14 (200 mg, 310 mol, 48% yield, 96.8% purity) was obtained as a white solid.

[0587] LCMS: RT = 2.017min, MS cal.: 624.16, [M+H]+= 625.2

[0588] SFC: RT = 1.222min, ee% = 100

[0589] NMR (400 MHz, CHLOROFORM -d4) = 7.98 (d, J = 1.2 Hz, 1H), 7.73 (s, 1H), 7.62 (s, 1H), 7.56 (dd, J = 1.6, 7.4 Hz, 1H), 7.41 - 7.36 (m, 1H), 7.33 (t, J = 74.4 Hz, 1H), 7.30 - 7.23 (m, 2H), 5.65 - 5.48 (m, 2H), 4.24 (d, J = 14.0 Hz, 1H), 4.07 - 4.00 (m, 1H), 3.97 (s, 3H), 3.95 (s, 3H), 3.93 - 3.84 (m, 1H), 3.03 (br d, J = 3.2 Hz, 1H), 2.87 - 2.63 (m, 3H), 1.50 (br d, J = 6.8 Hz, 3H)General procedure for preparation of Final Compound 11 (15):

[0590] A mixture of Compound 14 (70 mg, 112 mol, 1 eq), LiOH.H2O (9.40 mg, 224 mol, 2 eq) in THF (0.7 mL) and H2O (0.3 mL) was degassed and purged with N23 times, and then the mixture was stirred at 25°C for 12 hrs under N2 atmosphere. LC-MS showed Compound 14 was consumed completely and one main peak with desired mass was detected. The reaction mixture was diluted with ACN 0.5 mL. The liquid was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150*40mm*10um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient: 35%- 65% B over 8.0 min). (S)-2-((2-((2-Chlorobenzyl)oxy)-8-methyl-3-(trifluoromethyl)-5,8- dihydro-1,7-naphthyridin-7(6H)-yl)methyl)-4-(difluoromethoxy)-1-methyl-1H- benzo[d]imidazole-6-carboxylic acid (27.9 mg, 45.4 mol, 41% yield, 99.4% purity) was obtained as a white solid.

[0591] LCMS: RT = 0.490min, MS cal.:610.14, [M+H]+= 611.1

[0592] 8.11 - 8.06 (m, 1H), 7.76 (s, 1H), 7.69 (s, 1H), 7.52 (dd, J = 3.6, 5.7 Hz, 1H), 7.40 (dd, J = 3.6, 5.7 Hz, 1H), 7.31 - 7.26 (m, 2H), 7.24 (t, J = 74 Hz, 1H), 5.62 - 5.49 (m, 2H), 4.25 (d, J = 14.0 Hz, 1H), 4.07 (d, J = 14.0 Hz, 1H), 3.98 (s, 3H), 3.87 (q, J = 6.4 Hz, 1H), 3.13 - 3.03 (m, 1H), 2.93 - 2.83 (m, 1H), 2.79 - 2.65 (m, 2H), 1.48 (d, J = 6.8 Hz, 3H) Example B1: GLP-1R Cell Assay

[0593] Stable cell lines expressing high and low GLP-1R surface expression were generated in CHO-K1 cells transfected (Fugene 6) with a puromycin selectable DNA plasmid encoding human GLP-1R receptor (accession number: NM_002062.5) under control of an EF1A promoter. Transfected cells were seeded into 24-well plates (9,000 cells / well) containing complete mediumand incubated in a humidified incubator at 37 C with 5% carbon dioxide. After overnightincubation, medium was replaced with complete medium supplemented with puromycin (6 g / mL) and refreshed every 2-3 days to select for stably transfected cells. Individual pools of selected cells were expanded prior to analysis for responsiveness to GLP-1 control peptide usinga TR-FRET assay to detect cAMP (LANCE Ultra cAMP Assay, Perkin Elmer). Briefly, cells were collected in Versene solution, plated in 384-well plates (1,000 cells / well) and combined with serially diluted GLP-1R control peptide (10 nL) using an acoustic dispenser (ECHO). Plates wereincubated for 30 minutes at 25 C prior to the addition of EU-cAMP tracer (5 L) and Ulight-anti-cAMP (5 L) reagents to each well, followed by 15 minutes incubation at 25 C. TR-FRET signalwas detected using an EnVision Multimode Plate Reader (excitation=320 nm; emission= 615 and 655 nm). Dose-response curves were used to generate EC50values as a measure of responsiveness to the GLP-1R control peptide. Selected cell lines were monitored for responsiveness over multiple passages to ensure stability. CHO-K1_hGLP-1Rhigh_clone16 and CHO-K1_hGLP- 1Rlow_clone10 showed consistently high and low responsiveness to GLP-1R control peptide, respectively, and were chosen for further analysis to determine relative levels of GLP-1R surface expression. Briefly, GLP-1R expression was analyzed by flow cytometry using a fluorescein- labeled Exendin-4 peptide fluorescent probe (FLEX). Cells were harvested in Versene solution and washed 3-times with PBS+0.5% BSA before incubation with FLEX reagent (10 M) for 2 hours at room temperature. After incubation, cells were washed 3-times in PBS+0.5% BSA before final resuspension in PBS prior to analysis by flow cytometry to measure FLEX mean fluorescence intensity (MFI) as a measure of GLP-1R expression on the cell surface. Both cell lines showed higher MFI values relative to control CHO-K1 cells, confirming GLP-1R surface expression; CHO-K1_hGLP-1Rhigh_clone16 cells showed significantly higher MFI levels relative to CHO- K1-hGLP-1low_clone10 cells.

