Benzimidazole carboxylic acids 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 / 261,717, filed September 27, 2021, the disclosure of which is incorporated herein by reference in its entirety for all purposes. [Background technology]

[0002] 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.

[0003] 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 additionally been approved as a treatment for obesity.

[0004] 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).

[0005] 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).

[0006] 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.

[0007] 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

[0008] 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.

[0009] In one aspect, there is provided a compound selected from the group consisting of a compound of formula (I), including compounds of formulas (II)-(VIII), as detailed herein, or a compound listed in Table 1, or a pharma- ceutically acceptable salt thereof.

[0010] Further provided is a pharmaceutical composition comprising a compound of formula (I), including compounds of formulas (II)-(VIII), or a compound selected from the group consisting of the compounds listed in Table 1, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier or excipient.

[0011] 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 of formula (I), including compounds of formulae (II)-(VIII), or a compound selected from the group consisting of the compounds 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.

[0012] Also provided is a compound of formula (I), including compounds of formulas (II)-(VIII), as detailed herein, or a compound selected from the group consisting of the compounds listed in Table 1, or a pharma- ceutically acceptable salt thereof, for treatment.

[0013] Also provided is the use of a compound of formula (I), including compounds of formulae (II)-(VIII), or a compound selected from the group consisting of the compounds listed in Table 1, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treatment, as detailed herein.

[0014] Additionally provided are kits comprising a compound of formula (I), including compounds of formulas (II)-(VIII), or a compound selected from the group consisting of the compounds listed in Table 1, or a pharma- ceutically acceptable salt thereof. In some embodiments, the kit comprises instructions for use in accordance with the methods described herein.

[0015] In yet another aspect, there is provided a method for preparing a compound of formula (I), including compounds of formulas (II)-(VIII), or a compound selected from the group consisting of the compounds listed in Table 1, or a pharma- ceutically acceptable salt thereof. Also provided are compound intermediates useful in the synthesis of a compound of formula (I), including compounds of formulas (II)-(VIII), or a compound selected from the group consisting of the compounds listed in Table 1, or a pharma- ceutically acceptable salt thereof.

[0016] In one aspect, the present disclosure provides a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein: X is N or CH; Y is N or CR 4 and n is 0 or 1, R is hydrogen; R 1 -C 1 -C 6 Alkylene-R 5 and R 2 is hydrogen, oxo, or C 1 -C 6 is alkyl, R 3 is hydrogen, oxo, or C 1 -C 6 is alkyl, R 4 is hydrogen, OH, or C 1 -C 6 is alkyl, Or, R 3 and R4 are halo or C together with the carbon atom to which they are attached. 1 -C 3 C optionally substituted by alkyl 3 -C 6 Forming a cycloalkyl, R 5 is a 5-membered heterocyclyl or a 5-membered heteroaryl, each containing 1, 2, or 3 heteroatoms independently selected from O, N, and S, where R 5 at least one heteroatom in is S, and R 5 Ha, Halo, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkenyl, or C 1 -C 6 optionally substituted by haloalkyl; Ring A is a 5- to 12-membered heterocyclyl or a 5- to 12-membered heteroaryl, each independently selected from halo, CN, C 3 -C 6 Cycloalkyl, or C optionally substituted by halo or OH 1 -C 6 may be substituted by alkyl, L is a bond, -O-, C 1 -C 6 Alkylene, *-OC 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, ** represents the point of attachment to ring B, L is *-OC 1 -C 6 C of L is alkylene-** 1 -C 6 Alkylene is R L where each R L is independently C 1 -C 6alkyl or halo, or two R L together with the carbon atom or atoms to which they are attached. 3 -C 6 forming a cycloalkyl or 3- to 6-membered heterocyclyl; L is C 1 -C 6 When it is alkylene, C 1 -C 6 Alkylene is R L1 where each R L1 are independently halo, OH, oxo, or C 1 -C 6 Alkyl or two R L1 together with the carbon atom or atoms to which they are attached. 3 -C 6 forming a cycloalkyl or 3- to 6-membered heterocyclyl; R 6 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 halo, CN, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -COCH 3 , -CONH 2 , -S(O) 2 CH 3 and phenyl.

[0017] In some embodiments, X is N. In some embodiments, X is CH.

[0018] In some embodiments, Y is N. In some embodiments, Y is CR 4 In some embodiments, Y is CR4 and R 3 and R 4 together with the carbon atom to which they are attached form a cyclopropyl group.

[0019] In some embodiments, n is 0. In some embodiments, n is 1.

[0020] In some embodiments, R 1 is -CH 2 -R 5 In some embodiments, R 5 is a 5-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from O, N, and S, where R 5 at least one heteroatom in is S, and R 5 Ha, Halo, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkenyl, or C 1 -C 6 In some embodiments, R 5 is a 5-membered heteroaryl containing 1 or 2 heteroatoms selected from S and N, where R 5 one heteroatom is S and R 5 Ha, Halo, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkenyl, or C 1 -C 6 In some embodiments, R 5 are thiazolyl or isothiazolyl, respectively, halo, -OC 1-6 Alkyl, C 1 -C 6 Alkyl, C 1-6 Alkenyl, or C 1 -C 6 In some embodiments, R 5 is thiazol-2-yl or thiazol-5-yl, respectively, C 1 -C6 In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] It is.

[0021] In some embodiments, ring A is halo, CN, C 3 -C 6 Cycloalkyl, or C optionally substituted by halo or OH 1 -C 6 In some embodiments, ring A is a 5-6 membered heteroaryl optionally substituted with alkyl. 3 -C 6 Cycloalkyl, or C optionally substituted by halo or OH 1 -C 6 In some embodiments, Ring A is benzodioxolyl, pyridyl, pyrimidinyl, or pyrazinyl, each of which is selected from the group consisting of halo, CN, C, C-C ... 3 -C 6 Cycloalkyl, or C optionally substituted by halo or OH 1 -C 6 In some embodiments, Ring A is benzodioxolyl, pyridyl, pyrimidinyl, or pyrazinyl. In some embodiments, Ring A is [ka] In some embodiments, ring A is [ka] It is.

[0022] In some embodiments, L is R L may be replaced by *-OC 1 -C 6 In some embodiments, L is -O-CH 2 -** or *-O-CD 2 In some embodiments, L is -**. In some embodiments, L is -O-. In some embodiments, L is a bond. In some embodiments, L is *-C(O)-CH 2 -**.

[0023] In some embodiments, 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 C optionally substituted by 1 to 3 substituents independently selected from the group consisting of 6 -C 14 In some embodiments, 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 In some embodiments, ring B is phenyl, optionally substituted by 1 to 3 substituents each independently selected from the group consisting of halo, CN, and -CONH. 2 In some embodiments, Ring B is phenyl, optionally substituted with 1 to 3 substituents each independently selected from the group consisting of: [ka] In some embodiments, ring B is halo, CN, oxo, C 1 -C 6 Alkyl, C1 -C 6 Haloalkyl, -COCH 3 , -CONH 2 , -S(O) 2 CH 3 In some embodiments, ring B is a 4-12 membered heterocyclyl optionally substituted by 1-3 substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -COCH 3 , -CONH 2 , -S(O) 2 CH 3 In some embodiments, ring B is tetrahydroisoquinolinyl, optionally substituted by 1 to 3 substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -COCH 3 , -CONH 2 , -S(O) 2 CH 3 and phenyl, [ka] In some embodiments, ring B is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo and CN. [ka] In some embodiments, ring B is [ka] In some embodiments, ring B is halo, CN, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -COCH3 , -CONH 2 , -S(O) 2 CH 3 In some embodiments, ring B is a 5-12 membered heteroaryl optionally substituted by 1-3 substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -COCH 3 , -CONH 2 , -S(O) 2 CH 3 In some embodiments, Ring B is a 9-membered heteroaryl optionally substituted with 1-3 substituents independently selected from the group consisting of halo and CN. In some embodiments, Ring B is a 9-membered heteroaryl optionally substituted with 1-2 substituents independently selected from the group consisting of: [ka] It is.

[0024] In some embodiments, the compound is of formula VIII: [ka] In the formula, R 7 is hydrogen, chloro, bromo, fluoro, methyl, or vinyl, and R 8 teeth, [ka] It is.

[0025] In some embodiments, R 7 is hydrogen.

[0026] In some embodiments, the compound is a meglumine salt.

[0027] In one aspect, the disclosure provides a compound or a pharma- ceutically acceptable salt thereof, wherein the compound is selected from any one of the compounds in Table 1 other than Reference Compound A.

[0028] In some embodiments, the compound selected from any one of the compounds in Table 1 other than Reference Compound A is a meglumine salt.

[0029] In some embodiments, the disclosure provides a pharmaceutical composition comprising a compound of Formula I-VIII or compound 1-31, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0030] In some embodiments, the disclosure provides a method of treating a disease mediated by the glucagon-like peptide-1 receptor (GLP-1R) in an individual in need of such treatment, comprising administering to the individual any one of the compounds disclosed herein, or a pharma- ceutically acceptable salt thereof, or any pharmaceutical composition disclosed herein. In some embodiments, the disease is a liver disease. In some embodiments, the liver disease is primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), drug-induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition-associated cholestasis (PNAC), 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. In some embodiments, the disease is diabetes. In some embodiments, the disease is cardiometabolic disease. In some embodiments, the disease is obesity.

[0031] In some embodiments, the present disclosure provides the use of any one of the compounds disclosed herein, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease mediated by GLP-1R.

[0032] In some embodiments, the present disclosure provides a method of reducing food intake in an individual in need thereof, the method comprising administering to the individual any one of the compounds disclosed herein, pharma- ceutically acceptable salts thereof, or pharmaceutical compositions.

[0033] In some embodiments, the present disclosure provides a method of increasing glucose tolerance in an individual in need thereof, the method comprising administering to the individual any one of the compounds disclosed herein, pharma- ceutically acceptable salts thereof, or pharmaceutical compositions. [Brief description of the drawings]

[0034] [Figure 1] FIG. 1 shows plasma concentrations of Compound 2 and reference Compound A following oral (PO) administration (3 mg / kg) to rats. [Diagram 2] FIG. 1 shows plasma concentrations of compounds 2, 3, and 4 following oral (PO) administration (0.3 mg / mL, 3 mg / kg) to rats. [Diagram 3] FIG. 1 shows plasma concentrations of compounds 2 and 14 following oral (PO) administration (0.6 mg / mL, 3 mg / kg) to rats. [Figure 4] 1 is a timeline showing the experimental design of a food intake study in C57BL / 6 mice. [Diagram 5] FIG. 1 shows the reduction in food intake caused by Compound 2, Reference Compound A, and Liraglutide in C57BL / 6 mice expressing human GLP-1R. [Figure 6] 1 is a timeline showing the experimental design of a glucose tolerance study in C57BL / 6 mice. [Figure 7]FIG. 1 shows glucose concentration over time in the blood of C57BL / 6 mice expressing human GLP-1R following administration of an IP glucose bolus and Compound 2, Reference Compound A, and Liraglutide. [Figure 8] FIG. 8 shows the area under the glucose concentration versus time curves shown in FIG. [Figure 9] FIG. 1 shows glucose concentrations in the blood of C57BL / 6 mice expressing wild-type mouse GLP-1R (triangles) and humanized GLP-1R (circles) following IP glucose bolus and administration of Compound 2 or liraglutide. [Figure 10] FIG. 10 shows the area under the glucose concentration versus time curves shown in FIG. [Figure 11] A and B show total Compound 2 (11A) and unbound Compound 2 (11B) in hGLP-1R mice from an IPGTT assessment with varying amounts of Compound 2. [Figure 12A] FIG. 1 shows the sum of reference compound A in hGLP-1R mice from IPGTT evaluation with various amounts of reference compound A. [Figure 12B] FIG. 1 shows unbound reference compound A in hGLP-1R mice from an IPGTT evaluation with various amounts of reference compound A. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0035] In one aspect, the present disclosure relates to compounds that the inventors have discovered that stimulate the GLP-1R. For example, the inventors have discovered compounds that have superior pharmacokinetic properties (e.g., Cmax, AUC 0-lastWe have discovered that novel GLP-1R agonists having the general formula (I) and (II) are potent agonists of GLP-1R and are effective in improving disease-related phenotypes such as food intake and glucose tolerance in humanized animal models. Importantly, the benefits of the presently disclosed compounds could not have been predicted a priori. The present disclosure also relates to compositions comprising the GLP-1R agonists disclosed herein, and to uses of the GLP-1R agonists in the treatment of disease.

[0036] definition As used herein, the following definitions shall apply unless otherwise indicated. Furthermore, if any term or symbol used herein is not defined as set forth below, it shall have the meaning it ordinarily has in the art.

[0037] 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.

[0038] As used herein, and unless otherwise specified, the terms "about" and "approximately," when used in reference to a dose, amount, or weight percent of a component of a composition or dosage form, refer to a dose, amount, or weight percent 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 percent. Specifically, the terms "about" and "approximately," when used in reference to a value, refer to a variation within ±10% 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."

[0039] "Comprising" is intended to mean that the compositions and methods include the recited elements, but do not exclude other elements. When used to define compositions and methods, "Consisting essentially of" 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, for example, excluding more than trace amounts of other components and substantial method steps as described. Embodiments defined by each of these transition terms are within the scope of the present invention.

[0040] The term "excipient" as used herein refers to an inert or inactive substance that may be used in the manufacture of a drug or pharmaceutical product, such as a tablet, that contains a compound of the present invention as an active ingredient. A variety of substances may be encompassed under the term excipient, including, but not limited to, any substance used as a binder, disintegrant, coating, compression / encapsulation aid, cream or lotion, lubricant, parenteral solution, chewable tablet material, sweetener or flavoring agent, suspending / gelling agent, or wet granulation agent. 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.

[0041] "Pharmaceutically acceptable" refers to safe and non-toxic, preferably for in vivo, and more preferably for human administration.

[0042] "Pharmaceutically acceptable salt" refers to a salt that is pharma- ceutically acceptable. The compounds described herein may be administered as a pharma- ceutically acceptable salt.

[0043] "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 and non-limiting cations useful for pharma-ceutically acceptable salts include Na, K, Rb, Cs, NH4, Ca, Ba, imidazolium, and ammonium cations based on naturally occurring amino acids, as well as ammonium cations not based on naturally occurring amino acids (such as meglumine). When the compounds provided 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 acid, and phosphoric acid. Exemplary, non-limiting anions useful in pharma- ceutically acceptable salts include oxalate, maleate, acetate, fumarate, propionate, succinate, tartrate, chloride, sulfate, bisulfate, monobasic, dibasic, and tribasic phosphates, mesylate, tosylate, and the like.

[0044] "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.

[0045] 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.

[0046] 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.

[0047] In some embodiments, the term "glucose tolerance" refers to a subject's ability to handle a glucose load or a subject's glycemic control.

[0048] A "therapeutically effective amount" or dose of a compound or composition refers to that amount of the compound or composition that results in the reduction or inhibition of symptoms, or the prolongation of survival, in a patient. The result may require multiple administrations of the compound or composition.

[0049] "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, methyl (CH 3 -), ethyl (CH 3 CH 2 -), n-propyl (CH 3 CH 2 CH 2 -), isopropyl ((CH 3 ) 2 CH-), n-Butyl (CH 3 CH 2 CH 2 CH 2 -), isobutyl ((CH 3 ) 2 CHCH 2 -), sec-butyl ((CH 3 )(CH 3 CH 2 )CH-), t-butyl ((CH 3 ) 3 C-), n-pentyl (CH 3 CH 2 CH 2 CH 2 CH 2 -), and neopentyl ((CH 3 ) 3 CCH 2 -), Cx alkyl refers to an alkyl group having x carbon atoms.

[0050] "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, methylene (-CH 2 -), ethylene (-CH 2 CH 2 - or -CH(Me)-), propylene (-CH 2 CH 2 CH 2 - or -CH(Me)CH 2 -, -CH(Et)-, or -CH(Et)-.

