Compounds as GLP-1R agonists

Abstract

The present application provides compounds, or pharma- ceutically acceptable salts thereof, that can be used as glucagon-like peptide-1 receptor (GLP-1R) agonists. Also provided are pharmaceutical compositions comprising such compounds or pharma- ceutically acceptable salts thereof. Also provided are methods of preparing these compounds and compositions, and methods of using these compounds and compositions to treat or prevent diseases or conditions mediated by GLP-1R.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 313,160, filed February 23, 2022, which is incorporated by reference herein in its entirety for all purposes.

[0002] FIELD OF THEINVENTION The present invention relates to compositions and methods for modulating the glucagon-like peptide-1 (GLP-1) receptor. [Background technology]

[0003] Diabetes mellitus has become a major public health concern due to its increasing prevalence and associated health risks. The disease is characterized by hyperglycemia 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, which regulates blood sugar. Type 1 diabetes patients need to receive insulin through injections or pumps to survive. Type 2 diabetes mellitus (T2DM) usually begins with insulin resistance or when there is not enough insulin production to maintain acceptable blood sugar levels.

[0004] Currently, various pharmacological approaches are available for the treatment of hyperglycemia and subsequent T2DM (Hampp, C. et al. Use of Antidiabetic Drugs in the US, 2003-2012, Diabetes Care 2014, 37, 1367-1374). One of them is the glucagon-like peptide 1 receptor (GLP-1R) agonists (e.g., liraglutide, albiglutide, exenatide, lixisenatide, dulaglutide, semaglutide), which act on the beta cells of the pancreas to promote insulin secretion. Commercially available GLP-1R agonists are peptides administered by subcutaneous injection. Liraglutide has further been approved as a treatment for obesity.

[0005] GLP-1 is a 30 amino acid long incretin hormone secreted by L-cells in the intestine in response to food ingestion. GLP-1 has been shown to stimulate insulin secretion in a physiological and glucose-dependent manner, decrease glucagon secretion, inhibit gastric emptying, reduce appetite, and stimulate beta cell proliferation. In preclinical experiments, GLP-1 promotes continued beta cell capacity by stimulating the transcription of genes important for glucose-dependent insulin secretion and promoting beta cell neogenesis (Meier et al. Biodrugs. 2003;17(2):93-102).

[0006] In healthy individuals, GLP-1 plays a key role in regulating postprandial blood glucose levels by stimulating glucose-dependent insulin secretion by the pancreas and increasing peripheral glucose absorption. GLP-1 also inhibits glucagon secretion, leading to reduced hepatic glucose output. In addition, GLP-1 delays gastric emptying and slows small intestinal motility, slowing food absorption. In patients with T2DM, the normal postprandial rise in GLP-1 is absent or reduced (Vilsboll T, et al. Diabetes. 2001.50;609-613).

[0007] Holst (Physiol. Rev. 2007, 87, 1409) and Meier (Nat. Rev. Endocrinol. 2012, 8, 728) explain that GLP-1 receptor agonists such as liraglutide and exendin-4 have three main pharmacological activities that improve glycemic control in patients with T2DM by lowering fasting and postprandial plasma glucose levels (FPG and PPG): (i) increasing glucose-dependent insulin secretion (improving phase 1 and phase 2), (ii) glucagon suppression activity under hyperglycemic conditions, and (iii) slowing the absorption of glucose from a meal by slowing the rate of gastric emptying.

[0008] There remains a need to develop GLP-1 receptor agonists for the prevention and / or treatment of cardiometabolic and related disorders that are easily administered. Summary of the Invention

[0009] Disclosed are compounds that can be used as glucagon-like peptide-1 receptor (GLP-1R) agonists, compositions containing these compounds, and methods of treating diseases and / or conditions mediated by the GLP-1R.

[0010] In one aspect, there is provided a compound selected from the group consisting of a compound of Formula (0), Formula (1), or any of the foregoing subformulas, including compounds of Formulas (2)-(10), as detailed herein, or a compound listed in Table 1, or a pharma- ceutically acceptable salt thereof.

[0011] Further provided is a pharmaceutical composition comprising a compound selected from the group consisting of a compound of Formula (0), Formula (1), or any of the foregoing subformulas, including compounds of Formulas (2)-(10), or the compounds listed in Table 1, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier or excipient.

[0012] In another aspect, there is provided a method of treating a disease or condition mediated by GLP-1R in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound selected from the group consisting of a compound of Formulae (2)-(10), or any of the preceding subformulas, or a compound listed in Table 1, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disease or condition is a cardiometabolic disease. In some embodiments, the disease or condition is diabetes. In some embodiments, the disease or condition is a liver disease.

[0013] Also provided is a compound selected from the group consisting of a compound of Formula (0), Formula (1), or any of the foregoing subformulas, including compounds of Formulas (2)-(10), as detailed herein, or the compounds listed in Table 1, or a pharma- ceutically acceptable salt thereof, for treatment.

[0014] Also provided is the use of a compound selected from the group consisting of a compound of Formula (0), Formula (1), or any of the foregoing subformulas, including compounds of Formulas (2)-(10), or the compounds listed in Table 1, or a pharma- ceutical acceptable salt thereof, in the manufacture of a medicament for treatment, as detailed herein.

[0015] Additionally provided are kits comprising a compound selected from the group consisting of a compound of Formula (0), Formula (1), or any of the foregoing subformulas, including compounds of Formulas (2)-(10), or the compounds listed in Table 1, or a pharma- ceutically acceptable salt thereof. In some embodiments, the kits include instructions for use in accordance with the methods described herein.

[0016] In yet another aspect, there is provided a method for preparing a compound selected from the group consisting of a compound of formula (0), formula (1), or any of the foregoing subformulas, including compounds of formulas (2)-(10), or a compound listed in Table 1, or a pharma- ceutically acceptable salt thereof. Also provided is a compound intermediate useful in the synthesis of a compound of formula (0), formula (1), or any of the foregoing subformulas, including compounds of formulas (2)-(10), or a compound selected from the group consisting of a compound listed in Table 1, or a pharma- ceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] definition As used herein, the following definitions shall apply unless otherwise indicated. Furthermore, any term or symbol used herein shall have its ordinary meaning in the art, unless defined as set forth below.

[0018] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include the plural forms unless the content clearly dictates otherwise.

[0019] As used herein, and unless otherwise specified, the terms "about" and "approximately," when used in reference to a dose, amount, or weight percentage of a component of a composition or dosage form, refer to a dose, amount, or weight percentage that would be recognized by a person skilled in the art to produce an equivalent pharmacological effect to that obtained from the specified dose, amount, or weight percentage. Specifically, the terms "about" and "approximately," when used in reference to a value, refer to a variation within ±15%, ±10%, ±5%, ±4%, ±3%, ±2%, ±1%, or ±0.5% of the specified value. Reference herein to "about" a value or parameter includes (and describes) embodiments that are directed to the value or parameter itself. For example, a statement that refers to "about X" includes a statement of "X."

[0020] "Comprising" is intended to mean that the compositions and methods include the recited elements, but do not exclude other elements. "Consisting essentially of," when used to define compositions and methods, is intended to mean excluding other elements of any essential importance to the combination. For example, a composition consisting essentially of the elements defined herein does not exclude other elements that do not materially affect the basic and novel feature(s) of the claimed invention. "Consisting of" is intended to mean excluding more than trace amounts, e.g., of other ingredients and more than substantial method steps recited. Embodiments defined by each of these transitional phrases are within the scope of the present invention.

[0021] The term "excipient" as used herein refers to an inert or inactive substance that can be used in the manufacture of a drug or pharmaceutical product, such as a tablet, that contains the compound of the present invention as an active ingredient.Various substances can be encompassed by the term excipient, including, but not limited to, binding substances, disintegrating substances, coatings, compression aids / encapsulation aids, creams or lotions, lubricants, solutions for parenteral administration, materials for chewable tablets, sweeteners or flavoring substances, suspending / gelling agents, or any substance used as a wet granulator. Binders include, for example, carbomer, povidone, xanthan gum, and the like; coatings include, for example, cellulose acetate phthalate, ethylcellulose, gellan gum, maltodextrin, enteric coatings, and the like; compression / encapsulation aids include, for example, calcium carbonate, dextrose, fructose dc (dc = "directly compressible"), honey dc, lactose (anhydrous or monohydrate; optionally in combination with aspartame, cellulose, or microcrystalline cellulose), starch dc, sucrose, and the like; disintegrants include, for example, croscarmellose sodium, gellan gum, sodium starch glycolate, and the like; creams or lotions include, for example, , maltodextrin, carrageenan, etc.; lubricants include, for example, magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; chewable tablet materials include, for example, dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.; suspending / gelling agents include, for example, carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, for example, aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc.; wet granulating agents include, for example, calcium carbonate, maltodextrin, microcrystalline cellulose, etc.

[0022] "Pharmaceutically acceptable" refers to safe and non-toxic, preferably for in vivo, and more preferably for human administration.

[0023] "Pharmaceutically acceptable salt" refers to a pharma-ceutically acceptable salt. The compounds described herein may be administered as a pharma-ceutically acceptable salt.

[0024] "Salt" refers to an ionic compound formed between an acid and a base. When the compounds provided herein contain an acidic functional group, such salts include, but are not limited to, alkali metal, alkaline earth metal, and ammonium salts. As used herein, ammonium salts include salts containing protonated nitrogen bases and alkylated nitrogen bases. Exemplary, non-limiting cations useful in pharma-ceutically acceptable salts include Na, K, Rb, Cs, NH4, Ca, Ba, imidazolium, and ammonium cations based on naturally occurring amino acids. When the compounds utilized herein contain a basic functional group, such salts include, but are not limited to, salts of organic acids (such as carboxylic and sulfonic acids) and mineral acids (such as hydrogen halides, sulfuric acids, phosphoric acids, and the like). Exemplary, non-limiting anions useful in pharma- ceutically acceptable salts include oxalate, maleate, acetate, propionate, succinate, tartrate, chloride, sulfate, bisulfate, monobasic, dibasic, and tribasic phosphates, mesylate, tosylate, and the like.

[0025] "Stereoisomer" or "stereoisomers" refer to compounds that differ in the stereochemistry of their constituent atoms, for example, but not limited to, with respect to the chirality of one or more stereocenters, or the cis or trans configuration of carbon-carbon or carbon-nitrogen double bonds. Stereoisomers include enantiomers and diastereomers.

[0026] As used herein, the term "subject" refers to an animal, including, but not limited to, a primate (e.g., a human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein in reference to a mammalian subject, such as, for example, a human.

[0027] As used herein, "treatment" or "treating" is an approach to obtain beneficial or desired results, including clinical results. For purposes of this disclosure, beneficial or desired results include, but are not limited to, one or more of the following: reducing one or more symptoms caused by a disease or disorder, reducing the extent of a disease or disorder, stabilizing a disease or disorder (e.g., preventing or delaying the worsening of a disease or disorder), delaying the onset or recurrence of a disease or disorder, delaying or slowing the progression of a disease or disorder, improving the condition of a disease or disorder, providing remission (partial or complete) of a disease or disorder, reducing the dose of one or more other drugs required to treat a disease or disorder, enhancing the effect of another drug used to treat a disease or disorder, slowing the progression of a disease or disorder, improving the quality of life, and / or prolonging the survival of a patient. "Treatment" also encompasses the reduction of pathological consequences of a disease or disorder. The methods of the present disclosure contemplate any one or more of these aspects of treatment.

[0028] A "therapeutically effective amount" or dose of a compound or composition refers to that amount of the compound or composition that results in a reduction or inhibition of symptoms or prolonged survival in a patient. The result may require multiple administrations of the compound or composition.

[0029] "Alkyl" refers to monovalent saturated aliphatic hydrocarbyl groups having 1 to 12 carbon atoms, preferably 1 to 10 carbon atoms, and more preferably 1 to 6 carbon atoms. This term includes, by way of example, straight-chain and branched-chain hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), t-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-). Cx alkyl refers to an alkyl group having x carbon atoms.

[0030] "Alkylene" refers to a divalent saturated aliphatic hydrocarbyl group having 1 to 12 carbon atoms, preferably 1 to 10 carbon atoms, and more preferably 1 to 6 carbon atoms. This term includes, by way of example, straight-chain and branched-chain hydrocarbyl groups such as methylene (-CH-), ethylene (-CHCH- or -CH(Me)-), propylene (-CHCHCH- or -CH(Me)CH-, or -CH(Et)-).

[0031] "Alkoxy" refers to the group -O-alkyl, where alkyl is defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, and n-pentoxy.

[0032] "Aryl" refers to a monovalent aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring (e.g., phenyl (Ph)) or multiple condensed rings (e.g., naphthyl or anthryl) (e.g., 2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-on-7-yl, etc.), which may or may not be aromatic, provided that the point of attachment is at an aromatic carbon atom. Suitable aryl groups include phenyl and naphthyl.

[0033] "Cyano" refers to the group -C≡N.

[0034] "Cycloalkyl" refers to a saturated or unsaturated but non-aromatic cyclic alkyl group of 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, and more preferably 3 to 6 carbon atoms, having single or multiple cyclic rings, including fused, bridged, and spiro ring systems. Cx cycloalkyl refers to a cycloalkyl group having x ring carbon atoms. Examples of suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl. One or more of the rings can be aryl, heteroaryl, or heterocyclic, provided that the point of attachment is through a non-aromatic, non-heterocyclic saturated carbocyclic ring. "Substituted cycloalkyl" includes oxo, thione, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cyclo "cycloalkyl" refers to a cycloalkyl group having 1 to 5, or preferably 1 to 3, substituents selected from the group consisting of alkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocycle, substituted heterocycle, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein the substituents are defined herein.

[0035] "Halo" or "halogen" refers to fluoro, chloro, bromo, and iodo, preferably fluoro or chloro.

[0036] "Hydroxy" or "hydroxyl" refers to the group --OH.

[0037] "Heteroaryl" refers to an aromatic group of 1-10 carbon atoms and 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur in the ring. Such heteroaryl groups can have a single ring (e.g., pyridinyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl), which may or may not be aromatic and / or contain heteroatoms, provided that the point of attachment is through an atom of the aromatic heteroaryl group. In one embodiment, the nitrogen and / or sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide an N-oxide (N→O), sulfinyl, or sulfonyl moiety. Preferred heteroaryls include 5- or 6-membered heteroaryls such as pyridinyl, pyrrolyl, thiophenyl, and furanyl. Other preferred heteroaryls include 9- or 10-membered heteroaryls such as indolyl, quinolinyl, quinolonyl, isoquinolinyl, and isoquinolonyl.

[0038] "Heterocycle" or "heterocyclic" or "heterocycloalkyl" or "heterocyclyl" refers to a saturated or partially saturated, but not aromatic, group having 1-10 ring carbon atoms, preferably 1-8 carbon atoms, more preferably 1-6 carbon atoms, and 1-4 ring heteroatoms, preferably 1-3 heteroatoms, more preferably 1-2 heteroatoms, selected from the group consisting of nitrogen, sulfur, or oxygen. Cx heterocycloalkyl refers to a heterocycloalkyl group having x ring atoms, including a ring heteroatom. Heterocycle encompasses single or multiple fused rings, where fused rings include fused ring systems, bridged ring systems, and spiro ring systems. In fused ring systems, one or more of the rings can be cycloalkyl, aryl, or heteroaryl, provided that the point of attachment is through a non-aromatic ring. In one embodiment, the nitrogen and / or sulfur atom(s) of the heterocycle group are optionally oxidized to provide N-oxide, sulfinyl (S(O)), or sulfonyl (S(O)2) moieties.

[0039] Examples of heterocyclyl and heteroaryl include azetidinyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazyl, pyrimidyl, pyridazyl, indolizyl, isoindolyl, indolyl, dihydroindolyl, indazolyl, purinyl, quinolidinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthylpyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, acridinyl, phenanthrolinyl, isothiazolyl, phenazinyl, and isoxazolyl. , phenoxazinyl, phenothiazinyl, imidazolidinyl, imidazolinyl, piperidinyl, piperazinyl, indolinyl, phthalimidyl, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrobenzo[b]thiophenyl, thiazolyl, thiazolidinyl, thiophenyl, benzo[b]thiophenyl, morpholinyl, thiomorpholinyl (also referred to as thiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidinyl, and tetrahydrofuranyl.

[0040] "Oxo" refers to the atom (=O) or (O).

[0041] The term "optional" or "optionally," as used throughout this specification, means that the subsequently described event or circumstance can, but need not, occur, and that the description encompasses instances in which the event or circumstance occurs as well as instances in which it does not occur. For example, "a nitrogen atom is optionally oxidized to provide an N-oxide (N→O) moiety" means that the nitrogen atom can, but does not need to be oxidized, and that the description encompasses situations in which the nitrogen atom is not oxidized as well as situations in which the nitrogen atom is oxidized.

[0042] "Optionally substituted" means that, unless otherwise specified, a group is unsubstituted or may be substituted with one or more (e.g., 1, 2, 3, 4, or 5) of the substituents listed for that group, which may be the same or different. In one embodiment, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In another embodiment, an optionally substituted group has four substituents. In some embodiments, an optionally substituted group has 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, or 2-5 substituents. In one embodiment, an optionally substituted group is unsubstituted.

[0043] It is understood that an optionally substituted moiety can be substituted with more than five substituents, if the number of valences available for substitution on that moiety permits. For example, a propyl group can be substituted with seven halogen atoms to give a perhalopropyl group. The substituents can be the same or different.

[0044] compound In one embodiment, a compound of formula (0): [ka] or a pharma- ceutical acceptable salt thereof, wherein R 13 is -C(O)OH or [ka] and X is N or CR x where R x is hydrogen, OH, or C1-C6 alkyl; Y is N or CR y where R y is hydrogen, OH, or C1-C6 alkyl; n is 0 or 1, Q is -C(R 7 )(R 8 )-, -O-, -N(R 9 )-, and -S-, wherein R 7 and R 8 are independently hydrogen, halogen, or C1-C6 alkyl; R 9 is hydrogen or C1-C6 alkyl, R 1 is an optionally substituted -C1-C6 alkylene or -C1-C6 alkylene-R 5 where R 5 is a C3-C6 cycloalkyl, a 3- to 6-membered heterocyclyl, or a 5- to 6-membered heteroaryl, each of which is independently optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, oxo, CN, C1-C6 alkyl, C3-C6 cycloalkyl, and -OC1-C6 alkyl, and each C1-C6 alkyl, C3-C6 cycloalkyl, and -OC1-C6 alkyl substituent is independently optionally substituted with halo or CN; R 2 and R 3 together with the carbon atom to which they are attached form an optionally substituted C3-C4 cycloalkyl ring, or R 2 and R xwhen present, together with the carbon atom to which they are attached form an optionally substituted C3-C5 cycloalkyl ring; R 3 is hydrogen, oxo, or C1-C6 alkyl; m is 0, 1, 2, or 3; R 4 is oxo or C1-C6 alkyl, Ring A is C6~C 14 , a 5-12 membered heterocyclyl, or a 5-12 membered heteroaryl, each of which is independently optionally substituted by halo, OH, CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted by halo or OH; L is a bond, -O-, C1-C6 alkylene, *-O-C1-C6 alkylene-**, *-C1-C6 alkylene-O-**, or *-NR 6 -C1-C6 alkylene-**, where * represents the point of attachment to ring A and ** represents the point of attachment to ring B; L is C1-C6 alkylene, *-O-C1-C6 alkylene**, *-C1-C6 alkylene-O-**, or *-NR 6 When -C1-C6 alkylene-, L is optionally selected from 1 to 3 R L Substituted by substituents, where each R L are independently halo, OH, or C1-C6 alkyl, or two R L together with the carbon atom or atoms to which they are attached form a C3-C6 cycloalkyl or a 3- to 6-membered heterocyclyl; R 6 is, if present, hydrogen or C1-C6 alkyl; Ring B is C3~C 10 Cycloalkyl, C6-C 14aryl, 4-12 membered heterocyclyl, or 5-12 membered heteroaryl, each of which is independently optionally substituted by 1-3 substituents independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl optionally substituted by halo or CN, -OC1-C6 alkyl optionally substituted by halo or CN, -COCH3, -CONH2, -S(O)2CH3, and phenyl optionally substituted by halo or CN.

[0045] In one embodiment, the compound of formula (1): [ka] or a pharma- ceutical acceptable salt thereof, wherein X is N or CR x where R x is hydrogen, OH, or C1-C6 alkyl; Y is N or CR Y where R Y is hydrogen, OH, or C1-C6 alkyl; n is 0 or 1, Q is -C(R 7 )(R 8 )-, -O-, -N(R 9 )-, and -S-, wherein R 7 and R 8 are independently hydrogen, halogen, or C1-C6 alkyl; R 9 is hydrogen or C1-C6 alkyl, R 1 is -C1~C6 alkylene-R 5 where R 5is a 3- to 6-membered heterocyclyl, or a 5- to 6-membered heteroaryl, each of which is independently optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, oxo, CN, C1-C6 alkyl, C3-C6 cycloalkyl, and -OC1-C6 alkyl, and each C1-C6 alkyl, C3-C6 cycloalkyl, and -OC1-C6 alkyl substituent is independently optionally substituted with halo or CN; R 2 and R 3 together with the carbon atom to which they are attached form an optionally substituted C3-C4 cycloalkyl ring, or R 2 and R x when present, together with the carbon atom to which they are attached form an optionally substituted C3-C5 cycloalkyl ring; R 3 is hydrogen, oxo, or C1-C6 alkyl; m is 0, 1, 2, or 3; R 4 is oxo or C1-C6 alkyl, Ring A is C6~C 14 , a 5-12 membered heterocyclyl, or a 5-12 membered heteroaryl, each of which is independently optionally substituted by halo, OH, CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted by halo or OH; L is a bond, -O-, C1-C6 alkylene, *-O-C1-C6 alkylene-**, *-C1-C6 alkylene-O-**, or *-NR 6 -C1-C6 alkylene-**, where * represents the point of attachment to ring A and ** represents the point of attachment to ring B; L is C1-C6 alkylene, *-O-C1-C6 alkylene**, *-C1-C6 alkylene-O-**, or *-NR 6 When -C1-C6 alkylene-, L is optionally selected from 1 to 3 R L Substituted by substituents, where each R L are independently halo, OH, or C1-C6 alkyl, or two R Ltogether with the carbon atom or atoms to which they are attached form a C3-C6 cycloalkyl or a 3- to 6-membered heterocyclyl; R 6 is, if present, hydrogen or C1-C6 alkyl; Ring B is C3~C 10 Cycloalkyl, C6-C 14 aryl, 4-12 membered heterocyclyl, or 5-12 membered heteroaryl, each of which is independently optionally substituted by 1-3 substituents independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl optionally substituted by halo or CN, -OC1-C6 alkyl optionally substituted by halo or CN, -COCH3, -CONH2, -S(O)2CH3, and phenyl optionally substituted by halo or CN.

[0046] In some embodiments of Formula (0) or Formula (1), at least one of X and Y is N. In other embodiments of Formula (0) or Formula (1), both X and Y are N.

[0047] In some embodiments of Formula (0) or Formula (1), R 2 and R 3 taken together with the carbon atom to which they are attached form an optionally substituted C3-C4 cycloalkyl ring. In some embodiments, the formula (2): [ka] or a pharma- ceutical acceptable salt thereof, wherein p is 0, 1, or 2; and each R 10 is a halo, X, Y, n, Q, R 1 , m, R 4 , Ring A, L, and Ring B are as detailed herein for Formula (0) or Formula (1).

[0048] In some embodiments of formula (2), at least one of X and Y is N. In other embodiments of formula (2), both X and Y are N.

[0049] In some embodiments of formula (2), L is *-OCH2-** and ring B is phenyl. In some embodiments, formula (3): [ka] or a pharma- ceutical acceptable salt thereof, wherein q is 0, 1, 2, or 3; 11 is selected from the group consisting of halo, CN, C1-C6 alkyl optionally substituted with halo or CN, -OC1-C6 alkyl optionally substituted with halo or CN, -COCH3, -CONH2, -S(O)2CH3, and phenyl optionally substituted with halo or CN; p and R 10 are as detailed herein for formula (2), and X, Y, n, Q, R 1 , m, R 4 and ring A are as detailed herein for formula (0) or formula (1).

[0050] In some embodiments, each R 11 is independently selected from halo and CN. In some embodiments of formula (3), at least one of X and Y is N. In other embodiments of formula (3), both X and Y are N.

[0051] In some embodiments of formula (3), ring A is pyridinyl. In some embodiments, formula (4): [ka] or a pharma- ceutical acceptable salt thereof, wherein q and R 11 is as detailed herein for formula (3), and p and R 10 are as detailed herein for formula (2), and X, Y, n, Q, R 1 , m, and R 4 is as detailed herein for formula (0) or formula (1).

[0052] In some embodiments, each R 11 is independently selected from halo and CN. In some embodiments of formula (4), at least one of X and Y is N. In other embodiments of formula (4), both X and Y are N.

[0053] In some embodiments of formula (0) or formula (1) (including compounds of formula (2) and subformulas thereof, if applicable), R 1 is -C1~C6 alkylene-R 5 where R 5 is a 3- to 6-membered heterocyclyl, or a 5- to 6-membered heteroaryl, each of which is independently optionally substituted with 1-3 substituents independently selected from the group consisting of halo, oxo, CN, C1-C6 alkyl, C3-C6 cycloalkyl, and -OC1-C6 alkyl, and each C1-C6 alkyl, C3-C6 cycloalkyl, and -OC1-C6 alkyl substituent is independently optionally substituted with halo or CN. 1 is -CH2-R 5 It is.

[0054] In some embodiments, the compound of formula (5): [ka] or a pharma- ceutical acceptable salt thereof, wherein p and R 10 are as detailed herein for formula (2), and X, Y, n, Q, R 5 , m, R 4 , Ring A, L, and Ring B are as detailed herein for Formula (0) or Formula (1).

[0055] In some embodiments of formula (5), at least one of X and Y is N. In other embodiments of formula (5), both X and Y are N.

[0056] In some embodiments of formula (5), L is *-OCH2-** and ring B is phenyl. In some embodiments, formula (6): [ka] or a pharma- ceutical acceptable salt thereof, wherein q is 0, 1, 2, or 3; 11 is halo, CN, C1-C6 alkyl optionally substituted with halo or CN, -OC1-C6 alkyl optionally substituted with halo or CN, -COCH3, -CONH2, -S(O)2CH3, or phenyl optionally substituted with halo or CN; p and R 10 are as detailed herein for formula (2), and X, Y, n, Q, R 5 , m, R 4 and ring A are as detailed herein for formula (0) or formula (1).

[0057] In some embodiments, each R 11 is independently selected from halo and CN. In some embodiments of formula (6), at least one of X and Y is N. In other embodiments of formula (6), both X and Y are N.

[0058] In some embodiments of formula (6), ring A is pyridinyl. In some embodiments, formula (7): [ka] wherein q and R 11 is as defined herein for formula (6), and p and R 10 are as detailed herein for formula (2), and X, Y, n, Q, R 5 , m, and R 4 is as detailed herein for formula (0) or formula (1).

[0059] In some embodiments, each R 11 is independently selected from halo and CN. In some embodiments of formula (7), at least one of X and Y is N. In other embodiments of formula (7), both X and Y are N.

[0060] In some embodiments of the compound of Formula (0) or Formula (1), X is CR x and R 2 and R 3 taken together with the carbon atom to which they are attached form an optionally substituted C3-C4 cycloalkyl ring. In some embodiments, the formula (8): [ka] or a pharma- ceutical acceptable salt thereof, wherein p is 0, 1, or 2; 10 is a halo, n, Q, R 1 , R 3 , m, R 4 , Ring A, L, and Ring B are as detailed herein for Formula (0) or Formula (1).

[0061] In some embodiments of formula (8), R 2 and R x taken together with the carbon atom to which they are attached form an optionally substituted C3 cycloalkyl ring. In another embodiment of formula (8), R 2 and R x together with the carbon atom to which they are attached form an optionally substituted C3 cycloalkyl ring.

[0062] In some embodiments of the compound of formula (8), L is *-OCH2-** and ring B is phenyl. In some embodiments, the compound of formula (9): [ka] or a pharma- ceutically acceptable salt thereof, wherein q is 0, 1, 2, or 3; 11 is halo, CN, C1-C6 alkyl optionally substituted with halo or CN, -OC1-C6 alkyl optionally substituted with halo or CN, -COCH3, -CONH2, -S(O)2CH3, or phenyl optionally substituted with halo or CN; p and R 10are as detailed herein for formula (8), and n, Q, R 1 , R 3 , m, R 4 and ring A are as detailed herein for formula (0) or formula (1).

[0063] In some embodiments of the compound of formula (9), ring A is pyridinyl. In some embodiments, the compound of formula (10): [ka] or a pharma- ceutical acceptable salt thereof, wherein p and R 10 is as detailed herein for formula (8), and q and R 11 are as detailed herein for formula (9), and n, Q, R 1 , R 3 , m, and R 4 is as detailed herein for formula (0) or formula (1).

[0064] In some embodiments of the compounds of formula (0) or formula (1) (including compounds of formulas (2)-(10) and subformulas thereof), R 5 is an optionally substituted 3-6 membered heterocyclyl. In some embodiments, R 5 teeth, [ka] and each of which is optionally substituted. In some embodiments, R 5 teeth, [ka] and each of which is optionally substituted. In some embodiments of any of the foregoing, R 5is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, oxo, CN, C1-C6 alkyl, C3-C6 cycloalkyl, and -OC1-C6 alkyl, and each C1-C6 alkyl, C3-C6 cycloalkyl, and -OC1-C6 alkyl substituent is independently and optionally substituted with halo or CN. In some such embodiments, R 5 is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, oxo, CN, C1-C6 alkyl, C3-C6 cycloalkyl, and -OC1-C6 alkyl. In some such embodiments, R 5 is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, oxo, CN, C1-C6 alkyl, and -OC1-C6 alkyl. In some such embodiments, R 5 is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, oxo, CN, C1-C3 alkyl, and -OC1-C3 alkyl. In some such embodiments, R 5 is optionally substituted with 1 to 3 substituents independently selected from the group consisting of Cl, F, Br, oxo, CN, C1-C3 alkyl, and -OC1-C3 alkyl. In some such embodiments, R 5 is optionally substituted with 1 to 3 substituents independently selected from the group consisting of Cl, F, Br, C1-C3 alkyl, and -OC1-C3 alkyl. In some such embodiments, R 5 is optionally substituted with 1 to 3 substituents independently selected from the group consisting of Cl, F, Br, and C1-C3 alkyl. 5 is non-substituted.