[0594] For compound testing in the CHO-K1_hGLP-1Rlow_clone10 cell line, cells were seeded in 384-well plates (1,000 cells / well). Test compounds were serially diluted in DMSO (10-point, 3-fold dilution), added to wells using an ECHO dispenser (10 nL / well) and plates were centrifugedfor 1 min and agitated for 2 min at room temperature prior to 30-minute incubation at 25 C. Afterincubation, Eu-cAMP (5 L) and Ulight-anti-cAMP (5 L) reagents were added to each well, followed by centrifugation for 1 minute, agitation for 2 minutes at room temperature, and finalincubation of the plates at 25 C for 15 minutes. Plates were read using an EnVision microplatereader (excitation=320 nm; emission= 615 and 655 nm). Dose-response curves were generated from duplicate wells based on percent activation calculated relative to a control GLP-1 peptide agonist that was run in parallel. EC50 values were determined by fitting percent activation as a function of compound concentration using the Hill equation (XLfit).The EC50 values of exemplary compounds in the low expression assay are shown in Table 2 below, wherein “+” indicates thatthe EC50is >1,000 nM; “++” indicates EC50is <1,000 nM and >100 nM; “+++” indicates that the EC50is <100 nM and >10 nM; and “++++” indicates that the EC50is <10 nM. The maximum activation values (Emax) of exemplary compounds are shown in Table 2a below, wherein “+” indicates that the Emax is <25%; “++” indicates Emax is <50 % and >25 %; “+++” indicates that the Emax is <85 % and >50 %; and “++++” indicates that the Emax is >85 %.

[0595] The compounds tested were compound samples prepared according to the General Procedures described in the Examples section. Table 2Table 2aExample B2: Rat Pharmacokinetics

[0596] Intravenous dosing: Compounds were formulated at 1.0 mg / mL in a solution comprising5% polyethylene glycol 400 and 95% (12% (w / v) sulfobutyl- -cyclodextrin in water) (v / v).Formulated compounds were sterile filtered through a 0.22 micron filter before dosing. Compounds were administered to male, 7–11-week-old Sprague-Dawley rats by jugular vein cannula infusion over 30 minutes at a dose of 1 mg / kg.

[0597] Oral dosing: Compounds were formulated at 1.0 mg / mL in a solution comprising 5%polyethylene glycol 400 and 95% (12% (w / v) sulfobutyl- -cyclodextrin in water) (v / v).Formulated compounds were administered to male, 7-11 week old Sprague-Dawley rats by oral gavage at a dose of 10 mg / kg or 3 mg / kg.

[0598] Sample collection: Blood collections of about 0.2 mL per time point were performed from jugular vein or other suitable site of each animal, into pre-chilled commercial EDTA-K2 tubes and placed on wet ice until centrifugation. Blood samples were processed for plasma by centrifugation at approximately 4°C, 3,200 g for 10 min. Plasma was collected and transferredinto pre-labeled 96 well plate or polypropylene tubes, quick frozen over dry ice and kept at -60or lower until LC-MS / MS analysis.

[0599] Data analysis: Plasma concentration versus time data was plotted in graph and analyzed by non-compartmental approaches using the Phoenix WinNonlin 6.3 software program. Related PK parameters were calculated according to dosing route, e.g., CL, Vdssand C0for intravenous administration, Cmax, Tmax or %F for extravascular administration, and T½, AUC(0-t), AUC(0-inf), MRT(0-t), MRT(0-inf) for all routes.