[0051] "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.

[0052] "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.

[0053] "Cyano" refers to the group -C≡N.

[0054] "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, carbo xyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, 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, SO 3 H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein the substituents are as defined herein.

[0055] "Halo" or "halogen" refers to fluoro, chloro, bromo, and iodo, preferably fluoro or chloro.

[0056] "Hydroxy" or "hydroxyl" refers to the group --OH.

[0057] "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, thiazole, and furanyl. Other preferred heteroaryls include 9- or 10-membered heteroaryls such as indolyl, quinolinyl, quinolonyl, isoquinolinyl, and isoquinolonyl.

[0058] "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 may 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 N-oxide, sulfinyl (S(O)), sulfonyl moiety (S(O)), 2 ) part.

[0059] 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.

[0060] "Oxo" refers to the atom (=O) or (O).

[0061] The term "optional" or "optionally" as used throughout this specification means that the subsequently described event or circumstance may, but need not, occur, and that the description includes cases where the event or circumstance occurs and cases where 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 may, but need not, be oxidized, and the description includes situations where the nitrogen atom is not oxidized and situations where the nitrogen atom is oxidized.

[0062] "Optionally substituted" means that the group is unsubstituted or optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) of the substituents recited for that group, unless otherwise specified, the substituents can be the same or different. In one embodiment, the optionally substituted group has one substituent. In another embodiment, the optionally substituted group has two substituents. In another embodiment, the optionally substituted group has three substituents. In another embodiment, the optionally substituted group has four substituents. In some embodiments, the optionally substituted group has 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, or 2 to 5 substituents. In one embodiment, the optionally substituted group is unsubstituted.

[0063] 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.

[0064] compound In one embodiment, provided is a compound of formula (I) [ka] or a pharma- ceutically acceptable salt thereof, X is N or CH; Y is N or CR 4 and n is 0 or 1, R is hydrogen; R 1 -C 1 -C 6 Alkylene-R 5 and R 2 is hydrogen, oxo, or C 1 -C 6 is alkyl, R 3 is hydrogen, oxo, or C 1 -C 6 is alkyl, R 4 is hydrogen, OH, or C 1 -C 6 is alkyl, Or, R 3 and R 4 are halo or C together with the carbon atom to which they are attached. 1 -C 3 C optionally substituted by alkyl 3 -C 6 Forming a cycloalkyl, R 5 is a 5-membered heterocyclyl or a 5-membered heteroaryl, each containing 1, 2, or 3 heteroatoms independently selected from O, N, and S, where R 5 at least one heteroatom in is S, and R 5 Ha, Halo, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkenyl, or C 1 -C 6 optionally substituted by haloalkyl; Ring A is a 5- to 12-membered heterocyclyl or a 5- to 12-membered heteroaryl, each independently selected from halo, CN, C 3 -C 6 Cycloalkyl, or C optionally substituted by halo or OH 1 -C6 may be substituted by alkyl, L is a bond, -O-, C 1 -C 6 Alkylene, *-OC 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, ** represents the point of attachment to ring B, L is *-OC 1 -C 6 C of L is alkylene-** 1 -C 6 Alkylene is R L where each R L is independently C 1 -C 6 alkyl or halo, or two R L together with the carbon atom or atoms to which they are attached. 3 -C 6 forming a cycloalkyl or 3- to 6-membered heterocyclyl; L is C 1 -C 6 When it is alkylene, C 1 -C 6 Alkylene is R L1 where each R L1 are independently halo, OH, oxo, or C 1 -C 6 Alkyl or two R L1 together with the carbon atom or atoms to which they are attached. 3 -C 6 forming a cycloalkyl or 3- to 6-membered heterocyclyl; R 6 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 halo, CN, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -COCH 3 , -CONH 2 , -S(O) 2 CH 3 and phenyl.

[0065] In the description 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, R 1 All descriptions, variations, embodiments or aspects provided herein with respect to may be combined with all descriptions, variations, embodiments or aspects of Ring A, as if all combinations were specifically and individually recited.

[0066] In some embodiments of Formula (I), X and Y are each N. In some embodiments, X is N and Y is CR 4 In some embodiments, X is N and Y is CR 4 and R 4 is H, OH, or C 1 -C 6 In some embodiments, X is N and Y is CR 4 and R 4 is H, OH, or C 1 -C 3 In some embodiments, X is N and Y is CR 4 and R 4 is H or C 1 -C 3 In some such embodiments, X is N and Y is CR 4and R 4 is H or OH. In some embodiments, X is N and Y is CR 4 and R 4 is H. In some embodiments, X is N and Y is CR 4 and R 3 and R 4 are, together with the carbon atom to which they are attached, halo or C 1 -C 3 In some embodiments, X is N and Y is CR 4 and R 3 and R 4 together with the carbon atom to which they are attached form a cyclopropyl group which may be substituted by fluoro or methyl.

[0067] In some embodiments of Formula (I), provided is a compound of Formula (II) [ka] or a pharma- ceutically acceptable salt thereof, wherein X, Y, n, R 2 , R 3 , R 5 , ring A, L, and ring B are as defined for formula (I).

[0068] In some embodiments of formula (I) or (II), X is N and Y is CR 4 In some embodiments, the compound is of formula (II-a): [ka] or a pharma- ceutically acceptable salt thereof, 2 , R 3 , R 4 , R 5 , ring A, L, and ring B are as defined for formula (I).

[0069] In some embodiments of formula (I) or (II), X is N and Y is CR 4and R 3 and R 4 are, together with the carbon atom to which they are attached, halo or C 1 -C 3 In some embodiments, the compound is of formula (II-b), (II-b1), or (II-b2): [ka] In the formula, n, R 2 , R 5 , ring A, L, and ring B are as defined for formula (I).

[0070] In some embodiments of Formula (II), X and Y are each N. In some embodiments, the compound is of Formula (II-c): [ka] In the formula, n, R 2 , R 3 , R 5 , ring A, L, and ring B are as defined for formula (I).

[0071] In some embodiments of formula (II), ring A is a 6-membered heteroaryl containing 1, 2, or 3 heteroatoms. In some embodiments, the compound is of formula (III): [ka] In the formula, V and W are independently N or CR A And each R A H, halo, CN, C 3 -C 6 Cycloalkyl, or C optionally substituted by halo or OH 1 -C 6 In some embodiments, V is N and W is CR A In some embodiments, V is CR A and W is N. In some embodiments, V and W are each CRA In some embodiments, V and W are each N. In some embodiments, V is N and W is CH. In some embodiments, V is CH and W is N. In some embodiments, V and W are each CH. In some embodiments of formula (III), X is N and Y is CR 4 In some embodiments, the compound is of formula (III-a): [ka] In the formula, n, R 2 , R 3 , R 4 , R 5 , L, and ring B are as defined for formula (I), and V and W are as defined for formula (III).

[0072] In some embodiments of formula (III), X is N and Y is CR 4 and R 3 and R 4 are, together with the carbon atom to which they are attached, halo or C 1 -C 3 In some embodiments, the compound is of formula (III-b), (III-b1), or (III-b2): [ka] In the formula, n, R 2 , R 5 , L, and ring B are as defined for formula (I), and V and W are as defined for formula (III). In some embodiments, the compound is of formula (III-b-3): [ka] In the formula, n, R 2 , R 5 , L, and ring B are as defined for formula (I).

[0073] In some embodiments of formula (III), X and Y are each N. In some embodiments, the compound is of formula (III-c): [ka] In the formula, n, R 2 , R 3 , R 5 , L, and ring B are as defined for formula (I), and V and W are as defined for formula (III).

[0074] In some embodiments of Formula (III), L is R as described for Formula (I). L may be replaced by *-OC 1 -C 6 In some embodiments, L is -O-CH 2 In some embodiments, the compound is of formula (IV): [ka] In the formula, n, R 2 , R 3 , R 5 and ring B are as defined for formula (I), and V and W are as defined for formula (III).

[0075] In some embodiments of formula (IV), X is N and Y is CR 4 In some embodiments, the compound is of formula (IV-a): [ka] In the formula, n, R 2 , R 3 , R 4 , R 5 and ring B are as defined for formula (I), and V and W are as defined for formula (III).

[0076] In some embodiments of formula (IV), X is N and Y is CR 4 and R3 and R 4 are, together with the carbon atom to which they are attached, halo or C 1 -C 3 In some embodiments, the compound is of formula (IV-b), (IV-b1), or (IV-b2): [ka] In the formula, n, R 2 , R 5 and ring B is as defined for formula (I), and V and W are as defined for formula (III). In some embodiments, the compound is of formula (IV-b-3): [ka] In the formula, n, R 2 , R 5 , L, and ring B are as defined for formula (I).

[0077] In some embodiments of the compound of Formula (III), L is -O-. In some embodiments, the compound is of Formula (V): [ka] In the formula, n, R 2 , R 3 , R 5 and ring B are as defined for formula (I), and V and W are as defined for formula (III).

[0078] In some embodiments of formula (V), X is N and Y is CR 4 In some embodiments, the compound is of formula (Va): [ka] In the formula, n, R 2 , R 3 , R 4 , R 5and ring B are as defined for formula (I), and V and W are as defined for formula (III).

[0079] In some embodiments of formula (I) or (V), X is N and Y is CR 4 and R 3 and R 4 are, together with the carbon atom to which they are attached, halo or C 1 -C 3 In some embodiments, the compound is of formula (Vb), (V-b1), or (V-b2): [ka] In the formula, n, R 2 , R 5 and ring B is as defined for formula (I), and V and W are as defined for formula (III). In some embodiments, the compound is of formula (Vb-3): [ka] In the formula, n, R 2 , R 5 , L, and ring B are as defined for formula (I).

[0080] In some embodiments of formula (I) (including compounds of formulas (II)-(V) and subformulas thereof, if applicable), X is N and Y is CR 4 ;R 3 and R 4 along with the carbon atom to which they are attached, C 3 -C 6 Forming a cycloalkyl; n, R 2 , Ring A, and Ring B are as detailed herein for Formula (I). In some embodiments of Formula (I) (including compounds of Formulas (II)-(V) and subformulas thereof, where applicable), Y is CR 4 ;R 3 and R 4 along with the carbon atom to which they are attached, C3 -C 6 Ring B may be substituted by phenyl; X, n, R 2 and ring A are as detailed herein for formula (I). In some of the foregoing embodiments, R 3 and R 4 C along with the carbon atom to which they are attached 3 In some of the foregoing embodiments, X is N. In some of the foregoing embodiments, n is 1. In some of the foregoing embodiments, R 2 is H. In some of the aforementioned embodiments, ring A is pyridinyl. In some of the aforementioned embodiments, X is N, n is 1, and R 2 is H.

[0081] In some embodiments of formula (I) (including compounds of formulas (II)-(V) and subformulas thereof, if applicable), X is N and Y is CR 4 and R 4 is H, n, R 2 , R 3 , Ring A, and Ring B are as detailed herein for Formula (I). In some embodiments of Formula (I) (including compounds of Formulas (II)-(V) and subformulas thereof, where applicable), X is N and Y is CR 4 ;R 4 is H; ring B is C 3 -C 10 cycloalkyl, 4- to 12-membered heterocyclyl, or 5- to 12-membered heteroaryl, each of which is independently halo, CN, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -COCH 3 , -CONH 2 , -S(O) 2 CH 3 and phenyl; n, R 2 , R 3and ring A are as detailed herein for formula (I). In some embodiments of formula (I) (including compounds of formulas (II)-(V) and subformulas thereof, where applicable), X is N and Y is CR 4 ;R 4 is H; Ring B is a 4- to 12-membered heterocyclyl, or a 5- to 12-membered heteroaryl, each of which is independently halo, CN, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -COCH 3 , -CONH 2 , -S(O) 2 CH 3 and phenyl; n, R 2 , R 3 and ring A are as detailed herein for formula (I). In some embodiments of formula (I) (including compounds of formulas (II)-(V) and subformulas thereof, where applicable), X is N and Y is CR 4 ;R 4 is H; n is 1; R 2 and R 3 are each H; ring A is pyridyl; ring B is 4- to 12-membered heterocyclyl, or 5- to 12-membered heteroaryl, each of which is independently halo, CN, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -COCH 3 , -CONH 2 , -S(O) 2 CH 3 and phenyl.

[0082] In some embodiments of formula (I) (including compounds of formulas (II)-(V) and subformulas thereof, if applicable), X and Y are each N; ring B is C 3 -C 10cycloalkyl, 4- to 12-membered heterocyclyl, or 5- to 12-membered heteroaryl, each of which is independently halo, CN, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -COCH 3 , -CONH 2 , -S(O) 2 CH 3 and phenyl; n, R 2 , R 3 and ring A are as detailed herein for formula (I). In some embodiments of formula (I) (including compounds of formulas (II)-(V) and subformulas thereof, where applicable), X and Y are each N; ring B is C 3 -C 10 cycloalkyl, 4- to 12-membered heterocyclyl, or 5- to 12-membered heteroaryl, each of which is independently halo, CN, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -COCH 3 , -CONH 2 , -S(O) 2 CH 3 and phenyl; n is 1; R 2 and R 3 are each H; ring A is as detailed herein for formula (I). In some embodiments of formula (I) (including compounds of formulas (II)-(V) and subformulae thereof, where applicable), X and Y are each N; ring B is a 4-12 membered heterocyclyl, or a 5-12 membered heteroaryl, each of which is independently selected from halo, CN, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -COCH 3 , -CONH 2 , -S(O) 2 CH3 and phenyl; n is 1; R 2 and R 3 are each H; ring A is as detailed herein for formula (I). In some embodiments of formula (I) (including compounds of formulas (II)-(V) and subformulas thereof, where applicable), X and Y are each N; ring B is C 3 -C 10 cycloalkyl, 4- to 12-membered heterocyclyl, or 5- to 12-membered heteroaryl, each of which is independently halo, CN, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -COCH 3 , -CONH 2 , -S(O) 2 CH 3 and phenyl; n is 1; R 2 and R 3 are each H; Ring A is pyrazolyl or pyridyl, each of which is halo, CN, C 3 -C 6 Cycloalkyl, or C optionally substituted by halo or OH 1 -C 6 It may be substituted by alkyl.

[0083] In some embodiments of Formula (I) (including compounds of Formulas (II)-(V) and subformulas thereof, if applicable), X is N, Y is CH, n is 1, and R 2 and R 3 are both hydrogen and ring A is [ka] It is.

[0084] In some embodiments of Formula (I) (including compounds of Formulas (II)-(V) and subformulas thereof, if applicable), X is N, Y is CH, n is 1, and R 2 and R 3 are both hydrogen, ring A is pyridinyl, and ring B is a 5-12 membered heteroaryl, each of which is independently halo, CN, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -COCH 3 , -CONH 2 , -S(O) 2 CH 3 and phenyl.