[0065] In some embodiments of the compounds of formula (0) or formula (1) (including compounds of formulas (2)-(10) and subformulas thereof), R 5 is an optionally substituted 5-6 membered heteroaryl. In some embodiments, R 5is an optionally substituted 5-membered heteroaryl. In some embodiments, R 5 is pyrrolyl, oxazolyl, imidazolyl, triazolyl, thiazolyl, or isothiazolyl, each of which is optionally substituted. In some embodiments, R 5 is oxazolyl, triazolyl, or thiazolyl, each of which is optionally substituted. In some embodiments, R 5 is an optionally substituted triazolyl. In some embodiments, R 5 is an optionally substituted thiazolyl. In some embodiments, R 5 teeth, [ka] and each of which is optionally substituted. In some embodiments, R 5 teeth, [ka] and each of which is optionally substituted. In some embodiments, R 5 teeth, [ka] and each of which is optionally substituted. In some embodiments, R 5 teeth, [ka] and each of which is optionally substituted. In some embodiments, R 5 teeth, [ka] and each of which is optionally substituted. In some embodiments, R 5 teeth, [ka] where Ak is an alkyl group (e.g., C1~4 In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] and each of which is optionally substituted. In some embodiments of any of the foregoing, R 5 is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, oxo, CN, C1-C6 alkyl, C3-C6 cycloalkyl, and -OC1-C6 alkyl, C6 The alkyl, C-C cycloalkyl, and -OC-C alkyl substituents are independently optionally substituted with halo or CN. In some such embodiments, R 5 is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, oxo, CN, C1-C6 alkyl, C3-C6 cycloalkyl, and -OC1-C6 alkyl. In some such embodiments, R 5 is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, oxo, CN, C1-C6 alkyl, and -OC1-C6 alkyl. In some such embodiments, R 5 is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, oxo, CN, C1-C3 alkyl, and -OC1-C3 alkyl. In some such embodiments, R 5 is optionally substituted with 1 to 3 substituents independently selected from the group consisting of Cl, F, Br, oxo, CN, C1-C3 alkyl, and -OC1-C3 alkyl. In some such embodiments, R5 is optionally substituted with 1 to 3 substituents independently selected from the group consisting of Cl, F, Br, C1-C3 alkyl, and -OC1-C3 alkyl. In some such embodiments, R 5 is optionally substituted with 1 to 3 substituents independently selected from the group consisting of Cl, F, Br, and C1-C3 alkyl, such as methyl, ethyl, propyl, or isopropyl. 5 is non-substituted.

[0066] In some embodiments of the compounds of Formula (0) or Formula (1) (including compounds of Formulas (2)-(10) and subformulas thereof, if applicable), X is N, Y is N, and R 2 and R 3 together with the carbon atom to which they are attached form a C3-C4 cycloalkyl ring. In some embodiments, X is CR x where R x is hydrogen, OH, or C1-C6 alkyl, Y is N, and R 2 and R 3 together with the carbon atom to which they are attached form a C3-C4 cycloalkyl ring. In some embodiments, X is N and Y is CR y where R y is hydrogen, OH, or C1-C6 alkyl; R 2 and R 3 together with the carbon atom to which they are attached form a C3-C4 cycloalkyl ring. In some embodiments, X is CR x and R x together with R and the carbon atom to which they are attached form an optionally substituted C-C cycloalkyl ring; Y is N; and R 3 In some embodiments of any of the foregoing, Q is CR 7 R 8 It is.

[0067] In some embodiments, Q is -O-, -N(R 9 )-, or -S-, then X is CR x where R x is hydrogen, OH, or C1-C6 alkyl, Y is N, and R 2 and R 3 together with the carbon atom to which they are attached form a C3-C4 cycloalkyl ring. In some embodiments, Q is -O-, -N(R 9 )-, or -S-, then X is CR x and R x is R 2 and together with the carbon atom to which they are attached form an optionally substituted C3-C4 cycloalkyl ring, Y is N, and R 3 is hydrogen, oxo, or C1-C6 alkyl.

[0068] In some embodiments of the compounds of Formula (0) or Formula (1) (including compounds of Formulas (2)-(10) and subformulas thereof), or a pharma- ceutically acceptable salt thereof, n is 0. In other embodiments, n is 1.

[0069] In some embodiments of the compounds of Formula (0) or Formula (1) (including, where applicable, the compounds of Formulas (2)-(10) and subformulas thereof), or a pharma- ceutical acceptable salt thereof, the moiety [ka] teeth, [ka] In some embodiments of the compounds of Formula (0) or Formula (1) (including compounds of Formulas (2)-(10) and subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, Q is CR 7 R 8 and the part [ka] teeth, [ka] In some embodiments of the compounds of Formula (0) or Formula (1) (including compounds of Formulas (2)-(10) and subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, Q is CR 7 R 8 and the part [ka] teeth, [ka] In some such embodiments, Q is CR 7 R 8 and the part [ka] teeth, [ka] In some such embodiments, Q is CR 7 R 8 and the part [ka] teeth, [ka] In some such embodiments, Q is CR 7 R 8 and the part [ka] teeth, [ka] In other embodiments of the compounds of formula (0) or formula (1) (including the compounds of formulas (2)-(10) and subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, Q is -O-, -N(R 9 )- or -S-, and the moiety [ka] teeth, [ka] In some such embodiments, Q is -O-, -N(R 9 )- or -S-, and the moiety [ka] teeth, [ka] In some such embodiments, Q is -O-, -N(R 9 )- or -S-, and the moiety [ka] teeth, [ka] It is.

[0070] In some embodiments of a compound of Formula (0) or Formula (1) (including compounds of Formulas (2)-(10) and subformulas thereof), or a pharma- ceutically acceptable salt thereof, m is 0, 1, 2, or 3. In other embodiments, m is 0, 1, or 2. In other embodiments, m is 0 or 1. In some embodiments of any of the foregoing, each R 4 is oxo or C1-C6 alkyl. In some such embodiments, each R 4 In some embodiments, m is 0.

[0071] In some embodiments of the compounds of Formula (0) or Formula (1) (including compounds of Formulas (2)-(10) and subformulas thereof, if applicable), Q is -C(R 7 )(R 8 )-, -O-, -N(R 9)-, and -S-, wherein R 7 and R 8 are independently hydrogen, halogen, or C1 ~ C6 is alkyl, R 9 is hydrogen or C1-C6 alkyl. In some embodiments, Q is -C(R 7 )(R 8 )-, -O-, -N(R 9 )-, and -S-, wherein R 7 is hydrogen, halogen, or C1-C6 alkyl; R 8 is halogen or C1-C6 alkyl, R 9 is hydrogen or C1-C6 alkyl. Examples of suitable Q groups include -CH2-, -CHF-, -C(H)(CH3)-, -CF2, -C(CH3)2-, -NH-, -N(CH3)-, -O-, -S-, and the like. In some embodiments, Q is not -CH2-.

[0072] In some embodiments of the compounds of Formula (0) or Formula (1) (including compounds of Formulas (2)-(10) and subformulas thereof), or a pharma- ceutically acceptable salt thereof, Ring A is an optionally substituted 5-12 membered heterocyclyl. In some embodiments, Ring A is [ka] and each of which is optionally substituted. In some embodiments, ring A is [ka] and each of which is optionally substituted. In some embodiments of any of the foregoing, ring A is optionally substituted with halo, OH, CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted with halo or OH. In some such embodiments, ring A is optionally substituted with halo or OH. In some such embodiments, ring A is optionally substituted with halo. In some embodiments, ring A is unsubstituted.

[0073] In some embodiments of the compounds of Formula (0) or Formula (1) (including compounds of Formulas (2)-(10) and subformulas thereof), or a pharma- ceutically acceptable salt thereof, Ring A is an optionally substituted 5-12 membered heteroaryl. In some embodiments, Ring A is [ka] and each of which is optionally substituted. In some embodiments, ring A is [ka] and each of which is optionally substituted. In some embodiments, ring A is [ka] and each of which is optionally substituted. In some embodiments, ring A is [ka] and is optionally substituted. In some embodiments of any of the foregoing, ring A is optionally substituted with halo, OH, CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted with halo or OH. In some such embodiments, ring A is optionally substituted with halo or OH. In some such embodiments, ring A is optionally substituted with halo. In some embodiments, ring A is unsubstituted.

[0074] In some embodiments of the compounds of Formula (0) or Formula (1) (including compounds of Formulas (2)-(10) and subformulas thereof, where applicable), or a pharma- ceutically acceptable salt thereof, L is a bond. In some embodiments, L is -O-. In some embodiments, L is C1-C6 alkylene. In some embodiments, L is unsubstituted C1-C6 alkylene. In some embodiments, L is R L and each R is a C1-C6 alkylene optionally substituted by Lare independently halo, OH, oxo, or C1-C6 alkyl, or two R L together with the carbon atom or atoms to which they are attached form a C3-C6 cycloalkyl or a 3-6 membered heterocyclyl. In some embodiments, L is an unsubstituted C1-C2 alkylene. In some embodiments, L is R L is a C1-C2 alkylene optionally substituted by L is independently halo, OH, oxo, or C1-C6 alkyl. In some embodiments, L is an unsubstituted C2 alkylene. In some embodiments, L is R L is a C alkylene optionally substituted by L is independently halo, OH, oxo, or C1-C6 alkyl. In some embodiments, L is [ka] In some embodiments, L is C1-C6 alkylene, *-O-C1-C6 alkylene-**, *-C1-C6 alkylene-O-**, or *-NR 6 -C1-C6 alkylene-**, where * represents the point of attachment to ring A, ** represents the point of attachment to ring B, and R 6 is hydrogen or C1-C6 alkyl. For example, L can be *-OCH2-**. In some embodiments, L is C1-C6 alkylene, *-O-C1-C6 alkylene**, *-C1-C6 alkylene-O-**, or *-NR 6 -C1-C6 alkylene-**, L is R L where each R L are independently C1-C6 alkyl or halo, or two R L together with the carbon atom or atoms to which they are attached form a C3-C6 cycloalkyl or a 3-6 membered heterocyclyl. L )2-**, then two R Ltogether with the carbon atom or atom to which they are attached form a C3-C6 cycloalkyl or a 3-6 membered heterocyclyl. In some embodiments, L is *-O-C1-C6 alkylene-**. In some embodiments, L is *-O-C1-C3 alkylene-**. In some embodiments, L is *-OCH2-**.

[0075] In some embodiments of the compounds of Formula (0) or Formula (1) (including compounds of Formulas (0)-(10) and subformulas thereof, if applicable), Ring B is an optionally substituted C3-C 10 Cycloalkyl. Exemplary C3-C 10 Cycloalkyl includes: [ka] Examples of such rings include, but are not limited to, each of which is independently optionally substituted. In some of the foregoing embodiments, ring B is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl optionally substituted with halo or CN, OC1-C6 alkyl optionally substituted with halo or CN, -COCH3, -CONH2, -S(O)2CH3, and phenyl optionally substituted with halo or CN. In some such embodiments, ring B is optionally substituted with 1-3 substituents independently selected from the group consisting of halo and CN. In some embodiments, ring B is substituted with 2 substituents independently selected from F, Cl, and CN.

[0076] In some embodiments of the compounds of Formula (0) or Formula (1) (including compounds of Formulas (2)-(10) and subformulas thereof, if applicable), Ring B is an optionally substituted C6-C 14 Aryl. For example, C6-C 14 The aryl is [ka] each of which is independently optionally substituted. In some embodiments, ring B is phenyl and is optionally substituted. In some embodiments of any of the foregoing, ring B is optionally substituted with 1-3 substituents each independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -COCH3, -CONH2, -S(O)2CH3, and phenyl. In some such embodiments, ring B is optionally substituted with 1-3 substituents independently selected from the group consisting of halo and CN. In some embodiments, ring B is substituted with 2 substituents independently selected from F, Cl, and CN.

[0077] In some embodiments of compounds of Formula (0) or Formula (1) (including compounds of Formulas (2)-(10) and subformulas thereof, where applicable), Ring B is an optionally substituted 4-12 membered heterocyclyl. Exemplary 4-12 membered heterocyclyls include: [ka] In some embodiments of any of the foregoing, ring B is optionally substituted with 1-3 substituents each independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -COCH3, -CONH2, -S(O)2CH3, and phenyl. In some such embodiments, ring B is optionally substituted with 1-3 substituents independently selected from the group consisting of halo and CN. In some embodiments, ring B is substituted with 2 substituents independently selected from F, Cl, and CN.

[0078] In some embodiments, Ring B is an optionally substituted 5-12 membered heteroaryl. Exemplary 5-12 membered heteroaryls include: [ka] In some embodiments of any of the foregoing, ring B is optionally substituted with 1-3 substituents each independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -COCH3, -CONH2, -S(O)2CH3, and phenyl. In some such embodiments, ring B is optionally substituted with 1-3 substituents each independently selected from the group consisting of halo and CN.

[0079] In some embodiments of formula (2)-(10), or subformulas thereof, where applicable, p is 0, 1, or 2; 10 is halo, if present. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 2 and each R 10 is halo. For example, in some embodiments, the moiety [ka] teeth, [ka] It is.

[0080] In some embodiments of formulas (3), (4), (6), (7), (9), and (10), or subformulas thereof, where applicable, q is 0, 1, 2, or 3. In some embodiments, q is 2 or 3. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 2 and each R 11 is independently selected from halo or CN.

[0081] In the descriptions herein, it is understood that any description, variation, embodiment, or aspect of a moiety / variable can be combined with any description, variation, embodiment, or aspect of any other moiety / variable, as if all combinations of descriptions were specifically and individually recited, for example, as shown in the subformulas below. [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0082] Formula (1A), (1A-i), (1A-ii), (1A-iii), (1B), (1C), (1D), (2A), (2A-i), (2A-ii), (2A-iii), (2B), (2C), (2D), (3A), (3A-i), (3A-ii), (3A-ii) i), (3B), (3C), (3D), (4A), (4A-i), (4A-ii), (4A-iii), (4B), (4C), (4D), (5A), (5A-i), (5A-ii), (5A-iii), (5B), (5C), (5D), (6A), (6A-i In some embodiments of (6A-ii), (6A-iii), (6B), (6C), (6D), (7A), (7A-i), (7A-ii), (7A-iii), (7B), (7C), (7D), (8A), (8A-i), (8A-ii), (8A-iii), (8B), (8C), (8D), (9A), (9A-i), (9A-ii), (9A-iii), (9B), (9C), (9D), (10A), (10A-i), (10A-ii), (10A-iii), (10B), (10C), and (10D), R 5 is triazolyl or thiazolyl, each of which is optionally substituted. In some embodiments, R 5 is unsubstituted triazolyl. In some embodiments, R 5 is triazolyl, optionally substituted. In some embodiments of any of the foregoing, R 5 is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, oxo, CN, C1-C6 alkyl, C3-C6 cycloalkyl, and -OC1-C6 alkyl, and each C1-C6 alkyl, C3-C6 cycloalkyl, and -OC1-C6 alkyl substituent is independently and optionally substituted with halo or CN. In some such embodiments, R 5 is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, oxo, CN, C1-C6 alkyl, C3-C6 cycloalkyl, and -OC1-C6 alkyl. In some such embodiments, R 5is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, oxo, CN, C1-C6 alkyl, and -OC1-C6 alkyl. In some such embodiments, R 5 is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, oxo, CN, C1-C3 alkyl, and -OC1-C3 alkyl. In some such embodiments, R 5 is optionally substituted with 1 to 3 substituents independently selected from the group consisting of Cl, F, Br, oxo, CN, C1-C3 alkyl, and -OC1-C3 alkyl. In some such embodiments, R 5 is optionally substituted with 1 to 3 substituents independently selected from the group consisting of Cl, F, Br, C1-C3 alkyl, and -OC1-C3 alkyl. In some such embodiments, R 5 is optionally substituted with 1 to 3 substituents independently selected from the group consisting of Cl, F, Br, and C1-C3 alkyl, such as methyl, ethyl, propyl, or isopropyl. 5 is non-substituted.

[0083] Formula (1A), (1A-i), (1A-ii), (1A-iii), (1B), (1C), (1D), (2A), (2A-i), (2A-ii), (2A-iii), (2B), (2C), (2D), (3A), (3A-i), (3A-ii), (3A-ii) i), (3B), (3C), (3D), (4A), (4A-i), (4A-ii), (4A-iii), (4B), (4C), (4D), (5A), (5A-i), (5A-ii), (5A-iii), (5B), (5C), (5D), (6A), (6A-i In some embodiments of (6A-ii), (6A-iii), (6B), (6C), (6D), (7A), (7A-i), (7A-ii), (7A-iii), (7B), (7C), (7D), (8A), (8A-i), (8A-ii), (8A-iii), (8B), (8C), (8D), (9A), (9A-i), (9A-ii), (9A-iii), (9B), (9C), (9D), (10A), (10A-i), (10A-ii), (10A-iii), (10B), (10C), and (10D), R 5 teeth, [ka] where R 12 is C1-C6 alkyl. In some such embodiments, R 12 In other such embodiments, R 12 In other such embodiments, R 12 In other such embodiments, R 12 is isobutyl.

[0084] The present disclosure also includes any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms, of the compounds described. Compounds of any formula described herein may have asymmetric centers and therefore may exist in different enantiomeric or diastereomeric forms. All optical isomers and stereoisomers of the compounds of the general formula, as well as mixtures thereof in any ratio, are considered to be within the scope of the formula. Thus, any formula given herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof in any ratio, unless a specific stereochemistry is otherwise indicated. When a compound of a formula or Table 1 is shown in a specific stereochemical configuration, any alternative stereochemical configuration of the compound, as well as mixtures of the stereoisomers of the compound in any ratio, are also provided herein. For example, when a compound of a formula or Table 1 has a stereocenter in the "S" stereochemical configuration, the enantiomer of the compound in which that stereocenter is in the "R" stereochemical configuration is also provided herein. Similarly, when a compound of a formula or Table 1 has a stereocenter in the "R" configuration, enantiomers of the compound in the "S" stereochemical configuration are also provided herein. Also provided are mixtures of compounds having both the "S" and "R" stereochemical configurations. As another example, in formulae (0)-(7) and subformulas thereof, the moiety [ka] is that the formula [ka] This includes variations having the form: [ka] Also provided are mixtures containing both forms. [ka] has the formula [ka] Variations having the form: [ka] Also provided are mixtures comprising both forms. In some embodiments, one diastereomeric form may be preferred, for example, compounds of formula (2) or subformulas thereof may be preferred in the configurations shown in formulas (2.1), (2.1a), and (2.1b) over the configurations shown in formulas (2.2), (2.2a), and (2.2b), respectively. [ka] [ka]

[0085] The compounds provided herein may exist as salts even when no salt is provided, and it is understood that the present disclosure encompasses all salts and solvates of the compounds provided herein, as well as non-salt and non-solvated forms of the compounds, as would be well understood by one of ordinary skill in the art. In some embodiments, the salts of the compounds provided herein are pharma- ceutically acceptable salts.

[0086] The present invention also contemplates isotopically labeled and / or isotopically enriched forms of the compounds described herein. The compounds herein may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. In some embodiments, the compounds are isotopically labeled, such as isotopically labeled compounds of formula (0) or formula (1) described herein (including compounds of formulas (2)-(10), or any subformulae above), or variations thereof, in which a portion of one or more atoms are replaced by an isotope of the same element. Exemplary isotopes that can be incorporated into the compounds of the present invention include: 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 O.17 O. 32 P, 35 S, 18 F, 36 These include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, and chlorine, such as Cl. Certain isotopically labeled compounds (e.g. 3 H or 14 C) is useful for compound or substrate tissue distribution studies. 2 Incorporation of heavier isotopes, such as H), can offer certain therapeutic advantages resulting from greater metabolic stability, e.g., increased half-life in vivo or reduced dosage requirements, and therefore may be preferred in some cases.

[0087] Isotopically labeled compounds of the invention may generally be prepared by standard methods and techniques known to those skilled in the art, or by procedures analogous to those described in the accompanying examples, substituting the appropriate isotopically labeled reagent for the corresponding unlabeled reagent.

[0088] The invention also includes any or all of the metabolic products of any of the described compounds. Metabolites can include any chemical species produced by the biotransformation of any of the described compounds, including intermediates and products of the metabolism of the compounds, as produced in vivo following administration to humans.

[0089] Representative compounds are listed in Table 1 below. In some embodiments, a compound selected from compound numbers 1 to 46 in Table 1, or a pharma- ceutically acceptable salt thereof, is provided. In some embodiments, a compound that is compound number 1 in Table 1, or a pharma- ceutically acceptable salt thereof, is provided. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11]

[0090] Pharmaceutically Acceptable Compositions and Formulations Pharmaceutically acceptable compositions, or simply "pharmaceutical compositions," of any of the compounds detailed herein are encompassed by the present invention. Thus, the present invention includes pharmaceutical compositions comprising a compound of formula (0), formula (1) (including compounds of formulas (2)-(10)), or any of the foregoing subformulas, or a pharma- ceutical acceptable salt thereof, and a pharma- ceutical acceptable carrier or excipient.

[0091] In some embodiments, pharma- ceutically acceptable salts are acid addition salts, such as salts formed with inorganic or organic acids.Pharmaceutical compositions according to the invention may be in a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration, or in a form suitable for administration by inhalation.

[0092] The compounds detailed herein may, in one aspect, be in purified form, and compositions comprising the compounds in purified form are detailed herein. Compositions comprising the compounds detailed herein or salts thereof, e.g., compositions of substantially pure compounds, are provided. In some embodiments, compositions containing the compounds detailed herein or salts thereof are in substantially pure form. In one variation, "substantially pure" contemplates a composition containing 35% or less impurities, where impurities refer to compounds other than the compound or salts thereof that make up the majority of the composition. For example, a composition of a substantially pure compound contemplates a composition containing 35% or less impurities, where impurities refer to compounds other than the compound or salts thereof. In one variation, a composition of a substantially pure compound or salts thereof is provided, where the composition contains 25% or less impurities. In another variation, a composition of a substantially pure compound or salts thereof is provided, where the composition contains 20% or less impurities. In yet another variation, a composition of a substantially pure compound or salts thereof is provided, where the composition contains 10% or less impurities. In a further variation, a composition of a substantially pure compound or salts thereof is provided, where the composition contains 5% or less impurities. In another variation, a composition of a substantially pure compound or salts thereof is provided, where the composition contains 3% or less impurities. In yet another variation, a composition of a substantially pure compound or a salt thereof is provided, wherein the composition contains 1% or less of impurities. In a further variation, a composition of a substantially pure compound or a salt thereof is provided, wherein the composition contains 0.5% or less of impurities. In yet another variation, a composition of a substantially pure compound means that the composition contains 15% or less of impurities, or preferably 10% or less, or more preferably 5% or less, or even more preferably 3% or less, and most preferably 1% or less of impurities, which may be compounds of different stereochemical forms.

[0093] In one variation, the compounds herein are synthetic compounds prepared for administration to an individual, such as a human. In another variation, compositions containing the compounds in substantially pure form are provided. In another variation, the invention encompasses pharmaceutical compositions comprising the compounds detailed herein and a pharma- ceutically acceptable carrier or excipient. In another variation, methods of administering the compounds are provided. The purified forms, pharmaceutical compositions, and methods of administering the compounds are suitable for any of the compounds detailed herein or forms thereof.

[0094] The compounds may be formulated for any available delivery route, including oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., intramuscular, subcutaneous, or intravenous), topical, or transdermal delivery forms. The compounds may be formulated with suitable carriers to provide a delivery form, including, but not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal sprays or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions), solutions, and elixirs.

[0095] The compounds described herein can be used to prepare formulations such as pharmaceutical preparations by combining the compound as an active ingredient with a pharma- ceutical acceptable carrier, such as those described above. Depending on the treatment form of the system (e.g., transdermal patch vs. oral tablet), the carrier can be in various forms. In addition, the pharmaceutical preparations can contain preservatives, solubilizing substances, stabilizing substances, rewetting agents, emulsifying substances, sweetening substances, dyes, adjusting substances, and salts for adjusting osmotic pressure, buffers, coating agents, or antioxidants. The preparations containing the compounds can also contain other substances that have valuable therapeutic properties. The pharmaceutical preparations can be prepared by known pharmaceutical methods. Suitable formulations can be found, for example, in Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21st ed. (2005), which is incorporated herein by reference.

[0096] The compounds described herein can be administered to an individual (e.g., a human) in the form of generally acceptable oral compositions, such as tablets, coated tablets, and gel capsules with hard or soft shells, emulsions or suspensions. Carriers that can be used to prepare such compositions include lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. Acceptable carriers for gel capsules with soft shells include, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols, etc. In addition, pharmaceutical preparations can contain preservatives, solubilizing agents, stabilizing agents, rewetting agents, emulsifying agents, sweetening agents, dyes, adjusting agents, and salts for adjusting osmotic pressure, buffers, coating agents, or antioxidants.

[0097] Compositions comprising two compounds utilized herein are described. Any of the compounds described herein can be formulated into any dosage form tablet described herein. In some embodiments, the composition comprises a compound of formula (0), formula (1) (including compounds of formulas (2)-(10)) or any of the subformulas described herein, or a pharma- ceutically acceptable salt thereof. In some embodiments, a dosage form comprising a therapeutically effective amount of a compound of formula (0), formula (1) (including compounds of formulas (2)-(10)) or any of the subformulas described herein, or a pharma-ceutically acceptable salt thereof is provided herein. In some embodiments, the compound, or a pharma-ceutically acceptable salt thereof, is selected from compound numbers 1-46 in Table 1.

[0098] Method and use The compounds and compositions described herein can, in some aspects, be used to treat the diseases and / or conditions described herein, e.g., diseases and / or conditions mediated by GLP-1R. In some embodiments, a method of treating a disease or condition in a subject in need of treatment comprises administering to the subject a compound of Formula (0), Formula (1) (including compounds of Formulas (2)-(10)), or any of the subformulas above, or a pharma- ceutical acceptable salt thereof. In some embodiments, a method of treating a disease or condition in a subject in need of treatment comprises administering to the subject a therapeutically effective amount of a compound selected from compound numbers 1-46 of Table 1, or a pharma-ceutical acceptable salt thereof.

[0099] According to the present application, the disease or condition to be treated and / or prevented is selected from the group consisting of cardiometabolic and related diseases, including diabetes (T1D and / or T2DM, including prediabetes), idiopathic T1D (type 1b), latent autoimmune diabetes in adults (LADA), early onset T2DM (EOD), atypical diabetes of the young (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 injury, renal tubular hypercalcemia, renal failure ... dysfunction, inflammatory changes in the proximal tubules), diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, sleep apnea, obesity (including hypothalamic obesity and monogenic obesity) and associated comorbidities (e.g., osteoarthritis and urinary incontinence), eating disorders (including binge eating syndrome, bulimia nervosa, and syndromic obesity such as Prader-Willi syndrome and Bardet-Biedl syndrome), weight gain due to use of other medications (e.g., due to use of steroids or antipsychotics), excessive sugar cravings, dyslipidemia (hyperlipidemia, hypertriglyceridemia, increased total cholesterol, high LDL cholesterol, low HDL cholesterol, L-cholesterol), hyperinsulinemia, liver disease such as NAFLD, steatosis, NASH, fibrosis, cirrhosis, hepatocellular carcinoma, cardiovascular disease, atherosclerosis (including coronary artery disease), peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction (including necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial hyperlipidemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, and vitreous edema. disorders, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina, thrombosis, atherosclerosis, transient ischemic attack, vascular restenosis, glucose metabolism disorders, impaired fasting glucose level, hyperuricemia, gout, erectile dysfunction, skin and connective tissue diseases, psoriasis, foot ulcers, ulcerative colitis, hyperapo B lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome and intoxication (e.g., alcohol and / or drug abuse), prevention or treatment of polycystic ovary syndrome;and the treatment of addictions (e.g., alcohol and / or drug abuse).

[0100] In some embodiments, provided herein is a method of treating a cardiometabolic disease in a subject (e.g., a human patient) in need of treatment, the method comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharma- ceutical acceptable salt thereof.

[0101] 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 pharma- ceutically acceptable salt thereof. Exemplary diabetes includes, but is not limited to, T1 D, T2DM, prediabetes, idiopathic T1 D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, and gestational diabetes.

[0102] In some embodiments, provided herein is a method of treating liver damage in a subject (e.g., a human patient) in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharma- ceutical acceptable salt thereof. Exemplary liver damage includes, but is not limited to, 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), cholestasis associated with bacterial overgrowth or sepsis, 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, intrahepatic or extrahepatic malignancies, Sjogren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis, and oti-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 therapeutic method provided herein prevents or delays the progression of NAFLD to NASH. In one embodiment, the therapeutic method provided herein prevents or delays the progression of NASH. NASH can progress to one or more of the following: cirrhosis of the liver, liver cancer, and the like.In some embodiments, the liver disorder is NASH. In some embodiments, the patient has undergone a liver biopsy. In some embodiments, the method further comprises obtaining the results of the liver biopsy.

[0103] In accordance with the present application, the compounds described herein, or pharma- ceutically acceptable salts thereof, may be administered by any suitable route in the form of a pharmaceutical composition adapted for such route, in a dose effective for the intended treatment. In some embodiments, the compound is a compound of any of the embodiments of Formula (0), Formula (1) (including compounds of Formulas (2)-(10)), or any of the subformulas above, or a compound selected from the compounds of Table 1, or a pharma- ceutically acceptable salt thereof. The compounds and / or compositions described herein may be administered orally, rectally, vaginally, parenterally, or topically.

[0104] In some embodiments, the compounds and / or compositions may be administered orally, which may involve swallowing, so that the compound enters the gastrointestinal tract, or by buccal or sublingual administration, whereby the compound enters the bloodstream directly from the mouth.

[0105] In some embodiments, the compound and / or composition 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.

[0106] In some embodiments, the compounds and / or compositions may be administered topically to the skin or mucosa, i.e., 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.

[0107] Dosage regimens for the compounds and / or compositions described herein are based on a variety of factors, including the type, age, weight, sex, and medical condition of the patient, the severity of the condition, the route of administration, and the activity of the particular compound used. Thus, dosage regimens can vary widely. In some embodiments, the total daily dose of the compounds of the present application is typically about 0.001 to about 100 mg / kg (i.e., mg of compound per kg of body weight) for the treatment of the indicated conditions discussed herein. In one embodiment, the total daily dose of the compounds of the present application is about 0.01 to about 30 mg / kg, in another embodiment, about 0.03 to about 10 mg / kg, and in yet another embodiment, about 0.1 to about 3 mg / kg. It is not uncommon for the administration of the compounds of the present application to be repeated multiple times (typically no more than four times) per day. Typically, multiple doses per day can be used to increase the total daily dose, if necessary.

[0108] For oral administration, the compounds and / or compositions described herein may be provided in the form of tablets containing 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 30.0, 50.0, 75.0, 100, 125, 150, 175, 200, 250, and 500 milligrams of active ingredient, to allow for symptomatic adjustment of dosage to the patient. The medicament typically contains about 0.01 mg to about 500 mg of active ingredient, or in another embodiment, about 1 mg to about 100 mg of active ingredient. Intravenously, dosages may range from about 0.01 to about 10 mg / kg / min during a constant rate infusion.