[0600] Results: PK parameters in plasma after oral dosing are shown in Table 3.

[0601] The Cmaxvalues of exemplary compounds are shown in Table 3, wherein “+” indicates that the Cmax is <500 ng / mL, “++” indicates that the Cmax is <1000 ng / mL and >500 ng / mL, “+++” indicates that the Cmax is <2000 ng / mL and >1000 ng / mL, “++++” indicates that the Cmax is <5,000 ng / mL and >2,000 ng / mL, and “+++++” indicates that Cmax is >5,000 ng / mL.

[0602] The T1 / 2 values of exemplary compounds are shown in Table 3 below, wherein “+” indicates that the T1 / 2 is <1.5 h, “++” indicates that the T1 / 2 is <2.5h and >1.5h, and “+++” indicates that the T1 / 2 is 2.5 h.

[0603] The AUC values of exemplary compounds are shown in Table 3 below, wherein “+” indicates that the AUC is <500 ng.h / mL, “++” indicates that the AUC is <2,500 ng.h / mL and >500 ng.h / mL, and “+++” indicates that the AUC is <10,000 ng.h / mL and >2,500 ng.h / mL, and “++++” indicates that the AUC is >10,000 ng.h / ml.

[0604] The bioavailability values of exemplary compounds are shown in Table 3 below, wherein “+” indicates that the bioavailability is <25%; “++” indicates bioavailability is <50 % and >25 %; “+++” indicates that the bioavailability is <85 % and >50 %; and “++++” indicates that the bioavailability is >85 %. Table 3: Oral Dosing of Selected Compounds at 3 mg / kgEQUIVALENTS

[0605] The details of one or more embodiments of the disclosure are set forth in the accompanying description above. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms include plural referents unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated by reference.

[0606] The foregoing description has been presented only for the purposes of illustration and is not intended to limit the disclosure to the precise form disclosed, but by the claims appended hereto.

Claims

CLAIMS 1. A compound of Formula (I)or a pharmaceutically acceptable salt thereof, wherein: R1is C1-6alkyl or C1-6haloalkyl, wherein the alkyl is optionally substituted with deuterium; R2is C1-6 alkyl; R6is H or halogen; R3is H or C1-6 alkyl; R4is halogen, C1-6alkyl, or C1-6haloalkyl; n is 0 to 5; each R5independently is halo or -CN; and R7is -C(O)OH or 5- to 10-membered heteroaryl.

2. The compound of claim 1, wherein R1is C1-6alkyl.

3. The compound of claim 1 or 2, wherein R1is methyl.

4. The compound of any one of the preceding claims, wherein R1is ethyl.

5. The compound of any one of the preceding claims, wherein R1is CD2CH3.

6. The compound of any one of the preceding claims, wherein R1is C1-6 haloalkyl.

7. The compound of any one of the preceding claims, wherein R1is C1-6 fluoroalkyl.

8. The compound of any one of the preceding claims, wherein R1is -CHF2.

9. The compound of any one of the preceding claims, wherein R1is -CH2CH2F.

10. The compound of any one of the preceding claims, wherein R2is methyl.

11. The compound of any one of the preceding claims, wherein R6is H.

12. The compound of any one of the preceding claims, wherein R6is F.

13. The compound of any one of the preceding claims, wherein R3is H.

14. The compound of any one of the preceding claims, wherein R3is C1-6 alkyl.

15. The compound of any one of the preceding claims, wherein R3is methyl.

16. The compound of any one of the preceding claims, wherein R4is halogen.

17. The compound of any one of the preceding claims, wherein R4is chloro.

18. The compound of any one of the preceding claims, wherein R4is C1-6 alkyl.

19. The compound of any one of the preceding claims, wherein R4is methyl.

20. The compound of any one of the preceding claims, wherein R4is C1-6 haloalkyl.

21. The compound of any one of the preceding claims, wherein R4is C1-6 fluoroalkyl.

22. The compound of any one of the preceding claims, wherein R4is CF3.

23. The compound of any one of the preceding claims, wherein R3is methyl and R4is CF3.

24. The compound of any one of the preceding claims, wherein n is 1.

25. The compound of any one of the preceding claims, wherein n is 2.

26. The compound of any one of the preceding claims, wherein at least one R5is halo.

27. The compound of any one of the preceding claims, wherein at least one R5is fluoro.

28. The compound of any one of the preceding claims, wherein at least one R5is chloro.

29. The compound of any one of the preceding claims, wherein at least one R5is cyano.

30. The compound of any one of the preceding claims, wherein n is 1, and R5is chloro.

31. The compound of any one of the preceding claims, wherein n is 2, one R5is fluoro, andthe other R5is cyano.

32. The compound of any one of the preceding claims, wherein R7is -COOH.

33. The compound of any one of the preceding claims, wherein R7is 5- membered heteroaryl.

34. The compound of any one of the preceding claims, wherein R7is tetrazole.

35. The compound of any one of the preceding claims, wherein n is 2, one R5is fluoro, and the other R5is chloro.

36. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from any one of the compounds in Table 1.