[0085] In some embodiments of the compounds of Formula (I) (including compounds of Formulas (II)-(V) and subformulas thereof, if applicable), R 1 -C 1 -C 3 Alkylene-R 5 In some embodiments, R 1 is -CH 2 -R 5 In some embodiments of the compounds of formula (I) (including compounds of formulas (II)-(V) and subformulas thereof, if applicable), R 5 is a 5-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from O, N, and S, where R 5 At least one heteroatom in is S, and R 5 Ha, Halo, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkenyl, or C 1 -C 6 In some embodiments, R 5 is a 5-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from O, N, and S, where R 5 At least one heteroatom in is S, and R 5Ha, Halo, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkenyl, or C 1 -C 6 In some embodiments of the compounds of formula (I) (including the compounds of formulas (II)-(V) and subformulas thereof, if applicable), R 5 is a 5-membered heterocyclyl or a 5-membered heteroaryl, each of which contains 1 or 2 heteroatoms independently selected from N and S, where R 5 At least one heteroatom in is S, and R 5 Ha, Halo, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkenyl, or C 1 -C 6 In some embodiments of the compounds of formula (I) (including the compounds of formulas (II)-(V) and subformulas thereof, if applicable), R 5 is a 5-membered heterocyclyl or a 5-membered heteroaryl, each of which contains 1 or 2 heteroatoms selected from N or S, where R 5 one heteroatom in is S and R 5 Ha, Halo, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkenyl, or C 1 -C 6 In some embodiments, R 5 is thiazolyl, isothiazolyl, or thiophenyl, which are halo, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkenyl, or C 1 -C 6 In some embodiments, R 5 teeth [ka] These are halo and -OC, respectively. 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkenyl, or C 1 -C 6 In some embodiments, R 5 teeth [ka] These are halo and -OC, respectively. 1-3 Alkyl, C 1-3 Alkyl, C 2-6 Alkenyl, or C 1 -C 3 In some embodiments, R 5 teeth [ka] and -O-CH 3 , methyl, ethyl, or vinyl. In some embodiments, R 5 Ha, Halo, -OC 1-3 Alkyl, C 1-3 Alkyl, C 2-6 Alkenyl, or C 1 -C 3 Optionally substituted by haloalkyl [ka] In some embodiments, R 5 is a non-permutation [ka] In some embodiments, R 5 is thiazole optionally substituted with methyl, bromo, vinyl, ethyl, methoxy, chloro, or fluoro. In some embodiments, R 5 teeth, [ka] It is.

[0086] In some embodiments of the compounds of Formula (I) (including compounds of Formulas (II)-(V) and subformulas thereof, where applicable), X is N. In other embodiments, X is CH.

[0087] In some embodiments of compounds of Formula (I) (including compounds of Formulas (II)-(V) and subformulas thereof, where applicable), n is 0. In other embodiments, n is 1.

[0088] In some embodiments of the compounds of Formula (I) (including compounds of Formulas (II)-(V) and subformulas thereof, if applicable), Y is N. In other embodiments, Y is CR 4 where R 4 is hydrogen, OH, or C 1 -C 6 In another embodiment, Y is CR 4 and R 3 and R 4 are optionally joined together with the carbon atom to which they are attached by halo or C 1 -C 3 C optionally substituted by alkyl 3 -C 6 Forms a cycloalkyl. For example, C 3 -C 6 Cycloalkyl is halo, such as fluoro, or C, such as methyl. 1 -C 3 It may be cyclopropyl optionally substituted by alkyl.

[0089] In some embodiments of the compounds of Formula (I) (including compounds of Formulas (II)-(V) and subformulas thereof, if applicable), R 2 and R 3 are independently hydrogen, oxo, or C 1 -C 6 In some embodiments, R 2 and R 3 is hydrogen. In some embodiments, R 2 and R3 is oxo. In some embodiments, R 2 and R 3 is methyl.

[0090] In some embodiments of the compounds of formula (I) (including compounds of formulas (II)-(V) and subformulas thereof, if applicable), the moiety [ka] In some embodiments of the compounds of formula (I) (including compounds of formulas (II)-(V) and subformulas thereof, where applicable), the moiety [ka] It is.

[0091] In some embodiments of the compounds of formula (I) (including compounds of formulas (II)-(V) and subformulas thereof, if applicable), ring A is selected from halo, CN, C 3 -C 6 Cycloalkyl, or C optionally substituted by halo or OH 1 -C 6 In some embodiments, ring A is a 5- to 12-membered heterocyclyl optionally substituted by alkyl. [ka] , which are halo, CN, and C, respectively. 3 -C 6 Cycloalkyl, or C optionally substituted by halo or OH 1 -C 6 In some embodiments, ring A is optionally substituted with halo, CN, C 3 -C 6 Cycloalkyl, or C optionally substituted by halo or OH 1 -C 6 An exemplary ring A is: [ka] each independently represents halo, CN, C 3 -C 6 Cycloalkyl, or C optionally substituted by halo or OH 1 -C 6 In some embodiments, ring A is optionally substituted by alkyl. [ka] These are each independently halo, CN, C 3 -C 6 Cycloalkyl, or C optionally substituted by halo or OH 1 -C 6 In some embodiments, Ring A is benzodioxolyl, pyridyl, pyrimidinyl, or pyrazinyl. In some embodiments, Ring A is [ka] It is.

[0092] In some embodiments of the compounds of Formula (I) (including compounds of Formulas (II)-(V) and subformulas thereof, if applicable), L is a bond. In some embodiments, L is -O-. In some embodiments, L is C 1 -C 6 In some embodiments, L is an unsubstituted C 1 -C 6 In some embodiments, L is R L1 C may be substituted 1 -C 6 alkylene, where each R L1 are independently halo, OH, oxo, or C 1 -C 6 Alkyl or two R L1 together with the carbon atom or atoms to which they are attached. 3 -C 6In some embodiments, L is an unsubstituted C 1 -C 2 In some embodiments, L is R L1 C may be substituted 1 -C 2 alkylene, where each R L1 are independently halo, OH, oxo, or C 1 -C 6 In some embodiments, L is an unsubstituted C alkyl. 2 In some embodiments, L is R L1 C may be substituted 2 alkylene, where each R L1 are independently halo, OH, oxo, or C 1 -C 6 In some such embodiments, L is [ka] In some embodiments, L is *-OC 1 -C 6 alkylene-**, where * represents the point of attachment to ring A and ** represents the point of attachment to ring B. For example, L is *-OCH 2 In some embodiments, L can be *-OC. 1 -C 6 C of L is alkylene-** 1 -C 6 Alkylene is R L where each R L is independently C 1 -C 6 alkyl or halo, or two R L together with the carbon atom or atoms to which they are attached. 3 -C 6 In some embodiments, L is -OC. 1 -C 6 Alkylene-**, C 1-C 6 Alkylene is R L where each R L is independently C 1 -C 6 Alkyl or two R L together with the carbon atom or atoms to which they are attached. 3 -C 6 Forms a cycloalkyl or 3- to 6-membered heterocyclyl. Specific examples include L is -OC(R L ) 2 -**, then two R L C along with the carbon atom or atoms to which they are attached 3 -C 6 In some embodiments, L forms a cycloalkyl or a 3- to 6-membered heterocyclyl. 1 -C 6 In some embodiments, L is alkylene-O-**. In some embodiments, L is *-NR 6 -C 1 -C 6 alkylene-**, where R 6 is hydrogen or C 1 -C 6 In some embodiments, L is an alkyl group. In some embodiments, L includes an isotope of hydrogen, such as deuterium. In some embodiments, L is *-O-CH 2 -** or *-O-CD 2 In some embodiments, L is -O-CD 2 -**. In some embodiments, L comprises an oxo group. In some embodiments, L is *-C(O)-CH 2 -**.

[0093] In some embodiments of the compounds of formula (I) (including compounds of formulas (II)-(V) and subformulas thereof, if applicable), ring B is halo, CN, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -COCH 3 , -CONH 2 , -S(O) 2 CH 3C optionally substituted by 1 to 3 substituents independently selected from the group consisting of 3 -C 10 Cycloalkyl. Exemplary C 3 -C 10 Cycloalkyl is [ka] These include, but are not limited to, each independently selected from halo, CN, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -COCH 3 , -CONH 2 , -S(O) 2 CH 3 In some embodiments, ring B is optionally substituted with 1 to 3 substituents independently selected from the group consisting of 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 by 1 to 3 substituents independently selected from the group consisting of 6 -C 14 Aryl. For example, C 6 -C 14 The aryl is [ka] each of which independently represents halo, CN, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -COCH 3 , -CONH 2 , -S(O) 2 CH 3In some embodiments, ring B is optionally substituted with 1 to 3 substituents each independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -COCH 3 , -CONH 2 , -S(O) 2 CH 3 and phenyl. Exemplary 4-12 membered heterocyclyls are: [ka] These include, but are not limited to, each independently selected from halo, CN, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -COCH 3 , -CONH 2 , -S(O) 2 CH 3 In some embodiments, ring B is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -COCH 3 , -CONH 2 , -S(O) 2 CH 3 and phenyl. Exemplary 5-12 membered heteroaryls are: [ka] These include, but are not limited to, each independently selected from halo, CN, oxo, C 1 -C 6 Alkyl, C 1 -C6 Haloalkyl, -COCH 3 , -CONH 2 , -S(O) 2 CH 3 In some embodiments, ring B is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, CN, and -CONH. 2 In some embodiments, Ring B is phenyl, optionally substituted with 1 to 3 substituents each independently selected from the group consisting of: [ka] In some embodiments, ring B is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo and CN. [ka] In some embodiments, ring B is [ka] In some embodiments, Ring B is a 9-membered heteroaryl optionally substituted with 1-2 substituents independently selected from the group consisting of halo and CN. In some embodiments, Ring B is [ka] It is.

[0094] In some embodiments of formula (I) (including compounds of formulas (II)-(V) and subformulas thereof, if applicable), X, n, R, R 1 , R 2 , ring A, and L are as described for formula (I), and ring B is halo, CN, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -COCH 3 , -CONH 2 , -S(O) 2 CH3 C optionally substituted by 1 to 3 substituents independently selected from the group consisting of 3 -C 10 It is cycloalkyl.

[0095] In some embodiments of formula (I) (including compounds of formulas (II)-(V) and subformulas thereof, if applicable), X, n, R, R 1 , R 2 , ring A, and L are as described for formula (I), and 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 C optionally substituted by 1 to 3 substituents independently selected from the group consisting of 6 -C 14 It is aryl.

[0096] In some embodiments of formula (I) (including compounds of formulas (II)-(V) and subformulas thereof, if applicable), X, n, R, R 1 , R 2 , ring A, and L are as described for formula (I), and 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 C optionally substituted by 1 to 3 substituents independently selected from the group consisting of 6 It is aryl.

[0097] In some embodiments of formula (I) (including compounds of formulas (II)-(V) and subformulas thereof, if applicable), X, n, R, R 1 , R 2, ring A, and L are as described for formula (I), and L is *-OCH 2 -**, and 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 C optionally substituted by 1 to 3 substituents independently selected from the group consisting of 6 It is aryl.

[0098] In some embodiments of formula (I) (including compounds of formulas (II)-(V) and subformulas thereof, if applicable), X, n, R, R 1 , R 2 , ring A, and L are as described for formula (I), and 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.

[0099] In some embodiments of formula (I) (including compounds of formulas (II)-(V) and subformulas thereof, if applicable), X, n, R, R 1 , R 2 , ring A, and L are as described for formula (I), and ring B is halo, CN, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -COCH 3 , -CONH 2 , -S(O) 2 CH 3and phenyl.

[0100] In some embodiments of formula (I) (including compounds of formulas (II)-(V) and subformulas thereof, if applicable), X is N, n is 1, and ring A is halo, CN, C 3 -C 6 Cycloalkyl, or C optionally substituted by halo or OH 1 -C 6 9-10 membered heterocyclyl optionally substituted by alkyl, R, R 1 , R 2 , L, and ring B are as described for formula (I).

[0101] In some embodiments of formula (I) (including compounds of formulas (II)-(V) and subformulas thereof, if applicable), X is N, n is 1, and ring A is halo, CN, C 3 -C 6 Cycloalkyl, or C optionally substituted by halo or OH 1 -C 6 R, R are 5-12 membered heteroaryl optionally substituted by alkyl. 2 , L, and ring B are as described for formula (I). In some such embodiments, ring A is a 5-6 membered heteroaryl. In some such embodiments, ring A is halo, CN, C 3 -C 6 Cycloalkyl, or C optionally substituted by halo or OH 1 -C 6 In some such embodiments, ring A is a 6-membered heteroaryl optionally substituted by alkyl. [ka] and each of them is halo, CN, C 3 -C 6 Cycloalkyl, or C optionally substituted by halo or OH1 -C 6 In some such embodiments, ring A is optionally substituted by alkyl. [ka] and each of them is halo, CN, C 3 -C 6 Cycloalkyl, or C optionally substituted by halo or OH 1 -C 6 It may be substituted by alkyl.

[0102] In some embodiments of formula (I) (including compounds of formulas (II)-(V) and subformulas thereof, if applicable), X is N, n is 1, and 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 C optionally substituted by 1 to 3 substituents independently selected from the group consisting of 3 -C 10 Cycloalkyl, R, R 1 , R 2 , ring A, and L are as described for formula (I).

[0103] In some embodiments of formula (I), (V), (Va), or (Vb), ring A is halo, CN, C 3 -C 6 Cycloalkyl, or C optionally substituted by halo or OH 1 -C 6 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 C optionally substituted by 1 to 3 substituents independently selected from the group consisting of 3 -C 10 cycloalkyl; R, R 1 , R 2 and L is as described for formula (I). In some such embodiments, ring A is [ka] In other such embodiments, ring A is: [ka] In yet another such embodiment, ring A is: [ka] In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is as described for formula (I). In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is a 5-membered heteroaryl containing one S heteroatom and one N heteroatom, halo, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkenyl, or C 1 -C 6 It may be substituted by haloalkyl.

[0104] In some embodiments of formula (I) (including compounds of formulas (II)-(V) and subformulas thereof, if applicable), ring A is halo, CN, C 3 -C 6 Cycloalkyl, or C optionally substituted by halo or OH 1 -C6 L is a 5-6 membered heteroaryl optionally substituted by alkyl; R is as described for formula (I). L may be replaced by *-OC 1 -C 6 alkylene-**; 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 C optionally substituted by 1 to 3 substituents independently selected from the group consisting of 3 -C 10 R and R are cycloalkyl; 2 is as described for formula (I). In some such embodiments, L is *-O-CH 2 For example, in some embodiments, [ka] teeth, [ka] and the like, optionally substituted as described herein for ring A, L, and ring B. In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is as described for formula (I). In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is a 5-membered heteroaryl containing one S heteroatom and one N heteroatom, halo, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkenyl, or C 1 -C 6It may be substituted by haloalkyl.

[0105] In some embodiments of formula (I) (including compounds of formulas (II)-(V) and subformulas thereof, if applicable), ring A is halo, CN, C 3 -C 6 Cycloalkyl, or C optionally substituted by halo or OH 1 -C 6 L is a bond; 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 C optionally substituted by 1 to 3 substituents independently selected from the group consisting of 3 -C 10 R and R are cycloalkyl; 2 is as described for formula (I). For example, in some embodiments, [ka] teeth, [ka] and the like, optionally substituted as described herein for Ring A and Ring B. In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is as described for formula (I). In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is a 5-membered heteroaryl containing one S heteroatom and one N heteroatom, halo, -OC 1-6Alkyl, C 1-6 Alkyl, C 1-6 Alkenyl, or C 1 -C 6 It may be substituted by haloalkyl.

[0106] In some embodiments of formula (I) (including compounds of formulas (II)-(V) and subformulas thereof, if applicable), ring A is halo, CN, C 3 -C 6 Cycloalkyl, or C optionally substituted by halo or OH 1 -C 6 L is -O-; 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 C optionally substituted by 1 to 3 substituents independently selected from the group consisting of 3 -C 10 cycloalkyl; R and R 2 is as described for formula (I). For example, in some embodiments, [ka] teeth, [ka] and the like, optionally substituted as described herein for Ring A and Ring B. In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is as described for formula (I). In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5and R 5 is a 5-membered heteroaryl containing one S heteroatom and one N heteroatom, halo, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkenyl, or C 1 -C 6 It may be substituted by haloalkyl.