[0109] The compounds and / or compositions described herein can be used alone or in combination with other therapeutic agents. Administering two or more agents "in combination" means that they are administered close enough in time that all agents can produce their respective biological effects in the same time frame. The presence of one agent may alter the biological effect of the other agent(s). Two or more agents may be administered simultaneously, in parallel, or sequentially. Additionally, simultaneous administration can be accomplished by mixing the agents prior to administration, or by administering the compounds at the same time, but as separate dosage forms, to the same or different administration sites.

[0110] The application provides any of the uses, methods, or compositions defined herein, wherein a compound of any embodiment of formula (0), formula (1) (including compounds of formulas (2)-(10)), or a compound selected from any of the foregoing sub-formulas, or a compound in Table 1, or a pharma- ceutically acceptable salt thereof, is used in combination with one or more other therapeutic agents. This would include a pharmaceutical composition comprising a compound of any embodiment of formula (0), formula (1) (including compounds of formulas (2)-(10)), or a compound selected from any of the foregoing sub-formulas, or a compound in Table 1, or a pharma- ceutically acceptable salt thereof, as defined in any of the embodiments described herein, in admixture with at least one pharma- ceutically acceptable excipient and one or more other therapeutic agents.

[0111] In some embodiments, the one or more other therapeutic agents are 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), meglitinides (e.g., nateglinide, repaglinide), dipeptidyl peptidase 4 (DPP-4) inhibitors (e.g., sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, detogliptin, or omarigliptin), glitazones (e.g., pioglitazone, rosiglitazone, antidiabetic agents including, but not limited to, sodium glucose transporter type 2 (SGLT2) inhibitors (e.g., empagliflozin, canagliflozin, dapagliflozin, ipragliflozin, ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, or ertugliflozin), SGLT1 inhibitors, GPR40 agonists (FFAR1 / FFA1 agonists such as fasiglifam), glucose-dependent insulinotropic peptide (GIP) and analogs thereof, alpha-glucosidase inhibitors (e.g., voglibose, acarbose, or miglitol), or insulin or insulin analogs, including pharmaceutically acceptable salts of the specifically named agents, as well as pharmaceutically acceptable solvates of said agents and salts.

[0112] In some embodiments, the one or more other therapeutic agents are peptide YY or an analog thereof, a neuropeptide Y receptor type 2 (NPYR2) agonist, an NPYR1 or NPYR5 antagonist, a cannabinoid receptor type 1 (CB1R) antagonist, a lipase inhibitor (e.g., orlistat), a human islet-promoting peptide (HIP), a melanocortin receptor 4 agonist (e.g., setomelanotide), 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), norepinephrine / dopamine reuptake inhibitors (e.g., buproprion), opioid receptor antagonists (e.g., naltrexone), combinations of norepinephrine / dopamine reuptake inhibitors and opioid receptor antagonists (e.g., bupropion and naltrexone), GDF-15 analogs, sibutramine, cholecystokinin agonists, amylin and its analogs (e.g., pramlintide), leptin and its analogs (e.g., metroleptin), serotonin receptor antagonists (e.g., serotonin receptor antagonists), and combinations of norepinephrine / dopamine reuptake inhibitors and opioid receptor antagonists (e.g., bupropion and naltrexone). agonists (e.g., lorcaserin), methionine aminopeptidase 2 (MetAP2) inhibitors (e.g., beloranib or ZGN-1061), phendimetrazine, diethylpropionate, benzphetamine, SGLT2 inhibitors (e.g., empagliflozin, canagliflozin, dapagliflozin, ipragliflozin, ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, or ertugliflozin), SGLT1 inhibitors, SGLT2 / SGLT1 dual inhibitors, fibroblast growth factor Anti-obesity agents including, but not limited to, FGFR receptor modulators, AMP-activated protein kinase (AMPK) activators, biotin, MAS receptor modulators, or glucagon receptor agonists (alone or in combination with another GLP-1R agonist (e.g., liraglutide, exenatide, dulaglutide, albiglutide, lixisenatide, or semaglutide)), including pharmacologic agents, such as ...

[0113] In some embodiments, the one or more other therapeutic agents are selected from the group consisting of PF-05221304, FXR agonists (e.g., obeticholic acid), PPARα / d agonists (e.g., elafibranor), synthetic fatty acid-bile acid conjugates (e.g., aramchol), caspase inhibitors (e.g., emricasan), anti-lysyl oxidase homolog 2 (LOXL2) monoclonal antibodies (e.g., simtuzumab), galectin 3 inhibitors (e.g., GR-MD-02), MAPK5 inhibitors (e.g., GS-4997), dual antagonists of chemokine receptor 2 (CCR2) and CCR5 (e.g., cenicriviroc), fibroblast growth factor 21 (FGF21) agonists (e.g., BMS-986036), leukotrienes (e.g., cenicriviroc), leukotrienes (e.g., cenicriviroc), cenicriviroc, ... Agents for treating NASH, including, but not limited to, lenalidomide D4 (LTD4) receptor antagonists (e.g., tipelukast), niacin analogs (e.g., ARI3037MO), ASBT inhibitors (e.g., vorixibat), acetyl-CoA carboxylase (ACC) inhibitors (e.g., NDI010976), ketohexokinase (KHK) inhibitors, diacylglyceryl acyltransferase 2 (DGAT2) inhibitors, CB1 receptor antagonists, anti-CB1R antibodies, or apoptosis signal-regulating kinase 1 (ASK1) inhibitors, including pharmaceutically acceptable salts of the specifically named agents, as well as pharmaceutically acceptable solvates of said agents and salts.

[0114] Manufactured Products and Kits The present disclosure further provides a product comprising a compound according to the present application or a pharma- ceutically acceptable salt thereof, a composition described herein, or one or more unit doses described herein in suitable packaging.In certain embodiments, the product is for use in any of the methods described herein.Suitable packaging (e.g., containers) are known in the art, and include, for example, vials, containers, ampoules, bottles, jars, flexible packaging, and the like.The product may further be sterilized and / or sealed.

[0115] The kit may be in unit dosage form, bulk package (e.g., multi-dose package) or sub-unit dose. For example, a kit may be provided that contains a sufficient dose of a compound according to the present application or a pharma- ceutically acceptable salt thereof, a composition described herein, and / or one or more other therapeutic agents useful for the diseases detailed herein to provide effective treatment of an individual for an extended period of time, for example, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or longer. The kit may also contain a plurality of unit doses of the compounds / compositions described herein and instructions for use, packaged in sufficient quantities for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).

[0116] The kit may optionally include a set of instructions, typically written instructions, although electronic storage media (e.g., magnetic diskettes or optical disks) containing instructions are acceptable relating to the use of the component(s) of the disclosed methods. The instructions included in the kit generally include information regarding the components and their administration to an individual.

[0117] General synthesis scheme Scheme A. Preparation of 5-(6-(aryloxy)pyridin-2-yl)-2-azabicyclo[4.1.0]heptane intermediate A7. [ka]

[0118] The pyridine-substituted 2-azabicyclo[4.1.0]heptane intermediate A7 can be prepared by the S reaction of 2,6-dichloropyridine with the enolate A2, which is prepared from commercially available 2-(tert-butyl)5-methyl 2-azabicyclo[4.1.0]heptane-2,5-dicarboxylate and a base such as potassium or other alkaline bis(trimethylsilyl)amide. NThe intermediate ester A3 can be prepared by the Ar reaction. The intermediate ester A3 is saponified with alkali hydroxide and thermally decarboxylated. The chloropyridine A5 is reacted with a suitably substituted 2-(hydroxymethyl)aryl group under Buchwald-Hartwig etherification conditions, and the resulting Boc-protected intermediate A6 is deprotected with a strong acid such as trifluoroacetic acid to give A7 as a salt.

[0119] Scheme B. Preparation of 5-(6-(aryloxy)pyridin-2-yl)-2-azabicyclo[4.1.0]heptan-2-yl)methyl)-1-substituted-1H-benzo[d]imidazole-6-carboxylic acids B1, B2, B3, and B4. [ka]

[0120] The 5-(6-(aryloxy)pyridin-2-yl)-2-azabicyclo[4.1.0]heptane intermediate A7 is reacted with an appropriate R1-substituted benzimidazole-6-carboxylic acid ester B1 (prepared according to various known synthetic methods such as those described in WO2019239371) in the presence of an acid scavenger such as an alkali carbonate to obtain a mixture of four diastereomers with (1R,5R,6R), (1R,5S,6R), (1S,5R,6S) and (1S,5S,6S) configurations. The intermediate mixture of diastereomers is separated by supercritical fluid chromatography (SFC) and then each individual compound is saponified with an alkali hydroxide to obtain the final products B2, B3, B4, and B5. Alternatively, intermediate A7 can be prepared in a stereoselective synthesis or purified to obtain only the desired isomer for use in the subsequent steps.

[0121] Scheme C. Preparation of 2-(6-(aryloxy)pyridin-2-yl)-2,5-diazabicyclo[4.1.0]-heptane intermediate C4. [ka]

[0122] The pyridine-substituted 2,5-diazabicyclo[4.1.0]heptane intermediate C3 can be prepared by nucleophilic displacement of 2,6-dihalopyridine C1 with a suitably substituted 2-(hydroxymethyl)aryl group anion formed from C1A and a strong acid such as sodium hydride. The 2-(aryloxy)-6-halopyridine C2 is reacted with commercially available tert-butyl 2,5-diazabicyclo[4.1.0]heptane-2-carboxylate C2A under Buchwald-Hartwig amination conditions, and the resulting Boc-protected intermediate C3 is deprotected with a strong acid such as hydrochloric acid to give intermediate C4 as a salt.

[0123] Scheme D. Preparation of 2-((5-(6-(aryloxy)pyridin-2-yl)-2,5-diazabicyclo[4.1.0]-heptan-2-yl)methyl)-1-substituted-1H-benzo[d]imidazole-6-carboxylic acids D1 and D2. [ka]

[0124] The 2-(6-(aryloxy)pyridin-2-yl)-2,5-diazabicyclo[4.1.0]heptane intermediate C4 is reacted with an appropriate R1-substituted benzimidazole-6-carboxylic acid ester B1 (prepared according to various known synthetic methods such as those described in WO2019239371) in the presence of an acid scavenger such as an alkali carbonate to give a mixture of two diastereomers with (1R,6S) and (1S,6R) configurations. The intermediate mixture of diastereomers is separated by supercritical fluid chromatography (SFC) and then each individual compound is saponified with an alkali hydroxide to give the final products D1 and D2. Alternatively, intermediate C4 can be prepared in a stereoselective synthesis or purified to give only the desired isomer for use in the subsequent steps.

[0125] Scheme E. Preparation of (S)-4,4,5,5-tetramethyl-2-(2-methyl-2-(substituted-aryl)benzo[d][1,3]dioxol-4-yl)-13,2-dioxaborolane intermediate E6. [ka]

[0126] Seyfarth-Gilbert homologation affords the alkyne intermediate E2 from the appropriately substituted arylaldehyde E1 and dimethyl(diazomethyl)phosphonate. Addition of 3-bromocatechol to the alkyne E2 in the presence of triruthenium dodecacarbonyl affords the 4-bromo-2-methyl-2-arylbenzo[d][1,3]dioxole as a mixture of enantiomers E4 and E5, which can be separated by supercritical fluid chromatography (SFC) to give the desired (S)-isomer.

[0127] Scheme F. Preparation of 5-((S)-2-methyl-2-substituted-arylbenzo[d][1,3]dioxol-4-yl)-2-azabicyclo[4.1.0]heptane intermediate F7. [ka]

[0128] Metal-free cross-coupling between sulfonylhydrazine F2 and (S)-4,4,5,5-tetramethyl-2-(2-methyl-2-(substituted-aryl)benzo[d][1,3]dioxol-4-yl)-1,3,2-dioxaborolane intermediate E6 in the presence of a base such as cesium carbonate gives tert-butyl-((S)-2-methyl-2-substituted-arylbenzo[d][1,3]dioxol-4-yl)-3,4-dihydropyridine-1(2H)-carboxylate F3. Reaction of F3 with the dibromocarbene generated under phase transfer conditions gives gem-dibromocyclopropane adduct F5 which is reductively dehalogenated with tri-n-butyltin hydride. Deprotection of F6 with a strong acid such as HCl or TFA gives F7.

[0129] Scheme G. Alternative preparation of tert-butyl-((S)-2-methyl-2-substituted-arylbenzo[d][1,3]dioxol-4-yl)-3,4-dihydropyridine-1(2H)-carboxylate intermediate F3. [ka]

[0130] Alternatively, intermediate F3 can be prepared by Suzuki coupling of commercially available tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate with intermediate E4. The resulting dihydropyridine G1 is reduced and oxidized with catalytic ruthenium(III) chloride and sodium periodate to give lactam G3. Lactam G3 can be converted to dihydropyridine F3 with an organosilane such as tetramethyldisiloxane and catalytic Vaska reagent.

[0131] Scheme H. Alternative preparation of tert-butyl-((S)-2-methyl-2-substituted-arylbenzo[d][1,3]dioxol-4-yl)-3,4-dihydropyridine-1(2H)-carboxylate intermediate F3. [ka]

[0132] Alternatively, intermediate F3 can be prepared by rhodium-catalyzed cross-coupling of commercially available tert-butyl 6-oxo-3,6-dihydropyridine-1(2H)-carboxylate with intermediate E6. Reduction of lactam G3 gives hydroxypiperidine H1, which is treated with aqueous acid to give intermediate F3.

[0133] Scheme I. Alternative preparation of 5-((S)-2-methyl-2-substituted-arylbenzo[d]-[1,3]dioxol-4-yl)-2-azabicyclo[4.1.0]heptane intermediate F7. [ka]

[0134] Intermediate F7 can be obtained in very low yield from G4 under conventional Simmons-Misumi reaction conditions.

[0135] Scheme J. Preparation of 1-substituted-2-((5-((S)-2-methyl-2-substituted-phenylbenzo[d][1,3]dioxol-4-yl)-2-azabicyclo[4.1.0]heptan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acids J1, J2, J3, and J4. [ka]

[0136] The 5-((S)-2-methyl-2-substituted-arylbenzo[d][1,3]dioxol-4-yl)-2-azabicyclo[4.1.0]heptane intermediate F7 is reacted with the appropriate R1-substituted benzimidazole-6-carboxylic acid ester B1 (prepared according to various known synthetic methods such as those described in WO2019239371) in the presence of an acid scavenger such as an alkali carbonate to give a mixture of four diastereomers with (1R,5R,6R), (1R,5S,6R), (1S,5R,6S) and (1S,5S,6S) configurations. The intermediate mixture of diastereomers is separated by supercritical fluid chromatography (SFC) and then each individual compound is saponified with alkali hydroxide to give the final products J1, J2, J3 and J4. Alternatively, intermediate F7 can be prepared in a stereoselective synthesis or purified to yield only the desired isomer for use in subsequent steps.

[0137] Scheme K. Preparation of 2-((S))-2-methyl-2-substituted-arylbenzo[d][1,3]dioxol-4-yl)-2,5-diazabicyclo[4.1.0]heptane intermediate K2. [ka]

[0138] Commercially available tert-butyl 2,5-diazabicyclo[4.1.0]heptane-2-carboxylate is reacted with E4 under Buchwald amination conditions and the resulting intermediate is deprotected with strong acid to give K2.

[0139] Scheme L. 1-Substituted-2-((5-((S)-2-methyl-2-substituted-arylbenzo[d][1,3]dioxol-4-yl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acids L1 and L2. [ka]

[0140] The 2-((S))-2-methyl-2-substituted-arylbenzo[d][1,3]dioxol-4-yl)-2,5-diazabicyclo[4.1.0]heptane intermediate K2 is reacted with the appropriate R1-substituted benzimidazole-6-carboxylic acid ester B1 (prepared according to various known synthetic methods such as those described in WO2019239371) in the presence of an acid scavenger such as an alkali carbonate to obtain a mixture of two diastereomers with (1R,6S) and (1S,6R) configurations. The intermediate mixture of diastereomers is separated by supercritical fluid chromatography (SFC) and then each individual compound is saponified with an alkali hydroxide to obtain the final products L1 and L2. Alternatively, intermediate K2 can be prepared in a stereoselective synthesis or purified to obtain only the desired isomer for use in the subsequent step.

[0141] Scheme M. Preparation of 2-((2-(6-(aryloxy)pyridin-2-yl)-2-azabicyclo[4.1.0]-heptan-5-yl)methyl)-1-substituted-1H-benzo[d]imidazole-6-carboxylic acids M7. [ka]

[0142] Horner-Wadsworth-Emmols olefination of commercially available tert-butyl 5-oxo-2-azabicyclo[4.1.0]heptane-2-carboxylate and phosphonate M2A gives 2-((2-(tert-butoxycarbonyl)-2-azabicyclo[4.1.0]heptane-5-ylidene)methyl)-1-substituted-1H-benzo[d]imidazole-6-carboxylate M3, which is reduced and deprotected with strong acid. Amination of 2-(aryloxy)-6-bromopyridine C2 under Buchwald conditions gives M6, which is then saponified with alkali hydroxide to give M7 as a mixture of four diastereomers. Alternatively, M6 can be separated by supercritical fluid chromatography (SFC) to give the (1S,5R,6S), (1S,5S,6S), (1R,5R,6R), and (1R,5S,6R) individual isomers, which are saponified with alkali hydroxide to give the final product. Alternatively, intermediate M6 can be prepared in a stereoselective synthesis or purified to give only the desired isomer for use in the subsequent step.

[0143] Scheme N. Preparation of 2-((5-(6-substituted-aryloxy)pyridin-2-yl)-2-azabicyclo[4.1.0]heptan-2-yl)methyl)-1-substituted-6-(1H-tetrazol-5-yl)-1H-benzo[d]imidazoles N6. [ka]

[0144] Nucleophilic displacement of commercially available 3-fluoro-4-nitrobenzonitrile with the desired amine, R1NH2, followed by reduction and condensation with 2-chloro-1,1,1-trimethoxyethane gives 2-(chloromethyl)-1-substituted-1H-benzo[d]imidazole-6-carbonitriles N4. Reaction of N4 with 5-(6-(aryloxy)pyridin-2-yl)-2-azabicyclo[4.1.0]heptane intermediate A7 in the presence of an acid scavenger such as an alkali carbonate gives N5. Cycloaddition of N5 with azidotrimethylsilane in the presence of a catalyst such as tri-n-butyltin oxide gives N6 as a mixture of four diastereomers. The mixture of diastereomers can be separated by supercritical fluid chromatography (SFC) if necessary.

[0145] Scheme O. Preparation of 3-(2-((5-(6-(substituted-aryloxy)pyridin-2-yl)-2-azabicyclo[4.1.0]heptan-2-yl)methyl)-1-substituted-1H-benzo[d]imidazol-6-yl)-1,2,4-oxadiazol-5(4H)-ones O2. [ka]

[0146] Reaction of N5 with hydroxylamines gives 2-((5-(6-(substituted-aryloxy)pyridin-2-yl)-2-azabicyclo[4.1.0]heptan-2-yl)methyl)-N'-hydroxy-1-substituted-1H-benzo[d]imidazole-6-carboximidamides O1, which are further cyclized with 1,1'-carbonyldiimidazole or phosgene in the presence of base to give O2. Reactions may be carried out with individual diastereomers N5 or with a mixture of the four diastereomers separated by supercritical fluid chromatography (SFC).

[0147] Scheme P. Preparation of 5-(2-((5-(6-(substituted-aryloxy)pyridin-2-yl)-2-azabicyclo[4.1.0]heptan-2-yl)-1-substituted-1H-benzo[d]imidazol-6-yl)isoxazol-3(2H)-ones P10. [ka]

[0148] 2-(Chloromethyl)-6-iodo-1-substituted-1H-benzo[d]imidazole P4 is prepared following a similar method used to synthesize N4. Conversion to the TBS ether and Sonogashira coupling with ethyl propionate gives the alkyne P6, which is cyclized with hydroxylamine to give the isoxazol-3-one P7. Deprotection, mesylation, and reaction with 5-(6-(aryloxy)pyridin-2-yl)-2-azabicyclo[4.1.0]heptane intermediate A7 in the presence of an acid scavenger such as an alkali carbonate gives P10. Reactions may be performed with individual diastereomer A7 or with a mixture of the four diastereomers separated by supercritical fluid chromatography (SFC).

[0149] Scheme Q. Preparation of alternative 2-((5-(6-substituted-aryloxy)pyridin-2-yl)-2-azabicyclo[4.1.0]heptan-2-yl)methyl)-1-substituted-6-(1H-tetrazol-5-yl)-1H-benzo[d]imidazoles N6. [ka]

[0150] When Y=CN, it is advantageous to introduce the tetrazole heterocycle early in the synthesis. Azide cycloaddition of N2 gives N-substituted 2-nitro-5-(1H-tetrazol-5-yl)anilines Q1, which are reduced and condensed with 2-chloro-1,1,1-trimethoxyethane to give 2-(chloromethyl)-1-substituted-6-(1H-tetrazol-5-yl)-1H-benzo[d]imidazoles Q3. Reaction of Q3 with 5-(6-(aryloxy)pyridin-2-yl)-2-azabicyclo[4.1.0]heptane intermediates A7 in the presence of an acid scavenger such as an alkali carbonate gives N5.

[0151] GLP-1R Cellular Assay

[0152] Stable cell lines expressing high and low GLP-1R surface expression were generated in CHO-K1 cells (Fugene6) transfected with a puromycin-selectable DNA plasmid (deposition number: NM_002062.5) encoding the human GLP-1R receptor under the control of the EF1A promoter. Transfected cells were seeded in 24-well plates (9,000 cells / well) containing complete medium and incubated in a humidified incubator at 37 °C with 5% carbon dioxide. After overnight incubation, the medium was replaced with complete medium supplemented with puromycin (6 μg / mL) and refreshed every 2–3 days to select for stably transfected cells. Individual pools of selected cells were expanded and then analyzed for responsiveness to a GLP-1 control peptide using a TR-FRET assay for detecting cAMP (LANCE UltracAMP assay, PerkinElmer). Briefly, cells were harvested in Versene solution, plated in 384-well plates (1,000 cells / well) and mixed with serially diluted GLP-1R control peptide (10 nL) using an acoustic dispenser (ECHO). After incubating the plate for 30 min at 25°C, EU-cAMP tracer (5 μL) and Ulight-anti-cAMP reagent (5 μL) were added to each well, followed by incubation for 15 min at 25°C. TR-FRET signals were detected using an EnVision multimode plate reader (excitation = 320 nm, emission = 615 and 655 nm). Dose-response curves were used to measure EC as a measure of responsiveness to the GLP-1R control peptide. 50Values ​​were generated. The responsiveness of selected cell lines was monitored over multiple passages to ensure stability. CHO-K1_hGLP-1Rhigh_clone16 and CHO-K1_hGLP-1Rlow_clone10 showed consistently high and low responsiveness to the GLP-1R control peptide, respectively, and were selected for further analysis to determine the 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 three times with PBS+0.5% BSA before being incubated with FLEX reagent (10 μM) for 2 h at room temperature. After incubation, cells were washed three times with PBS+0.5% BSA and finally resuspended in PBS before analysis by flow cytometry to measure FLEX mean fluorescence intensity (MFI) as a measure of cell surface GLP-1R expression.

[0153] 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 dilutions) and added to the wells (10 nL / well) using an ECHO dispenser, the plates were centrifuged for 1 min, agitated for 2 min at room temperature, and then incubated for 30 min at 25°C. After incubation, Eu-cAMP (5 μL) and Ulight-anti-cAMP (5 μL) reagents were added to each well, followed by centrifugation for 1 min, agitation for 2 min at room temperature, and a final incubation of the plates for 15 min at 25°C. Plates were read using an EnVision microplate reader (excitation = 320 nm, emission = 615 and 655 nm). Dose-response curves were generated from duplicate wells based on percent activation calculated compared to a control GLP-1 peptide agonist run in parallel. EC 50 Values ​​were determined by fitting the percent activation as a function of compound concentration using the Hill equation (XLfit).

[0154] The EC50 values ​​of exemplary compounds 1 and 2 in the low expression assay are shown in the table below. The EC50 values ​​were compared with reference compound A and reference compound B. The compounds tested were compound samples prepared according to the general procedures described in the Examples section.

[0155] Metabolic stability of hepatocytes

[0156] Test compounds were incubated with human hepatocytes to assess stability from a stromal depilation approach. Test compounds were dissolved in dimethyl sulfoxide (DMSO) to make 10 mM stock solutions and further diluted to make 1000x 1 mM working stock solutions with DMSO in 96-well plates for test compounds and positive control (midazolam). Vials containing cryopreserved hepatocytes were removed from the liquid nitrogen tank and immediately immersed in a 37°C water bath. The vials were gently shaken until the contents were thawed and then immediately poured into 48 mL of pre-warmed HT medium in a 50 mL conical tube. The cells remaining in the vial were resuspended in 1.0 mL of pre-warmed HT medium and added to the conical tube. The tube was capped and then gently inverted several times to resuspend the hepatocytes. The cell suspension was centrifuged at 50 x g for 5 min at room temperature and the supernatant was discarded. The cell pellet was loosened by gently swirling the tube and resuspended in 4 mL of warm Dulbecco's Modified Eagle Medium (DMEM). Cell density was determined using a Nexcelom cell counter, and DMEM medium was added to obtain a target density of 1 x 106 cells / mL. The assay was performed in 96-well microtiter plates. Test compounds were added at 1 x 10 at 1 μM in DMEM. 6The mixtures were incubated with 10000 cells / mL hepatocytes for 0, 30, 60, 120 and 240 min. Incubations were performed at 37°C in a humidified atmosphere of 95% air / 5% CO2 with gentle shaking. The volume of the incubation mixture was 37 μL with 0.1% DMSO final. At each time point, the incubation was stopped by adding 150 μL of quenching solution (100% acetonitrile, 0.1% formic acid with bucetin as internal standard for positive ESI mode). The mixtures were then vortexed for 20 min and centrifuged at 4,000 RPM at 10°C. The supernatants (80 μL) were transferred to a clean 96-well plate and analyzed by LC-MS / MS. Midazolam at 1 μM with 0.1% DMSO final was included as a positive control to validate the assay performance. Percentage of parent remaining, intrinsic and predicted hepatic clearance, and t 1 / 2 was calculated. All samples were analyzed by LC-MS / MS using an AB Sciex API4000 instrument connected to a Shimadzu LC-20ADLC pump system. Separation was achieved using a Waters AtlantisT3 dC18 reversed-phase HPLC column (20mmx2.1mm) at a flow rate of 0.5mL / min. The mobile phase consisted of 0.1% formic acid in water (solvent A) and 0.1% formic acid in 100% acetonitrile (solvent B). The elution conditions are detailed below. [Table 2]

[0157] The ion optics for each test compound were optimized for declustering potential (DP), collection energy (CE), and collision cell exit potential (CXP) and used for selected ion monitoring experiments in positive ion mode. The peak area ratio of each test compound relative to the internal standard was then assessed for stability. The extent of metabolism was calculated based on the disappearance of the test compound compared to the initial concentration. The initial rate of clearance of the test compound was calculated using a linear regression plot of the semi-log % remaining of the compound versus time. The elimination rate constant (k) from the linear regression plot was then used to calculate the t using the following equation: 1 / 2and inherent clearance (CL int ) was determined, where C 肝細胞 (million cells / mL) is the cell density of the incubation: k=-slope t 1 / 2 =0.693 / k CL int =k / C 肝細胞

[0158] This method of intrinsic clearance measurement assumes that the concentration of the test compound is much lower than the compound's Michaelis-Menten constant for its metabolic enzyme.

[0159] Predicted hepatic clearance (CL hep ) is the normalized CL based on liver weight int(インビボ) The mixture was calculated using the well-stirred method using the following formula: CL int(インビボ) =CL int × Hepatocellular × Liver weight CL hep予測値 =(CL int(インビボ) ×Q 肝臓 ) / (CL int(インビボ) +Q 肝臓 ) Here, Q 肝臓 (ml / min / kg) is the hepatic blood flow

[0160] Physiological parameters related to human liver weight, blood flow, and hepatocellularity are given below. [Table 3]

[0161] Passive permeability and flux ratio

[0162] Caco-2 cells (clone C2BBe1) were obtained, for example, from the American Type Culture Collection (Manassas, VA). Cell monolayers were grown to confluence on collagen-coated microporous membranes in 12-well assay plates. The permeability assay buffer was Hanks' balanced salt solution, pH 7.4, containing 10 mM HEPES and 15 mM glucose. The buffer in the receiver chamber also contained 1% bovine serum albumin. The concentration of the dosing solution was 5 μM of the test substance in assay buffer. Cell monolayers were dosed apically (A-to-B) or basolaterally (B-to-A) and incubated at 37°C with 5% CO2 in a humidified incubator. Samples were taken from the donor and receiver chambers at 120 min. Each measurement was performed in duplicate. Lucifer Yellow flux was also measured after the experiment for each monolayer to ensure that no damage was done to the cell monolayer during the flux period. All samples were analyzed by LC-MS / MS using electrospray ionization. app ) and the recovery rate were calculated as follows: P app =(dC r / dt) × V r / (A×C A ) (1) Recovery rate = 100 × ((V r ×C r 最終 )+(V d ×C d 最終 )) / (V d ×C N ) (2) In the formula, dC r / dt is the slope of the cumulative receiver concentration versus time (μMs -1 ) and V r is the volume of the receiver compartment (cm 3 ) and V d is the volume of the donor compartment (cm 3 ), and A is the area of ​​the insert (1.13 cm for 12 wells). 2 ) and C Ais the mean of the nominal dose concentration and the measured donor concentration over 120 min (μM), and C N is the nominal concentration of the dosing solution (μM), and C r 最終 is the cumulative receiver concentration at the end of the incubation period (μM), and C d 最終 is the donor concentration (μM) at the end of the incubation period. The efflux ratio (ER) is the ratio of P app (B-to-A) / P app It is defined as (A-to-B).

[0163] Pharmacokinetics in rats

[0164] Intravenous administration: Compounds were formulated at 0.5 mg / mL in a solution containing 5% polyethylene glycol 400 and 95% (12% (w / v) sulfobutyl-β-cyclodextrin in water) (v / v). Formulated compounds were sterile filtered through a 0.22 micron filter prior to administration. Compounds were administered to male 7-11 week old Sprague-Dawley rats via jugular vein cannula injection at a dose of 1 mg / kg over 30 minutes.

[0165] Oral administration: Compounds were formulated at 0.3 mg / mL or 0.6 mg / mL in a solution containing 5% polyethylene glycol 400 and 95% (12% (w / v) sulfobutyl-β-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.

[0166] Sample collection: Approximately 0.2 mL of blood was collected per time point from the jugular vein or other appropriate site of each animal into pre-chilled commercially available EDTA-K2 tubes and placed on wet ice until centrifugation. Blood samples were processed for plasma by centrifugation at 3,200 g for 10 min at approximately 4°C. Plasma was collected, transferred to pre-labeled 96-well plates or polypropylene tubes, flash frozen on dry ice, and stored at or below -60°C until LC-MS / MS analysis.