37. A pharmaceutical composition comprising the compound of any one of the previous claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

38. A method of treating a disease mediated by glucagon-like peptide-1 receptor (GLP-1R) in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of the compound of any one of claims 1-36, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 37.

39. The method of claim 38, wherein the disease is a liver disease.

40. The method of claim 39, wherein the liver disease is primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), drug induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition associated cholestasis (PNAC), bacterial overgrowth or sepsisassociated cholestasis, autoimmune hepatitis, viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), graft versus host disease, transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intra- or extrahepatic malignancy, Sjogren’s syndrome, sarcoidosis, Wilson’s disease, Gaucher’s disease, hemochromatosis, or alpha-1-antitrypsin deficiency.

41. The method of claim 38, wherein the disease is diabetes.

42. The method of claim 38, wherein the disease is a cardiometabolic disease.

43. The method of claim 38, wherein the disease is obesity.

44. A method of decreasing food intake in an individual in need thereof, comprising administering to the individual a compound, or a pharmaceutically acceptable salt thereof, of any one of claims 1-36 or the pharmaceutical composition of claim 37.

45. A method of increasing glucose tolerance in an individual in need thereof, comprising administering to the individual a compound, or a pharmaceutically acceptable salt thereof, of any one of claims 1-36 or the pharmaceutical composition of claim 37.

46. Use of the compound of any one of claims 1-36, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 37, in the preparation of a medicament for the treatment of a disease mediated by glucagon-like peptide-1 receptor (GLP-1R).

47. The use of claim 46, wherein the disease is a liver disease.

48. The use of claim 47, wherein the liver disease is primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), drug induced cholestasis, intrahepatic cholestasis of pregnancy,parenteral nutrition associated cholestasis (PNAC), bacterial overgrowth or sepsis associated cholestasis, autoimmune hepatitis, viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), graft versus host disease, transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intra- or extrahepatic malignancy, Sjogren’s syndrome, sarcoidosis, Wilson’s disease, Gaucher’s disease, hemochromatosis, or alpha-1-antitrypsin deficiency.

49. The use of claim 46, wherein the disease is diabetes.

50. The use of claim 46, wherein the disease is a cardiometabolic disease.

51. The use of claim 46, wherein the disease is obesity.

52. Use of the compound, or a pharmaceutically acceptable salt thereof, of any one of claims 1-36 or the pharmaceutical composition of claim 37 for use in the manufacture of a medicament for decreasing food intake.

53. Use of the compound, or a pharmaceutically acceptable salt thereof, of any one of claims 1-36 or the pharmaceutical composition of claim 37 for use in the manufacture of a medicament for increasing glucose tolerance.

54. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 37, for use in treating a disease mediated by glucagon- like peptide-1 receptor (GLP-1R).

55. The compound, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to claim 54, wherein the disease is a liver disease.

56. The compound, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to claim 55, wherein the liver disease is primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), drug induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition associated cholestasis (PNAC), bacterial overgrowth or sepsis associated cholestasis, autoimmune hepatitis, viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), graft versus host disease, transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intra- or extrahepatic malignancy, Sjogren’s syndrome, sarcoidosis, Wilson’s disease, Gaucher’s disease, hemochromatosis, or alpha-1-antitrypsin deficiency.

57. The compound, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to claim 54, wherein the disease is diabetes.

58. The compound, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to claim 54, wherein the disease is a cardiometabolic disease.

59. The compound, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition, for use according to claim 54, wherein the disease is obesity.

60. The compound, or a pharmaceutically acceptable salt thereof, of any one of claims 1-36 or the pharmaceutical composition of claim 37 for use in decreasing food intake.

61. The compound, or a pharmaceutically acceptable salt thereof, of any one of claims 1-36 or the pharmaceutical composition of claim 37 for use in increasing glucose tolerance.

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