[0107] In some embodiments of formula (I) (including compounds of formulas (II)-(V) and subformulas thereof, if applicable), 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 C optionally substituted by 1 to 3 substituents independently selected from the group consisting of 6 -C 14 aryl; R, R 2 , ring A, and L are as described for formula (I). In some embodiments of formula (I) (including compounds of formulas (II)-(V) and subformulas thereof, if applicable), X is N, n is 1, and 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 C optionally substituted by 1 to 3 substituents independently selected from the group consisting of 6 -C 14 aryl; R, R 2 , ring A, and L are as described for formula (I). In some embodiments of formula (I) (including compounds of formulas (II)-(V) and subformulas thereof, if applicable), X is N, n is 1, and ring B is halo, CN, oxo, C 1 -C 6Alkyl, C 1 -C 6 Haloalkyl, -COCH 3 , -CONH 2 , -S(O) 2 CH 3 C optionally substituted by 1 to 3 substituents independently selected from the group consisting of 6 aryl; R, R 2 , ring A, and L are as described for formula (I). In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is as described for formula (I). In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is a 5-membered heteroaryl containing one S heteroatom and one N heteroatom, halo, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkenyl, or C 1 -C 6 It may be substituted by haloalkyl.

[0108] In some embodiments of formula (I) (including compounds of formulas (II)-(V) and subformulas thereof, if applicable), ring A is halo, CN, C 3 -C 6 Cycloalkyl, or C optionally substituted by halo or OH 1 -C 6 ring B is halo, CN, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -COCH 3 , -CONH 2 , -S(O) 2 CH 3C optionally substituted by 1 to 3 substituents independently selected from the group consisting of 6 aryl; R, R 1 , R 2 and L is as described for formula (I). In some such embodiments, ring A is [ka] In other such embodiments, ring A is: [ka] In yet another such embodiment, ring A is: [ka] It is.

[0109] In some embodiments of formula (I) (including compounds of formulas (II)-(V) and subformulas thereof, if applicable), ring A is halo, CN, C 3 -C 6 Cycloalkyl, or C optionally substituted by halo or OH 1 -C 6 L is a 5-6 membered heteroaryl optionally substituted by alkyl; R is as described for formula (I). L may be replaced by *-OC 1 -C 6 alkylene-**; 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 C optionally substituted by 1 to 3 substituents independently selected from the group consisting of 6 aryl; R and R 2 is as described for formula (I). In some such embodiments, L is *-O-CH2 For example, in some embodiments, [ka] teeth, [ka] and the like, optionally substituted as described herein for rings A, L, and B. For example, in some embodiments, [ka] teeth [ka] In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is as described for formula (I). In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is a 5-membered heteroaryl containing one S heteroatom and one N heteroatom, halo, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkenyl, or C 1 -C 6 It may be substituted by haloalkyl.

[0110] In some embodiments of formula (I) (including compounds of formulas (II)-(V) and subformulas thereof, if applicable), ring A is halo, CN, C 3 -C 6 Cycloalkyl, or C optionally substituted by halo or OH 1 -C 6 L is a bond; Ring B is halo, CN, oxo, C1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -COCH 3 , -CONH 2 , -S(O) 2 CH 3 C optionally substituted by 1 to 3 substituents independently selected from the group consisting of 6 aryl; R and R 2 is as described for formula (I). In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is as described for formula (I). In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is a 5-membered heteroaryl containing one S heteroatom and one N heteroatom, halo, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkenyl, or C 1 -C 6 It may be substituted by haloalkyl.

[0111] In some embodiments of formula (I) (including compounds of formulas (II)-(V) and subformulas thereof, if applicable), ring A is halo, CN, C 3 -C 6 Cycloalkyl, or C optionally substituted by halo or OH 1 -C 6 L is -O-; Ring B is halo, CN, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -COCH 3 , -CONH 2 , -S(O) 2 CH 3C optionally substituted by 1 to 3 substituents independently selected from the group consisting of 6 aryl; R and R 2 is as described for formula (I). In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is as described for formula (I). In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is a 5-membered heteroaryl containing one S heteroatom and one N heteroatom, halo, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkenyl, or C 1 -C 6 It may be substituted by haloalkyl.

[0112] In some embodiments of formula (I) (including compounds of formulas (II)-(V) and subformulas thereof, if applicable), 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 R, R 2 , Ring A, and L are as described for formula (I). In some such embodiments, Ring A is [ka] In other such embodiments, ring A is: [ka] In yet another such embodiment, ring A is: [ka] In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is as described for formula (I). In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is a 5-membered heteroaryl containing one S heteroatom and one N heteroatom, halo, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkenyl, or C 1 -C 6 It may be substituted by haloalkyl.

[0113] In some embodiments of formula (I) (including compounds of formulas (II)-(V) and subformulas thereof, if applicable), 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 R, R 2 , ring A, and L are as described for formula (I). In some embodiments of formula (I), (V), (Vα), or (Vb), ring B is halo, CN, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -COCH 3 , -CONH 2 , -S(O) 2 CH3 R, R 2 , ring A, and L are as described for formula (I). In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is as described for formula (I). In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is a 5-membered heteroaryl containing one S heteroatom and one N heteroatom, halo, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkenyl, or C 1 -C 6 It may be substituted by haloalkyl.

[0114] In some embodiments of formula (I) (including compounds of formulas (II)-(V) and subformulas thereof, if applicable), ring A is halo, CN, C 3 -C 6 Cycloalkyl, or C optionally substituted by halo or OH 1 -C 6 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 R, R 2 and L is as described for formula (I). In some such embodiments, ring A is [ka] In other such embodiments, ring A is: [ka] In yet another such embodiment, ring A is: [ka] In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is as described for formula (I). In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is a 5-membered heteroaryl containing one S heteroatom and one N heteroatom, halo, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkenyl, or C 1 -C 6 It may be substituted by haloalkyl.

[0115] In some embodiments of formula (I) (including compounds of formulas (II)-(V) and subformulas thereof, if applicable), ring A is halo, CN, C 3 -C 6 Cycloalkyl, or C optionally substituted by halo or OH 1 -C 6 L is a 5-6 membered heteroaryl optionally substituted by alkyl; R is as described for formula (I). L may be replaced by *-OC 1 -C 6 alkylene-**; Ring B is halo, CN, oxo, C 1 -C 6 Alkyl, C 1 -C6 Haloalkyl, -COCH 3 , -CONH 2 , -S(O) 2 CH 3 and phenyl; R and R are 4- to 12-membered heterocyclyl optionally substituted by 1 to 3 substituents independently selected from the group consisting of 2 is as described for formula (I). In some such embodiments, L is *-O-CH 2 For example, in some embodiments of formula (I), (V), (Va), or (Vb), [ka] teeth, [ka] and the like, optionally substituted as described herein for Ring A and Ring B. In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is as described for formula (I). In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is a 5-membered heteroaryl containing one S heteroatom and one N heteroatom, halo, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkenyl, or C 1 -C 6 It may be substituted by haloalkyl.

[0116] In some embodiments of formula (I) (including compounds of formulas (II)-(V) and subformulas thereof, if applicable), ring A is halo, CN, C 3 -C 6 Cycloalkyl, or C optionally substituted by halo or OH 1 -C6 L is a bond; 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; R and R are 9- to 12-membered heterocyclyl optionally substituted by 1 to 3 substituents independently selected from the group consisting of 2 is as described for formula (I). For example, in some embodiments, [ka] teeth, [ka] and the like, optionally substituted as described herein for Ring A and Ring B. In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is as described for formula (I). In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is a 5-membered heteroaryl containing one S heteroatom and one N heteroatom, halo, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkenyl, or C 1 -C 6 It may be substituted by haloalkyl.

[0117] In some embodiments of formula (I) (including compounds of formulas (II)-(V) and subformulas thereof, if applicable), ring A is halo, CN, C 3 -C 6Cycloalkyl, or C optionally substituted by halo or OH 1 -C 6 L is -O-; 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; R and R are 9- to 12-membered heterocyclyl optionally substituted by 1 to 3 substituents independently selected from the group consisting of 2 is as described for formula (I). In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is as described for formula (I). In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is a 5-membered heteroaryl containing one S heteroatom and one N heteroatom, halo, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkenyl, or C 1 -C 6 It may be substituted by haloalkyl.

[0118] In some embodiments of formula (I) (including compounds of formulas (II)-(V) and subformulas thereof, if applicable), ring B is halo, CN, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -COCH 3 , -CONH 2 , -S(O) 2 CH 3R, R 2 , ring A, and L are as described for formula (I). In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is as described for formula (I). In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is a 5-membered heteroaryl containing one S heteroatom and one N heteroatom, halo, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkenyl, or C 1 -C 6 It may be substituted by haloalkyl.

[0119] In some embodiments of formula (I) (including compounds of formulas (II)-(V) and subformulas thereof, if applicable), ring A is halo, CN, C 3 -C 6 Cycloalkyl, or C optionally substituted by halo or OH 1 -C 6 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 R, R 2 and L is as described for formula (I). In some such embodiments, ring A is [ka] In other such embodiments, ring A is: [ka] In yet another such embodiment, ring A is: [ka] In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is as described for formula (I). In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is a 5-membered heteroaryl containing one S heteroatom and one N heteroatom, halo, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkenyl, or C 1 -C 6 It may be substituted by haloalkyl.

[0120] In some embodiments of formula (I) (including compounds of formulas (II)-(V) and subformulas thereof, if applicable), ring A is halo, CN, C 3 -C 6 Cycloalkyl, or C optionally substituted by halo or OH 1 -C 6 L is a 5-6 membered heteroaryl optionally substituted by alkyl; R is as described for formula (I). L may be replaced by *-OC 1 -C 6 alkylene-**; Ring B is halo, CN, oxo, C 1 -C 6 Alkyl, C 1 -C 6Haloalkyl, -COCH 3 , -CONH 2 , -S(O) 2 CH 3 R and R are 5-12 membered heteroaryl optionally substituted by 1 to 3 substituents independently selected from the group consisting of phenyl, 2 is as described for formula (I). In some such embodiments, L is *-O-CH 2 For example, in some embodiments of formula (I), (V), (Va), or (Vb), [ka] teeth, [ka] and the like, optionally substituted as described herein for ring A, L, and ring B. In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is as described for formula (I). In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is a 5-membered heteroaryl containing one S heteroatom and one N heteroatom, halo, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkenyl, or C 1 -C 6 It may be substituted by haloalkyl.

[0121] In some embodiments of formula (I) (including compounds of formulas (II)-(V) and subformulas thereof, if applicable), ring A is halo, CN, C 3 -C 6 Cycloalkyl, or C optionally substituted by halo or OH 1 -C 6L is a bond; 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 R and R are 5-12 membered heteroaryl optionally substituted by 1 to 3 substituents independently selected from the group consisting of phenyl, 2 is as described for formula (I). In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is as described for formula (I). In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is a 5-membered heteroaryl containing one S heteroatom and one N heteroatom, halo, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkenyl, or C 1 -C 6 It may be substituted by haloalkyl.

[0122] In some embodiments of formula (I) (including compounds of formulas (II)-(V) and subformulas thereof, if applicable), ring A is halo, CN, C 3 -C 6 Cycloalkyl, or C optionally substituted by halo or OH 1 -C 6 L is -O-; 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 R and R are 5-12 membered heteroaryl optionally substituted by 1 to 3 substituents independently selected from the group consisting of phenyl, 2 is as described for formula (I). In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is as described for formula (I). In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is a 5-membered heteroaryl containing one S heteroatom and one N heteroatom, halo, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkenyl, or C 1 -C 6 It may be substituted by haloalkyl.

[0123] In some embodiments of Formula (I), ring B is a fused bicyclic ring system comprising fused rings C and D. In some embodiments of Formula (I), provided are compounds of formula (VI): [ka] or a pharma- ceutically acceptable salt thereof, X, Y, n, R, R 1 , R 2 , R 3 , ring A, and L are as described for formula (I); [ka] is a fused bicyclic ring system comprising fused rings C and D, wherein Ring C is C 5 -C 6 cycloalkyl, 5- to 7-membered heterocyclyl, or 5- to 6-membered heteroaryl; Ring D is C 6 Cycloalkyl, C 6 is aryl or 6-membered heteroaryl; wherein ring C and ring D are halo, CN, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -COCH 3 , -CONH 2 , -S(O) 2 CH 3 and phenyl.

[0124] In some embodiments of formula (VI), ring D is C 6 aryl, ring C is C 5 -C 6 cycloalkyl, 5- to 7-membered heterocyclyl, or 5- to 6-membered heteroaryl, where rings C and D are halo, CN, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -COCH 3 , -CONH 2 , -S(O) 2 CH 3 In some embodiments of any of the foregoing, ring A is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, CN, C 3 -C 6 Cycloalkyl, or C optionally substituted by halo or OH 1 -C 6 It is a 5- to 6-membered heteroaryl optionally substituted by alkyl.

[0125] In some embodiments of formula (VI), ring D is C 6 aryl, ring C is C 5 -C 6 In some such embodiments, ring C and ring D are halo, CN, oxo, C 1 -C 6 Alkyl, C1 -C 6 Haloalkyl, -COCH 3 , -CONH 2 , -S(O) 2 CH 3 and phenyl, [ka] In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is C 1 -C 6 In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is as described for formula (I). In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is a 5-membered heteroaryl containing one S heteroatom and one N heteroatom, halo, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkenyl, or C 1 -C 6 It may be substituted by haloalkyl.

[0126] In some embodiments of formula (VI), ring D is C 6 In some such embodiments, ring C is aryl and ring C is 5-7 membered heterocyclyl. In some such embodiments, rings C and D are halo, CN, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -COCH 3 , -CONH 2 , -S(O)2 CH 3 and phenyl, [ka] In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is C 1 -C 6 In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is as described for formula (I). In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is a 5-membered heteroaryl containing one S heteroatom and one N heteroatom, halo, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkenyl, or C 1 -C 6 It may be substituted by haloalkyl.

[0127] In some embodiments of formula (VI), ring D is C 6 In some such embodiments, ring C is aryl and ring C is a 5-6 membered heteroaryl. In some such embodiments, rings C and D are halo, CN, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -COCH 3 , -CONH 2 , -S(O) 2 CH 3 and phenyl, [ka] In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is C 1 -C 6 In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is as described for formula (I). In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is a 5-membered heteroaryl containing one S heteroatom and one N heteroatom, halo, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkenyl, or C 1 -C 6 It may be substituted by haloalkyl.

[0128] In some embodiments of Formula (VI), ring D is a 6-membered heteroaryl and ring C is C 5 -C 6 cycloalkyl, 5- to 7-membered heterocyclyl, or 5- to 6-membered heteroaryl, where rings C and D are halo, CN, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -COCH 3 , -CONH 2 , -S(O) 2 CH 3 In some embodiments of any of the foregoing, X is N, n is 1, and R 1Ha-CH 2 -R 5 and R 5 is as described for formula (I). In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is a 5-membered heteroaryl containing one S heteroatom and one N heteroatom, halo, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkenyl, or C 1 -C 6 It may be substituted by haloalkyl.

[0129] In some embodiments of Formula (VI), ring D is a 6-membered heteroaryl and ring C is C 5 -C 6 cycloalkyl, where rings C and D are halo, CN, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -COCH 3 , -CONH 2 , -S(O) 2 CH 3 In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is as described for formula (I). In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is a 5-membered heteroaryl containing one S heteroatom and one N heteroatom, halo, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkenyl, or C 1 -C 6It may be substituted by haloalkyl.

[0130] In some embodiments of formula (VI), ring D is a 6-membered heteroaryl and ring C is a 5-7 membered heterocyclyl, where rings C and D are selected from halo, CN, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -COCH 3 , -CONH 2 , -S(O) 2 CH 3 In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is as described for formula (I). In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is a 5-membered heteroaryl containing one S heteroatom and one N heteroatom, halo, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkenyl, or C 1 -C 6 It may be substituted by haloalkyl.

[0131] In some embodiments of formula (VI), ring D is a 6-membered heteroaryl and ring C is a 5-6 membered heteroaryl. In some embodiments, rings C and D are selected from halo, CN, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, -COCH 3 , -CONH 2 , -S(O) 2 CH 3 and phenyl, [ka] In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is as described for formula (I). In some embodiments of any of the foregoing, X is N, n is 1, and R 1 Ha-CH 2 -R 5 and R 5 is a 5-membered heteroaryl containing one S heteroatom and one N heteroatom, halo, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkenyl, or C 1 -C 6 It may be substituted by haloalkyl.