[0167] Data Analysis: Plasma concentration versus time data were plotted on graphs and analyzed by a non-compartmental approach using the Phoenix WinNonlin 6.3 software program. Relevant PK parameters were calculated according to the route of administration, e.g., CL, V for intravenous administration, and ΔP, V for intravenous administration. dss and C0, and C for extravascular administration. max , T max or %F, T for all routes 1 / 2 , AUC (0-t) , AUC (0-inf) , MRT (0-t) , and MRT (0-inf) was calculated. EXAMPLES

[0168] For illustrative purposes, neutral compounds of formula (0) and formula (1) are synthesized and tested in the Examples. The neutral compounds of formula (0) and formula (1) can be converted to pharma- ceutically acceptable salts of the corresponding compounds using techniques in the art (e.g., by saponification of the ester to a carboxylate salt, or by hydrolysis of the amide to form the corresponding carboxylic acid and then converting the carboxylic acid to a carboxylate salt).

[0169] It is understood that values ​​given in the examples are approximations and are subject to experimental and procedural variations. Abbreviation: [Table 4-1] [Table 4-2]

[0170] Example 1 (Synthesis of Compound 1) Compound 1 was prepared by the synthetic method shown in Scheme 1. Scheme 1 [ka]

[0171] Procedure for the preparation of compound S3 [ka] A mixture of compound S1 (500 mg, 2.52 mmol, 1.1 equiv), compound S2 (704.12 mg, 2.29 mmol, 1 equiv), Pd2(dba)3 (104.97 mg, 114.63 umol, 0.05 equiv), rac-BINAP (142.76 mg, 229.27 umol, 0.1 equiv), and t-BuONa (661.00 mg, 6.88 mmol, 3 equiv) in Tol. (1 mL) was degassed and purged with N2 three times, then the mixture was stirred at 100 °C under N2 atmosphere for 2 h. LC-MS showed that compound S1 was completely consumed. The reaction mixture was cooled to 20 °C, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1). Compound S3 (440 mg, 1.04 mmol, 45% yield) was obtained as a white solid. LCMS:RT=2.142min, MS cal.:424.2,[M+H] + =325.2 1 H NMR(400MHz,CHLOROFORM-d)δ=0.39(br s,1H)1.02-1.21(m,1H)1.50(s,10H)2.75-2.91(m,1H)3.05-3.60(m,4H)3.83-4.08(m,1H)5.41-5.51(m,2H)6.18(d,J=7.82Hz,1H)6.34(br s,1H)7.37(dd,J=9.29,1.22Hz,1H)7.43-7.51(m,2H)7.59-7.66(m,1H).

[0172] General procedure for the preparation of compound S4 [ka] A mixture of compound S3 (400 mg, 942.36 umol, 1 equiv.) in DCM (3 mL), TFA (1 mL) was degassed and purged with N 3 times, then the mixture was stirred under N atmosphere at 100° C. for 2 h, at which point the reaction mixture was concentrated under reduced pressure. Compound S4 was used directly as a yellow oil.

[0173] General procedure for the preparation of compounds S6A and S6B [ka] A mixture of compound S4, compound S5 (300 mg, 924.92 umol, 1 eq.), K2CO3 (383.49 mg, 2.77 mmol, 3 eq.) in CH3CN (5 mL) was degassed and purged with N2 three times, then the mixture was stirred under N2 atmosphere at 50°C for 3 h. The reaction mixture was filtered and partitioned with 5 mL of H2O. The mixture was extracted with EtOAc (10 mL x 3). The organic layers were combined, washed with 10 mL of brine, and concentrated under reduced pressure. The residue was purified by preparative HPLC (neutral condition column: Waters Xbridge Prep OBDC 18150*40mm*10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 45%-80%, 8 min) to give the desired compound (400mg, 90% yield, 90% purity) as a white solid, which was further separated by SFC (condition: column: DAICEL CHIRALCEL OD (250mm*30mm, 10um); mobile phase: [0.1% NH3H2OMEOH]; B%: 50%-50%, 15 min). Compound S6A (120mg, 196.83μmol, 21.28% yield) was obtained as a white solid. LCMS:RT=2.532min,MS cal.:617.2,[M+H] + =618.2 1H NMR(400MHz,CHLOROFORM-d)δ=0.46-0.61(m,1H)0.79(q,J=6.30Hz,1H)1.22(d,J=6.00Hz,1H)1.25-1.31(m,1H)2. 37-2.45(m,1H)2.58-2.66(m,1H)2.72-2.83(m,2H)3.00-3.09(m,1H)3.96(s,3H)4.01-4.08(m,1H)4.10-4.21(m,3 H)5.37-5.52(m,2H)5.86(s,2H)6.16(d,J=7.88Hz,1H)6.31(d,J=8.00Hz,1H)7.34(d,J=9.26Hz,1H)7.41-7.51(m, 2H)7.61(t,J=7.50Hz,1H)7.79(d,J=8.38Hz,1H)7.90(s,1H)8.02(d,J=8.50Hz,1H)8.15(s,1H)8.74-8.77(m,1H). Compound S6B (80 mg, 131.22umol, yield 14.19%) was obtained as a white solid. LCMS: RT = 2.534 minutes, MS cal.: 617.2, [M+H] + =618.2 1 H NMR(400MHz,CHLOROFORM-d)δ=0.50-0.60(m,1H)0.79(q,J=6.34Hz,1H)1.20-1.29(m,1H)2.39-2.47(m,1H)2 .59-2.67(m,1H)2.72-2.84(m,3H)3.05(ddd,J=12.38,9.76,2.25Hz,1H)3.96(s,4H)4.03-4.21(m,4H)5.37-5 .50(m,2H)5.86(s,2H)6.16(d,J=7.88Hz,1H)6.31(d,J=8.13Hz,1H)7.34(d,J=9.38Hz,1H)7.41-7.50(m,3H)7 .61(t,J=7.44Hz,1H)7.79(d,J=8.50Hz,1H)7.90(s,1H)8.02(d,J=8.50Hz,1H)8.15(s,1H)8.74-8.77(m,1H).

[0174] The preparation of compound 1 is generally smooth.

change

[0175] Example 2 (Synthesis of Compound 2) Compound 2 was prepared from compound S6B, the preparation of which is described in Example 1. [ka]

[0176] To a solution of compound S6B (70 mg, 114.82 umol, 1 equiv.) in THF (0.7 mL) was added LiOH.H2O (9.64 mg, 229.63 umol, 2 equiv.) in H2O (0.3 mL). The mixture was stirred at 25 °C for 12 h. The mixture was directly purified. The residue was purified by preparative HPLC (neutral condition column: Waters Xbridge BEHC18100 * 30 mm * 10 um; mobile phase: [water (NH4HCO3)-ACN]; B%: 30% ~ 60%, 8 min). Compound 2 (35 mg, 58.76 umol, 51.18% yield) was obtained as a white solid. LCMS:Rt=2.474min,MS cal.:595.65,[M+H] + =596.6 HPLC: Rt=11.346 min 1 H NMR(400MHz,METHANOL-d4)δ=0.47-0.54(m,1H)0.68-0.78(m,1H)2.35-2.45(m,1H)2.65(td,J=7.43 ,5.56Hz,1H)2.73-2.85(m,2H)2.93-3.02(m,1H)4.06-4.25(m,3H)5.44(s,2H)5.98(s,2H)6.11(d,J= 7.70Hz,1H)6.34(d,J=8.07Hz,1H)7.46(t,J=7.95Hz,1H)7.51-7.58(m,2H)7.60-7.66(m,1H)7.71(d, J=8.44Hz,1H)7.99(dd,J=8.56,1.47Hz,1H)8.05(s,1H)8.27(d,J=0.86Hz,1H)8.92(d,J=0.73Hz,1H)

[0177] Example 3 (Synthesis of Compound 16) 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-azabicyclo[4.1.0]heptan-2-yl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, mixture of four diastereomers [ka]

[0178] Preparation of 2-(tert-butyl) 5-methyl 2-azabicyclo[4.1.0]heptane-2,5-dicarboxylate (2) [ka] A mixture of 2-(tert-butoxycarbonyl)-2-azabicyclo[4.1.0]heptane-5-carboxylic acid (2.5 g, 10.4 mmol, 1 equiv.), CHI (2.94 g, 20.7 mmol, 1.29 mL, 2 equiv.), KCO (2.15 g, 15.5 mmol, 1.5 equiv.) in DMF (30 mL) was degassed and purged with N three times, then the mixture was stirred under N atmosphere at 25° C. for 1 h. TLC (petroleum ether / ethyl acetate=5 / 1, R f =0.46) indicated that the starting material was completely consumed. The combined reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL*2). The combined organic phase was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / Purification with ethyl acetate=100 / 1 to 0 / 1) gave the product as an oil (2.4 g, 9.40 mmol, 90.7% yield). 1 H NMR(400MHz,DMSO-d6)δ3.67(d,J=10.8Hz,3H),3.45-3.38(m,0.5H),3.04-2.90(m,0.5H),2.89-2.61(m,2H),1.86 -1.71(m, 1H), 1.70-1.55(m, 1H), 1.45-1.40(m, 9.5H), 1.33-1.19(m, 0.5H), 0.88-0.73(m, 1H), 0.34~0.26(m, 1H).

[0179] Preparation of 2-(tert-butyl) 5-methyl 5-(6-chloropyridin-2-yl)-2-azabicyclo[4.1.0]heptane-2,5-dicarboxylate (3) [ka] To a solution of 2-(tert-butyl) 5-methyl 2-azabicyclo[4.1.0]heptane-2,5-dicarboxylate (1.5 g, 5.88 mmol, 1 equiv.) and 2,6-dichloropyridine (869 mg, 5.88 mmol, 1 equiv.) in THF (15 mL), a solution of KHMDS (1 M, 6.46 mL, 1.1 equiv.) was added slowly to control the internal temperature within -10 to -3 °C. Then the reaction mixture was kept stirring at -10 to -5 °C for 1.5 to 2 h. TLC showed that the starting material was completely consumed. The reaction mixture was poured into water (50 mL) and extracted with EA (50 mL*2). The combined organic phase was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to give the product as a white solid (1.5 g, 4.09 mmol, yield 69.6%).

[0180] Preparation of 2-(tert-butoxycarbonyl)-5-(6-chloropyridin-2-yl)-2-azabicyclo[4.1.0]heptane-5-carboxylic acid (4) [ka] A mixture of 2-(tert-butyl) 5-methyl 5-(6-chloropyridin-2-yl)-2-azabicyclo[4.1.0]heptane-2,5-dicarboxylate (1.4 g, 3.82 mmol, 1 eq.), NaOH (2M, 5.72 mL, 3 eq.) in MeOH (15 mL) was degassed and purged with N2 three times, then the mixture was stirred at 45°C under N2 atmosphere for 12 h. LCMS showed that the starting material was completely consumed. The solution was concentrated under vacuum at about 40°C to remove about 1 / 2 of the solvent. The aqueous layer was neutralized with aqueous HCl (2N, about 7 mL, 3.5 eq.) at -5°C to 5°C to pH about 3-5. A white suspension was formed during neutralization. The reaction mixture was filtered and the filter cake was washed with H2O (10 mL*3). The filter cake was dissolved in DCM (30 mL), washed with brine (30 mL) and concentrated under reduced pressure to give the product as a white solid (1.3 g, 3.68 mmol, 96.6% yield); LCMS: RT=1.262 min, MS cal.: 352.82, [M-55] + =297.1.

[0181] Preparation of tert-butyl 5-(6-chloropyridin-2-yl)-2-azabicyclo[4.1.0]heptane-2-carboxylate (5) [ka] A mixture of 2-(tert-butoxycarbonyl)-5-(6-chloropyridin-2-yl)-2-azabicyclo[4.1.0]heptane-5-carboxylic acid (1.3 g, 3.68 mmol, 1 equiv) in dioxane (13 mL) was degassed and purged with N2 three times, then the mixture was stirred at 100° C. under N2 atmosphere for 12 h. LCMS showed that the starting material was completely consumed. The reaction mixture was concentrated to give the crude product as a white solid (1.2 g, crude); LCMS: RT=2.127 min, MS cal.: 308.81, [M-55] + =253.1.

[0182] Preparation of tert-butyl 5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-azabicyclo[4.1.0]heptane-2-carboxylate (6) [ka] A mixture of tert-butyl 5-(6-chloropyridin-2-yl)-2-azabicyclo[4.1.0]heptane-2-carboxylate (0.8 g, 2.59 mmol, 1 equiv.), 3-fluoro-4-(hydroxymethyl)benzonitrile (392 mg, 2.59 mmol, 1 equiv.), Cs2CO3 (1.77 g, 5.44 mmol, 2.1 equiv.), Pd2(dba)3 (237 mg, 259 mmol, 0.1 equiv.) and BINAP (323 mg, 518 mmol, 0.2 equiv.) in dioxane (12 mL) Degassed and purged with N2 three times, then the mixture was stirred at 100°C under N2 atmosphere for 12 h. LCMS showed that the starting material was completely consumed. The combined reaction mixture was poured into water (50mL) and extracted with ethyl acetate (50mL*2). The combined organic phase was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=100 / 1 to 0 / 1) to give the product as a white solid (0.8g, 1.89mmol, yield 72.9%); 1 H NMR(400MHz,DMSO-d6)δ=7.94-7.83(m,1H),7.75-7.63(m,3H),7.09-6.9 9(m,1H),6.82-6.72(m,1H),5.53-5.43(m,2H),3.87-3.66(m,1H),3.27-3 .15(m,1H),2.93-2.81(m,1H),2.66-2.57(m,1H),1.84-1.74(m,1H),1.4 6-1.41(m, 10H), 0.91-0.79(m, 1H), 0.72-0.60(m, 1H), 0.44-0.31(m, 1H).

[0183] Preparation of 4-(((6-(2-azabicyclo[4.1.0]heptan-5-yl)pyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile (7) [ka] A mixture of tert-butyl 5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-azabicyclo[4.1.0]heptane-2-carboxylate (0.7 g, 1.65 mmol, 1 eq.), TFA (3.08 g, 27.0 mmol, 2 mL, 16.3 eq.) in DCM (5 mL) was degassed and purged with N2 three times, then the mixture was stirred at 25° C. under N2 atmosphere for 1 h. LCMS showed that the starting material was completely consumed. The reaction mixture was concentrated to give the crude product as a white solid (0.73 g, crude, TFA); LCMS: RT=0.899 min, MS cal.: 323.37, [M+H] + =324.2.

[0184] Preparation of methyl 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-azabicyclo[4.1.0]heptan-2-yl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (8) [ka] A mixture of 4-(((6-(2-azabicyclo[4.1.0]heptan-5-yl)pyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile (483 mg, 1.50 mmol, 0.9 equiv.), methyl 2-(chloromethyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (0.73 g, 1.67 mmol, 1 equiv., TFA), K2CO3 (1.38 g, 10.0 mmol, 6 equiv.) in ACN (5 mL) was degassed and purged with N2 three times, then the mixture was stirred at 60° C. under N2 atmosphere for 2 h. LCMS showed that the starting material was completely consumed. TLC (petroleum ether / ethyl acetate 0 / 1R) f=0.45) indicated that the starting material was completely consumed. The combined reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL*2). The combined organic phase was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=100 / 1 to 0 / 1) to give the product as a white solid (0.6 g, 986 mmol, yield 59.1%); LCMS: RT=1.029 min, MS cal.: 608.89, [M+H] + =609.3.

[0185] Preparation of 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-azabicyclo[4.1.0]heptan-2-yl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 16) [ka] A mixture of methyl 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-azabicyclo[4.1.0]heptan-2-yl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (50 mg, 82.1 mmol, 1 equiv.), LiOH.H2O (5.17 mg, 123 mmol, 1.5 equiv.) in THF (0.7 mL) and H2O (0.3 mL) was degassed and purged with N2 three times, then the mixture was stirred at 30 °C under N2 atmosphere for 12 h. LCMS showed that the starting material was completely consumed. The reaction mixture was filtered and the filtrate was concentrated. The crude product was purified by reverse phase HPLC (column: Phenomenex C1875*30mm*3um; mobile phase: [water (NH4HCO3)-ACN]; B%: 25%~60%, 8min) to give the product as a white solid (24.8mg, 39.2umol, yield 47.7%, purity 94%); LCMS: RT=1.654min, MS cal.: 594.67, [M+H] + =595.2;HPLC:RT=9.205min, purity:95.41%; 1H NMR(400MHz,METHANOL-d4)δ8.92(s,1H),8.23(s,1H),8.04(s,1H),8.01-7.94(m, 1H),7.72-7.49(m,5H),7.00(d,J=8.0Hz,1H),6.72(d,J=8.0Hz,1H),6.03(s,2H), 5.57(s,2H),4.23-4.08(m,2H),3.28-3.20(m,1H),2.74-2.60(m,2H),2.55-2.45( m,1H),1.75-1.62(m,2H),1.49-1.38(m,1H),0.67-0.60(m,1H),0.44-0.32(m,1H).

[0186] Intermediates of Examples 4 to 6 [ka] Methyl 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-azabicyclo[4.1.0]heptan-2-yl)methyl)-1-(thiazol)-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (0.58 g) was purified by SFC (column: DAICEL CHIRALPAKAD (250 mm*30 mm, 10 mm); mobile phase: [0.1% NH3H2 OIPA]; B%: 40% to 40%, 12 min) to give intermediate 9A as a white solid (50 mg, 82.1 mmol, 8.62% yield), intermediate 9B as a white solid (50 mg, 82.1 mmol, 8.62% yield), intermediate 9C as a white solid (50 mg, 82.14 mmol, 8.62% yield), and intermediate 9D as a white solid (50 mg, 82.14 mmol, 8.62% yield).

[0187] Example 4 (Synthesis of Compound 4) 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-azabicyclo[4.1.0]heptan-2-yl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, diastereomer 1 [ka] A mixture of methyl 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-azabicyclo[4.1.0]heptan-2-yl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (Intermediate 9A, 50 mg, 82.1 mmol, 1 equiv.), LiOH.H2O (5.17 mg, 123 umol, 1.5 equiv.) in THF (0.7 mL) and H2O (0.3 mL) was degassed and purged with N2 three times, then the mixture was stirred at 30° C. under N2 atmosphere for 12 h. LCMS showed that the starting material was completely consumed and one major peak with the desired mass was detected. The reaction mixture was filtered and the filtrate was concentrated. The crude product was purified by reversed-phase HPLC (column: Waters Xbridge Prep OBDC 18150*40mm*10mm; mobile phase: [water (NH4HCO3)-ACN]; B%: 20%-50%, 8 min). The crude product was purified by reversed-phase HPLC (column: C18-1150*30mm*5mm; mobile phase: [water (FA)-ACN]; B%: 15%-40%, 20 min) to give the product as a white solid (6.37mg, 10.5umol, yield 12.7%, purity 97.71%); LCMS: RT=2.274min, MS cal.: 594.67, [M+H] + =595.2;HPLC:RT=9.259min, purity:97.71%;SFC:RT=10.562min, purity:99.34%; 1H NMR(400MHz,METHANOL-d4)δ=8.93(s,1H),8.25(s,1H),8.05(s,1H),7.98(d,J=8.4Hz,1H),7.71- 7.67(m,2H),7.62(m,1H),7.56-7.50(m,2H),6.91(d,J=8.0Hz,1H),6.69(d,J=8.0Hz,1H),6.02(s, 2H),5.58-5.47(m,2H),4.22-4.15(d,J=13.6Hz,1H),4.09-4.03(d,J=13.6Hz,1H),2.84-2.79(m,1 H),2.71-2.66(m,1H),2.42-2.33(m,2H),1.78-1.66(m,2H),1.30-1.24(m,1H),0.56-0.49(m,2H).

[0188] Example 5 (Synthesis of Compound 5) 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-azabicyclo[4.1.0]heptan-2-yl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, diastereomer 2 [ka] A mixture of methyl 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-azabicyclo[4.1.0]heptan-2-yl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (Intermediate 9B, 100 mg, 164 mmol, 1 equiv.), LiOH.H2O (10.34 mg, 246 mmol, 1.5 equiv.) in THF (0.7 mL) and H2O (0.3 mL) was degassed and purged with N2 three times, then the mixture was stirred at 30 °C under N2 atmosphere for 12 h. LCMS showed that the starting material was completely consumed and one major peak with the desired mass was detected. The reaction mixture was filtered and the filtrate was concentrated. The crude product was purified by reverse phase HPLC (column: Waters Xbridge Prep OBDC 18150*40mm*10mm; mobile phase: [water (NH4HCO3)-ACN]; B%: 20%-50%, 8 min) to give the product as a white solid (51.4 mg, 83.3 mmol, yield 50.7%, purity 96.4%); LCMS: RT=2.258 min, MS cal.: 594.67, [M+H] + =595.2;HPLC:RT=9.326min, purity:96.40%;SFC:RT=9.504min, purity:98.74%; 1 H NMR(400MHz,DMSO-d6)δ=9.03(s,1H),8.21(s,1H),8.09(s,1H),7.92(d,J=10.1Hz, 1H),7.81(d,J=8.4Hz,1H),7.74-7.65(m,4H),7.03(d,J=8.0Hz,1H),6.76(d,J=8.0 Hz,1H),5.97(s,2H),5.56-5.46(m,2H),4.14-4.01(m,2H),3.27-3.17(m,1H),2.70 -2.54(m,3H),1.69-1.54(m,2H),1.41-1.33(m,1H),0.53(m,1H),0.32-0.25(m,1H).

[0189] Example 6 (Synthesis of Compound 14) 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-azabicyclo[4.1.0]heptan-2-yl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, diastereomer 3 [ka] A mixture of methyl 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-azabicyclo[4.1.0]heptan-2-yl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (Intermediate 9C, 100 mg, 164 mmol, 1 equiv.), LiOH.H2O (10.3 mg, 246 mmol, 1.5 equiv.) in THF (0.7 mL) and H2O (0.3 mL) was degassed and purged with N2 three times, then the mixture was stirred at 30° C. under N2 atmosphere for 12 h. LCMS showed that the starting material was completely consumed. The reaction mixture was filtered and the filtrate was concentrated. The crude product was purified by reverse phase HPLC (column::Waters Xbridge Prep OBDC 18150*40mm*10m; mobile phase: [water (NH4HCO3)-ACN]; B%: 30%~60%, 8 min) to give the product as a white solid (39.1mg, 65.8umol, 40.0% yield); LCMS: RT=1.646min, MS cal.: 594.67, [M+H] + =595.3;HPLC:RT=9.197min, purity:96.20%;SFC:RT=17.233min, purity:98.01%; 1H NMR(400MHz,DMSO-d6)δ=9.02(s,1H),8.27-8.15(m,1H),8.08(m,1H),7.93-7.87(m,1 H),7.85-7.75(m,1H),7.69(m,4H),7.02(d,J=8.0Hz,1H),6.76-6.72(d,J=8.0Hz,1H), 6.00-5.88(s,2H),5.55-5.44(m,2H),4.18-3.95(s,2H),3.22(m,2H),2.59-2.54(m,2 H),2.49-2.40(m,1H),1.60(m,2H),1.35(m,1H),0.62-0.47(m,1H),0.35-0.23(m,1H).

[0190] Example 7 (Synthesis of Compound 15) 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-azabicyclo[4.1.0]heptan-2-yl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, diastereomer 4 [ka] A mixture of methyl 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-azabicyclo[4.1.0]heptan-2-yl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (Intermediate 9D, 30 mg, 49.3 mmol, 1 equiv.), LiOH.H2O (3.10 mg, 73.9 mmol, 1.5 equiv.) in THF (0.7 mL) and H2O (0.3 mL) was degassed and purged with N2 three times, then the mixture was stirred at 30° C. under N2 atmosphere for 12 h. LCMS showed that the starting material was completely consumed. The mixture was used directly without workup. The crude product was purified by reverse phase HPLC (column: Waters Xbridge Prep OBDC 18150*40mm*10mm; mobile phase: [water (NH4HCO3)-ACN]; B%: 20%~50%, 8 min) to give the product as a white solid (12.7mg, 21.4mmol, 43.3% yield); LCMS: RT=1.628min, MS cal.: 594.67, [M+H] + =595.2;HPLC:RT=9.290min, purity:97.42%;SFC:RT=8.630min, purity:99.60%; 1 H NMR(400MHz,DMSO-d6)δ=8.98(s,1H),8.19(s,1H),8.08(s,1H),7.89-7.84(m,1H),7.83-7.79(m,1H),7 .75-7.63(m,4H),6.96-6.92(d,J=8.0Hz,1H),6.76-6.71(d,J=8.0Hz,1H),5.97(s,2H),5.52-5.43(m,2H) ),4.16-4.08(d,J=13.6Hz,1H),3.98(d,J=13.6Hz,1H),2.81-2.74(m,1H),2.66-2.57(m,1H),2.44-2.3 6(m,1H),2.31-2.21(m,1H),1.67-1.58(m,2H),1.22-1.13(m,1H),0.55-0.46(m,1H),0.44-0.35(m,1H).

[0191] Example 8 (Synthesis of Compound 21) 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-azabicyclo[4.1.0]heptan-2-yl)methyl)-1-((R)-2-methoxypropyl)-1H-benzo[d]imidazole-6-carboxylic acid, mixture of four diastereomers [ka]

[0192] Preparation of methyl (R)-3-((2-methoxypropyl)amino)-4-nitrobenzoate (2) [ka] A mixture of methyl 3-fluoro-4-nitrobenzoate (2 g, 10.0 mmol, 1 equiv), (R)-2-methoxypropan-1-amine (1.26 g, 10.0 mmol, 1 equiv), TEA (3.35 g, 33.1 mmol, 4.61 mL, 3.3 equiv) in THF (20 mL) was degassed and purged with N2 three times at 20 °C, then the mixture was stirred under N2 atmosphere at 60 °C for 16 h. LCMS showed that the starting material was completely consumed and one major peak with the desired mass was detected. The residue was diluted with H2O (100 mL) and extracted with 150 mL of EtOAc (50 mL * 3). The combined organic layer was washed with 15 mL of H2O (5 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=100 / 1 to 10 / 1) to give the product as a yellow solid (6 g, 9.69 mmol, yield 96.50%); LCMS: RT=0.746 min, MS cal.: 268.2, [M+H] + =269.0.

[0193] Preparation of methyl (R)-4-amino-3-((2-methoxypropyl)amino)benzoate (3) [ka] To a solution of methyl (R)-3-((2-methoxypropyl)amino)-4-nitrobenzoate (2.5 g, 9.32 mmol, 1 equiv.) in THF (30 mL) was added Pd / C (1 g, 10% purity) at 25° C. under N2 atmosphere. The suspension was degassed and purged with H2 three times. The mixture was stirred under H2 (15 Psi) at 25° C. for 2 h. LCMS showed that the starting material was completely consumed and one major peak with the desired mass was detected. The reaction was filtered, the filter cake was washed with ethyl acetate and concentrated under reduced pressure to give the product as a white solid (2.2 g, 9.23 mmol, 99.1% yield); LCMS: RT=0.494 min, MS cal.: 238.2, [M+H] + =239.0; 1 H NMR(400MHz,CHLOROFORM-d)δ=7.46(d,J=8.0Hz,1H),7.35(s,1H),6.69(d,J=8.0Hz,1H),3.91-3.85(s,3H),3.80(br s,2H),3.71-3.63(m,1H),3.40(s,3H),3.25(m,1H),3.08(m,1H),1.27(d,J=6.0Hz,3H).

[0194] Preparation of methyl (R)-2-(chloromethyl)-1-(2-methoxypropyl)-1H-benzo[d]imidazole-6-carboxylate (4) [ka] A mixture of methyl (R)-4-amino-3-((2-methoxypropyl)amino)benzoate (1 g, 4.20 mmol, 1 equiv), 2-chloro-1,1,1-trimethoxyethane (1.95 g, 12.6 mmol, 1.69 mL, 3 equiv), TosOH (72.3 mg, 420 umol, 0.1 equiv) in CH3CN (10 mL) was degassed and purged with N2 three times at 20°C, then the mixture was stirred at 60°C under N2 atmosphere for 1 h. LCMS showed that the starting material was completely consumed and one major peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=100 / 1 to 10 / 1) to give the product as a white solid (1 g, 3.37 mmol, 80.3% yield); LCMS: RT=1.651 min, MS cal.: 296.7, [M+H] + =297.0.

[0195] Preparation of methyl 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-azabicyclo[4.1.0]heptan-2-yl)methyl)-1-((R)-2-methoxypropyl)-1H-benzo[d]imidazole-6-carboxylate (5) [ka] A mixture of methyl (R)-2-(chloromethyl)-1-(2-methoxypropyl)-1H-benzo[d]imidazole-6-carboxylate (91.8 mg, 309 mmol, 1 equiv.), 4-(((6-(2-azabicyclo[4.1.0]heptan-5-yl)pyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile (100 mg, 309 mmol, 1 equiv.), K2CO3 (128 mg, 928 mmol, 3 equiv.) in CH3CN (1 mL) was degassed and purged with N2 three times at 20 °C, then the mixture was stirred at 60 °C under N2 atmosphere for 2 h. LCMS showed that the starting material was completely consumed and one major peak with the desired mass was detected. The residue was diluted with H2O (1 mL), extracted with EtOAc (3 mL*3), dried over Na2SO4, filtered and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1) to give the product as a white solid (100 mg, 171 mmol, yield 55.4%); LCMS: RT = 2.420 min, MS cal.: 583.6, [M+H] + =584.2.

[0196] Preparation of 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-azabicyclo[4.1.0]heptan-2-yl)methyl)-1-((R)-2-methoxypropyl)-1H-benzo[d]imidazole-6-carboxylic acid, a mixture of four diastereomers (compound 21) [ka] A mixture of methyl 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-azabicyclo[4.1.0]heptan-2-yl)methyl)-1-((R)-2-methoxypropyl)-1H-benzo[d]imidazole-6-carboxylate (120 mg, 206 mmol, 1 equiv.), LiOH.HO (12.9 mg, 308 mmol, 1.5 equiv.) in THF (1.4 mL) / HO (0.6 mL) was degassed and purged with N three times at 20 °C, then the mixture was rinsed with N 2Stirred at 20°C under atmosphere for 12 hours. LCMS showed that the starting material was completely consumed and one major peak with the desired mass was detected. The reaction mixture was filtered and the filtrate was concentrated. The crude product was purified by reverse phase HPLC (column: WatersXbridgeBEHC18100*25mm*5mm; mobile phase: [water(NH4HCO3)-ACN]; B%: 30%~65%, 8 min) to give the product as a white solid (36.8mg, 61.3mmol, yield 29.8%, purity 94.88%); LCMS: RT=2.660min, MS cal.: 569.6, [M+H] + =570.3; 1 H NMR(400MHz,CHLOROFORM-d)δ=8.24(s,1H)8.06(d,J=8.4Hz,1H)7.82(d,J=8.4Hz,1H)7.67-7 .52(m,2H)7.48-7.34(m,2H)6.99-6.85(d,J=8.4Hz,1H)6.68(d,J=8.4Hz,1H)5.51(s,2H)4.61 (m,1H)4.45-4.05(m,3H)3.89-3.75(m,1H)3.32-3.14(m,4H)2.74-2.60(m,2H)2.43-2.57(m, 1H)1.84-1.57(m,2H)1.47-1.38(m,1H)1.34-1.26(m,3H)0.66-0.57(m,1H)0.53-0.39(m,1H).