[0132] In some embodiments of Formula (I), provided is a compound of Formula (VII): [ka] In the formula, X, Y, n, R 2 , R 3 , ring A, L, and ring B are as described for formula (I), and R 5a H, halo, -OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkenyl, or C 1 -C 6 In some embodiments of formula (VII), R 5a is H or -CH 3 It is.

[0133] In some embodiments of formula (VII), X is N and Y is CR 4 In some embodiments, the compound is of formula (VII-a): [ka] In the formula, n, R 2 , R 3 , R 4 , ring A, L, and ring B are as described for formula (I), and R 5α is as described for formula (VII).

[0134] In some embodiments of formula (VII), X is N and Y is CR 4 and R 3 and R 4 are, together with the carbon atom to which they are attached, halo or C 1 -C 3 In some embodiments, the compound is of formula (VII-b), (VII-b1), or (VII-b2): [ka] In the formula, n, R 2 , R 3 , R 4 , ring A, L, and ring B are as described for formula (I), and R 5α is as described for formula (VII).

[0135] In some embodiments of formula (VII) (including subformulas thereof), 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 C optionally substituted by 1 to 3 substituents independently selected from the group consisting of 6 In some embodiments of formula (VII), 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 C, which may be substituted by 1 to 2 substituents independently selected from the group consisting of phenyl, 6 In some embodiments of formula (VII), ring B is C, optionally substituted with 1 to 2 substituents independently selected from the group consisting of halo and CN. 6 In some embodiments of any of the foregoing, L is -O-CH 2 -**. In some embodiments, the compound is of formula (VII-c): [ka] In the formula, X, Y, n, R 2 , R 3 and ring A is as described for formula (I), R 5a is as described for formula (VII), and R B1 and R B2 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. In some embodiments, R B1 and R B2 is independently selected from the group consisting of halo and CN.

[0136] In some embodiments of formula (VII-c), X is N and Y is CR 4 and R 3 and R 4 are, together with the carbon atom to which they are attached, halo or C 1 -C 3 In some embodiments, the compound is of formula (VII-d), (VII-d1), or (VII-d2): [ka] In the formula, R 2 and ring A is as described for formula (I), R 5a is as described for formula (VII), and R B1 and R B2 is as described for formula (VII-c).

[0137] In some embodiments, the compound of formula VII is of formula VII-e: [ka] In the formula, X 2 is N or CH, R 10 is Cl or CN.

[0138] In some embodiments, the compound of formula VII-e is of formula VII-ei [ka]

[0139] In some embodiments, the compound of formula VII-e is of formula VII-eii [ka]

[0140] In some embodiments, the compound of formula I is of formula VIII: [ka] In the formula, R 7 is hydrogen, chloro, bromo, fluoro, methyl, or vinyl, and R 8 teeth, [ka] It is.

[0141] In some embodiments, the compound of formula I is of formula VIII-a: [ka] In the formula, X 1 is N or CH, and R 9 is H or -OCH 3 It is.

[0142] Representative compounds are listed in Table 1 below. In some embodiments, a compound set forth in Table 1, or a pharma- ceutically acceptable salt thereof, is provided. In some embodiments, a compound selected from compound numbers 1-16 in Table 1, or a pharma- ceutically acceptable salt thereof, is provided. In some embodiments, a compound selected from compound numbers 1-31 in Table 1, or a pharma- ceutically acceptable salt thereof, is provided. The compounds were prepared as described in the general procedures provided in the Examples. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7]

[0143] In another aspect, there is provided a method for preparing a compound of formula (I) (including formulae (II)-(V), (VI), (VII), (VIII) and subformulas thereof), or a compound selected from the group consisting of the compounds listed in Table 1, or a pharma- ceutically acceptable salt of any of the foregoing. The compounds described herein may be prepared according to general procedures and general schemes as illustrated by the examples. When following the general procedures, minor variations in starting materials, temperatures, concentrations, reaction times, and other parameters may be made without substantial effect on the outcome of the procedure.

[0144] Also provided are compound intermediates useful in the synthesis of a compound of formula (I), including compounds of formulas (II)-(VIII), or a compound selected from the group consisting of the compounds listed in Table 1, or a stereoisomer, tautomer, or a pharma- ceutically acceptable salt of any of the foregoing.

[0145] The compounds provided herein may exist as salts even when no salt is provided, and as will be appreciated by those skilled in the art, 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.In some embodiments, the salts of the compounds provided herein are pharma-ceutically acceptable salts.When one or more tertiary amine moieties are present in the compound, N-oxides are also provided and described.

[0146] When tautomers exist for any of the compounds described herein, all tautomers are intended, even if only one or some of the tautomers are explicitly shown. The specifically shown tautomer may or may not be the predominant form in solution or when used in accordance with the methods described herein.

[0147] 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 in 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 in 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, if a compound of Table 1 has a stereocenter in the "R" configuration, then enantiomers of the compound in the "S" stereochemical configuration are also provided herein. Also provided are mixtures of the compound having both the "S" and "R" stereochemical configurations.

[0148] 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 the isotopically labeled compounds of formula (I) or modifications thereof described herein, 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.

[0149] 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.

[0150] 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.

[0151] In some embodiments, the present disclosure also includes salts, such as pharma- ceutically acceptable salts, of any of the compounds disclosed herein. In some embodiments, the present disclosure provides a meglumine salt of any one of the compounds disclosed herein, such as a 1:1 compound:meglumine salt, a 2:1 compound:meglumine salt, or a 1:2 compound:meglumine salt.

[0152] 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 (I) (including compounds of formulas (II)-(VIII)) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0153] 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.

[0154] 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, impurities referring to compounds other than the compound comprising the majority of the composition or salts thereof. For example, a composition of a substantially pure compound contemplates a composition containing 35% or less impurities, impurities referring to compounds other than the compound or salts thereof. In one variation, a composition of a substantially pure compound or salts thereof is provided, the composition containing 25% or less impurities. In another variation, a composition of a substantially pure compound or salts thereof is provided, the composition containing 20% ​​or less impurities. In yet another variation, a composition of a substantially pure compound or salts thereof is provided, the composition containing 10% or less impurities. In a further variation, a composition of a substantially pure compound or salts thereof is provided, the composition containing 5% or less impurities. In another variation, a composition of a substantially pure compound or salts thereof is provided, the composition containing 3% or less impurities. In yet another variation, a composition of a substantially pure compound or salt thereof is provided, the composition containing 1% or less of impurities. In a further variation, a composition of a substantially pure compound or salt thereof is provided, the composition containing 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, 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 different stereochemical forms of the compound.

[0155] 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.

[0156] 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.

[0157] 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- ceutically 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, pharmaceutical preparations can include preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, dyes, regulators, and salts for adjusting osmotic pressure, buffers, coating agents, or antioxidants. Preparations containing the compounds can also contain other substances that have valuable therapeutic properties. 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.

[0158] 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. The 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 include preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, dyes, regulators, and salts for adjusting osmotic pressure, buffers, coating agents, or antioxidants.

[0159] Compositions comprising two compounds utilized herein are described. Any of the compounds described herein can be formulated into any dosage form of tablet described herein. In some embodiments, the composition comprises a compound of formula (I) (including compounds of formulas (II)-(VIII)) or a pharma- ceutically acceptable salt thereof as described herein. In some embodiments, a dosage form comprising a therapeutically effective amount of a compound of formula (I) (including compounds of formulas (II)-(VIII)) 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 1-11 in Table 1. In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is selected from compound numbers 1-31 in Table 1.

[0160] Method and use The compounds and compositions described herein can, in some aspects, be used to treat 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 therapeutically effective amount of a compound of formula (I) (including a compound of formulas (II)-(VI)), or a pharma- ceutically 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 any one of the compounds in Table 1, or a pharma- ceutically acceptable salt thereof.

[0161] In some embodiments, a method of treating a disease or condition in a subject in need of treatment comprises administering to the subject an effective amount of a compound of Formula (I) (including compounds of Formulas (II)-(VIII)), or a pharma- ceutically 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 an effective amount of a compound selected from any one of the compounds in Table 1, or a pharma- ceutically acceptable salt thereof.

[0162] 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 tubule dysfunction, ... renal tubule dysfunction, renal tubule dysfunction, renal tubule dysfunction, renal tubule dysfunction, renal tubule dysfunction, renal tubule dysfunction, renal tubule dysfunction, renal tubule dysfunction, renal tubule dysfunction, renal tubule dysfunction, renal tubule dysfunction, renal tubule dysfunction, renal tubule dysfunction, renal tubule dysfunction, renal tubule dysfunction, renal tubule dysfunction, renal tubule dysfunction, renal tubule dysfunction, renal tubule dysfunction, renal tubule dysfunction, renal tubule dysfunction, renal tubule dysfunction, renal tubule dysfunction, renal tubule dysfunction, renal tubule dysfunction, renal tubule dysfunction, renal tubule dysfunction, renal tubule dysfunction, renal tubule dysfunction, renal renal 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 (including 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 in the white retina. 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).

[0163] 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- ceutically acceptable salt thereof.

[0164] In some embodiments, provided herein are methods 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.

[0165] 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- ceutically 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.

[0166] In some embodiments, the present disclosure provides a method for reducing food intake in a subject in need thereof, the method comprising administering to the subject an effective amount of any one of the compounds or pharmaceutical compositions disclosed herein. In some embodiments, administration of the compound disclosed herein reduces the subject's food intake by at least 10%, for example, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%, relative to the subject's food intake in the absence of the compound disclosed herein. In some embodiments, the subject's food intake is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% for at least 1 hour after administration, e.g., at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 12 hours, at least 1 day, or at least 2 days after administration.

[0167] In some embodiments, the present disclosure provides a method for improving glucose tolerance in a subject in need of such improvement. In some embodiments, after glucose ingestion, e.g., glucose ingestion caused by food consumption, and administration of a compound disclosed herein, the glucose concentration in the blood of the subject is lower than the glucose concentration in the blood when the compound disclosed herein is not administered to the subject, e.g., 10% lower, 20% lower, 30% lower, 40% lower, 50% lower, 60% lower, 70% lower, 80% lower, 90% lower, 100% lower, 200% lower, 500% lower, 1000% lower.

[0168] According to the present application, the compounds described herein or pharma- ceutically acceptable salts thereof can be administered by any suitable route in the form of a pharmaceutical composition adapted for such route in an effective dose for the intended treatment. In some embodiments, the compound is a compound of any embodiment of formula (I), or a compound selected from the compounds of Table 1, or a pharma- ceutically acceptable salt thereof. The compounds and / or compositions described herein can be administered orally, rectally, vaginally, parenterally, or topically.

[0169] 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.

[0170] 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.

[0171] 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.

[0172] 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.

[0173] 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.

[0174] 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.

[0175] The present application provides any of the uses, methods, or compositions defined herein, wherein a compound of any of the embodiments of formula (I) or a compound selected from the compounds of Table 1 described herein, 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 of the embodiments of formula (I) or a compound selected from the compounds of Table 1, as defined in any of the embodiments described herein, or a pharma- ceutically acceptable salt thereof, in admixture with at least one pharma- ceutically acceptable excipient and one or more other therapeutic agents.

[0176] 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.

[0177] 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 ...

[0178] 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 / δ 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), leukotriene D4 (LTD4) receptor antagonists (e.g., tipelukast), niacin analogs (e.g., ARI 3037MO), ASBT inhibitors (e.g., vorixibat), acetyl-CoA carboxylase (ACC) inhibitors (e.g., NDI 010976), ketohexokinase (KHK) inhibitors, diacylglyceryl acyltransferase 2 (DGAT2) inhibitors, CB1 receptor antagonists, anti-CB1R antibodies, or apoptosis signal-regulating kinase 1 (ASK1) inhibitors, including pharmacologic agents, such as pharmacologic agents, such as acetaminophen, cerebrospinal fluid (EC 603.1.1), cerebrospinal fluid (EC 603.1.2), cerebrospinal fluid (EC 603.1.3), cerebrospinal fluid (EC 603.1.4), cerebrospinal fluid (EC 603.1.5), cerebrospinal fluid (EC 603.1.6), cerebrospinal fluid (EC 603.1.7), cerebrospinal fluid (EC 603.1.8), cerebrospinal fluid (EC 603.1.9), cerebrospinal fluid (EC 603.1.1), cerebrospinal fluid (EC 603.1.2), cerebrospinal fluid (EC 603.1.3), cerebrospinal fluid (EC 603.1.4), cerebrospinal fluid (EC 603.1.5), cerebrospinal fluid (EC 603.1.6), cerebrospinal fluid (EC 603.1.8), cerebrospinal fluid (EC 603.1.9), cerebrospinal fluid (EC 603.1.1), cerebrospinal fluid (EC 603.1.2), cerebrospinal fluid (EC 603.1.4), ce

[0179] 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 be further sterilized and / or sealed.

[0180] 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).

[0181] 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.

[0182] Method of synthesis In some aspects, the disclosure provides methods of preparing the disclosed compounds.

[0183] In some aspects, the disclosure provides methods of preparing compounds comprising one or more steps described herein.

[0184] In some aspects, the disclosure provides compounds that are obtainable by, obtained by, or obtained directly by the methods of preparing the compounds described herein.

[0185] In some aspects, the disclosure provides intermediates described herein that are suitable for use in the methods of preparing the compounds described herein.

[0186] The compounds of the present disclosure can be prepared by any suitable technique known in the art. Certain processes for these compounds are further illustrated in the accompanying Examples.

[0187] In the descriptions of synthetic methods described herein, and in any reference synthetic methods used to prepare starting materials, it is understood that all proposed reaction conditions, including the choice of solvents, reaction atmospheres, reaction temperatures, experiment durations and work-up procedures, can be selected by one of ordinary skill in the art.

[0188] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions employed.

[0189] It will be understood that during the synthesis of the compounds of the present disclosure in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituents to prevent their undesired reactions. The skilled chemist will understand when such protection is necessary and how such protecting groups are placed and subsequently removed. For examples of protecting groups, see one of the many general texts on the subject, for example "Protective Groups in Organic Synthesis" by Theodora Green (Publisher: John Wiley & Sons). Protecting groups can be removed by any convenient method described in the literature or known to the skilled chemist that is suitable for the removal of the protecting group in question, and such methods are selected to achieve the removal of the protecting group with minimal effect on other groups in the molecule. Thus, when a reactant contains a group such as, for example, amino, carboxy or hydroxy, it may be desirable to protect that group in some of the reactions described herein.

[0190] For example, suitable protecting groups for amino or alkylamino groups are, for example, acyl groups, e.g., alkanoyl groups such as acetyl, alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl groups, arylmethoxycarbonyl groups such as benzyloxycarbonyl, or aroyl groups such as benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, acyl groups such as alkanoyl or alkoxycarbonyl groups or aroyl groups can be removed by hydrolysis with a suitable base, e.g., an alkali metal hydroxide, e.g., lithium hydroxide or sodium hydroxide. Alternatively, acyl groups such as tert-butoxycarbonyl groups can be removed by treatment with a suitable acid, e.g., hydrochloric acid, sulfuric acid or phosphoric acid, or trifluoroacetic acid, and arylmethoxycarbonyl groups such as benzyloxycarbonyl groups can be removed by hydrogenation, e.g., with a catalyst such as palladium on carbon, or by treatment with a Lewis acid, e.g., tris(boron trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

[0191] Suitable protecting groups for hydroxyl groups are, for example, acyl groups, e.g., alkanoyl groups such as acetyl, aroyl groups such as benzoyl, or arylmethyl groups such as benzyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, acyl groups such as alkanoyl or aroyl groups can be removed by hydrolysis with a suitable base, e.g., an alkali metal hydroxide, e.g., lithium hydroxide, sodium hydroxide, or ammonia. Alternatively, arylmethyl groups such as benzyl groups can be removed by hydrogenation over a catalyst, e.g., palladium on carbon.

[0192] A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or ethyl group which can be removed by hydrolysis with a base such as sodium hydroxide, or, for example, a tert-butyl group which can be removed by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or, for example, a benzyl group which can be removed by hydrogenation over a catalyst such as palladium on carbon.

[0193] Once a compound of formula (I) has been synthesised by any one of the processes defined herein, the process may further comprise the additional steps of: (i) removing any protecting groups present; (ii) converting the compound of formula (I) into another compound of formula (I); (iii) forming a pharma- ceutically acceptable salt, hydrate or solvate thereof; and / or (iv) forming a prodrug thereof.

[0194] The resulting compound of formula (I) can be isolated and purified using techniques well known in the art.

[0195] Conveniently, the reaction of the compounds is carried out in the presence of a suitable solvent, preferably inert under the respective reaction conditions. Examples of suitable solvents include hydrocarbons such as hexane, petroleum ether, benzene, toluene, or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane, chloroform, or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentyl methyl ether (CPME), methyl tert-butyl ether (MTBE), or dioxane; ethylene glycol, ethylene glycol ether ... Examples of suitable solvents include, but are not limited to, glycol ethers such as glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones such as acetone, methyl isobutyl ketone (MIBK), or butanone; amides such as acetamide, dimethylacetamide, N,N-dimethylformamide (DMF), or N-methylpyrrolidinone (NMP); nitriles such as acetonitrile; sulfoxides such as dimethylsulfoxide (DMSO); nitro compounds such as nitromethane and nitrobenzene; esters such as ethyl acetate or methyl acetate, or mixtures of said solvents or with water.

[0196] The reaction temperature is suitably about -100°C to 300°C depending on the reaction step and conditions used.

[0197] The reaction time generally ranges from a few minutes to a few days, depending on the reactivity of each compound and the respective reaction conditions.The appropriate reaction time can be easily determined by methods known in the art, such as reaction monitoring.Based on the above reaction temperature, the appropriate reaction time generally ranges from 10 minutes to 48 hours.

[0198] Moreover, by utilizing the procedures described herein in conjunction with one of ordinary skill in the art, additional compounds of the present disclosure can be readily prepared. Those of ordinary skill in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.

[0199] As will be appreciated by those skilled in the art of organic synthesis, the compounds of the present disclosure are readily accessible by a variety of synthetic routes, some of which are illustrated in the accompanying examples. Those skilled in the art will readily recognize what types of reagents and reaction conditions should be used to obtain the compounds of the present disclosure, and how they should be applied and adapted in a particular case, whenever necessary or useful. In addition, some of the compounds of the present disclosure can be easily synthesized by converting one particular functional group present in the compounds of the present disclosure, or its suitable precursor molecule, into another by reacting other compounds of the present disclosure under appropriate conditions, for example by applying standard synthetic methods such as reduction, oxidation, addition, substitution reactions, and the like, which are well known to those skilled in the art. Similarly, those skilled in the art will apply synthetic protection (or protective) groups whenever necessary or useful. Suitable protecting groups, as well as methods for introducing and removing them, are well known to those skilled in the art of chemical synthesis and are described in more detail, for example, in PGM Wuts, T.W. Greene, "Greene's Protective Groups in Organic Synthesis", 4th edition (2006) (John Wiley & Sons).

[0200] Routes for preparing the compounds of the present disclosure are described in the Examples.

[0201] General routes for preparing compounds of the present disclosure are depicted in general Schemes AD herein.

[0202] General Scheme A [ka]

[0203] General Scheme B shows a general method for the preparation of a variety of compounds.

[0204] General Scheme B [ka]

[0205] General Scheme C General Scheme C shows the preparation of compounds from cores 1i, 2i, and 3i. [ka]

[0206] General Scheme D shows a general method for the preparation of compounds containing core 4i.

[0207] General Scheme D [ka]

[0208] Biological assays Once generated, compounds designed, selected, and / or optimized by the methods described above can be characterized using a variety of assays known to those of skill in the art to determine whether the compounds have biological activity. For example, molecules can be characterized by conventional assays, including but not limited to the assays described below, to determine whether they have the predicted activity, binding activity, and / or binding specificity.

[0209] Furthermore, the use of high throughput screening can speed up the analysis using such assays. As a result, it may be possible to rapidly screen the molecules described herein for activity using techniques known in the art. General methodologies for carrying out high throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker, and U.S. Patent No. 5,763,263. High throughput assays can use one or more different assay techniques, including but not limited to those described below.

[0210] A variety of in vitro or in vivo biological assays may be suitable for detecting the effects of the compounds of the present disclosure. These in vitro or in vivo biological assays may include, but are not limited to, enzyme activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and assays described herein.

[0211] In some embodiments, the biological assays are described in the Examples herein.

[0212] GLP-1R Cellular Assay Stable cell lines expressing high and low GLP-1R surface expression were generated by cloning a puromycin-selectable DNA plasmid encoding the human GLP-1R receptor under the control of the EF1A promoter (accession number: NM 002062.5) were generated in transfected CHO-K1 cells (Fugene6). 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 to detect cAMP (LANCE Ultra cAMP assay, Perkin Elmer). 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 determine EC as a measure of responsiveness to the GLP-1R control peptide. 50 To ensure stability, the responsiveness of selected cell lines was monitored over multiple passages. CHO-K1 hGLP-1Rhigh Clone 16 and CHO-K1 hGLP-1Rlow Clone10 showed consistently high and low responsiveness to GLP-1R control peptide, respectively, and was 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, washed three times with PBS+0.5% BSA, and then 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 Clone 16 cells are CHO-K1-hGLP-1low The MFI level was significantly higher than that of clone 10 cells.

[0213] CHO-K1 hGLP-1Rlow For compound testing in the 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, and 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 50Values ​​were determined by fitting the percent activation as a function of compound concentration using the Hill equation (XLfit).

[0214] Hepatic clearance Hepatic clearance, the ability of the liver to extract and metabolize drugs as they pass through the liver, is controlled by hepatic blood flow (Q), protein binding (fu), and the intrinsic ability of hepatic enzymes to metabolize the drug (CLint). CLint is a measure of the theoretical unlimited maximum clearance of unbound drug by excretory organs in the absence of blood flow or plasma protein binding limitations. This term relates to the functional reserve of the organ. CLint can be determined in vitro using enzyme kinetics. In vitro hepatocyte stability assays can be performed to determine the unlimited maximum hepatic clearance of unbound test drugs compared to the clearance of a reference standard. EXAMPLES

[0215] General synthetic procedure Part I: Preparation of compounds from cores 1i, 2i, 3i, and 4i Scheme 1: General scheme for the preparation of core 1i [ka]

[0216] General procedure for preparation of Core 1i [ka]

[0217] Step 1: A mixture of intermediate 1f (3.8 g, 16.81 mmol, 1 equiv), Pd(PPh3)4 (1.94 g, 1.68 mmol, 0.1 equiv), Zn(CN)2 (2.96 g, 25.22 mmol, 1.60 mL, 1.5 equiv) in DMF (10 mL) was degassed and purged with N2 (3x), then the mixture was stirred under N2 atmosphere at 100 °C for 16 h. TLC (petroleum ether:ethyl acetate = 2:1, product Rf = 0.45) showed that intermediate 1f was consumed. The reaction was then quenched with H2O (50 mL). The solution was extracted with ethyl acetate (2x50 mL) and the organic layers were combined. The resulting mixture was washed with brine (2x50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1). Intermediate 2f (2.4 g, 13.94 mmol, 82.93% yield) was obtained as a white solid. LCMS: RT = 0.409 min, MS calculated: 172.04, [M+H] + = 173.0. 1 H NMR (400 MHz, chloroform-d) δ = 9.64 (br s, 1 H), 8.75 - 8.83 (m, 1 H), 8.05 (br s, 1 H), 7.70 - 7.81 (m, 1 H), 7.43 (br d, J = 9.29 Hz, 1 H), 7.24 - 7.27 (m, 1 H). [ka]

[0218] Step 2: NaBH 4 (417.53 mg, 11.04 mmol, 1 equiv.) was added to a solution of intermediate 2f (1.9 g, 11.04 mmol, 1 equiv.) in AcOH (10 mL) at 15° C. The solution was stirred at 15° C. for 15 min. Then, NaBH 4 (417.53 mg, 11.04 mmol, 1 equiv.) was added to the solution at 15° C. The solution was stirred at 15° C. for 15 min. TLC (petroleum ether / ethyl acetate=2 / 1, product R f= 0.45) indicated that intermediate 2f was completely consumed. 2 CO 3 The mixture was quenched with DCM (50 mL x 3) until pH 8. The mixture was extracted with DCM (50 mL x 3). The combined DCM was washed with brine (15 mL) and added Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give intermediate 3f (1.6 g, 9.08 mmol, 82.28% yield) as a white solid. 1 H NMR (400 MHz, chloroform-d) δ = 7.24 (s, 1 H) 7.15 (d, J = 8.80 Hz, 1 H) 4.05 - 4.12 (m, 2 H) 3.15 (t, J = 5.87 Hz, 2 H) 2.85 (t, J = 5.75 Hz, 2 H) 1.94 - 1.99 (m, 1 H). [ka]

[0219] Step 3: Intermediate 3f (2 g, 6.74 mmol, 1 equiv), intermediate 4f (1.42 g, 8.09 mmol, 1.2 equiv), BINAP (839.20 mg, 1.35 mmol, 0.2 equiv), Cs in toluene (80 mL) 2 CO 3 (4.39 g, 13.48 mmol, 2 equiv.) and Pd 2 (dba) 3 A mixture of (617.08 mg, 673.87 μmol, 0.1 equiv.) was degassed and diluted with N 2 The mixture was then purged three times with N at 100 °C. 2 The mixture was stirred under atmospheric pressure for 3 h. LC-MS showed that intermediate 3f was consumed and one major peak with the desired mass was detected. The residue was purified by H 2 The mixture was diluted with 20 mL of 2H2O and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (30 mL) and 2 SO 4 The residue was purified by column chromatography (SiO 2The crude product was purified by reverse phase HPLC (column: Welch Xtimate C18 250*70mm#10um; mobile phase: [water (10mM NH 4 HCO 3 )-ACN]; B%: 55%-85%, 20 min). 1ia (7.3 g, 16.72 mmol, 82.72% yield) was obtained as a yellow solid. LCMS: RT = 0.973 min, MS calculated: 436.52, [M+H] + = 437.3 1 H NMR (400 MHz, chloroform-d) δ = 7.44 - 7.53 (m, 1 H) 7.29 (s, 1 H) 7.21 (d, J = 8.88 Hz, 1 H) 6.56 (br dd, J = 15.51, 7.75 Hz, 2 H) 4.73 (s, 2 H) 4.22 (br s, 2 H) 3.93 (br d, J=5.50 Hz, 2 H) 3.03 - 3.04 (m, 1 H) 2.99 (br s, 2 H) 2.85 (br t, J = 11.57 Hz, 2 H) 2.71 (br s, 1 H) 1.90 (br d, J = 12.51 Hz, 2 H) 1.65 - 1.79 (m, 2 H) 1.59 (s, 1 H) 1.50 (s, 9 H).

[0220] Deprotection of 1ia to the secondary amine 1i was carried out immediately prior to use under acidic conditions similar to those described for the preparation of intermediate 3i. Scheme 2: General scheme for the preparation of core 2i [ka]

[0221] General procedure for preparation of Core 2i [ka]

[0222] Step 1: Intermediate 5f (50 g, 161.70 mmol, 1 equiv.), Intermediate 6f (38.31 g, 161.70 mmol, 1 equiv.), Pd(dppf)Cl 2 ·CH 2 Cl 2 (13.21g, 16.17mmol, 0.1eq), K 2 CO 3 A mixture of (44.70 g, 323.41 mmol, 2 equiv.) and HO (160 mL) in dioxane (800 mL) was degassed and diluted with N 2 Purge the mixture three times with N 2 The mixture was stirred at 90° C. for 2 hours under atmospheric pressure. 2 The mixture was diluted with 2×O (500 mL) and extracted with EtOAc (700 mL×2). The combined organic layers were washed with brine (100 mL) and 2 SO 4 The residue was purified by column chromatography (SiO 2 , Petroleum ether / ethyl acetate = 100 / 1 to 0 / 1. Petroleum ether / ethyl acetate = 3 / 1, product R f =0.5). Intermediate 7f (70 g, 206.35 mmol, 63.81% yield) was obtained as a colorless oil. LCMS: RT = 0.965 min, MS calculated: 339.23, [MC 4 H 8 +H] + = 282.9 1 H NMR (400 MHz, chloroform-d) δ = 7.41 - 7.46 (m, 1 H) 7.20 - 7.26 (m, 1 H) 6.63 (br s, 1 H) 4.07 (br d, J = 2.69 Hz, 2 H) 3.57 (br t, J = 5.38 Hz, 2 H) 2.50 - 2.56 (m, 2 H) 1.42 (s, 9 H). [ka]

[0223] Step 2: To a mixture of intermediate 7f (15 g, 44.22 mmol, 1 equiv.) in EtOAc (200 mL), 2 Under PtO 2 (3.13 g, 13.76 mmol) was added. The suspension was degassed under vacuum and H 2 The mixture was purged with H 2 (15 psi) at 20° C. for 8 h. LC-MS showed that intermediate 7f was completely consumed and one major peak with the desired mass was detected. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 100 / 1 to 0 / 1, TLC-petroleum ether / ethyl acetate = 3 / 1, product R f =0.5). Intermediate 8f (5 g, 14.65 mmol, 16.57% yield) was obtained as a yellow colorless oil. LCMS: RT = 0.982 min, MS calculated: 341.24, [MC 4 H 8 +H] + = 285.0 1 H NMR (400 MHz, chloroform-d) δ = 7.44 - 7.51 (m, 1 H) 7.32 (d, J = 7.88 Hz, 1 H) 7.10 (d, J = 7.63 Hz, 1 H) 4.24 (br s, 2 H) 2.74 - 2.89 (m, 3 H) 1.92 (br d, J = 12.88 Hz, 2 H) 1.59 - 1.75 (m, 2 H) 1.47 (s, 9 H). [ka]

[0224] Step 3: A mixture of intermediate 8f (10 g, 29.30 mmol, 1 equiv.), intermediate 9f (5.31 g, 35.17 mmol, 1.2 equiv.), t-BuONa (8.45 g, 87.91 mmol, 3 equiv.), and Xphos Pd G4 (2.52 g, 2.93 mmol, 0.1 equiv.) in toluene (100 mL) is degassed and cooled with N 2 Purge the mixture three times with N 2The mixture was stirred at 100° C. under atmospheric pressure for 2 hours. LC-MS showed that intermediate 8f was completely consumed and one major peak with the desired mass was detected. The residue was purified by H 2 The mixture was diluted with 20 mL of 2H2O (30 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (10 mL) and 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 100 / 1 to 10 / 1, TLC-petroleum ether / ethyl acetate = 3 / 1, product R f =0.5). Intermediate 2ia (6.8 g, 16.53 mmol, 56.39% yield) was obtained as a wine-red solid. LCMS: RT = 1.049 min, MS calculated: 411.47, [MC 4 H 8 +H] + = 356.2 1 H NMR (400 MHz, chloroform-d) δ = 7.62 (t, J = 7.50 Hz, 1 H) 7.54 (t, J = 7.75 Hz, 1 H) 7.45 (d, J = 8.00 Hz, 1 H) 7.38 (d, J = 9.26 Hz, 1 H) 6.75 (d, J = 7.25 Hz, 1 H) 6.66 (d, J = 8.25 Hz, 1 H) 5.50 (s, 2 H) 4.21 (br s, 1 H) 4.16 - 4.30 (m, 1 H) 4.12 (q, J = 7.13 Hz, 1 H) 2.82 (br t, J = 12.19 Hz, 1H) 2.71 (tt, J = 11.79, 3.66 Hz, 1 H) 2.65 - 2.88 (m, 1 H) 2.05 (s, 1 H) 1.83 (br d, J = 12.51 Hz, 2 H) 1.65 - 1.71 (m, 2 H) 1.49 (s, 9 H) 1.26 (t, J = 7.19 Hz, 1 H).