[0197] Example 9 (Synthesis of Compound 46) 2-((2-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-azabicyclo[4.1.0]heptan-5-yl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, mixture of four diastereomers [ka]

[0198] Preparation of methyl 2-((diethoxyphosphoryl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (4c) [ka] To a mixture of methyl 2-(chloromethyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (5 g, 15.5 mmol, 1 equiv.) in toluene (50 mL) was added triethyl phosphite (3.87 g, 23.3 mmol, 4.00 mL, 1.5 equiv.) in one portion at 20 °C. The mixture was stirred at 100 °C for 12 h. LC-MS showed about 58% starting material remaining. LC-MS showed some new peaks and about 31% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to give the product as a yellow oil (1.9 g, 4.49 mmol, 28.9% yield); LCMS: RT = 0.564 min, MS cal.: 423.10, [M+H] + =424.1;LCMS:RT=1.395 min, MS cal.:423.10, [M+H] + =424.1;1H NMR(400MHz,CHLOROFORM-d)δ=8.75(s,1H),8.12(s,1H),8.03-7.97(m,1H),7.81-7.70(m,2H),5. 89(s,2H), 4.13(q,J=7.2Hz,4H),3.94(s,3H),3.59-3.51(d,J=21.6Hz,2H),1.30(t,J=7.2Hz,6H)

[0199] Preparation of tert-butyl 4-hydroxy-3,4-dihydropyridine-1(2H)-carboxylate (2) [ka] Et2O (1000 mL) was charged into a 2L three-necked round bottom flask, then tert-butyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (25 g, 125 mmol, 1 equiv) was added at 20°C. At -78°C, n-BuLi (2.5 M, 151 mL, 3 equiv) was added dropwise to the reaction mixture at -78°C within 1 h. After addition, the mixture was stirred at -78°C for 1 h. The resulting mixture was stirred at 25°C for 1 h. TLC showed that the starting material was completely consumed and many new spots were formed. According to TLC, the reaction was messy. The reaction mixture was quenched with saturated aqueous NaHCO3 (350 mL) at 0°C within 30 min. The mixture was extracted with EtOAc (200 mL*3). The organic phase was then washed with aqueous NaCl (300 mL). The organics were dried over Na2SO4, filtered and concentrated under reduced pressure at 30 °C to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 15 / 1 to 6 / 1) to give the product as a yellow oil (17 g, 85.3 mmol, 34% yield); LCMS: Rt = 1.368 min, MS cal.: 199.12, [M-tBu-OH] + =126.1;1H NMR (400MHz, CHLOROFORM-d)δ=7.06-6.77(m,1H),5.12-4.89(m,1H),4.19(m,1H),3.85(m,1H),3.33(m,1H),1.89-1.80(m,2H),1.48(s,9H).

[0200] Preparation of tert-butyl 5-hydroxy-2-azabicyclo[4.1.0]heptane-2-carboxylate (3) [ka] Et2O (80mL) was charged into a 500mL three-neck round bottom flask, then the material tert-butyl 4-hydroxy-3,4-dihydropyridine-1(2H)-carboxylate (8g, 40.2mmol, 1eq) was added at 20°C. At 0°C, ZnEt2 (1M, 100mL, 2.5eq) was added dropwise to the reaction mixture within 1h at 0°C. CH2I2 (43g, 161mmol, 13mL, 4eq) was added dropwise to the reaction mixture within 0.5h at 0°C. After addition, the mixture was stirred at 20°C for 12h. TLC showed that the starting material was completely consumed and many new spots were formed. The reaction mixture was added to H2O (100ml) within 0.5h at 0°C. The mixture was extracted with EtOAc (50mL*3). The organic phase was then washed by NaCl (50mL*1). The organics were dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=10 / 1 to 3 / 1) to give the product as a yellow oil (3.5 g, 16.4 mmol, 20.4% yield); LCMS: RT=1.307 min, MS cal.: 213.14, [M-tBu+H] + =158.1.

[0201] Preparation of tert-butyl 5-oxo-2-azabicyclo[4.1.0]heptane-2-carboxylate (4) [ka] NMO (2.47 g, 21.1 mmol, 2.23 mL, 3 equiv.) was added to a solution of tert-butyl [5-hydroxy-2-azabicyclo[4.1.0]heptane-2-carboxylate (1.5 g, 7.03 mmol, 1 equiv.), molecular sieves 3A (2.5 g), and TPAP (247 mg, 703 mmol, 0.1 equiv.) in DCM (25 mL) at 0 °C. The reaction mixture was warmed to 20 °C and stirred for 2 h. TLC showed that the starting material was completely consumed and one new spot was formed. The reaction was clean by TLC. The reaction mixture was diluted with DCM (5 mL) and filtered through silica gel. The organic layer was washed with saturated Na2S2O3 (5 mL), water (2 mL), brine (2 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=15 / 1 to 8 / 1) to give the product as a yellow solid (1.05 g, 4.97 mmol, 70.7% yield); 1 H NMR (400MHz, CHLOROFORM-d)δ=4.21-3.89(m,1H),3.58-3.21(m,2H),2.46-2.21(m,2H),1.87(m,1H),1.49(m,10H),1.23-1.06(m,1H).

[0202] Methyl (Z)-2-((2-(tert-butoxycarbonyl)-2-azabicyclo[4.1.0]heptan-5-ylidene)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (5) [ka] THF (10 mL) was charged into a 25 mL three-neck round bottom flask followed by methyl 2-((diethoxyphosphoryl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (1.82 g, 4.30 mmol, 1 equiv). At 0°C, NaH (275 mg, 6.89 mmol, 60% purity, 1.6 equiv) was added portionwise to the reaction mixture. After 30 min, tert-butyl 5-oxo-2-azabicyclo[4.1.0]heptane-2-carboxylate (1 g, 4.73 mmol, 1.1 equiv) was added to the reaction mixture at 0°C. The mixture was stirred at 20°C for 2 h. TLC showed that the starting material was completely consumed. The reaction mixture was added to NaHCO3 at 0°C. The mixture was extracted with EtOAc (10 mL*2). The organic phase was then washed with 10 mL of brine. The organics were dried over Na2SO4, filtered and concentrated under reduced pressure at 30°C to give a residue. The residue was purified by column chromatography (SiO2, DCM:MeOH=100 / 1 to 50 / 1) to give the product as an oil (1.3 g, 2.71 mmol, 62.9% yield); LCMS: RT=0.633 min, MS cal.: 480.10, [M+H] + =481.1, 1H NMR(400MHz,CHLOROFORM-d)δ=8.75(s,1H),8.09(s,1H),8.00(d,J=8.4Hz,1H),7.83-7.73( m,2H),6.56-6.34(m,1H),5.63(s,2H),4.16-3.97(m,0.5H),3.95(s,3H),3.93-3.81(m,1H) ,3.53-3.44(m,0.5H),3.35-3.18(m,1H),3.01-2.74(m,1H),2.48-2.36(m,1H),2.34-2.18( m, 0.5H), 2.10-1.96 (m, 0.5H), 1.71-1.57 (m, 0.5H), 1.53-1.48 (m, 9.5H), 0.96-0.82 (m, 1H).

[0203] Methyl 2-((2-(tert-butoxycarbonyl)-2-azabicyclo[4.1.0]heptan-5-yl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (6) [ka] To methyl (Z)-2-((2-(tert-butoxycarbonyl)-2-azabicyclo[4.1.0]heptan-5-ylidene)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (1 g, 2.08 mmol, 1 equiv.) in MeOH (100 mL) was added Pd / C (1 g, 10% purity) under N2 atmosphere. The suspension was degassed and purged with H2 three times. The mixture was stirred at 25 °C under H2 (50 psi) for 4 h. LC-MS showed that the starting material was completely consumed and the 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, petroleum ether / ethyl acetate=10 / 1 to 0 / 1) to give the product as a white solid (1 g, 2.07 mmol, 99.6% yield); LCMS: RT=1.306 min, MS cal.: 482.2, [M+H] + =483.3.

[0204] Methyl 2-((2-azabicyclo[4.1.0]heptan-5-yl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (7) [ka] To methyl 2-((2-(tert-butoxycarbonyl)-2-azabicyclo[4.1.0]heptan-5-yl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (0.3 g, 622 mmol, 1 equiv.) in DCM (3 mL), TFA (924 mg, 8.10 mmol, 600.00 mL, 13.04 equiv.) was added. The mixture was stirred at 20 °C for 1 h. TLC showed that the starting material was completely consumed and one new spot was formed. The reaction mixture was diluted with Na2CO3 until pH = 8-9 and extracted with 30 mL of DCM (15 mL*2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give the product as a yellow solid (200 mg, 523 mmol, 84.1% yield); LCMS: RT=0.740 min, MS cal.: 382.15, [M+H] + =383.1.

[0205] Methyl 2-((2-(6-fluoropyridin-2-yl)-2-azabicyclo[4.1.0]heptan-5-yl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (8) [ka] A mixture of methyl 2-((2-azabicyclo[4.1.0]heptan-5-yl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (143 mg, 375 mmol, 1.1 equiv), 2-bromo-6-fluoropyridine (60 mg, 341 mmol, 1 equiv), K2CO3 (141 mg, 1.02 mmol, 3 equiv) in DMF (2 mL) was degassed and purged with N2 three times, then the mixture was stirred at 80 °C under N2 atmosphere for 12 h. LC-MS showed that the starting material was completely consumed and the desired mass was detected. The residue was diluted with H2O (20 mL) and extracted with 20 mL of EtOAc (10 mL*2). 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=10 / 1 to 0 / 1) to give the product as a white solid (100 mg, 186 umol, 54.5% yield); LCMS: RT=0.947 min, MS cal.: 477.17, [M+H] + =478.2.

[0206] Preparation of methyl 2-((2-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-azabicyclo[4.1.0]heptan-5-yl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (9) [ka] A mixture of methyl 2-((2-(6-fluoropyridin-2-yl)-2-azabicyclo[4.1.0]heptan-5-yl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (100 mg, 186 mmol, 1 equiv.), 3-fluoro-4-(hydroxymethyl)benzonitrile (28.07 mg, 186 mmol, 1 equiv.), XphosPdG4 (16 mg, 18.6 mmol, 0.1 equiv.), t-BuONa (44.6 mg, 464 mmol, 2.5 equiv.) in toluene (2 mL) was degassed and purged with N2 three times, then the mixture was stirred at 100° C. for 2 h under N2 atmosphere. LC-MS showed that the starting material was completely consumed and the desired mass was detected. The residue was diluted with H2O (20 mL) and extracted with 20 mL of EtOAc (20 mL*3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=10 / 1 to 0 / 1) to give the product (70 g, 115 mmol, 61.9% yield); LCMS: Rt=2.689 min, MS cal.: 608.2, [M+H] + =609.2

[0207] Preparation of 2-((2-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-azabicyclo[4.1.0]heptan-5-yl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, a mixture of four diastereomers (compound 46) [ka] To a solution of methyl 2-((2-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-azabicyclo[4.1.0]heptan-5-yl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (65 mg, 107 mmol, 1 equiv.) in THF (0.7 mL) was added LiOH.HO (5.38 mg, 128 mmol, 1.2 equiv.) in HO (0.3 mL). The mixture was stirred at 20 °C for 12 h. LC-MS showed that the starting material was completely consumed and the desired mass was detected. The residue was purified by preparative HPLC (neutral condition; column: Waters Xbridge Prep OBDC 18150*40mm*10mm; mobile phase: [water (NH4HCO3)-ACN]; B%: 30%-70%, 8 min) to give the product as a white solid (28 mg, 47.1 mmol, 44.1% yield); LCMS: RT=1.986 min, MS cal.: 594.18, [M+H] + = 595.2; HPLC: RT = 3.096 min; 1 H NMR(400MHz,DMSO-d6)δ9.00(s,1H)8.27(s,1H)7.99(s,1H)7.90-7.85(m,1H)7.81(m,1H)7.72 -7.62(m,3H)7.51-7.42(m,1H)6.35-6.28(m,1H)6.10-6.03(m,1H)5.96-5.88(m,2H)5.44-5.3 6(m,2H)4.40~4.31(m,1H)3.12-3.02(m,1H)3.00-2.90(m,1H)2.84-2.68(m,2H)2.61-2.55(m, 1H)1.76-1.68(m,1H)1.54-1.43(m,1H)1.00-0.82(m,1H)0.79-0.69(m,1H),0.25-0.21(m,1H).

[0208] Intermediates of Examples 10-11 [ka]

[0209] Preparation of tert-butyl 5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (2) [ka] A mixture of tert-butyl 2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (500 mg, 2.52 mmol, 1.1 equiv), 4-(((6-bromopyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile (704 mg, 2.29 mmol, 1 equiv), Pd2(dba)3 (105 mg, 115 mmol, 0.05 equiv), BINAP (143 mg, 229 mmol, 0.1 equiv), and t-BuONa (661 mg, 6.88 mmol, 3 equiv) in toluene (5 mL) was degassed and purged with N2 three times, then stirred at 100 °C under N2 atmosphere for 1 h. LCMS showed that the starting material was completely consumed and one major peak with the desired mass was detected. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (50 mL). The organic layer was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1) to give the product as a white solid (440 mg, 1.04 mmol, 45% yield); RT = 2.142 min, MS cal.: 424.2, [M+H] + =325.2; 1 H NMR(400MHz,CHLOROFORM-d)δ7.66-7.59(m,1H),7.51-7.43(m,2H),7.37(d,J=9.2Hz,1H),6.34(m,1H),6.18(d,J=7.6Hz,1H ),5.51-5.41(m,2H),4.08-3.83(m,1H),3.60-3.05(m,4H),2.91-2.75(m,1H),1.50(s),9H),1.21-1.02(m,1H),0.39(m,1H).

[0210] Preparation of 4-(((6-(2,5-diazabicyclo[4.1.0]heptan-2-yl)pyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile (3) [ka] A mixture of tert-butyl 5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-azabicyclo[4.1.0]heptane-2-carboxylate 400 mg, 942 mmol, 1 equiv), TFA (107 mg, 942 mmol, 69.8 mL, 1 equiv) in DCM (4 mL) was degassed and purged with N2 three times, then the mixture was stirred under N2 atmosphere at 20 °C for 1 h. TLC showed complete consumption of starting material and one new spot formed. The reaction was clean by TLC. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC (neutral conditions: column: Waters Xbridge Prep OBDC 18150*40mm*10um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 45%~80%B8min) to give the desired compound as a white solid (300mg, yield 45%, purity 95%).

[0211] Preparation of methyl 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (4A) and (4B) [ka] A mixture of 4-(((6-(2,5-diazabicyclo[4.1.0]heptan-5-yl)pyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile (298 mg, 925 mmol, 1 equiv.), K2CO3 (383 g, 2.77 mmol, 3 equiv.) in CH3CN (5 mL) was degassed and purged with N2 three times, then the mixture was stirred at 60° C. under N2 atmosphere for 3 h. LCMS showed that the starting material was completely consumed and one major peak with the desired mass was detected. The resulting product was dissolved in EtOAc (20 ml) and filtered to remove insoluble material. The filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (neutral conditions column: Waters Xbridge Prep OBDC 18150*40mm*10mm; mobile phase: [water (NH4HCO3)-ACN]; B%: 45%-80%, 8 min) to give a mixture of intermediates 4A&4B (400mg, 90% yield, 90% purity) as a white solid, which was further separated by SFC (conditions: column: DAICEL CHIRALCEL OD (250mm*30mm, 10mm); mobile phase: [0.1% NH3H2OMEOH]; B%: 50%-50%, 15 min). Intermediate 4A-isomer 1 was obtained as a white solid (120mg, 197mmol, 21.3% yield). RT=2.532min, MS cal: 617.2, [M+H] + =618.2; 1H NMR(400MHz,CHLOROFORM-d)δ8.77(s,1H),8.15(s,1H),8.02(d,J=8.4Hz,1H),7.90(s,1H),7.79(d,J=8. 4Hz,1H),7.61(t,J=7.6Hz,1H),7.51-7.41(m,2H),7.34(d,J=9.2Hz,1H),6.31(d,J=8.0Hz,1H),6.16(d,J = 8.0 Hz, 1H), 5.86(s, 2H), 5.52-5.37(m, 2H), 4.21-4.10(m, 3H), 4.08-4.01(m, 1H), 3.96(s, 3H), 3.09-3.00(m, 1H), 2.83-2.72(m, 2H), 2.66-2.58(m, 1H), 2.45-2.37(m, 1H), 0.81-0.79(m, 1H), 0.61-0.46(m, 1H). Intermediate 4B-isomer 1 was obtained as a white solid (80 mg, 131 mmol, 14.2% yield). RT = 2.534 min, MS cal: 617.2, [M+H] + =618.2; 1 H NMR(400MHz,CHLOROFORM-d)δ=8.77(s,1H),8.15(s,1H),8.02(d,J=8.4Hz,1H),7.90(s,1H),7.79( d,J=8.4Hz,1H),7.61(t,J=7.6Hz,1H),7.50-7.41(m,2H),7.34(d,J=9.4Hz,1H),6.31(d,J=8.0Hz,1 H),6.16(d,J=8.0Hz,1H),5.86(s,2H),5.50-5.37(m,2H),4.21-4.03(m,4H),3.96(s,3H),3.05(m, 1H),2.84-2.72(m,2H),2.67-2.59(m,1H),2.47-2.39(m,1H),0.81-0.79(m,1H),0.60-0.50(m,1H).

[0212] Example 10 (Synthesis of Compound 2) 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, diastereomer 1 [ka] A mixture of methyl 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (90 mg, 148 mmol, 1 equiv.), LiOH.HO (12.4 mg, 295 mmol, 2 equiv.) in THF (0.7 mL) and HO (0.3 mL) was degassed and purged with N three times, and the mixture was stirred at 25° C. under N atmosphere for 12 h. LCMS showed that the starting material was completely consumed and one major peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC (neutral condition, column: Waters Xbridge Prep OBDC 18150×40mm×10mm; mobile phase: [water (NH4HCO3)-ACN]; B%: 20%-50%, 8 min) to give the product as a white solid (29.9mg, 50.2mmol, 34% yield); RT=2.508min, MS cal.: 595.2, [M+H] + =596.1; 1 H NMR(400MHz,METHANOL-d4)δ=8.94(s,1H),8.27(s,1H),8.06(s,1H),8.01(d,J=8.4Hz,1H) ,7.71(d,J=8.4Hz,1H),7.68-7.62(m,1H),7.57-7.53(m,2H),7.48(t,J=8.0Hz,1H),6.36( d,J=8.0Hz,1H),6.13(d,J=8.0Hz,1H),6.00(s,2H),5.46(s,2H),4.24-4.08(m,3H),3.00( m,1H),2.85-2.76(m,2H),2.67(m,1H),2.45-2.37(m,1H),0.75(m,1H),0.55-0.49(m,1H).

[0213] Example 11 (Synthesis of Compound 1) 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, diastereomer 2 [ka] To a solution of methyl 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (70 mg, 115 mmol, 1 equiv.) in THF (0.7 mL) was added LiOH.HO (9.64 mg, 230 mmol, 2 equiv.) in HO (0.3 mL). The mixture was stirred at 25 °C for 12 h. LC-MS showed that the starting material was completely consumed and the desired mass was detected. The residue was purified by preparative HPLC (neutral condition: column: WatersXbridgeBEHC18100*30mm*10um; mobile phase: [water(NH4HCO3)-ACN]; B%: 30%~60%, 8min) to give the product as a white solid (35mg, 58.76mmol, yield 51.2%); RT=1.843min, MS cal.: 595.65, [M+H] + =596; 1 H NMR(400MHz,METHANOL-d4)δ8.93(s,1H),8.26(s,1H),8.04(s,1H),7.99(d,J=8.4Hz,1H) ,7.72(d,J=8.4Hz,1H),7.67-7.62(m,1H),7.55-7.51(m,2H),7.45(t,J=8.0Hz,1H),6.34( d,J=8.0Hz,1H),6.11(d,J=8.0Hz,1H),6.07(s,2H),5.43(s,2H),4.24-4.06(m,3H),2.97( m,1H),2.79-2.76(m,2H),2.65(m,1H),2.45-2.38(m,1H),0.75(m,1H),0.51-0.48(m,1H).

[0214] Intermediates of Examples 12-13 [ka]

[0215] Preparation of 4-(((2-chloropyrimidin-4-yl)oxy)methyl)-3-fluorobenzonitrile (2) [ka] t-BuOK (4.14 g, 36.9 mmol, 1.1 equiv) was added in portions to 3-fluoro-4-(hydroxymethyl)benzonitrile (5.33 g, 35.2 mmol, 1.05 equiv) in THF (40 mL) at 20° C. and then stirred until complete dissolution. This solution was added dropwise to 2,4-dichloropyrimidine (5 g, 33.6 mmol, 1 equiv) in DMF (60 mL) at <−65° C. under N2 atmosphere over 1.5 h. The reaction mixture was slowly warmed to 10° C. over 1.5 h and stirred for 0.5 h. LCMS showed 0.3% starting material and 85.9% product. The reaction mixture was slowly poured into H2O (300 mL) at 0° C., forming a solid. The mixture was stirred for 15 min and filtered. The solid was collected, dissolved in DCM (100 mL), washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product (5 g). The crude product was stirred in MTBE (10 mL), stirred for 5 min, n-hexane (50 mL) was added to the mixture, stirred for 10 min, filtered and the filter cake was collected. The cake was added in MTBE (5 mL), stirred for 5 min, n-hexane (25 mL) was added to the mixture, stirred for 5 min, filtered, the cake was collected and dried in vacuum for 20 min to give the product as a yellow solid (4 g, 15.2 mmol, 45.2% yield); RT=2.056 min, MS cal.: 263.0, [M+H] + =264.0; 1H NMR (400MHz, CHLOROFORM-d)δ=8.40(d,J=5.6Hz,1H)7.64(t,J=7.2Hz,1H)7.55-7.39(m,2H)6.80-6.71(d,J=5.6Hz,1H,1H)5.55(s,2H).

[0216] Preparation of tert-butyl 5-4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (3) [ka] A mixture of 4-(((2-chloropyrimidin-4-yl)oxy)methyl)-3-fluorobenzonitrile (500 mg, 1.90 mmol, 1 equiv.), tert-butyl [2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (490 mg, 2.09 mmol, 1.1 equiv., HCl), K2CO3 (786 mg, 5.69 mmol, 3 equiv.) in DMF (5 mL) was degassed and purged with N2 three times, then the mixture was stirred at 100 °C under N2 atmosphere for 1 h. LC-MS showed that the starting material was completely consumed and the desired mass was detected. The residue was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x 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 = 20 / 1 to 0 / 1) to give the product as a white solid (500 mg, 1.18 mmol, 61.9% yield); RT = 2.522 min, MS cal.: 425.19, [M+H] + =426.2, 1 H NMR(400MHz,CHLOROFORM-d)δ=8.24(s,1H)7.66-7.59(m,1H)7.53(d,J=9.6Hz,1H)7.42(d,J=9.6Hz,1H)6.19(d ,J=5.6Hz,1H)5.60(s,2H)3.94-3.72(m,1H)3.71-3.31(m,3H)3.29-3.05(m,2H)1.59-1.70(m,1H)1.53(s,9H).

[0217] Preparation of 4-(((2-(2,5-diazabicyclo[4.1.0]heptan-2-yl)pyrimidin-4-yl)oxy)methyl)-3-fluorobenzonitrile (4) [ka] To a solution of tert-butyl 5-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (0.3 g, 705 mol, 1 eq.) in DCM (3 mL) was added TFA (1.54 g, 13.5 mmol, 1.00 mL, 19.2 eq.). The mixture was stirred at 25° C. for 1 h. LC-MS showed that the starting material was completely consumed and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to give the product as a yellow oil (220 mg, 676 umol, 95.9% yield); RT=0.777 min, MS cal.: 325.13, [M+H] + =326.3.

[0218] Preparation of methyl 2-((5-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (6A and 6B) [ka] To a solution of 4-(((2-(2,5-diazabicyclo[4.1.0]heptan-2-yl)pyrimidin-4-yl)oxy)methyl)-3-fluorobenzonitrile (210 mg, 645 mmol, 1 equiv.) in CH3CN (1 mL) was added K2CO3 (268 mg, 1.94 mmol, 3 equiv.) and methyl 2-(chloromethyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (208 mg, 645 mmol, 1 equiv.). The mixture was stirred at 60 °C for 1 h. LC-MS showed that the starting material was completely consumed and the desired mass was detected. The residue was diluted with H2O (30 mL) and extracted with EtOAc (30 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 = 0 / 1 to dichloromethane / methanol = 10 / 1). The residue was further separated by SFC (conditions: column: DAICELCHIRALPAKAD (250mm*30mm, 10um), mobile phase: [0.1% NH3H2OMEOH], B%: 60% to 60%, 5 min) to give intermediate 6A as a white solid (120mg, 197mmol, yield 30.4%); LCMS: RT=2.229min, MS cal.: 610.19, [M+H] + = 611.2; SFC: RT = 1.174 min, ee%: 100.0%, and intermediate 6B was obtained as a white solid (120 mg, 197 mmol, 30.4% yield); LCMS: RT = 2.229 min, MS cal.: 610.19, [M+H] + = 611.1; SFC: RT = 1.685 min, ee%: 97.9%.

[0219] Example 12 (Synthesis of Compound 20) 2-((5-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid [ka] To a solution of methyl 2-((5-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (100 mg, 164 mmol, 1 equiv.) in THF (1.4 mL) was added LiOH.HO (13.7 mg, 328 mmol, 2 equiv.) in HO (0.6 mL). The mixture was stirred at 20 °C for 12 h. LC-MS showed that the starting material was completely consumed and the desired mass was detected. The residue was purified by preparative HPLC (neutral condition: column: Waters Xbridge Prep OBDC 18150*40mm*10mm; mobile phase: [water (NH4HCO3)-ACN]; B%: 20%~60%, 8 min) to give the product as a white solid (29mg, 48.6umol, 29.7% yield); LCMS: RT=1.626min, MS cal.: 596.18, [M+H] + = 597.2;SFC: RT = 1.312 min, ee%: 99.64%; 1 H NMR(400MHz,METHANOL-d4)δ=8.94(s,1H)8.27(s,1H)8.16-8.04(m,2H)8.00(d, J=8.4Hz,1H)7.71(d,J=8.4Hz,1H)7.69-7.63(m,1H)7.60-7.53(m,2H)6.19(d,J= 5.6Hz,1H)6.01(s,2H)5.67(s,2H)4.26-4.15(m,2H)4.13-4.08(m,1H)3.13-2.9 8(m,2H)2.87-2.78(m,1H)2.45-2.61(m,1H)2.55-2.42(m,1H)0.83-0.53(m,2H).

[0220] Example 13 (Synthesis of Compound 19) 2-((5-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid [ka] A mixture of methyl 2-((5-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (110 mg, 180 mmol, 1 equiv.), LiOH.HO (15.1 mg, 360 mmol, 2 equiv.) in THF (3 mL) and HO (1.2 mL) was degassed and purged with N three times, then the mixture was stirred at 25° C. under N atmosphere for 12 h. LC-MS showed complete consumption of starting material and one major peak with desired m / z. The reaction solution was adjusted to pH=7 with citric acid. The residue was purified by preparative HPLC (neutral condition: column: Waters Xbridge Prep OBDC 18150*40mm*10mm; mobile phase: [water (NH4HCO3)-ACN]; B%: 10%~45%, 8 min) to give the product as a white solid (26.2mg, 43.8mmol, 24.3% yield), LCMS: RT=1.631min, MS cal.: 596.18, [M+H] + = 597.2;SFC: RT = 1.381 min, ee%: 99.70%; 1 H NMR(400MHz,METHANOL-d4)δ=ppm8.94(s,1H)8.27(s,1H)8.12-8.07(m,1H) 8.05(s,1H)7.99(d,J=8.6Hz,1H)7.73-7.63(m,2H)7.60-7.54(m,2H)6.19(d ,J=5.6Hz,1H)5.99(s,2H)5.52(s,2H)4.27-4.15(m,2H)4.14-4.08(m,1H)3. 14-3.00(m,2H)2.82(m,1H)2.66(m,1H)2.52-2.43(m,1H)0.84-0.52(m,2H).

[0221] Intermediate of Examples 14-15 [ka]

[0222] Preparation of methyl 4-amino-3-(((1-ethyl-1H-1,2,3-triazol-5-yl)methyl)amino)benzoate (2) [ka] A mixture of intermediate 1 (1 g, 3.28 mmol, 1 equiv), Fe (915 mg, 16.4 mmol, 5 equiv), NH4Cl (876 mg, 16.4 mmol, 5 equiv) in MeOH (10 mL) and HO (5 mL) was stirred at 70 °C under N2 atmosphere for 2 h. TLC showed that the starting material was completely consumed and one new spot was formed. The reaction mixture was filtered and the filtrate was concentrated. The residue was diluted with HO (100 mL) and extracted with DCM (40 mL * 3). The combined organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give the product as a white solid (800 mg, 2.91 mmol, 88.7% yield), which was used directly in the next step.

[0223] Preparation of methyl 2-(chloromethyl)-1-((1-ethyl-1H-1,2,3-triazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (3) [ka] A mixture of methyl 4-amino-3-(((1-ethyl-1H-1,2,3-triazol-5-yl)methyl)amino)benzoate (300 mg, 1.09 mmol, 1 equiv.), 2-chloroacetyl chloride (110.77 mg, 980.73 mmol, 78.00 mL, 0.9 equiv.) and TosOH (37.53 mg, 217.94 mmol, 0.2 equiv.) in CH3CN (5 mL) was stirred at 60 °C under N2 atmosphere for 1 h. LCMS showed that the starting material was completely consumed and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to give the product as a brown solid (360 mg, 1.08 mmol, 99% yield), which was used directly in the next step; LCMS: RT = 0.697 min, MS cal.: 333.8, [M+H] + =334.2

[0224] Preparation of methyl 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)methyl)-1-((1-ethyl-1H-1,2,3-thiazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (4A and 4B) [ka] To a solution of methyl 2-(chloromethyl)-1-((1-ethyl-1H-1,2,3-triazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (320 mg, 958.74 mmol, 1 equiv.) and 4-(((6-(2,5-diazabicyclo[4.1.0]heptan-2-yl)pyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile (311 mg, 959 mmol, 1 equiv.) in CH3CN (5 mL) was added K2CO3 (398 mg, 2.88 mmol, 3 equiv.). The mixture was stirred at 50 °C for 4 h. LCMS showed that the starting material was completely consumed and the desired mass was detected. 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), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO2, dichloromethane:methanol = 100 / 1 to 10 / 1) to give the product as a yellow solid (405 mg, 651 mmol, 68% yield), LCMS: RT = 2.439 min, MS cal.: 621.7, [M+H] + =622.3.