[0225] Deprotection of 2ia to the secondary amine 2i was carried out immediately prior to use under acidic conditions similar to those described for the preparation of intermediate 3i. Scheme 3: General scheme for the preparation of core 3i [ka]

[0226] General procedure for preparation of Core 3i [ka]

[0227] Step 1: To a solution of intermediate 10f (1.5 g, 9.73 mmol, 1 equiv) in pyridine (12 mL), DMAP (118.90 mg, 973.29 μmol, 0.1 equiv) was added, followed by acetyl chloride (916.81 mg, 11.68 mmol, 833.46 μL, 1.2 equiv) at 0 °C. The mixture was stirred at 0-30 °C for 16 h. LC-MS showed that intermediate 10f was consumed. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 100 / 1 to 1 / 1). Intermediate 11f (3.6 g, 17.80 mmol, 91.45% yield, 97% purity) was obtained as a white solid. LCMS: RT = 0.635 min, MS calculated: 196.1, [M+H] + =197.2 1 H NMR (400 MHz, methanol-d 4 ) δ = 7.47-7.62 (m, 2H), 4.86 (s, 1H), 2.12-2.27 (m, 3H). [ka]

[0228] Step 2: Degas a mixture of intermediate 11f (1.3 g, 6.63 mmol, 1 equiv.), Lawesson's reagent (1.61 g, 3.98 mmol, 0.6 equiv.) in toluene (20 mL) and rinse with N 2Purge the mixture three times with N 2 The mixture was stirred at 120° C. under atmospheric pressure for 3 h. TLC (petroleum ether / EtOAc=5:1) showed that intermediate 11f was completely consumed to a single new intermediate. The crude product was used directly in the next step without purification. Crude intermediate 12f (2.81 g, 13.24 mmol, 100.00% yield) was obtained as a yellow liquid. [ka]

[0229] Step 2: To a solution of intermediate 12f (1.4 g, 6.60 mmol, 1 equiv) in toluene (20 mL), Cs 2 CO 3 (5.37 g, 16.49 mmol, 2.5 equiv.) was added. The mixture was stirred at 120° C. for 3 h. The residue was dissolved in H 2 The reaction mixture was diluted with 200 mL of 2H2O (10 mL) and extracted with EtOAc (15 mL x 3). The reaction mixture was separated and 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 100 / 1 to 1 / 1). Intermediate 13f (2 g, 10.41 mmol, 78.86% yield) was obtained as a white solid. LCMS: RT = 0.789 min, MS calculated: 192.2, [M+H] + =193.2. 1 H NMR (400 MHz, chloroform-d) δ = 7.97-7.99 (m, 1H), 7.44 (dd, J = 1.38, 9.63 Hz, 1H), 2.94 (s, 3H). [ka]

[0230] Step 3: CCl 4A mixture of intermediate 13f (600 mg, 3.12 mmol, 1 equiv.), NBS (833.38 mg, 4.68 mmol, 1.5 equiv.), and AIBN (51.26 mg, 312.15 μmol, 0.1 equiv.) in (6 mL) was degassed and cooled with N 2 Purge the mixture three times with N 2 The mixture was stirred at 80° C. for 12 hours under atmospheric conditions. 2 The mixture was diluted with 200 mL of HO (30 mL) and extracted with DCM (30 mL × 3). The combined organic layers were washed with aqueous NaCl (10 mL × 3) and 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 100 / 1 to 1 / 1). Intermediate 14f (400 mg, 1.48 mmol, 16.68% yield) was obtained as a white solid. LCMS: RT = 0.719 min, MS calculated: 271.1, [M+H] + =272.1 1 H NMR (400 MHz, chloroform-d) δ = 8.04 (s, 1H), 7.49 (dd, J = 1.21, 9.54 Hz, 1H), 4.85 (s, 2H). [ka]

[0231] Step 4: DMSO (15 mL) and H 2 Intermediate 6f (2.8 g, 9.06 mmol, 1 equiv.), intermediate 15f (2.63 g, 9.96 mmol, 1.1 equiv.), Pd(dppf)Cl in O (1.5 mL) 2 ·CH 2 Cl 2 (369.75mg, 452.77μmol, 0.05eq), K 2 CO 3 A mixture of (3.75 g, 27.17 mmol, 3 equiv.) was degassed and diluted with N 2 Purge the mixture three times with N 2 The mixture was stirred at 80° C. for 2 hours under atmospheric conditions. 2The mixture was diluted with 10 mL of O and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with NaCl (5 mL) and NaSO 4 The residue was purified by column chromatography (SiO 2 The mixture was purified with petroleum ether / ethyl acetate = 100 / 1 to 1 / 1) to give intermediate 16f (2.7 g, 7.37 mmol, 81.37% yield, 100% purity) as a colorless oil. 1 H NMR (400 MHz, chloroform-d) δ = 7.56 (t, J = 7.82 Hz, 1H), 7.47 (d, J = 7.21 Hz, 2H), 7.39 (t, J = 7.27 Hz, 2H), 7.29-7.35 (m, 1H), 6.95 (d, J = 7.46 Hz, 1H), 6.67-6.76 (m, 2H), 5.43 (s, 2H), 4.15 (br d, J = 1.83 Hz, 2H), 3.66 (br s, 2H), 2.62 (br s, 2H), 1.51 (s, 9H). [ka]

[0232] Step 5: To a solution of intermediate 16f (1.3 g, 3.55 mmol, 1 equiv) in MeOH (15 mL) was added Pd / C (300 mg, 10% purity). The mixture was diluted with H 2 The mixture was stirred at 20° C. under (15 psi) for 1 h. LC-MS showed that intermediate 16f was completely consumed and the desired mass was detected. The reaction mixture was filtered and the pad cake was washed with DCM (20 mL×3). The mixture was concentrated under reduced pressure to give a residue. Intermediate 17f (1.7 g, 6.11 mmol, 86.08% yield) was obtained as a white solid. LCMS: RT = 0.857 min, MS calculated: 278.3, [M+H] + =279.4 [ka]

[0233] Step 6: Intermediate 17f (410 mg, 1.47 mmol, 1 equiv.), intermediate 14f (399.34 mg, 1.47 mmol, 1 equiv.), Ag in toluene (7 mL). 2 CO 3 A mixture of (812.34 mg, 2.95 mmol, 2 equiv.) was degassed and diluted with N 2 Purge the mixture three times with N 2 The mixture was stirred at 100° C. under atmospheric pressure for 3 h. LC-MS showed complete consumption of intermediate 17f with one major peak of the desired product. The reaction mixture was diluted with H 2 The mixture was diluted with 20 mL of 2H2O and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with NaCl (10 mL x 3) and 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 100 / 1 to 1 / 1). Intermediate 18f (330 mg, 704.31 μmol, 47.82% yield) was obtained as a yellow solid. LCMS: RT = 1.056 min, MS calculated: 468.5, [M+H] + =469.5 1 H NMR (400 MHz, chloroform-d) δ = 8.02 (s, 1H), 7.62 (t, J = 7.78 Hz, 1H), 7.47 (dd, J = 1.21, 9.54 Hz, 1H), 6.74-6.87 (m, 2H), 5.88 (s, 2H), 4.20 (br d, J = 12.28 Hz, 2H), 2.69-2.87 (m, 3H), 1.86 (br d, J = 12.50 Hz, 2H), 1.67 (dq, J = 4.28, 12.53 Hz, 2H), 1.48 (s, 9H). [ka]

[0234] Step 7: A mixture of intermediate 18f (190 mg, 405.51 μmol, 1 equiv.) in EtOAc (2 mL), HCl / EtOAc (4 M, 2.85 mL, 28.11 equiv.) was degassed and cooled with N 2 Purge the mixture three times with N 2 The mixture was stirred at 25° C. under ambient conditions for 0.5 h. LC-MS showed complete consumption of intermediate 18f with one major peak of the desired product. The reaction mixture was concentrated under reduced pressure. Core 3i (150 mg, 370.47 μmol, 91.36% yield, as HCl salt) was obtained as a white solid. LCMS: RT = 0.735 min, MS calculated: 368.1, [M+H] + =369.1 1 H NMR (400 MHz, DMSO-d 6 ) δ = 8.91 (br s, 1H), 8.69 (br s, 1H), 8.60 (d, J = 1.10 Hz, 1H), 8.01 (dd, J = 1.28, 10.57 Hz, 1H), 7.78 (t, J = 7.82 Hz, 1H), 6.86-7.01 (m, 2H), 5.89 (s, 2H), 3.29 (br d, J = 12.59 Hz, 2H), 2.88-3.02 (m, 3H), 1.97 (br d, J = 14.79 Hz, 2H), 1.79-1.91 (m, 2H).

[0235] Scheme 4: General scheme for the preparation of intermediate cores 4i [ka]

[0236] General procedure for the preparation of intermediate 20f [ka]

[0237] Step 1: To a solution of diethylzinc (1M, 303.01 mL, 8 equiv.) in DCM (50 mL) was slowly added TFA (34.55 g, 303.01 mmol, 22.44 mL, 8 equiv.) in DCM (50 mL) at -15 °C and the mixture was stirred at -15 °C for 1 h. 2 I 2 (162.31 g, 606.02 mmol, 48.89 mL, 16 equiv) was added to the mixture at −15° C. and the mixture was stirred at −15° C. for 1 h. Then, intermediate 19f (13 g, 37.88 mmol, 1 equiv) in DCM (50 mL) was added slowly to the reaction mixture at −15° C. and the mixture was stirred at 25° C. for 16 h. The mixture was diluted with NaCO 3 The reaction mixture was quenched with 100 mL of DCM until pH 8. The reaction mixture was filtered and the filter was extracted with DCM (300 mL x 3). The combined DCM layers were washed with brine (500 mL) and diluted with Na 2 SO 4 The residue was purified by column chromatography (SiO 2 The mixture was purified with petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to give intermediate 20f (9 g, 25.19 mmol, 66.51% yield) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ ppm 7.28 - 7.40 (m, 5 H) 5.11 - 5.16 (m, 2 H) 3.83 - 3.96 (m, 1 H) 3.43 - 3.67 (m, 2 H) 2.87 - 3.05 (m, 1 H) 2.07 - 2.17 (m, 1 H) 1.49 - 1.61 (m, 1 H) 1.21 (s, 13 H) 0.91 (br s, 1 H) 0.41 - 0.48 (m, 1 H). [ka]

[0238] Step 2: To a solution of intermediate 20f (9 g, 25.19 mmol, 1 equiv) in MeOH (90 mL), KHF 2(13.77 g, 176.35 mmol, 5.81 mL, 7 equiv) was added at 25° C. The mixture was stirred at 90° C. for 16 h. The reaction mixture was concentrated under reduced pressure to remove MeOH. The solid was triturated with a solution of petroleum ether:MTBE=5:1 (30 mL). The mixture was filtered. The filter cake was dried in vacuum to give the crude product as a white solid. The crude product was dissolved in hot MeCN (50 mL) and filtered. The filtrate was concentrated under reduced pressure to give a white solid. Core 4i (6.4 g, 18.98 mmol, 75.34% yield, K + ) was obtained as a white solid. LCMS: RT =0.779 min, MS calculated: 337.19, [M+H] + = 276.0 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.26 - 7.40 (m, 5 H) 4.98 - 5.08 (m, 2 H) 3.44 - 3.62 (m, 2 H) 3.10 - 3.25 (m, 1 H) 2.88 - 3.03 (m, 1 H) 1.75 - 1.87 (m, 1 H) 1.22 - 1.37 (m, 1 H) 0.62 (br s, 1 H) 0.25 (br d, J = 5.50 Hz, 1 H) -0.25 (br s, 1 H).

[0239] Scheme 5: General scheme for the preparation of compounds from cores 1i, 2i, and 3i. [ka]

[0240] Scheme 6: General scheme for the preparation of compounds from core 4i. [ka]

[0241] Part II: Synthesis Examples Example 1: Preparation of Compound 2 [ka]

[0242] Step 1: Preparation of intermediate 23f [ka]

[0243] A mixture of intermediate 21f (1 g, 5.02 mmol, 1 equiv.), intermediate 22f (939.51 mg, 5.02 mmol, 1 equiv., 2HCl), and TEA (2.03 g, 20.09 mmol, 2.80 mL, 4 equiv.) in THF (10 mL) and MeOH (7.5 mL) was degassed and cooled with N 2 Purge the mixture three times with N 2 The reaction mixture was stirred at 60° C. for 16 hours under atmospheric conditions. 2 Dilute with 200 mL of O (100 mL), extract with EtOAc (100 mL x 3), and 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 100 / 1 to 1 / 1). Intermediate 23f (2.68 g, 9.14 mmol, 90.98% yield) was obtained as a yellow solid. LCMS: RT = 0.694 min, MS calculated: 293.1, [M+H] + =294.1 1 H NMR (400 MHz, chloroform-d) δ = 8.81 (s, 1H), 8.24-8.34 (m, 2H), 7.92 (s, 1H), 7.64 (d, J = 1.59 Hz, 1H), 7.35 (dd, J = 1.65, 8.86 Hz, 1H), 7.27 (s, 1H), 4.86 (d, J = 5.26 Hz, 2H), 3.95 (s, 3H), 2.19 (br s, 1H).

[0244] Step 2: Preparation of intermediate 24f [ka]

[0245] A mixture of intermediate 23f (500 mg, 1.70 mmol, 1 equiv.), Pd / C (125 mg, 1.70 mmol, 10 wt%, 1 equiv.) in MeOH (5 mL) was degassed and washed with H 2 The mixture was then purged three times with H 2 The mixture was stirred under atmosphere at 25° C. for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. Intermediate 24f (860 mg, 3.27 mmol, 95.79% yield) was obtained as a green solid. LCMS: RT = 0.614 min, MS calculated: 263.1, [M+H] + =264.0 1 H NMR (400 MHz, chloroform-d) δ = 8.77 (s, 1H), 7.87 (s, 1H), 7.54 (td, J = 0.86, 8.07 Hz, 1H), 7.46 (s, 1H), 6.73 (d, J = 8.19 Hz, 1H), 4.60 (s, 2H), 3.87 (s, 3H).

[0246] Step 3: Preparation of intermediate 26f [ka]

[0247] CH 3 Degas a mixture of intermediate 24f (160 mg, 607.64 μmol, 1 equiv.), intermediate 25f (54.90 mg, 486.11 μmol, 38.66 μL, 0.8 equiv.), and p-TsOH (20.93 mg, 121.53 μmol, 0.2 equiv.) in CN (3 mL) and rinse with N 2 Purge the mixture three times with N 2 The mixture was stirred at 60° C. under atmospheric pressure for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. Intermediate 26f (192 mg, 596.68 μmol, 98.20% yield) was obtained as a white solid. LCMS: RT = 0.633 min, MS calculated: 321.0, [M+H] + =322.1

[0248] Step 4: Preparation of intermediate 27f [ka]

[0249] CH 3 Intermediate 26f (200 mg, 642.36 μmol, 1 equiv.), core 2i (190 mg, 590.46 μmol, 9.19e-1 equiv.) and K 2 CO 3 A mixture of (266.33 mg, 1.93 mmol, 3 equiv.) was degassed and diluted with N 2 Purge the mixture three times with N 2 The mixture was stirred at 60° C. for 1 hour under atmospheric pressure. 2 Dilute with 20 mL of O (80 mL), extract with EtOAc (40 mL x 3), and add Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 100 / 1 to 1 / 1). Intermediate 27f (260 mg, 435.75 μmol, 67.84% yield) was obtained as a green solid. LCMS: RT = 0.790 min, MS calculated: 596.2, [M+H] + =597.2 1H NMR (400 MHz, chloroform-d) δ = 8.75 (s, 1H), 8.15 (s, 1H), 8.01 (br d, J = 8.51 Hz, 1H), 7.87 (s, 1H), 7.78 (d, J = 8.51 Hz, 1H), 7.64 (br t, J = 7.44 Hz, 1H), 7.52-7.57 (m, 1H), 7.45 (d, J = 8.25 Hz, 1H), 7.37 (dd, J = 1.31, 9.32 Hz, 1H), 6.76 (d, J = 7.38 Hz, 1H), 6.66 (d, J = 8.13 Hz, 1H), 5.51 (s, 2H), 3.96 (s, 4H), 3.86-3.92 (m, 1H), 2.89-3.07 (m, 2H), 2.63 (br s, 1H), 2.24-2.38 (m, 2H), 2.03-2.14 (m, 1H), 1.68-1.94 (m, 3H), 1.22-1.32 (m, 1H).