[0225] The product (400mg) was further separated by SFC (conditions, column: DAICELCHIRALPAKAD (250mm*30mm,10um); mobile phase: [0.1%NH3H2OMEOH]; B%: 60%~60%, 20min) to give intermediate 4A-isomer 1 as a yellow solid (150mg, 241mmol, 35% yield); LCMS: RT=2.448min, MS cal.: 621.7, [M+H] +=622.3; SFC: RT = 1.678 min, ee%: 100%; 1 H NMR (400 MHz, CHLOROFORM - d) δ = 8.04 (d, J = 8.0 Hz, 1H), 8.03 (s, 1H), 7.82 (d, J = 9.2 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.49 - 7.41 (m, 2H), 7.34 (d, J = 9.2 Hz, 1H), 7.23 (s, 1H), 6.28 (d, J = 8.0 Hz, 1H), 6.15 (d, J = 8.0 Hz, 1H), 5.74 (s, 2H), 5.47 (d, J = 14 Hz, 1H), 5.42 (d, J = 14 Hz, 1H), 4.40 (q, J = 7.2 Hz, 2H), 4.09 - 3.97 (m, 3H), 3.95 (s, 3H), 2.92 - 2.83 (m, 1H), 2.75 - 2.61 (m, 2H), 2.57 - 2.49 (m, 1H), 2.38 - 2.29 (m, 2H)m, 1H), 1.56 - 1.43 (t, J = 7.2 Hz, 3H), 0.76 - 0.73 (m, 1H), 0.53 - 0.47 (m, 1H) and Intermediate 4B - Isomer 2 was obtained as a yellow solid (154 mg, 248 mmol, yield 36%); LCMS: RT = 2.454 min, MS cal.: 621.7, [M + H] + =622.3; SFC: RT = 2.220 min, ee%: 100%; 1 H NMR (400 MHz, CHLOROFORM - d) δ = 8.07 - 8.02 (m, 2H), 7.83 (d, J = 9.2 Hz, 1H), 7.61 (t, J = 7.2 Hz, 1H), 7.49 - 7.41 (m, 2H), 7.34 (d, J = 9.2 Hz, 1H), 7.24 (s, 1H), 6.28 (d, J = 8.0 Hz, 1H), 6.16 (d, J = 8.0 Hz, 1H), 5.74 (s, 2H), 5.46 (d, J = 14 Hz, 1H), 5.38 (d, J = 14 Hz, 1H), 4.40 (q, J = 7.2 Hz, 2H), 4.11 - 4.01 (m, 2H), 4.00 - 3.95 (m, 1H), 3.95 (s, 3H), 2.93 - 2.83 (m, 1H), 2.76 - 2.61 (m, 2H), 2.53 (m, 1H), 2.35 (m, 1H), 1.50 (t, J = 7.2 Hz, 3H), 0.76 (m, 1H), 0.51 (m, 1H).

[0226] Example 14 (Synthesis of Compound 45) 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)methyl)-1-((1-ethyl-1H-1,2,3-triazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid [ka] To a solution of methyl 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)methyl)-1-((1-ethyl-1H-1,2,3-triazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (80 mg, 129 mmol, 1 equiv.) in THF (0.7 mL) was added LiOH.HO (9.64 mg, 230 mmol, 2 equiv.) in HO (0.3 mL). The mixture was stirred at 25 °C for 12 h. LCMS showed that the starting material was completely consumed and one major peak with the desired mass was detected. The reaction solution was adjusted to pH 6-7 with citric acid. After concentration of the reagents, the residue was purified by preparative HPLC (neutral condition, column: Waters Xbridge Prep OBDC 18150*40mm*10mm; mobile phase: [water (NH4HCO3)-ACN]; B%: 20%~60% 8min) to give the product as a white solid (43.93mg, 72.30umol, yield 56.18%); LCMS: RT=2.491min, MS cal.: 607.7, [M+H] + =608.1;SFC:RT=1.476min, ee%:100%;HPLC:RT=11.507min, purity:98.57%; 1H NMR(400MHz,METHANOL-d4)δ=8.17(s,1H),8.03(d,J=8.4Hz,1H),7.75(d,J=8.4Hz,1H),7.62(t, J=7.2Hz,1H),7.56-7.50(m,2H),7.44(t,J=8Hz,1H),7.20(s,1H),6.30(d,J=8.0Hz,1H),6.09(d ,J=8.0Hz,1H),5.94(s,2H),5.41(s,2H),4.52(q,J=7.2Hz,2H),4.20(d,J=14.0Hz,1H),4.01(m, 2H),2.71-2.54(m,4H),2.29-2.22(m,1H),1.50(t,J=7.2Hz,3H),0.69(m,1H),0.46-0.41(m,1H).

[0227] Example 15 (Synthesis of Compound 44) 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)methyl)-1-((1-ethyl-1H-1,2,3-triazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid [ka] A mixture of methyl 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)methyl)-1-((1-ethyl-1H-1,2,3-triazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (80 mg, 129 mmol, 1 equiv.) and LiOH.HO (10.8 mg, 257 mmol, 2 equiv.) in THF (0.7 mL) and HO (0.3 mL) was stirred at 25 °C for 12 h under N atmosphere. LCMS showed that the starting material was completely consumed and one major peak with the desired mass was detected. The reaction solution was adjusted to pH 6-7 with citric acid. After concentrating the reagents, the residue was purified by preparative HPLC (neutral condition; column: Waters Xbridge Prep OBDC 18150*40mm*10mm; mobile phase: [water (NH4HCO3)-ACN]; B%: 25%~55%, 8 min) to give the product as a white solid (26.9mg, 44.3mmol, 34% yield); LCMS: RT=2.491min, MS cal.: 607.7, [M+H] + =608.1;SFC:RT=1.530min, ee%:100%;HPLC:RT=11.539min, purity:98.67%; 1 H NMR(400MHz,METHANOL-d4)δ=8.15(s,1H)8.03(d,J=8.4Hz,1H)7.76(d,J=8.4Hz,1H)7.59-7. 65(m,1H)7.51-7.55(m,2H)7.44(t,J=8.0Hz,1H)7.20(s,1H)6.30(d,J=8.0Hz,1H)6.10(d,J=8 .0Hz,1H)5.93(s,2H)5.41(s,2H)4.52(q,J=7.2Hz,2H)4.20(d,J=14Hz,1H)3.95-4.05(m,2H) 2.66-2.73(m,1H)2.54-2.65(m,3H)2.26(m,1H)1.50(t,J=7.2Hz,3H)0.69(m,1H)0.44(m,1H).

[0228] Intermediates of Examples 16-17 [ka]

[0229] Preparation of methyl (S)-4-amino-3-((oxetan-2-ylmethyl)amino)benzoic acid (2) [ka] To a solution of methyl (S)-4-nitro-3-((oxetan-2-ylmethyl)amino)benzoic acid (0.5 g, 1.88 mmol, 1 equiv.) in THF (10 mL) was added Pd / C (0.1 g, 751 umol, 10% purity) under N2 atmosphere. The suspension was degassed and purged with H2 three times. The mixture was stirred under H2 (15 Psi) at 20°C for 4 h. TLC showed that the starting material was completely consumed and one new spot was formed. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the product as a colorless oil (400 mg, 1.69 mmol, 90.2% yield).

[0230] Preparation of methyl (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (3) [ka] To a solution of methyl (S)-4-amino-3-((oxetan-2-ylmethyl)amino)benzoic acid (0.3 g, 1.27 mmol, 1 equiv.) in CH3CN (3 mL) was added TosOH (21.9 mg, 127 mmol, 0.1 equiv.) and 2-chloro-1,1,1-trimethoxyethane (206 mg, 1.33 mmol, 179 mL, 1.05 equiv.). The mixture was stirred at 60° C. for 2 h. TLC showed that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure to give the product as a white solid (370 mg, 1.26 mmol, 99% yield); LCMS: RT=0.555 min, MS cal.: 294.74, [M+H] + = 295.9; 1H NMR (400 MHz, chloroform-d) δ = 8.15 (s, 1H) 8.03 (d, J = 8.4 Hz, 1H) 7.81-7.85 (d, J = 8.4 Hz, 1H) 5.22 (m, 1H) 5.08 (s, 2H) 4.68-4.51 (m, 3H) 4.35 (m, Hz, 1H) 3.97 (s, 3H) 2.83-2.72 (m, 1H) 2.50-2.39 (m, 1H).

[0231] Preparation of methyl 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (4A and 4B) [ka] To a solution of methyl (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (0.37 g, 1.26 mmol, 1 equiv.) in ACN (10 mL) was added K2CO3 (522 mg, 3.78 mmol, 3 equiv.) and 4-(((6-(2,5-diazabicyclo[4.1.0]heptan-2-yl)pyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile (409 mg, 1.26 mmol, 1 equiv.). The mixture was stirred at 60 °C for 2 h. LC-MS showed that the starting material was completely consumed and the desired mass was detected. The residue was diluted with H2O (30 mL) and extracted with 30 mL of EtOAc (30 mL*3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was separated by column ecchromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) followed by SFC (column: DAICELCHIRALPAKAD (250mm*30mm, 10um); mobile phase: [0.1%NH3H2OMEOH]; B%: 50% to 50%, 40min) to give the product 4A-isomer 1 as a white solid (180mg, 309mmol, 36% yield) and 4B-isomer 2 as a white solid (180mg, 309mmol, 36% yield); LCMS: RT=2.587min, MS cal.: 582.64, [M+H] + =583.2

[0232] Example 16 (Synthesis of Compound 43) 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid [ka] To a solution of 4A-isomer 1 (100 mg, 172 umol, 1 equiv.) in THF (0.6 mL) was added LiOH.H2O (14.4 mg, 343 umol, 2 equiv.) in H2O (0.2 mL). The mixture was stirred at 20 °C for 12 h. TLC showed that the starting material was completely consumed and one new spot was formed. The mixture was purified by preparative HPLC (neutral condition; column: Waters Xbridge Prep OBDC 18150*40 mm*10 mm; mobile phase: [water (NH4HCO3)-ACN]; B%: 20%-60%, 8 min) to give the product as a white solid (53 mg, 93.2 mmol, 54.3% yield); LCMS: RT=2.368 min, MS cal.: 568.61, [M+H] + =569.2;HPLC:RT=10.178min, purity:99.30%;SFC:RT=1.443min, ee%:100%; 1 H NMR(400MHz,METHANOL-d4)δ=8.32(s,1H)7.97(d,J=8.4Hz,1H)7.67(d,J=8.4Hz,1H)7.65-7.55(m,3 H)7.45(t,J=8.0Hz,1H)6.34(d,J=8.0Hz,1H)6.10(d,J=8.0Hz,1H)5.43(s,2H)5.24(m,1H)4.71(m,1H) )4.66-4.59(m,1H)4.46(m,1H)4.29(d,J=13.6Hz,1H)4.15-4.09(m,1H)4.06(d,J=13.6Hz,1H)3.07-2 .97(m,1H)2.84-2.64(m,4H)2.56-2.46(m,1H)2.42-2.33(m,1H)0.74-0.65(m,1H)0.48-0.40(m,1H).

[0233] Example 17 (Synthesis of Compound 42) 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid [ka] To a solution of 4B-isomer 2 (100 mg, 172 mmol, 1 equiv.) in THF (1.5 mL) was added LiOH·HO (14.41 mg, 343 mmol, 2 equiv.) in HO (0.3 mL). The mixture was stirred at 25 °C for 12 h. TLC showed that the starting material was completely consumed. Adjust the solution to neutral with citric acid and concentrate the solution. The residue was purified by preparative HPLC (neutral condition, column: Waters Xbridge Prep OBDC 18150*40 mm*10 mm; mobile phase: [water (NH4HCO3)-ACN]; B%: 15%-45%, 8 min) to give the product as a white solid (31.9 mg, 56.0 mmol, 32.6% yield); LCMS: RT=1.824 min, MS cal.: 568.61, [M+H] + =569.2;HPLC:RT=10.196min, purity:97.65%;SFC:RT=1.916min, ee%:99.14%; 1 H NMR(400MHz,METHANOL-d4)δ=8.33(s,1H)8.00(d,J=8.4Hz,1H)7.71(d,J=8.4Hz,1H)7.69-7.63(m,1H)7.60-7.53( m,2H)7.48-7.45(m,1H)6.33(d,J=7.2Hz,1H)6.11(d,J=7.2Hz,1H)5.43(s,2H)5.27-5.25(m,1H)4.90-4.88(m,1H) 4.75-4.73(m,1H)4.64-4.61(m,1H)4.50-4.48(m,1H),4.18(s,1H)4.17-4.15(m,1H)3.10-4.25(m,1H)2.73-2.77( m,3H)2.65-2.62(m,1H)4.50-4.48(m,1H)2.55-2.52(m,1H)2.45-2.49(m,1H)0.74-0.69(m,1H)0.47-0.44(m,1H).

[0234] Example 18 (Synthesis of Compound 34) 2-((5-(2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid [ka]

[0235] Preparation of 4-ethynyl-3-fluorobenzonitrile (2) [ka] A mixture of 3-fluoro-4-formylbenzonitrile (20 g, 134 mmol, 1 equiv.), dimethyl(1-diazo-2-oxopropyl)phosphonic acid (38.6 g, 201 mmol, 1.5 equiv.) K2CO3 (27.8 g, 201 mmol, 1.5 equiv.) in MeOH (200 mL) was degassed and purged with N2 three times, then the mixture was stirred under N2 atmosphere at 0° C. for 2 h. TLC (petroleum ether / ethyl acetate=5 / 1, R f =0.55) indicated the starting material was completely consumed. The combined reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL*2). The combined organic phase was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=100 / 1~0 / 1) to give the product as a white solid (12 g, 82.7 mmol, yield 61.7%).

[0236] Preparation of 4-(4-bromo-2-methylbenzo[d][1,3]dioxol-2-yl)-3-fluorobenzonitrile (3) [ka] 4-Ethynyl-3-fluorobenzonitrile (15.6 g, 82.7 mmol, 1 equiv.), 3-bromobenzene-1,2-diol (12 g, 82.7 mmol, 1 equiv.), PPh3 (2.17 g, 8.27 mmol, Ru(CO) in toluene (120 mL) 12 A mixture of (2.64g, 4.13mmol, 0.05eq) was degassed and purged with N2 three times, then the mixture was stirred at 100℃ under N2 atmosphere for 24h. HPLC showed that the starting material was completely consumed. The combined reaction mixture was poured into water (100mL) and extracted with ethyl acetate (50mL*2). The combined organic phase was concentrated in vacuo to give a residue. The crude product was purified by reverse phase HPLC (column: Welch Xtimate C18 250*100mm#10mm; mobile phase: [water((NH4HCO3)-ACN]; B%: 50%~85%, 20min) to give the product as a black oil (13g, 38.9mmol, 47% yield).

[0237] Preparation of tert-butyl 5-(2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (4) [ka] A mixture of tert-butyl 2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (11.1 g, 56.1 mmol, 1.5 equiv.) 4-(4-bromo-2-methylbenzo[d][1,3]dioxol-2-yl)-3-fluorobenzonitrile (12.5 g, 37.4 mmol, 1 equiv.) Cs2CO3 (18.3 g, 56.1 mmol, 1.5 equiv.) BINAP (2.33 g, 3.74 mmol, 0.1 equiv.) Pd(dba)3 (1.71 g, 1.87 mmol, 0.05 equiv.) in toluene (120 mL) was degassed and purged with N2 three times, then the mixture was stirred at 100° C. for 1 h under N2 atmosphere. LCMS showed that the starting material was completely consumed. TLC (petroleum ether / ethyl acetate=3:1 R f=0.4) indicated that the starting material was completely consumed. The combined reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL*2). The combined organic phase was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=100 / 1 to 10 / 1) to give the product as a yellow solid (5.6 g, 12.4 mmol, yield 33.2%); LCMS: RT=2.670 min, MS cal.: 451.5, [M-55] + =396.1.

[0238] Preparation of 4-(4-(2,5-diazabicyclo[4.1.0]heptan-2-yl)-2-methylbenzo[d][1,3]dioxol-2-yl)-3-fluorobenzonitrile (5) [ka] A mixture of tert-butyl 5-(2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (334 mg, 740 mmol, 1 equiv.) and HCl / EtOAc (4M, 1.67 mL, 9.03 equiv.) in DCM (2 mL) was degassed and purged with N2 three times, then the mixture was stirred at 25° C. under N2 atmosphere for 1 h. LCMS showed that the starting material was completely consumed. The reaction mixture was concentrated to give the crude product as a white solid (260 mg, crude); LCMS: RT=0.579 min, MS cal.: 351.3, [M+H] + =352.1.

[0239] Preparation of methyl 2-((5-(2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (6) [ka] A mixture of 4-(4-(2,5-diazabicyclo[4.1.0]heptan-2-yl)-2-methylbenzo[d][1,3]dioxol-2-yl)-3-fluorobenzonitrile (238 mg, 740 mmol, 1 equiv.), methyl 2-(chloromethyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (260 mg, 740 mmol, 1 equiv.), K2CO3 (307 mg, 2.22 mmol, 3 equiv.) in ACN (5 mL) was degassed and purged with N2 three times, then the mixture was stirred at 60° C. under N2 atmosphere for 2 h. LCMS showed that the starting material was completely consumed. The combined reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (50 mL*2). The combined organic phase was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to give the product as a white solid (330 mg, 518 mmol, 70% yield); LCMS: RT = 0.754 min, MS cal.: 636.70, [M+H] + =637.1 ;1 H NMR(400MHz,CHLOROFORM-d)δ=8.76(s,1H)8.15(s,1H)8.15-8.05(d,J=8.4Hz,1H)7.91 (s,1H)7.81-7.66(m,2H)7.47-7.42(m,1H)7.41-7.34(m,1H)6.77(m,1H)6.49(m,1H)6.4 0(m,1H)5.95(m,2H)4.19-4.08(m,1H)4.06-4.00(m,1H)3.99-3.92(m,3H)3.86-3.66(m, 1H)3.44-3.30(m,1H)2.96-2.83(m,2H)2.65-2.42(m,2H)2.01(s,3H)0.59-0.78(m,2H).

[0240] 2-((5-(2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 34) [ka] A mixture of methyl 2-((5-(2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (330 mg, 518 mmol, 1 equiv.), LiOH.H2O (30.5 mg, 726 mmol, 1.4 equiv.) in THF (2.8 mL) and H2O (1.2 mL) was degassed and purged with N2 three times, then the mixture was stirred at 25 °C under N2 atmosphere for 12 h. LCMS showed that the starting material was completely consumed. The reaction mixture was filtered and the filtrate was concentrated. The crude product was purified by reverse phase HPLC (column: Waters Xbridge Prep OBDC 18150*40mm*10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 25%~55%, 8 min) to give the product as a white solid (25.3mg, 37.3mmol, yield 7.2%, purity 92%); LCMS: RT=1.882min, MS cal.: 622.8, [M+H] + =623.2;HPLC:RT=11.63 min, purity:91.76%; 1 H NMR(400MHz,METHANOL-d4)δ=8.94(d,J=9.6Hz,1H)8.26(s,1H)8.06(s,1H)8.01- 7.97(m,1H)7.80-7.67(m,2H)7.64-7.53(m,2H)6.69-6.77(m,1H)6.50(m,1H)6.31 -6.36(m,1H)5.99(s,2H)4.24-4.14(m,1H)4.13-4.03(m,1H)3.80-3.71(m,1H)3. 29-3.23(m,1H)2.95-2.74(m,2H)2.67-2.43(m,2H)2.05(s,3H)0.74-0.50(m,2H).

[0241] Intermediates of Examples 19 to 22 [ka]

[0242] Example 19 (Synthesis of Compound 37) 2-((5-(2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid [ka] A mixture of methyl 2-((5-(2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (90 mg, 141 mmol, 1 equiv.), LiOH.H2O (8.90 mg, 212 mmol, 212 equiv.) in THF (0.7 mL) and H2O (0.3 mL) was degassed and purged with N2 three times, then the mixture was stirred at 30 °C under N2 atmosphere for 12 h. LCMS showed that the starting material was completely consumed. The reaction mixture was filtered and the filtrate was concentrated. The crude product was purified by reverse phase HPLC (column: Waters Xbridge Prep OBDC 18150*40mm*10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 30%~60%, 8 min) to give the product as a white solid (21.2mg, 34.1mmol, 24.1% yield); LCMS: RT=1.733min, MS cal.: 622.68, [M+H] + =623.2;HPLC:RT=11.74min, purity:94.48%;SFC:RT=5.660min, purity:100.00%; 1H NMR(400MHz,METHANOL-d4)δ=8.97(s,1H)8.27(sHz,1H)8.06(s,1H)7.99(d,J=8.4Hz,1H) 7.78(t,J=7.6Hz,1H)7.70(d,J=8.4Hz,1H)7.66-7.54(m,2H)6.69-6.78(m,1H)6.52-6.48( m,1H)6.36-6.33(m,1H)5.99(s,2H)4.22-4.16(m,1H)4.12-4.07(m,1H)3.80-3.73(m,1H) 3.29-3.24(m,1H)2.91(m,1H)2.80(m,1H)2.64-2.50(m,2H)2.03(s,3H)0.63-0.55(m,2H).

[0243] Example 20 (Synthesis of Compound 38) 2-((5-(2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid [ka] A mixture of methyl 2-((5-(2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (50 mg, 78.5 mmol, 1 equiv.), LiOH.H2O (4.94 mg, 118 mmol, 1.5 equiv.) in H2O (0.1 mL) THF (0.4 mL) was degassed and purged with N2 three times, then the mixture was stirred at 30 °C under N2 atmosphere for 12 h. 71% of the desired compound was detected by LC-MS. The solution was adjusted to neutral with citric acid and the solution was concentrated. The residue was further purified by preparative HPLC (neutral condition, column: Waters Xbridge Prep OBDC 18150*40mm*10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 30%-60%, 8 min) to give the product as a white solid (17.5mg, 28.1umol, 35.7% yield); LCMS: RT=1.722min, MS cal.: 622.68, [M+H] + =623.2;HPLC:RT=11.691 min, purity:91.87%; 1 H NMR(400MHz,METHANOL-d4)δ=8.93(s,1H),8.27(s,1H),8.06(s,1H),7.99(d,J=8.4Hz,1 H),7.78-7.68(m,2H),7.63-7.54(m,2H),6.77-6.71(m,1H),6.52(m,1H),6.37-6.32(m,1 H),5.99(s,2H),4.24-4.16(d,J=13.6Hz,1H),4.11-4.04(d,J=13.6Hz,1H),3.79-3.71(m ,1H),2.87-2.75(m,2H),2.67-2.60(m,1H),2.48(m,1H),2.02(s,3H),0.72-0.60(m,2H).

[0244] Example 21 (Synthesis of Compound 36) 2-((5-(2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid [ka] A mixture of methyl 2-((5-(2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (110 mg, 173 mmol, 1 equiv.), LiOH.H2O (10.9 mg, 259 mmol, 1.5 equiv.) in THF (0.7 mL) and H2O (0.3 mL) was degassed and purged with N2 three times, then the mixture was stirred at 30 °C under N2 atmosphere for 12 h. TLC showed that the starting material was completely consumed. The reaction mixture was filtered and the filtrate was concentrated. The crude product was purified by reverse phase HPLC (column: Waters Xbridge Prep OBDC 18150*40mm*10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 35%~65%, 8 min) to give the product as a white solid (15.2mg, 24.4mmol, 14.1% yield); LCMS: RT=1.733min, MS cal.: 622.68, [M+H] + =623.2;HPLC:RT=11.770min, purity:93.95%;SFC:RT=5.825min, purity:100.00%, 1H NMR (400 MHz, methanol-d4) δ = 8.92 (s, 1H) 8.26 (s, 1H) 8.06 (s, 1H) 7.99 (d, J = 8.4 Hz, 1H) 7.77-7.68 (m, 2H) 7.61-7.454 (m, 2H) 6.76-6.71 (m, 1H) 6.51 (m, 1H) 6.34 (m, 1H) 5. 98(s,2H)4.22-4.16(m,1H)4.10-4.04(m,1H)3.79-3.71(m,1H)3.29-3.23(m,1H)2 .85-2.76(m,2H)2.66-2.60(m,1H)2.50-2.44(m,1H)2.02(s,3H)0.71-0.60(m,2H).

[0245] Example 22 (Synthesis of Compound 35) 2-((5-(2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid [ka] To a solution of methyl 2-((5-(2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxyol-4-yl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)methyl)-1-(thiazol-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (100 mg, 157 mmol, 1 e eq) in THF (0.7 mL) was added LiOH.HO (9.89 mg, 236 mmol, 1.5 eq) in HO (0.3 mL). The mixture was stirred at 20 °C for 12 h. LC-MS showed that the starting material was completely consumed and the desired mass was detected. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBDC 18150*40mm*10um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 30%-60%B, 8 min) to give the product as a white solid (34.6mg, 55.5mmol, yield 35.3%); LCMS: RT=2.118min, MS cal.: 622.68, [M+H]+ =623.2;HPLC:RT=11.544min, purity:93.04%;SFC:RT=1.914min, purity:100.00%, 1 H NMR(400MHz,METHANOL-d4)δ=8.96(s,1H)8.27(s,1H)8.14(,1H)8.00(dd,J=8.4Hz,1H )7.78(t,J=7.6Hz,1H)7.70(d,J=8.4Hz,1H)7.66-7.53(m,2H)6.78-6.67(m,1H)6.50(m ,1H)6.41-6.30(m,1H)6.00(s,2H)4.30-4.04(m,2H)3.81-3.70(m,1H)3.29-3.24(m,1 H)2.98-2.88(m,1H)2.85-2.73(m,1H)2.65-2.43(m,2H)2.04(s,3H)0.67-0.53(m,2H).

[0246] Example 23 (Synthesis of compound 41): 2-((5-(2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, mixture of four diastereomers [ka]

[0247] Preparation of methyl (S)-4-amino-3-((oxetan-2-ylmethyl)amino)benzoic acid (2) [ka] To a solution of methyl (S)-4-nitro-3-((oxetan-2-ylmethyl)amino)benzoic acid (500 mg, 1.88 mmol, 1 equiv) in MeOH (5 mL) was added Pd / C (10%, 200 mg) under N2 atmosphere. The suspension was degassed and purged with H2 three times. The mixture was stirred under H2 (15 Psi) at 25 °C for 1 h. TLC showed that the starting material was completely consumed and one new spot was formed. The reaction was clean by TLC. The reaction solution was filtered and the filtrate was concentrated to give the product as a white solid (400 mg, 1.69 mmol, 90.2% yield).

[0248] Preparation of methyl (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (3) [ka] A mixture of methyl (S)-4-amino-3-((oxetan-2-ylmethyl)amino)benzoic acid (300 mg, 1.27 mmol, 1 equiv.), 2-chloro-1,1,1-trimethoxyethane (393 mg, 2.54 mmol, 341 mL, 2 equiv.), TosOH (43.7 mg, 254 mmol, 0.2 equiv.) in CH3CN (3 mL) was degassed and purged with N2 three times, then the mixture was stirred under N2 atmosphere at 60 °C for 1 h. TLC showed that the starting material was completely consumed and one new spot was formed. The reaction was clean by TLC. The reaction mixture was concentrated under reduced pressure to give the product as a white solid (350 mg, 1.19 mmol, 93.5% yield); LCMS: RT = 1.590 min, MS cal.: 294.74, [M+H] + =295.0.

[0249] Preparation of methyl 2-((5-(2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (4) [ka] A mixture of methyl (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (247 mg, 840 mmol, 1 equiv.), 4-(4-(2,5-diazabicyclo[4.1.0]heptan-2-yl)-2-methylbenzo[d][1,3]dioxol-2-yl)-3-fluorobenzonitrile (295 mg, 840 mmol, 1 equiv.), K2CO3 (232 mg, 1.68 mmol, 2 equiv.) in ACN (5 mL) was degassed and purged with N2 three times, then the mixture was stirred at 60° C. for 2 h under N2 atmosphere. LCMS showed that the starting material was completely consumed and one major peak with the desired mass was detected. The reaction mixture was diluted with H2O (50 mL), extracted with 150 mL of EtOAc (50 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=100 / 1 to 0 / 1) to give the product as a white solid (250 mg, 410 mmol, 49% yield); LCMS: RT=2.624 min, MS cal.: 609.66, [M+H] + =610.2.

[0250] 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-azabicyclo[4.1.0]heptan-2-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, mixture of four diastereomers (compound 41) [ka] A mixture of methyl 2-((5-(2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (110 mg, 173 mmol, 1 equiv.), LiOH.H2O (10.9 mg, 259 mmol, 1.5 equiv.) in THF (1.2 mL) and H2O (0.3 mL) was degassed and purged with N2 three times, then the mixture was stirred at 30 °C under N2 atmosphere for 12 h. LC-MS showed 22% starting material remaining. LC-MS showed some new peaks and 62% of the desired compound was detected. The solution was adjusted to neutral with citric acid and concentrated. The residue was purified by preparative HPLC (neutral condition, column: Waters Xbridge Prep OBDC 18150*40mm*10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 20%~60%, 8 min) to give the product as a white solid (30mg, 50.4mmol, 20.5% yield); LCMS: RT=1.865min, MS cal.: 595.63, [M+H] + =596.3;HPLC:RT=10.534 min, purity:96.05%; 1 H NMR(400MHz,METHANOL-d4)δ=8.33(s,1H)7.97(d,J=8.4Hz,1H)7.77-7.70(m,1H)7.68(d,J=8.4Hz,1H)7.66-7.60(m ,1H)7.55(d,J=8.0Hz,1H)6.73-6.72(m,1H)6.53-6.49(m,1H)6.35-6.32(m,1H)5.26-5.24(m,1H)4.90-4.89(m,1H) 4.74-4.70(m,1H)4.64-4.62(m,1H)4.47-4.46(m,1H)4.28-4.26(m,0.5H)4.17-4.18(m,1H)4.10-4.05(m,0.5H)3.7 06-3.7(m,1H)3.33-3.31(m,1H)2.80-2.78(m,4H)2.55-2.51(m,2H)2.03-2.01(d,J=4.8Hz,,3H)0.69-0.52(m,2H).

[0251] Example 24 (Synthesis of Compound 40) 2-((5-(2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)methyl)-1-((1-cyanocyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, mixture of four diastereomers [ka]

[0252] Preparation of methyl 3-(((1-cyanocyclopropyl)methyl)amino)-4-nitrobenzoate (2) [ka] A mixture of methyl 3-fluoro-4-nitrobenzoate (1.90 g, 9.55 mmol, 1 equiv.), 1-(aminomethyl)cyclopropane-1-carbonitrile (1.9 g, 14.3 mmol, 1.5 equiv.), TEA (3.87 g, 38.2 mmol, 5.32 mL, 4 equiv.) in THF (10 mL) and MeOH (10 mL) was degassed and purged with N2 three times, then the mixture was stirred under N2 atmosphere at 60° C. for 12 h. TLC (petroleum ether / ethyl acetate=3 / 1, R f =0.46) indicated the starting material was completely consumed and one new spot was formed. The reaction was clean by TLC. The residue was diluted with H2O (100mL) and extracted with ethyl acetate (100mL*3). The combined organic phase was washed with brine (100mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=100 / 1~0 / 1) to give the product as a yellow solid (2.5g, 9.08mmol, yield 95.07%); LCMS: RT=1.948min, MS cal.:275.26,[M+H] + = 276.2; 1H NMR(400MHz,CHLOROFORM-d)δ=8.25(d,J=8.8Hz,1H),8.15(br s,1H),7.58(s,1H),7.35(d,J=8.8Hz,1H),4.01(s,3H),3.57(d,J=5.6Hz,2H),1.48-1.42(m,2H),1.14-1.08(m,2H).

[0253] Preparation of methyl 4-amino-3-(((1-cyanocyclopropyl)methyl)amino)benzoate (3) [ka] A mixture of methyl 3-(((1-cyanocyclopropyl)methyl)amino)-4-nitrobenzoate (2.5 g, 9.08 mmol, 1 equiv.), Fe (5.07 g, 90.8 mmol, 10 equiv.), NH4Cl (4.86 g, 90.8 mmol, 10 equiv.) in HO (8 mL) was degassed and purged with N2 three times, then the mixture was stirred under N2 atmosphere at 70 °C for 2 h. TLC (petroleum ether / ethyl acetate = 3 / 1, R f =0.35) indicated complete consumption of the starting material and the formation of one new spot. The resulting product was dissolved in MeOH and filtered to remove insolubles. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to give the product as a yellow solid (1.94 g, 7.91 mmol, 87% yield); LCMS: RT = 1.529 min, MS cal.: 245.28, [M+H] + =246.1; 1 H NMR(400MHz,DMSO-d6)δ=7.22(d,J=8.0Hz,1H),7.04(s,1H),6.56(d,J=8.0Hz,1H),5.55(br s,2H),4.94(br t,J=5.6Hz,1H),3.72(s,3H),3.23(d,J=5.6Hz,2H),1.30-1.21(m,2H),1.10-1.01(m,2H).

[0254] Preparation of methyl 2-(chloromethyl)-1-((1-cyanocyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate (4) [ka] A mixture of methyl 4-amino-3-(((1-cyanocyclopropyl)methyl)amino)benzoate (300 mg, 1.22 mmol, 1 equiv.), 2-chloro-1,1,1-trimethoxyethane (567 mg, 3.67 mmol, 493 mL, 3 equiv.), TosOH (105 mg, 612 mmol, 0.5 equiv.) in ACN (5 mL) was degassed and purged with N2 three times, then the mixture was stirred at 60° C. under N2 atmosphere for 2 min. LC-MS showed that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure to give the product as a white solid (372 g, crude); LCMS: RT=1.588 min, MS cal.: 303.72, [M+H] + =304.1.

[0255] Preparation of methyl 2-((5-(2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)methyl)-1-((1-cyanocyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate (5) [ka] A mixture of methyl 2-(chloromethyl)-1-((1-cyanocyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate (216 mg, 711 mmol, 1 equiv.), 4-(4-(2,5-diazabicyclo[4.1.0]heptan-2-yl)-2-methylbenzo[d][1,3]dioxol-2-yl)-3-fluorobenzonitrile (250 mg, 711 mmol, 1 equiv.), K2CO3 (295 mg, 2.13 mmol, 3 equiv.) in ACN (5 mL) was degassed and purged with N2 three times, then the mixture was stirred at 50° C. under N2 atmosphere for 6 h. LC-MS showed that the starting material was completely consumed. TLC (petroleum ether / ethyl acetate 0 / 1R) f =0.47) indicated that the starting material was completely consumed. The residue was diluted with H2O (30 mL) and extracted with ethyl acetate (30 mL*3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to give the product as a yellow solid (240 mg, 388 mmol, yield 54.5%); LCMS: RT = 2.630 min, MS cal.: 618.66, [M+H] + =619.3.

[0256] Preparation of 2-((5-(2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)methyl)-1-((1-cyanocyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 40) [ka] A mixture of methyl 2-((5-(2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)methyl)-1-((1-cyanocyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate (100 mg, 162 mmol, 1 equiv.), LiOH.H2O (10.17 mg, 242.46 mmol, 1.5 equiv.) in THF (1.5 mL) and H2O (0.6 mL) was degassed and purged with N2 three times, then the mixture was stirred under N2 atmosphere at 20 °C for 16 h. LCMS showed that the starting material was completely consumed. The crude product was purified by reverse phase HPLC (column: Waters Xbridge Prep OBDC 18150*40mm*10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 20%~50%, 8min) to give the product as a white solid (18mg, 29.8umol, 18.4% yield); LCMS: RT=2.510min, MS cal.: 604.63, [M+H] + =605.3;HPLC:purity=93.9%; 1 H NMR(400MHz,METHANOL-d4)δ=8.35(s,1H),8.02(d,J=8.4Hz,1H),7.80-7.74(m,1H),7.73-7.69(m,1 H),7.65-7.59(m,1H),7.58-7.54(m,1H),6.73(m,1H),6.51(m,1H),6.37-6.31(m,1H),4.81-4.77(m ,2H),4.36-4.26(m,1H),4.20-4.13(m,1H),3.83-3.71(m,1H),3.40-3.33(m,1H),2.90-2.84(m,2H) ,2.68-2.60(m,1H),2.58-2.45(m,1H),2.02(d,J=4.6Hz,3H),1.52-1.43(m,4H),0.72-0.49(m,2H).

[0257] Example 25 (Synthesis of Compound 13) 3-Fluoro-4-(2-methyl-4-(5-((1-(thiazol-5-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-2-yl)methyl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)benzo[d][1,3]dioxol-2-yl)benzonitrile, mixture of four diastereomers [ka]

[0258] Preparation of 4-nitro-3-((thiazol-5-ylmethyl)amino)benzonitrile (2) [ka] To a solution of 3-fluoro-4-nitrobenzonitrile (2 g, 12.0 mmol, 1 equiv.) and thiazol-5-ylmethanamine (2.25 g, 12.0 mmol, 1 equiv., 2HCl) in THF (10 mL) and MeOH (10 mL) was added TEA (4.02 g, 39.7 mmol, 5.53 mL, 3.3 equiv.). The mixture was stirred at 60° C. for 5 h. TLC showed that the starting material was completely consumed and one new spot was formed. The reaction mixture was slowly poured into H2O (60 mL) at 0° C., forming a solid. The mixture was stirred for 15 min and filtered. The solid was collected under reduced pressure to give the product as a yellow solid (3 g, 11.5 mmol, 95.7% yield); LCMS: RT=0.774 min, MS cal.: 260.3, [M+H] + =261.1; 1 H NMR (400MHz, DMSO-d6) δ8.99(s,1H)8.72(br t,J=6.0Hz,1H)8.19(d,J=8.8Hz,1H)7.96(s,1H)7.67(s,1H)7.06(d,J=8.8Hz,1H)4.93(d,J=6.0Hz,2H).

[0259] Preparation of N'-hydroxy-4-nitro-3-((thiazol-5-ylmethyl)amino)benzimidamide (3) [ka] To a solution of 4-nitro-3-((thiazol-5-ylmethyl)amino)benzonitrile (1.3 g, 4.99 mmol, 1 eq.) in EtOH (15 mL) was added hydroxylamine (429 mg, 6.49 mmol, 50% purity, 1.3 eq.). The mixture was stirred at 90° C. for 1 h. LC-MS showed that the starting material was completely consumed and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The crude product was obtained as a yellow solid (1.46 g); LCMS: RT=1.290 min, MS cal.: 293.3, [M+H]+=294.0; 1 H NMR(400MHz,DMSO-d6)δ=10.10(br s,1H)8.98(s,1H)8.71(br t,J=6.0Hz,1H)8.03(d,J=9.2Hz), 1H)7.90(s,1H)7.34(s,1H)7.05(d,J=9.2Hz,1H)6.02(br s,2H)4.96(d,J=6.0Hz,2H).

[0260] Preparation of 2-nitro-N-(thiazol-5-ylmethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)aniline (4) [ka] To a solution of N'-hydroxy-4-nitro-3-((thiazol-5-ylmethyl)amino)benzimidamide (1.3 g, 4.43 mmol, 1 equiv.) in THF (8 mL) was added TFAA (1.40 g, 6.65 mmol, 924.76 mL, 1.5 equiv.). The mixture was stirred at 20 °C for 2 h. LC-MS showed that the starting material was completely consumed and the desired mass was detected. The residue was diluted with NaHCO3 (30 mL) and extracted with EtOAc (30 mL*2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 30 / 1 to 1 / 1) to give the product as a yellow solid (1.5 g, 4.04 mmol, 91% yield); LCMS: RT = 2.324 min, MS cal.: 371.3, [M+H] + =372.0; 1 H NMR (400MHz, CHLOROFORM-d)δ=8.81(s,1H)8.45(br s,1H)8.40(d,J=8.8Hz,1H)7.95(s,1H)7.72(s,1H)7.48(d,J=8.8Hz,1H)4.90(d,J=5.6Hz,2H).

[0261] Preparation of 2-nitro-N-(thiazol-5-ylmethyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)aniline (5) [ka] To a solution of 2-nitro-N-(thiazol-5-ylmethyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)aniline (0.8 g, 2.15 mmol, 1 equiv.) in EtOH (10 mL), NH2NH2.H2O (539 mg, 10.8 mmol, 524 mL, 5 equiv.) was added dropwise at 0-5 °C. The mixture was stirred at 60 °C for 2 h. LC-MS showed that the starting material was completely consumed and the desired mass was detected. The reaction mixture was concentrated under reduced pressure at 30 °C to give a residue. The residue was diluted with H2O (20 mL) and extracted with EtOAc / i-PrOH=2 / 1 (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 preparative HPLC (neutral condition; column: Phenomenexluna C18250*50mm*10um; mobile phase: [water (TFA)-ACN]; B%: 25%~55%, 10min) to give the product as a yellow solid (500mg, 1.35mmol, yield 62.7%); LCMS: RT=1.815min, MS cal.: 370.3, [M+H]+=371.1; 1 H NMR (400MHz,METHANOL-d4)δ=9.03(s,1H)8.36(d,J=8.8Hz,1H)8.01(s,1H)7.78(s,1H)7.35(d,J=8.8Hz,1H)5.02(s,2H).

[0262] Preparation of N1-(thiazol-5-ylmethyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)benzene-1,2-diamine (6) [ka] To a solution of 2-nitro-N-(thiazol-5-ylmethyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)aniline (130 mg, 351 mmol, 1 equiv.) in MeOH (5 mL) was added Pd / C under N2 atmosphere. The suspension was degassed and purged with H2 three times. The mixture was stirred under H2 (15 psi) at 20°C for 1 h. LC-MS showed that the starting material was completely consumed and the desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give the product as a yellow solid (119 mg, 350 umol, 99.6% yield); LCMS: Rt=1.327 min, MS cal.: 340.3, [M+H]+=341.0.

[0263] Preparation of 5-((2-(chloromethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-1-yl)methyl)thiazole (7) [ka] To a solution of N1-(thiazol-5-ylmethyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)benzene-1,2-diamine (0.11 g, 323 mmL, 1 eq.) in CH3CN (1 mL) was added TosOH (11.1 mg, 64.6 mmol, 0.2 eq.) and 2-chloro-1,1,1-trimethoxyethane (75 mg, 485 mmol, 65.2 mL, 1.5 eq.). The mixture was stirred at 60° C. for 1 h. LC-MS showed that the starting material was completely consumed and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to give the product as a yellow solid (120 mg, 301 mmol, 93.1% yield); LCMS: RT=1.284 min, MS cal.: 398.8, [M+H]+=399.0.

[0264] Preparation of 3-fluoro-4-(2-methyl-4-(5-((1-(thiazol-5-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-2-yl)methyl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)benzo[d][1,3]dioxol-2-yl)benzonitrile, a mixture of four diastereomers (compound 13) [ka] To a solution of 5-((2-(chloromethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-1-yl)methyl)thiazole (110 mg, 166 mmol, 60% purity, 1 equiv.) in CH3CN (2 mL) was added K2CO3 (91.5 mg, 662 mmol, 4 equiv.) and 4-(4-(2,5-diazabicyclo[4.1.0]heptan-2-yl)-2-methylbenzo[d][1,3]dioxol-2-yl)-3-fluorobenzonitrile (64 mg, 166 mmol, 1 equiv., HCl). The mixture was stirred at 60 °C for 1 h. LC-MS showed that the starting material was completely consumed and the desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (neutral condition, column: Phenomenex C1875*30mm*3um; mobile phase: [water (NH3H2O+NH4HCO3)-ACN]; B%: 40%~65%, 8 min) to give the product as a white solid (8.88mg, 12.4mmol, 7.5% yield); LCMS: RT=2.201min, MS cal.: 713.7, [M+H] +=714.2;HPLC:RT=4.071 min, purity:87.6%;1H NMR(400MHz,METHANOL-d4)δ=8.94(d,J=11.4Hz,1H),8.27(s,1H),8.10(s,1H),7.96-7.91(m,1H),7.83- 7.79(m,1H),7.79-7.73(m,1H),7.65-7.54(m,2H),6.74(dt,J=2.8,8.1Hz,1H),6.54-6.48(m,1H),6.35( dd,J=1.3,7.8Hz,1H),6.00(s,2H),4.24-4.17(m,1H),4.13-4.05(m,1H),3.80-3.72(m,1H),3.30-3.25( m,1H),2.95-2.77(m,2H),2.69-2.59(m,1H),2.59-2.45(m,1H),2.03(d,J=4.8Hz,3H),0.73-0.55(m,2H).

[0265] Example 26 (Synthesis of Compound 12) 3-Fluoro-4-(((6-(5-((1-(thiazol-5-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-2-yl)methyl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)pyridin-2-yl)oxy)methyl)benzonitrile, mixture of two diastereomers [ka]

[0266] Preparation of 5-((2-(chloromethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-1-yl)methyl)thiazole (2) [ka] A mixture of N1-(thiazol-5-ylmethyl)-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)benzene-1,2-diamine (100 mg, 294 mmol, 1 equiv.), 2-chloro-1,1,1-trimethoxyethane (114 mg, 735 mmol, 98.8 mL, 2.5 equiv.), TosOH (5.06 mg, 294 mmol, 0.1 equiv.) in CH3CN (2 mL) was degassed and purged with N2 three times, then the mixture was stirred at 60° C. under N2 atmosphere for 1 h. LCMS showed that the starting material was completely consumed and one major peak with the desired mass was detected. The reaction solution was concentrated to give the product as a white solid (80 mg, 201 mmol, 68.3% yield); LCMS: RT=1.140 min, MS cal.: 398.1, [M+H] + =399.0.

[0267] Preparation of 3-fluoro-4-(((6-(5-((1-(thiazol-5-ylmethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-2-yl)methyl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)pyridin-2-yl)oxy)methyl)benzonitrile (compound 12) [ka] A mixture of 5-((2-(chloromethyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-1-yl)methyl)thiazole (80 mg, 201 mmol, 1 equiv.), 4-(((6-(2,5-diazabicyclo[4.1.0]heptan-2-yl)pyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile (65.1 mg, 201 mmol, 1 equiv.), K2CO3 (55 mg, 401 mmol, 2 equiv.) in ACN (3 mL) was degassed and purged with N2 three times, then the mixture was stirred at 50° C. for 2 h under N2 atmosphere. LCMS showed that the starting material was completely consumed and one major peak with the desired mass was detected. The reaction mixture was diluted with H2O (630mL), extracted with EtOAc 60mL (20mL*3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (neutral condition, column::Waters Xbridge Prep OBDC 18150*40mm*10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 30%-70%, 8min) to give the product as a white solid (2.73mg, 3.98umol, yield 1.98%); LCMS: RT=2.673min, MS cal.: 686.1, [M+H] + =687.2;HPLC:RT=3.232min, purity:91.2%; 1 H NMR(400MHz,METHANOL-d4)δ=8.91(s,1H)8.27(s,1H)8.08(s,1H)7.94(d,J=8.4Hz,1H) 7.84-7.79(m,1H)7.64(t,J=7.6Hz,1H)7.56-7.51(m,2H)7.49-7.44(m,1H)6.37(d,J=8 .4Hz,1H)6.14(d,J=8.4Hz,1H)5.99(s,2H)5.44(s,2H)4.24-4.08(m,3H)2.98(m,1H)2. 84-2.74(m,2H)2.71-2.63(m,1H)2.44-2.36(m,1H)0.75-0.71(m,1H)0.54-0.47(m,1H).

[0268] Example 27 (Synthesis of Compound 39) 2-((5-(2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)methyl)-1-((R)-2-methoxypropyl)-1H-benzo[d]imidazole-6-carboxylic acid [ka]

[0269] Preparation of methyl 2-((5-(2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)methyl)-1-((R)-2-methoxypropyl)-1H-benzo[d]imidazole-6-carboxylate (2) [ka] A mixture of methyl (R)-2-(chloromethyl)-1-(2-methoxypropyl)-1H-benzo[d]imidazole-6-carboxylate (250 mg, 842 umol, 1.29 equiv.), 4-(4-(2,5-diazabicyclo[4.1.0]heptan-2-yl)-2-methylbenzo[d][1,3]dioxol-2-yl)-3-fluorobenzonitrile (230 mg, 655 umol, 1 equiv.), K2CO3 (271 mg, 1.96 mmol, 3 equiv.) in CH3CN (3 mL) was degassed and purged with N2 three times. 、 The mixture was then stirred at 60° C. for 1 h under N2 atmosphere. LCMS showed that the starting material was completely consumed and one major peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with H2O (25 mL) and extracted with 45 mL of DCM (15 mL*3). The combined organic layers were washed with 35 mL of H2O, dried over Na2SO4, filtered and concentrated under reduced pressure to give the product as a white solid (200 mg, 327 umol, 50% yield); LCMS: RT=2.437 min, MS cal.: 611.6, [M+H] + =612.2.

[0270] Preparation of 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-azabicyclo[4.1.0]heptan-2-yl)methyl)-1-((R)-2-methoxypropyl)-1H-benzo[d]imidazole-6-carboxylic acid, a mixture of four diastereomers (compound 39) [ka] A mixture of methyl 2-((5-(2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-2,5-diazabicyclo[4.1.0]heptan-2-yl)methyl)-1-((R)-2-methoxypropyl)-1H-benzo[d]imidazole-6-carboxylate (120 mg, 196 mmol, 1 equiv.), LiOH.H2O (12.4 mg, 294 mmol, 1.5 equiv.) in H2O (0.6 mL) / THF (1.4 mL) was degassed and purged with N2 three times, then the mixture was stirred under N2 atmosphere at 25 °C for 12 h. LCMS showed that the starting material was completely consumed and one major peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC (column: Phenomenex C1875*30mm*3um; mobile phase: [water (NH4HCO3)-ACN]; B%: 30%~65%, 8min) to give the product as a white solid (26mg, 43.5umol, 22.2% yield); LCMS: RT=2.427min, MS cal.: 597.6, [M+H] + =598.3; 1H NMR(400MHz,DMSO-d6)δ=8.19(s,1H)7.99-7.93(m,1H)7.80(d,J=8.4Hz,1H)7.76-7.69( m,2H)7.64(d,J=8.4Hz,1H)6.74(m,1H)6.45-6.53(m,1H)6.39(m,1H)4.52-4.37(m,2H)4. 23-4.13(m,1H)3.99-3.84(m,1H)3.82-3.74(m,1H)3.58-3.73(m,1H)3.21(m,1H)3.13(s ,3H)2.89-2.60(m,3H)2.47-2.29(m,1H)2.06(s,3H)1.27-1.17(m,3H)0.66-0.41(m,2H).

[0271] Biotechnology Example B1: GLP-1R cell アッセイ Stable cell lines expressing high and low GLP-1R surface expression were generated in CHO-K1 cells (Fugene6) transfected with a puromycin-selectable DNA plasmid (deposition number: NM_002062.5) encoding the human GLP-1R receptor under the control of the EF1A promoter. Transfected cells were seeded in 24-well plates (9,000 cells / well) containing complete medium and incubated in a humidified incubator at 37 °C with 5% carbon dioxide. After overnight incubation, the medium was replaced with complete medium supplemented with puromycin (6 μg / mL) and refreshed every 2–3 days to select for stably transfected cells. Individual pools of selected cells were expanded and then analyzed for responsiveness to a GLP-1 control peptide using a TR-FRET assay for detecting cAMP (LANCE UltracAMP assay, PerkinElmer). Briefly, cells were harvested in Versene solution, plated in 384-well plates (1,000 cells / well) and mixed with serially diluted GLP-1R control peptide (10 nL) using an acoustic dispenser (ECHO). After incubating the plate for 30 min at 25°C, EU-cAMP tracer (5 μL) and Ulight-anti-cAMP reagent (5 μL) were added to each well, followed by incubation for 15 min at 25°C. TR-FRET signals were detected using an EnVision multimode plate reader (excitation = 320 nm, emission = 615 and 655 nm). Dose-response curves were used to measure EC as a measure of responsiveness to the GLP-1R control peptide. 50Values ​​were generated. The responsiveness of selected cell lines was monitored over multiple passages to ensure stability. CHO-K1_hGLP-1Rhigh_clone16 and CHO-K1_hGLP-1Rlow_clone10 showed consistently high and low responsiveness to the GLP-1R control peptide, respectively, and were selected for further analysis to determine the 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 three times with PBS+0.5% BSA before being incubated with FLEX reagent (10 μM) for 2 h at room temperature. After incubation, cells were washed three times with PBS+0.5% BSA and finally resuspended in PBS before analysis by flow cytometry to measure FLEX mean fluorescence intensity (MFI) as a measure of cell surface GLP-1R expression. Both cell lines showed higher MFI values ​​compared to control CHO-K1 cells, confirming GLP-1R surface expression. CHO-K1_hGLP-1Rhigh_clone16 cells showed significantly higher MFI levels compared to CHO-K1-hGLP-1low_clone10 cells.

[0272] 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 dilutions) and added to the wells (10 nL / well) using an ECHO dispenser, the plates were centrifuged for 1 min, agitated for 2 min at room temperature, and then incubated for 30 min at 25°C. After incubation, Eu-cAMP (5 μL) and Ulight-anti-cAMP (5 μL) reagents were added to each well, followed by centrifugation for 1 min, agitation for 2 min at room temperature, and a final incubation of the plates for 15 min at 25°C. Plates were read using an EnVision microplate reader (excitation = 320 nm, emission = 615 and 655 nm). Dose-response curves were generated from duplicate wells based on percent activation calculated compared to a control GLP-1 peptide agonist run in parallel. EC 50 Values ​​were determined by fitting the percent activation as a function of compound concentration using the Hill equation (XLfit).

[0273] The EC50 values ​​of exemplary compounds in the low expression assay are shown in the table below. The EC50 values ​​were compared with reference compound A and reference compound B. The compounds tested were compound samples prepared according to the general procedures described in the Examples section. [Table 5-1] [Table 5-2]

[0274] Example B2: Metabolic stability of hepatocytes Test compounds were incubated with human hepatocytes to assess stability from a stromal depilation approach. Test compounds were dissolved in dimethyl sulfoxide (DMSO) to make 10 mM stock solutions and further diluted to make 1000x 1 mM working stock solutions with DMSO in 96-well plates for test compounds and positive control (midazolam). Vials containing cryopreserved hepatocytes were removed from the liquid nitrogen tank and immediately immersed in a 37°C water bath. The vials were gently shaken until the contents were thawed and then immediately poured into 48 mL of pre-warmed HT medium in a 50 mL conical tube. The cells remaining in the vial were resuspended in 1.0 mL of pre-warmed HT medium and added to the conical tube. The tube was capped and then gently inverted several times to resuspend the hepatocytes. The cell suspension was centrifuged at 50 x g for 5 min at room temperature and the supernatant was discarded. The cell pellet was loosened by gently swirling the tube and resuspended in 4 mL of warm Dulbecco's Modified Eagle Medium (DMEM). Cell density was determined using a Nexcelom cell counter, and DMEM medium was added to obtain a target density of 1 x 106 cells / mL. The assay was performed in 96-well microtiter plates. Test compounds were added at 1 x 10 at 1 μM in DMEM. 6 The mixtures were incubated with 10000 cells / mL hepatocytes for 0, 30, 60, 120 and 240 min. Incubations were performed at 37°C in a humidified atmosphere of 95% air / 5% CO2 with gentle shaking. The volume of the incubation mixture was 37 μL with 0.1% DMSO final. At each time point, the incubation was stopped by adding 150 μL of quenching solution (100% acetonitrile, 0.1% formic acid with bucetin as internal standard for positive ESI mode). The mixtures were then vortexed for 20 min and centrifuged at 4,000 RPM at 10°C. The supernatants (80 μL) were transferred to a clean 96-well plate and analyzed by LC-MS / MS. Midazolam at 1 μM with 0.1% DMSO final was included as a positive control to validate the assay performance. Percentage of parent remaining, intrinsic and predicted hepatic clearance, and t 1 / 2was calculated. All samples were analyzed by LC-MS / MS using an ABSciex API4000 instrument connected to a Shimadzu LC-20ADLC pump system. Separation was achieved using a Waters Atlantis T3d C18 reversed-phase HPLC column (20 mm x 2.1 mm) at a flow rate of 0.5 mL / min. The mobile phase consisted of 0.1% formic acid in water (solvent A) and 0.1% formic acid in 100% acetonitrile (solvent B). The elution conditions are detailed below. [Table 6]

[0275] The ion optics for each test compound were optimized for declustering potential (DP), collection energy (CE), and collision cell exit potential (CXP) and used for selected ion monitoring experiments in positive ion mode. The peak area ratio of each test compound relative to the internal standard was then assessed for stability. The extent of metabolism was calculated based on the disappearance of the test compound compared to the initial concentration. The initial rate of clearance of the test compound was calculated using a linear regression plot of the semi-log % remaining of the compound versus time. The elimination rate constant (k) from the linear regression plot was then used to calculate the t using the following equation: 1 / 2 and inherent clearance (CL int ) was determined, where C 肝細胞 (million cells / mL) is the cell density of the incubation: k=-slope t 1 / 2 =0.693 / k CL int =k / C 肝細胞

[0276] This method of intrinsic clearance measurement assumes that the concentration of the test compound is much lower than the compound's Michaelis-Menten constant for its metabolic enzyme.

[0277] Predicted hepatic clearance (CL hep ) is the normalized CL based on liver weight int(インビボ)The mixture was calculated using the well-stirred method using the following formula: CL int(インビボ) =CL int x Hepatocellular x Liver Weight CL hep予測値 =(CL int(インビボ) ×Q 肝臓 ) / (CL int(インビボ) +Q 肝臓 ) Here, Q 肝臓 (ml / min / kg) is the hepatic blood flow

[0278] Physiological parameters related to human liver weight, blood flow, and hepatocellularity are given below. [Table 7]

[0279] The results are shown in the table below for intrinsic clearance (mL / min / kg) and half-life (t1 / 2). [Table 8]

[0280] Example B3. Passive permeability and flux ratio Caco-2 cells (clone C2BBe1) were obtained from the American Type Culture Collection (Manassas, VA). Cell monolayers were grown to confluence on collagen-coated microporous membranes in 12-well assay plates. Plate and qualification details are as follows: Permeability assay buffer was Hanks' balanced salt solution, pH 7.4, containing 10 mM HEPES and 15 mM glucose. The buffer in the receiver chamber also contained 1% bovine serum albumin. The concentration of the dosing solution was 5 μM of the test substance in assay buffer. Cell monolayers were dosed apically (A-to-B) or basolaterally (B-to-A) and incubated at 37°C with 5% CO2 in a humidified incubator. Samples were taken from the donor and receiver chambers at 120 min. Each measurement was performed in duplicate. To ensure that no damage was done to the cell monolayer during the flux period, the flux of Lucifer Yellow was also measured after the experiment for each monolayer. All samples were analyzed by LC-MS / MS using electrospray ionization. Apparent transmittance (P app ) and the recovery rate were calculated as follows: P app =(dC r / dt) × V r / (A×C A ) (1) Recovery rate = 100 × ((V r ×C r 最終 )+(V d ×C d 最終 )) / (V d ×C N ) (2) In the formula, dC r / dt is the slope of the cumulative receiver concentration versus time (μMs -1 ) and V r is the volume of the receiver compartment (cm 3 ) and V d is the volume of the donor compartment (cm 3 ), and A is the area of ​​the insert (1.13 cm for 12 wells). 2) and C A is the mean of the nominal dose concentration and the measured donor concentration over 120 min (μM), and C N is the nominal concentration of the dosing solution (μM), and C r 最終 is the cumulative receiver concentration at the end of the incubation period (μM), and C d 最終 is the donor concentration (μM) at the end of the incubation period. The efflux ratio (ER) is the ratio of P app (B-to-A) / P app It is defined as (A-to-B). [Table 9]

[0281] Example B4: Pharmacokinetics in rats Intravenous administration: Compounds were formulated at 0.5 mg / mL in a solution containing 5% polyethylene glycol 400 and 95% (12% (w / v) sulfobutyl-β-cyclodextrin in water) (v / v). Formulated compounds were sterile filtered through a 0.22 micron filter prior to administration. Compounds were administered to male 7-11 week old Sprague-Dawley rats via jugular vein cannula injection at a dose of 1 mg / kg over 30 minutes.

[0282] Oral administration: Compounds were formulated at 0.3 mg / mL or 0.6 mg / mL in a solution containing 5% polyethylene glycol 400 and 95% (12% (w / v) sulfobutyl-β-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.

[0283] Sample collection: Approximately 0.2 mL of blood was collected per time point from the jugular vein or other appropriate site of each animal into pre-chilled commercially available EDTA-K2 tubes and placed on wet ice until centrifugation. Blood samples were processed for plasma by centrifugation at 3,200 g for 10 min at approximately 4°C. Plasma was collected, transferred to pre-labeled 96-well plates or polypropylene tubes, flash frozen on dry ice, and stored at or below -60°C until LC-MS / MS analysis.

[0284] Data Analysis: Plasma concentration versus time data were plotted on graphs and analyzed by a non-compartmental approach using the Phoenix WinNonlin 6.3 software program. Relevant PK parameters were calculated according to the route of administration, e.g., CL, V for intravenous administration, and ΔP, V for intravenous administration. dss and C0, and C for extravascular administration. max , T max or %F, T for all routes 1 / 2 , AUC (0-t) , AUC (0-inf) , MRT (0-t) , and MRT (0-inf) was calculated. [Table 10]

[0285] Exemplary embodiments Exemplary embodiment number 1. Formula (0): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 13 is -C(O)OH or [ka] and X is N or CR x where R x is hydrogen, OH, or C1-C6 alkyl; Y is N or CRy where R y is hydrogen, OH, or C1-C6 alkyl; n is 0 or 1, Q is -C(R 7 )(R 8 )-, -O-, -N(R 9 )-, and -S-, wherein R 7 and R 8 are independently hydrogen, halogen, or C1-C6 alkyl; R 9 is hydrogen or C1-C6 alkyl, R 1 is an optionally substituted -C1-C6 alkylene or -C1-C6 alkylene-R 5 where R 5 is a C3-C6 cycloalkyl, a 3- to 6-membered heterocyclyl, or a 5- to 6-membered heteroaryl, each of which is independently optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, oxo, CN, C1-C6 alkyl, C3-C6 cycloalkyl, and -OC1-C6 alkyl, and each C1-C6 alkyl, C3-C6 cycloalkyl, and -OC1-C6 alkyl substituent is independently optionally substituted with halo or CN; R 2 and R 3 together with the carbon atom to which they are attached form an optionally substituted C3-C4 cycloalkyl ring, or R 2 and R x when present, together with the carbon atom to which they are attached form an optionally substituted C3-C5 cycloalkyl ring; R 3 is hydrogen, oxo, or C1-C6 alkyl; m is 0, 1, 2, or 3; R 4 is oxo or C1-C6 alkyl, Ring A is C6~C 14, a 5-12 membered heterocyclyl, or a 5-12 membered heteroaryl, each of which is independently optionally substituted by halo, OH, CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted by halo or OH; L is a bond, -O-, C1-C6 alkylene, *-O-C1-C6 alkylene-**, *-C1-C6 alkylene-O-**, or *-NR 6 -C1-C6 alkylene-**, where * represents the point of attachment to ring A and ** represents the point of attachment to ring B; L is C1-C6 alkylene, *-O-C1-C6 alkylene**, *-C1-C6 alkylene-O-**, or *-NR 6 When -C1-C6 alkylene-, L is optionally selected from 1 to 3 R L Substituted by substituents, where each R L are independently halo, OH, or C1-C6 alkyl, or two R L together with the carbon atom or atoms to which they are attached form a C3-C6 cycloalkyl or a 3- to 6-membered heterocyclyl; R 6 is, if present, hydrogen or C1-C6 alkyl; Ring B is C3~C 10 Cycloalkyl, C6-C 14 aryl, 4-12 membered heterocyclyl, or 5-12 membered heteroaryl, each of which is independently optionally substituted by 1-3 substituents selected from the group consisting of halo, CN, oxo, C1-C6 alkyl optionally substituted by halo or CN, -OC1-C6 alkyl optionally substituted by halo or CN, -COCH3, -CONH2, -S(O)2CH3, and phenyl optionally substituted by halo or CN, or a pharma- ceutically acceptable salt thereof.

[0286] Exemplary embodiment number 2. Formula (1): [ka] or a pharma- ceutically acceptable salt thereof, wherein X is N or CR x where R x is hydrogen, OH, or C1-C6 alkyl; Y is N or CR y where R y is hydrogen, OH, or C1-C6 alkyl; n is 0 or 1, Q is -C(R 7 )(R 8 )-, -O-, -N(R 9 )-, and -S-, wherein R 7 and R 8 are independently hydrogen, halogen, or C1-C6 alkyl; R 9 is hydrogen or C1-C6 alkyl, R 1 is -C1~C6 alkylene-R 5 where R 5 is a 3- to 6-membered heterocyclyl, or a 5- to 6-membered heteroaryl, each of which is independently optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, oxo, CN, C1-C6 alkyl, C3-C6 cycloalkyl, and -OC1-C6 alkyl, and each C1-C6 alkyl, C3-C6 cycloalkyl, and -OC1-C6 alkyl substituent is independently optionally substituted with halo or CN; R 2 and R 3 together with the carbon atom to which they are attached form an optionally substituted C3-C4 cycloalkyl ring, or R 2 and R x when present, together with the carbon atom to which they are attached form an optionally substituted C3-C5 cycloalkyl ring; R 3 is hydrogen, oxo, or C1-C6 alkyl; m is 0, 1, 2, or 3; R 4is oxo or C1-C6 alkyl, Ring A is C6~C 14 , a 5-12 membered heterocyclyl, or a 5-12 membered heteroaryl, each of which is independently optionally substituted by halo, OH, CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted by halo or OH; L is a bond, -O-, C1-C6 alkylene, *-O-C1-C6 alkylene-**, *-C1-C6 alkylene-O-**, or *-NR 6 -C1-C6 alkylene-**, where * represents the point of attachment to ring A and ** represents the point of attachment to ring B; L is C1-C6 alkylene, *-O-C1-C6 alkylene**, *-C1-C6 alkylene-O-**, or *-NR 6 When -C1-C6 alkylene-, L is optionally selected from 1 to 3 R L Substituted by substituents, where each R L are independently halo, OH, or C1-C6 alkyl, or two R L together with the carbon atom or atoms to which they are attached form a C3-C6 cycloalkyl or a 3- to 6-membered heterocyclyl; R 6 is, if present, hydrogen or C1-C6 alkyl; Ring B is C3~C 10 Cycloalkyl, C6-C 14 aryl, 4-12 membered heterocyclyl, or 5-12 membered heteroaryl, each of which is independently optionally substituted by 1-3 substituents selected from the group consisting of halo, CN, oxo, C1-C6 alkyl optionally substituted by halo or CN, -OC1-C6 alkyl optionally substituted by halo or CN, -COCH3, -CONH2, -S(O)2CH3, and phenyl optionally substituted by halo or CN, or a pharma- ceutically acceptable salt thereof.

[0287] Exemplary embodiment no. 3. The compound has the formula (0'): [ka] or a pharma- ceutically acceptable salt thereof.

[0288] Exemplary embodiment number 4. 13 is -C(O)OH, or a pharma- ceutically acceptable salt thereof.

[0289] Exemplary embodiment number 5. Wherein R 13 but, [ka] or a pharma- ceutically acceptable salt thereof.

[0290] Exemplary embodiment number 6. Wherein X is N and Y is CR y or a pharma- ceutically acceptable salt thereof.

[0291] Exemplary embodiment number 7. Wherein X is CR x and Y is N, or a pharma- ceutically acceptable salt thereof.

[0292] Exemplary embodiment no. 8. A compound according to exemplary embodiment nos. 1-5, wherein X is N and Y is N, or a pharma- ceutically acceptable salt thereof.

[0293] Exemplary Embodiment No. 9. A compound according to Exemplary Embodiment Nos. 1-8, wherein n is 0.

[0294] Exemplary embodiment no. 10. A compound according to exemplary embodiment nos. 1-8, wherein n is 1, or a pharma- ceutically acceptable salt thereof.

[0295] Exemplary embodiment number 11. Wherein Q is -C(R7 )(R 8 )-, or a pharma- ceutically acceptable salt thereof.

[0296] Exemplary embodiment no. 12. A compound according to exemplary embodiment nos. 1-10, wherein Q is -CH2-, or a pharma- ceutically acceptable salt thereof.

[0297] Exemplary Embodiment No. 13. A compound according to Exemplary Embodiment Nos. 1-10, wherein Q is -O-, or a pharma- ceutically acceptable salt thereof.

[0298] Exemplary embodiment number 14. Wherein Q is -N(R 9 )-, or a pharma- ceutically acceptable salt thereof.

[0299] Exemplary embodiment number 15. 1 But -CH2-R 5 or a pharma- ceutically acceptable salt thereof.

[0300] Exemplary embodiment number 16. 5 halo, oxo, C1-C6 alkyl, C 1~6 alkenyl, or C1 The compound according to exemplary embodiments 1-15, wherein C3-C6 cycloalkyl is optionally substituted with -C6 haloalkyl, or a pharma- ceutically acceptable salt thereof.

[0301] Exemplary embodiment number 17. 5 halo, oxo, C1-C6 alkyl, C 1~6 The compound according to exemplary embodiment 16, which is cyclopropyl, optionally substituted with alkenyl, or C1-C6 haloalkyl, or a pharma- ceutically acceptable salt thereof.

[0302] Exemplary embodiment number 18. Wherein R 5 halo, oxo, C1-C6 alkyl, C 1~6Compounds according to exemplary embodiments 1-15, which is 4- or 5-membered heterocyclyl optionally substituted with alkenyl, or C1-C6 haloalkyl, or a pharma- ceutically acceptable salt thereof.

[0303] Exemplary embodiment number 19. 5 halo, oxo, C1-C6 alkyl, C 1~6 The compound according to exemplary embodiment 18, which is 4-membered heterocyclyl optionally substituted with alkenyl, or C1-C6 haloalkyl, or a pharma- ceutically acceptable salt thereof.

[0304] Exemplary embodiment number 20. 5 halo, oxo, C1-C6 alkyl, C 1~6 The compound according to exemplary embodiment 19, which is oxetanyl, optionally substituted with alkenyl, or C1-C6 haloalkyl, or a pharma- ceutically acceptable salt thereof.

[0305] Exemplary embodiment number 21. 5 But, Halo, -OC 1~6 Alkyl, C 1~6 Alkyl, C 1~6 Compounds according to exemplary embodiments 1-15, which is 5-membered heteroaryl optionally substituted with alkenyl, or C1-C6 haloalkyl, or a pharma- ceutically acceptable salt thereof.

[0306] Exemplary embodiment number 22. 5 But, Halo, -OC 1~6 Alkyl, C1-C6 alkyl, C 1~6 The compound according to exemplary embodiment 21, which is oxazolyl, triazolyl, thiazolyl, or isothiazolyl, optionally substituted with alkenyl, or C1-C6 haloalkyl; or a pharma- ceutically acceptable salt thereof.

[0307] Exemplary embodiment number 23. 5 But, Halo, -OC 1~6 Alkyl, C1-C6 alkyl, C 1~6The compound according to exemplary embodiment 22, which is triazolyl or thiazolyl, optionally substituted with alkenyl, or C1-C6 haloalkyl, or a pharma- ceutically acceptable salt thereof.

[0308] Exemplary embodiment number 24. 5 But, Halo, -OC 1~6 Alkyl, C1-C6 alkyl, C 1~6 optionally substituted with alkenyl, or C1-C6 haloalkyl; [ka] or a pharma- ceutically acceptable salt thereof.

[0309] Exemplary embodiment number 25. 5 But, Halo, -OC 1~6 Alkyl, C1-C6 alkyl, C 1~6 optionally substituted with alkenyl, or C1-C6 haloalkyl; [ka] or a pharma- ceutically acceptable salt thereof.

[0310] Exemplary embodiment number 26. 5 but, [ka] where R 12 is C1-C6 alkyl; or a pharma- ceutically acceptable salt thereof.

[0311] Exemplary embodiment number 27. 12 is methyl; or a pharma- ceutically acceptable salt thereof.

[0312] Exemplary embodiment number 28. 12is ethyl; or a pharma- ceutically acceptable salt thereof.

[0313] Exemplary embodiment number 29. A compound according to exemplary embodiment numbers 1-28, wherein ring A is a 5- or 6-membered heteroaryl optionally substituted with halo, CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted with halo or OH, or a pharma- ceutically acceptable salt thereof.

[0314] Exemplary embodiment number 30. A compound according to exemplary embodiment number 29, wherein ring A is a 6-membered heteroaryl optionally substituted with halo, CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted with halo or OH; or a pharma- ceutically acceptable salt thereof.

[0315] Exemplary embodiment number 31. A compound according to exemplary embodiment number 30, wherein Ring A is pyridyl, pyrimidinyl, or pyrazinyl, each of which is optionally substituted with halo, CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted with halo or OH; or a pharma- ceutically acceptable salt thereof.

[0316] Exemplary embodiment number 32. wherein ring A is [ka] or a pharma- ceutically acceptable salt thereof.

[0317] Exemplary embodiment number 33. wherein ring A is [ka] or a pharma- ceutically acceptable salt thereof.

[0318] Exemplary embodiment number 34. wherein ring A is [ka] or a pharma- ceutically acceptable salt thereof.

[0319] Exemplary embodiment no. 35. A compound according to exemplary embodiment nos. 1-28, wherein ring A is a 10-12 membered heteroaryl optionally substituted with halo, CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted with halo or OH, or a pharma- ceutically acceptable salt thereof.

[0320] Exemplary Embodiment No. 36. The compound according to Exemplary Embodiment 35, wherein Ring A is an optionally substituted benzodioxole, or a pharma- ceutically acceptable salt thereof.

[0321] Exemplary embodiment number 37. wherein ring A is [ka] or a pharma- ceutically acceptable salt thereof.

[0322] Exemplary embodiment number 38. wherein L is R L or a pharma- ceutically acceptable salt thereof.

[0323] Exemplary Embodiment No. 39. The compound according to Exemplary Embodiment 38, wherein L is *-O-CH2-**, or a pharma- ceutically acceptable salt thereof.

[0324] Exemplary Embodiment No. 40. A compound according to Exemplary Embodiment Nos. 1-37, wherein L is -O-, or a pharma- ceutically acceptable salt thereof.

[0325] Exemplary Embodiment No. 41. A compound according to Exemplary Embodiment Nos. 1-37, or a pharma- ceutically acceptable salt thereof, wherein L is a bond.

[0326] Exemplary embodiment number 42. wherein ring B is a C6-C alkyl group optionally substituted with 1-3 substituents independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -COCH3, -CONH2, -S(O)2CH3, and phenyl. 14 Compounds according to exemplary embodiment numbers 1-41, wherein is aryl, or a pharma- ceutically acceptable salt thereof.

[0327] Exemplary embodiment number 43. The compound according to exemplary embodiment number 42, wherein ring B is phenyl optionally substituted with 1-3 substituents independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -COCH3, -CONH2, -S(O)2CH3, and phenyl; or a pharma- ceutically acceptable salt thereof.

[0328] Exemplary embodiment number 44. wherein ring B is [ka] or a pharma- ceutically acceptable salt thereof.

[0329] Exemplary embodiment number 45. wherein ring B is [ka] or a pharma- ceutically acceptable salt thereof.

[0330] Exemplary embodiment number 46. A compound according to exemplary embodiment numbers 1-41, wherein ring B is a 4-12 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -COCH3, -CONH2, -S(O)2CH3, and phenyl, or a pharma- ceutically acceptable salt thereof.

[0331] Exemplary embodiment no. 47. The compound according to exemplary embodiment no. 46, wherein ring B is tetrahydroisoquinolinyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -COCH3, -CONH2, -S(O)2CH3, and phenyl; or a pharma- ceutically acceptable salt thereof.

[0332] Exemplary embodiment number 48. wherein ring B is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -COCH3, -CONH2, -S(O)2CH3, and phenyl. [ka] or a pharma- ceutically acceptable salt thereof.

[0333] Exemplary embodiment number 49. wherein ring B is [ka] or a pharma- ceutically acceptable salt thereof.

[0334] Exemplary embodiment no. 50. A compound according to exemplary embodiment nos. 1-41, wherein ring B is a 5-12 membered heteroaryl optionally substituted with 1-3 substituents independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -COCH3, -CONH2, -S(O)2CH3, and phenyl, or a pharma- ceutically acceptable salt thereof.

[0335] Exemplary embodiment number 51. A compound according to exemplary embodiment number 50, wherein ring B is a 9-membered heteroaryl optionally substituted with 1-3 substituents independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -COCH3, -CONH2, -S(O)2CH3, and phenyl; or a pharma- ceutically acceptable salt thereof.

[0336] Exemplary embodiment number 52. The compound is a compound of formula (8): [ka] or a pharma- ceutically acceptable salt thereof.

[0337] Exemplary embodiment number 53. A compound, or a pharma- ceutically acceptable salt thereof, wherein said compound is selected from any one of the compounds in Table 1, or a pharma- ceutically acceptable salt thereof.

[0338] Exemplary embodiment number 54. A pharmaceutical composition comprising a compound according to exemplary embodiment numbers 1-53, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0339] Exemplary embodiment number 55. A method for treating a disease mediated by the glucagon-like peptide-1 receptor (GLP-1R) in an individual in need of such treatment, comprising administering to said individual a therapeutically effective amount of a compound described in exemplary embodiment numbers 1-53, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described in exemplary embodiment number 54.

[0340] Exemplary embodiment number 56. The method of exemplary embodiment number 55, wherein the disease is a liver disease.

[0341] Exemplary embodiment number 57. The method according to exemplary embodiment number 56, wherein said liver disease is primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), drug-induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition-associated cholestasis (PNAC), cholestasis associated with bacterial overgrowth or sepsis, 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, intrahepatic or extrahepatic malignancies, Sjogren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis, or oti-antitrypsin deficiency.

[0342] Exemplary embodiment number 58. The method of exemplary embodiment number 55, wherein the disease is diabetes.

[0343] Exemplary embodiment number 59. The method of exemplary embodiment number 55, wherein the disease is a cardiometabolic disease.

[0344] Exemplary embodiment number 60. The method of exemplary embodiment number 55, wherein the disease is obesity.

[0345] Exemplary embodiment number 61. Use of a compound according to exemplary embodiment numbers 1-53, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease mediated by GLP-1R.

[0346] Equivalent It is understood that the present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The foregoing embodiments are therefore to be considered in all respects as illustrative rather than limiting the invention described herein. The scope of the present invention is therefore indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

1. Formula (0): 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, wherein R １３ is -C(O)OH or 【Chemistry 2】 and X is N or CR ｘ where R ｘ is hydrogen, OH, or C １ ~C ６ is alkyl, Y is N or CR ｙ where R ｙ is hydrogen, OH, or C １ ~C ６ is alkyl, n is 0 or 1; Q is -C(R ７ ) (R ８ )-, -O-, -N(R ９ )-, and -S-, wherein R ７ and R ８ are independently hydrogen, halogen, or C １ ~C ６ is alkyl, R ９ is hydrogen or C １ ~C ６ is alkyl, R １ is an optionally substituted -C １ ~C ６ Alkylene or -C １ ~C ６ Alkylene-R ５ where R ５ is C ３ ~C ６ cycloalkyl, 3- to 6-membered heterocyclyl, or 5- to 6-membered heteroaryl, each of which is independently optionally selected from halo, oxo, CN, C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl and -OC １ ~C ６ and each C is substituted with 1 to 3 substituents independently selected from the group consisting of alkyl, １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl and -OC １ ~C ６ The alkyl substituents are independently optionally substituted with halo or CN; R ２ and R ３ taken together with the carbon atom to which they are attached, represent an optionally substituted C ３ ~C ４ forming a cycloalkyl ring, or R ２ and R ｘ When present, together with the carbon atom to which they are attached, optionally substituted C ３ ~C ５ forms a cycloalkyl ring, R ３ is hydrogen, oxo, or C １ ~C ６ is alkyl, m is 0, 1, 2, or 3; R ４ is oxo or C １ ~C ６ is alkyl, Ring A is C ６ ~C １４ , 5-12 membered heterocyclyl, or 5-12 membered heteroaryl, each of which is independently optionally selected from halo, OH, CN, C ３ ~C ６ Cycloalkyl, or C optionally substituted by halo or OH １ ~C ６ is substituted by alkyl, L is a bond, —O—, C １ ~C ６ Alkylene, *-O-C １ ~C ６ Alkylene-**, *-C １ ~C ６ Alkylene-O-**, or *-NR ６ -C １ ~C ６ alkylene-**, where * represents the point of attachment to ring A and ** represents the point of attachment to ring B; L is C １ ~C ６ Alkylene, *-O-C １ ~C ６ Alkylene**, *-C １ ~C ６ Alkylene-O-**, or *-NR ６ -C １ ~C ６ When alkylene-**, L is optionally selected from 1 to 3 R Ｌ Substituted by substituents, where each R Ｌ are independently halo, OH, or C １ ~C ６ alkyl or two R Ｌ together with the carbon atom or atoms to which they are attached form C ３ ~C ６ forming a cycloalkyl or 3- to 6-membered heterocyclyl; R ６ When present, is hydrogen or C １ ~C ６ is alkyl, Ring B is C ３ ~C １０ Cycloalkyl, C ６ ~C １４ aryl, 4- to 12-membered heterocyclyl, or 5- to 12-membered heteroaryl, each of which is independently optionally substituted by halo, CN, oxo, C optionally substituted by halo or CN; １ ~C ６ Alkyl, optionally substituted by halo or CN １ ~C ６ Alkyl, -COCH ３ , -CONH ２ , -S(O) ２ CH ３ and phenyl optionally substituted by halo or CN, or a pharma- ceutically acceptable salt thereof.

2. Formula (1): 【Chemistry 3】 or a pharma- ceutically acceptable salt thereof, wherein X is N or CR ｘ where R ｘ is hydrogen, OH, or C １ ~C ６ is alkyl, Y is N or CR ｙ where R ｙ is hydrogen, OH, or C １ ~C ６ is alkyl, n is 0 or 1; Q is -C(R ７ ) (R ８ )-, -O-, -N(R ９ )-, and -S-, wherein R ７ and R ８ are independently hydrogen, halogen, or C １ ~C ６ is alkyl, R ９ is hydrogen or C １ ~C ６ is alkyl, R １ is -C １ ~C ６ Alkylene-R ５ where R ５ is a 3- to 6-membered heterocyclyl, or a 5- to 6-membered heteroaryl, each of which is independently optionally selected from halo, oxo, CN, C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl and -OC １ ~C ６ and each C is substituted with 1 to 3 substituents independently selected from the group consisting of alkyl, １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl and -OC １ ~C ６ The alkyl substituents are independently optionally substituted with halo or CN; R ２ and R ３ taken together with the carbon atom to which they are attached, represent an optionally substituted C ３ ~C ４ forming a cycloalkyl ring, or R ２ and R ｘ When present, together with the carbon atom to which they are attached, optionally substituted C ３ ~C ５ forms a cycloalkyl ring, R ３ is hydrogen, oxo, or C １ ~C ６ is alkyl, m is 0, 1, 2, or 3; R ４ is oxo or C １ ~C ６ is alkyl, Ring A is C ６ ~C １４ , 5-12 membered heterocyclyl, or 5-12 membered heteroaryl, each of which is independently optionally selected from halo, OH, CN, C ３ ~C ６ Cycloalkyl, or C optionally substituted by halo or OH １ ~C ６ is substituted by alkyl, L is a bond, —O—, C １ ~C ６ Alkylene, *-O-C １ ~C ６ Alkylene-**, *-C １ ~C ６ Alkylene-O-**, or *-NR ６ -C １ ~C ６ alkylene-**, where * represents the point of attachment to ring A and ** represents the point of attachment to ring B; L is C １ ~C ６ Alkylene, *-O-C １ ~C ６ Alkylene**, *-C １ ~C ６ Alkylene-O-**, or *-NR ６ -C １ ~C ６ When alkylene-**, L is optionally selected from 1 to 3 R Ｌ Substituted by substituents, where each R Ｌ are independently halo, OH, or C １ ~C ６ alkyl or two R Ｌ together with the carbon atom or atoms to which they are attached form C ３ ~C ６ forming a cycloalkyl or 3- to 6-membered heterocyclyl; R ６ When present, is hydrogen or C １ ~C ６ is alkyl, Ring B is C ３ ~C １０ Cycloalkyl, C ６ ~C １４ aryl, 4- to 12-membered heterocyclyl, or 5- to 12-membered heteroaryl, each of which is independently optionally substituted by halo, CN, oxo, C optionally substituted by halo or CN; １ ~C ６ Alkyl, optionally substituted by halo or CN １ ~C ６ Alkyl, -COCH ３ , -CONH ２ , -S(O) ２ CH ３ and phenyl optionally substituted by halo or CN, or a pharma- ceutically acceptable salt thereof.

3. The compound has the formula (0'): 【Chemistry 4】 3. The compound of claim 1 or 2, which is, or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable salt thereof.

4. R １３ is -C(O)OH or 【Chemistry 5】 10. A compound according to any one of the preceding claims, which is: or a pharma- ceutically acceptable salt thereof.

5. (i) X is N and Y is CR ｙ or (ii) X is CR ｘ and Y is N, or (iii) A compound according to any one of the preceding claims, wherein X is N and Y is N, or a pharma- ceutically acceptable salt thereof.

6. 10. A compound according to any one of the preceding claims, wherein n is 0 or 1, or a pharma- ceutically acceptable salt thereof.

7. Q is -C(R ７ ) (R ８ ) -, -CH ２ -, -O-, or -N(R ９ 2. A compound according to any one of the preceding claims, wherein R is -R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42

8. R １ But -CH ２ -R ５ 10. A compound according to any one of the preceding claims, which is: or a pharma- ceutically acceptable salt thereof.

9. R ５ but, (i) halo, oxo, C １ ~C ６ Alkyl, C １～６ Alkenyl, or C １ ~C ６ C optionally substituted with haloalkyl ３ ~C ６ cycloalkyl, or (ii) halo, oxo, C １ ~C ６ Alkyl, C １～６ Alkenyl, or C １ ~C ６ 4-5 membered heterocyclyl optionally substituted with haloalkyl; or (iii) halo, —O—C １～６ Alkyl, C １～６ Alkyl, C １～６ Alkenyl, or C １ ~C ６ 10. A compound according to any one of the preceding claims, which is 5-membered heteroaryl optionally substituted with haloalkyl, or a pharma- ceutically acceptable salt thereof.

10. R ５ but, (i) halo, oxo, C １ ~C ６ Alkyl, C １～６ Alkenyl, or C １ ~C ６ cyclopropyl optionally substituted with haloalkyl; (ii) halo, oxo, C １ ~C ６ Alkyl, C １～６ Alkenyl, or C １ ~C ６ oxetanyl optionally substituted with haloalkyl; or (iii) oxazolyl, triazolyl, thiazolyl, or isothiazolyl, each of which is halo, —O—C １～６ Alkyl, C １ ~C ６ Alkyl, C １～６ Alkenyl, or C １ ~C ６ 10. The compound of claim 9, or a pharma- ceutically acceptable salt thereof, optionally substituted by haloalkyl.

11. R ５ but, (i) halo, —O—C １～６ Alkyl, C １ ~C ６ Alkyl, C １～６ Alkenyl, or C １ ~C ６ Optionally substituted with haloalkyl 【Chemistry 6】 (ii) halo, —O—C １～６ Alkyl, C １ ~C ６ Alkyl, C １～６ Alkenyl, or C １ ~C ６ Optionally substituted with haloalkyl 【Chemistry 7】 or (iii) 【Chemistry 8】 (In the formula, R １２ is C １ ~C ６ 11. The compound of claim 10, or a pharma- ceutically acceptable salt thereof, wherein R is 0 or 1;

12. R １２ is methyl or ethyl, or a pharma- ceutically acceptable salt thereof.

13. Ring A is (i) Halo, CN, C ３ ~C ６ Cycloalkyl, or C optionally substituted with halo or OH １ ~C ６ a 5- or 6-membered heteroaryl optionally substituted with alkyl; or (ii) Halo, CN, C ３ ~C ６ Cycloalkyl, or C optionally substituted by halo or OH １ ~C ６ 10. A compound according to any one of the preceding claims, which is 10-12 membered heterocyclyl or 10-12 membered heteroaryl, optionally substituted by alkyl, or a pharma- ceutically acceptable salt thereof.

14. Ring A is (i) pyridyl, pyrimidinyl, or pyrazinyl, each of which is selected from the group consisting of halo, CN, C ３ ~C ６ Cycloalkyl, or C optionally substituted by halo or OH １ ~C ６ optionally substituted with alkyl; (ii) The compound of claim 13, which is an optionally substituted benzodioxole, or a pharma- ceutically acceptable salt thereof.

15. Ring A is 【Chemistry 9】 15. The compound of claim 14, wherein:

16. L is R Ｌ *-O-C optionally substituted １ ~C ６ 2. A compound according to any one of the preceding claims which is alkylene-**, or a pharma- ceutically acceptable salt thereof.

17. L is *-O-CH ２ 17. The compound of claim 16, which is -**, or a pharma- ceutically acceptable salt thereof.

18. L, (i) -O-, or (ii) A compound according to any one of the preceding claims, or a pharma- ceutically acceptable salt thereof, which is a bond.

19. Ring B is (i) halo, CN, oxo, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, -COCH ３ , -CONH ２ , -S(O) ２ CH ３ C optionally substituted with 1 to 3 substituents independently selected from the group consisting of phenyl, ６ ~C １４ is aryl, (ii) halo, CN, oxo, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, -COCH ３ , -CONH ２ , -S(O) ２ CH ３ and phenyl; or (iii) halo, CN, oxo, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, -COCH ３ , -CONH ２ , -S(O) ２ CH ３ 5-12 membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from the group consisting of:

20. Ring B is (i) halo, CN, oxo, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, -COCH ３ , -CONH ２ , -S(O) ２ CH ３ and phenyl, optionally substituted with 1 to 3 substituents each independently selected from the group consisting of phenyl; (ii) halo, CN, oxo, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, -COCH ３ , -CONH ２ , -S(O) ２ CH ３ and / or tetrahydroisoquinolinyl optionally substituted by 1 to 3 substituents independently selected from the group consisting of: (iii) halo, CN, oxo, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, -COCH ３ , -CONH ２ , -S(O) ２ CH ３ 20. The compound of claim 19, or a pharma- ceutically acceptable salt thereof, which is a 9-membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from the group consisting of:

21. Ring B is halo, CN, oxo, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, -COCH ３ , -CONH ２ , -S(O) ２ CH ３ and phenyl, 【Chemistry 10】 21. The compound of claim 20, wherein:

22. Ring B is 【Chemistry 11】 21. The compound of claim 20, wherein:

23. The compound has the formula (8): 【Chemistry 12】 2. The compound of claim 1, which is a compound of the formula:

24. A compound, or a pharma- ceutically acceptable salt thereof, wherein said compound is selected from any one of the compounds in Table 1, or a pharma- ceutically acceptable salt thereof.

25. 13. A pharmaceutical composition comprising a compound according to any one of the preceding claims, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

26. 26. A method for treating a disease mediated by the glucagon-like peptide-1 receptor (GLP-1R) in an individual in need of such treatment, comprising administering to said individual a therapeutically effective amount of a compound according to any one of claims 1 to 24, or a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition according to claim 25.

27. 27. The method of claim 26, wherein the disease is a liver disease.

28. 28. The method of claim 27, 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), cholestasis associated with bacterial overgrowth or sepsis, 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, intrahepatic or extrahepatic malignancies, Sjogren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis, or oti-antitrypsin deficiency.

29. The disease is (i) diabetes; (ii) a cardiometabolic disorder, and / or 27. The method of claim 26, wherein (iii) the patient is obese.

30. 13. Use of a compound according to any one of the preceding claims, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease mediated by GLP-1R.

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