[0250] Step 5: Preparation of Compound 2 [ka]

[0251] Intermediate 27f (120 mg, 201.12 μmol, 1 eq.) in THF (0.7 mL), LiOH H 2 O (25.32mg, 603.35μmol, 3eq) and MeOH / H 2 Degas the mixture with O (0.3 mL) and N 2 Purge the mixture three times with N 2 The mixture was stirred at 25°C under atmospheric conditions for 16 hours. The reaction mixture was adjusted to pH 7 with citric acid, and the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (TFA condition column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (10mM NH 4 HCO 3)-ACN]; B%: 20% to 50%, 8 min). Compound 2 (36.22 mg, 62.16 μmol, 30.91% yield) was obtained as a white solid. LCMS: RT = 1.573 min, MS calculated: 582.2, [M+H] + =583.2 1 H NMR (400 MHz, methanol-d 4 ) δ = 8.92 (s, 1H), 8.18 (s, 1H), 7.95-7.99 (m, 2H), 7.62-7.69 (m, 2H), 7.53-7.61 (m, 3H), 6.81 (d, J = 7.21 Hz, 1H), 6.67 (d, J = 8.19 Hz, 1H), 6.00 (s, 2H), 5.51 (s, 2H), 3.91 (s, 2H), 3.00 (br d, J = 11.49 Hz, 2H), 2.57-2.66 (m, 1H), 2.28 (dt, J = 3.55, 11.13 Hz, 2H), 1.74-1.82 (m, 4H).

[0252] Example 2: Preparation of Compound 3 General scheme for the preparation of compound 3 [ka]

[0253] Step 1: Preparation of intermediate 29f [ka]

[0254] CH 3 To a solution of intermediate 26f (300 mg, 932.31 μmol, 1 equiv) in CN (10 mL) was added K 2 CO 3 (386.55 mg, 2.80 mmol, 3 equiv.) was added, followed by freshly prepared core 1i (313.63 mg, 932.31 μmol, 1 equiv.) in N 2The mixture was stirred at 60° C. for 1 hour. The reaction mixture was filtered and the filtrate was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 55% to 85%, 8 min). Intermediate 29f (150 mg, 241.26 μmol, 25.88% yield) was obtained as a white solid. LCMS: RT =0.964 min, MS calculated: 621.2, [M+H] + =622.4 1 H NMR (400 MHz, methanol-d 4 ) δ = 8.96 (s, 1H), 8.23 ​​(s, 1H), 8.04 - 7.92 (m, 2H), 7.71 (d, J = 8.6 Hz, 1H), 7.55 - 7.28 (m, 3H), 6.79 - 6.44 (m, 2H), 6.03 (s, 2H), 4.78 (s, 2H), 3.94 - 3.91 (m, 5H), 3.88 (t, J = 5.8 Hz, 2H), 3.09 - 2.94 (m, 4H), 2.68 - 2.52 (m, 1H), 2.39 - 2.24 (m, 2H), 1.90 - 1.78 (m, 4H)

[0255] Step 2: Preparation of compound 3 [ka]

[0256] THF (1.5 mL) and H 2 A solution of intermediate 29f (100 mg, 160.84 μmol, 1 equiv) in 2H2O (0.6 mL) was added to LiOH H 2 O (13.50 mg, 321.69 μmol, 2 equiv.) was added. The mixture was stirred at 25° C. for 12 h. The reaction mixture was filtered. The filtrate was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 um; mobile phase: [water (NH 4 HCO 3)-ACN]; B%: 40%-60%, 8 min) to give compound 3 as an off-white solid. LCMS: RT =0.781 min, MS calculated: 607.2, [M+H] + =608.4. LCMS: RT =2.004 min, MS calculated: 607.2, [M+H] + =608.1. HPLC: RT =7.611 min 1 H NMR (400 MHz, methanol-d 4 ) δ = 8.94 (s, 1H), 8.18 (s, 1H), 8.01 - 7.92 (m, 2H), 7.64 (d, J = 8.3 Hz, 1H), 7.51 - 7.45 (m, 1H), 7.42 - 7.34 (m, 2H), 6.69 (d, J = 8.3 Hz, 1H), 6.55 (d, J = 7.2 Hz, 1H), 6.00 (s, 2H), 4.78 (s, 2H), 3.92 (s, 2H), 3.88 (t, J = 5.7 Hz, 2H), 3.06 - 2.94 (m, 4H), 2.68 - 2.52 (m, 1H), 2.35 - 2.23 (m, 2H), 1.88 - 1.77 (m, 4H).

[0257] Example 3: Preparation of Compound 4 General scheme for the preparation of compound 4 [ka]

[0258] Step 1: Preparation of intermediate 31f [ka]

[0259] H 2 Intermediate 30f (5 g, 39.32 mmol, 1 equiv.), hydroxylamine hydrochloride (5.46 g, 78.64 mmol, 2 equiv.) and Na in O (50 mL). 2 CO 3A mixture of (3.59 g, 43.25 mmol, 1.1 equiv.) was degassed and diluted with N 2 Purge the mixture three times with N 2 The mixture was stirred at 70° C. under atmospheric pressure for 1 h. LCMS showed the reaction was complete. The mixture was extracted with DCM (50 mL×3). The combined organic layers were washed with Na 2 SO 4 The mixture was dried over 1000 ml, filtered, and the filtrate was concentrated to give intermediate 31f (4.9 g, 34.46 mmol, 87.65% yield) as a yellow oil. LCMS: RT = 0.479 min, MS calculated: 142.0, [M+H] + =143.0

[0260] Step 2: Preparation of compound 32f [ka]

[0261] To a solution of intermediate 31f (4.9 g, 34.46 mmol, 1 equiv) in MeOH (50 mL) was added N 2 Raney Ni (980.00 mg, 11.44 mmol, 3.32 e-1 equiv.) was added under vacuum. The suspension was degassed under H 2 The mixture was purged with H 2 The mixture was stirred at 20° C. under (15 psi) for 2 h. Completion of the reaction was detected by LCMS. The suspension was filtered and the wet cake was washed with MeOH (50 mL×2). The combined filtrate was concentrated to dryness to give intermediate 32f (1.5 g, 11.70 mmol, 33.95% yield) as a yellow oil. LCMS: RT = 0.127 min, MS calculated: 128.1, [M+H] + =129.1 1 H NMR (400MHz, chloroform-d) δ = 8.62 (s, 1H), 4.03 (s, 2H), 2.42 (s, 3H).

[0262] Step 3: Preparation of intermediate 33f [ka]

[0263] A mixture of intermediate 32f (400 mg, 3.12 mmol, 1 equiv.), aryl ester (621.35 mg, 3.12 mmol, 1 equiv.) and TEA (394.67 mg, 3.90 mmol, 542.87 μL, 1.25 equiv.) in DMF (4 mL) was degassed and cooled with N 2 Purge the mixture three times with N 2 The mixture was stirred at 60° C. under atmospheric pressure for 16 hours. LCMS showed the reaction was complete. The mixture was diluted with H 2 The mixture was diluted with 200 mL of EtOAc (10 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=50 / 1 to 2 / 1) to give intermediate 33f (650 mg, 2.12 mmol, 67.78% yield) as a yellow solid. LCMS: RT = 0.826 min, MS calculated: 307.1, [M+H] + =308.1 1 H NMR (400MHz, chloroform-d) δ = 8.72 (s, 1H), 8.26 (d, J=8.9 Hz, 1H), 8.19 (br s, 1H), 7.60 (d, J=1.5 Hz, 1H), 7.35 (dd, J=1.6, 8.9 Hz, 1H), 4.72 (d, J=5.3 Hz, 2H), 3.95 (s, 3H), 2.59 (s, 3H).

[0264] Step 4: Preparation of intermediate 34f [ka]

[0265] To a solution of intermediate 33f (650 mg, 2.12 mmol, 1 equiv) in MeOH (12 mL), 2 Pd / C (120 mg, 10 wt%) was added under vacuum. The suspension was degassed under H 2The mixture was purged with H 2 The mixture was stirred at 20° C. under (15 psi) for 12 h. LCMS showed the reaction was complete. The suspension was filtered and the wet cake was washed with MeOH (5 mL×2). The combined filtrate was concentrated to dryness to give intermediate 34f (500 mg, 1.80 mmol, 85.24% yield) as a yellow solid. LCMS: RT = 0.671 min, MS calculated: 277.1, [M+H] + =278.1 1 H NMR (400MHz, chloroform-d) δ = 8.68 (s, 1H), 7.54 (dd, J=1.8, 8.1 Hz, 1H), 7.44 (d, J=1.8 Hz, 1H), 6.73 (d, J=8.1 Hz, 1H), 4.48 (s, 2H), 3.87 (s, 3H), 2.50 (s, 3H).

[0266] Step 5: Preparation of intermediate 35f [ka]

[0267] CH 3 A mixture of intermediate 34f (300 mg, 1.08 mmol, 1 equiv.), 25f (122.17 mg, 1.08 mmol, 86.04 μL, 1 equiv.) and p-TsOH (37.25 mg, 216.34 μmol, 0.2 equiv.) in CN (3 mL) was degassed and diluted with N 2 Purge the mixture three times with N 2 The mixture was stirred at 60° C. under atmospheric pressure for 2 hours. LCMS showed the reaction was complete. The reaction mixture was concentrated to dryness to give intermediate 35f (350 mg, 1.04 mmol, 96.35% yield) as a yellow solid. LCMS: RT = 0.752 min, MS calculated: 335.1, [M+H] + =336.1 1 H NMR (400MHz, DMSO-d 6) δ = 8.16 (d, J=1.0 Hz, 1H), 7.89 (dd, J=1.5, 8.5 Hz, 1H), 7.47 (d, J=8.1 Hz, 1H), 7.11 (d, J=7.9 Hz, 1H), 5.93 (s, 2H), 5.16 (s, 2H), 3.86 (s, 3H), 2.55 (s, 3H).

[0268] Step 6: Preparation of intermediate 36f [ka]

[0269] CH 3 Intermediate 35f (300 mg, 893.37 μmol, 1 equiv.), core 2i (278.15 mg, 893.37 μmol, 1 equiv.) and K in CN (3 mL) 2 CO 3 A mixture of (617.34 mg, 4.47 mmol, 5 equiv.) was degassed and diluted with N 2 Purge the mixture three times with N 2 The mixture was stirred at 50° C. under atmospheric pressure for 3 hours. LCMS showed the reaction was complete. The mixture was diluted with H 2 The mixture was diluted with 200 mL of EtOAc (10 mL × 3) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with Na 2 SO 4 The residue was purified by preparative HPLC (NH 4 HCO 3 ) to give intermediate 36f (150 mg, 245.62 μmol, 27.49% yield) as a white solid. LCMS: RT = 0.806 min, MS calculated: 610.1, [M+H] + =611.2 1H NMR (400MHz, chloroform-d) δ = 8.62 (s, 1H), 8.08 (d, J=1.1 Hz, 1H), 8.00 (dd, J=1.5, 8.5 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.63 (t, J=7.5 Hz, 1H), 7.54 (dd, J=7.4, 8.1 Hz, 1H), 7.44 (dd, J=1.3, 7.9 Hz, 1H), 7.36 (dd, J=1.4, 9.3 Hz, 1H), 6.75 (d, J=7.3 Hz, 1H), 6.66 (d, J=8.1 Hz, 1H), 5.84 (s, 2H), 5.51 (s, 2H), 3.95 (s, 3H), 3.87 (s, 2H), 2.95 (br d, J=11.6 Hz, 2H), 2.65 (s, 3H), 2.28 (dt, J=2.1, 11.7 Hz, 2H), 1.90 - 1.83 (m, 2H), 1.82 - 1.70 (m, 2H).

[0270] Step 7: Preparation of compound 4 [ka]

[0271] THF (1.5 mL) and H 2 Intermediate 36f (120 mg, 196.50 μmol, 1 equiv.) in LiOH H 2 Degas a mixture of O (24.74 mg, 589.49 μmol, 3 equiv.) and N 2 Purge the mixture three times with N 2 The reaction was stirred at 25° C. for 12 hours under atmospheric pressure. LCMS showed the reaction was complete. The reaction was 2 The crude product was purified by preparative HPLC (NH 4 HCO 3 ) to give compound 4 (38.48 mg, 64.49 μmol, 32.82% yield) as a white solid. LCMS: RT = 0.826 min, MS calculated: 596.1, [M+H] +=597.1 HPLC: RT = 7.829 min 1 H NMR (400MHz, chloroform-d) δ = 8.64 (s, 1H), 8.13 (s, 1H), 8.05 (br s, 1H), 7.81 (br d, J=8.4 Hz, 1H), 7.63 (br s, 1H), 7.54 (br t, J=7.8 Hz, 1H), 7.44 (br d, J=7.9 Hz, 1H), 7.36 (br d, J=9.0 Hz, 1H), 6.76 (br d, J=6.8 Hz, 1H), 6.66 (br d, J=7.9 Hz, 1H), 5.86 (br s, 2H), 5.51 (s, 2H), 3.91 (br s, 2H), 2.98 (br s, 2H), 2.68 (s, 3H), 2.32 (br s, 2H), 1.93 - 1.76 (m, 5H).

[0272] Example 4: Preparation of Compound 5 [ka]

[0273] Step 1: Preparation of intermediate 37f [ka]

[0274] CH 3 Compound 26f (130 mg, 404.00 μmol, 1 equiv.), core 3i (148.84 mg, 404.00 μmol, 1 equiv.), K 2 CO 3 A mixture of (167.51 mg, 1.21 mmol, 3 equiv.) was degassed and diluted with N 2 Purge the mixture three times with N 2 The mixture was stirred at 60° C. under atmospheric pressure for 1 h. LC-MS showed complete consumption of compound 26f with one major peak of the desired compound. The reaction mixture was diluted with H 2 Dilute with 20 mL of O (60 mL), extract with EtOAc (30 mL x 3), and 2 SO4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 100 / 1 to 1 / 1). Compound 37f (180 mg, 275.34 μmol, 68.15% yield) was obtained as a white solid. LCMS: RT = 2.542 min, MS calculated: 653.75, [M+H] + =654.1 1 H NMR (400 MHz, DMSO-d 6 ) δ = ppm 1.17 (dd, J = 6.25, 2.88 Hz, 2 H) 1.59 - 1.76 (m, 4 H) 1.96 (d, J = 2.88 Hz, 1 H) 2.17 (br t, J = 11.19 Hz, 2 H) 3.81 - 3.89 (m, 5 H) 5.83 - 5.99 (m, 4 H) 6.83 (br d, J = 8.00 Hz, 1 H) 6.93 (br d, J = 5.00 Hz, 1 H) 7.67 - 7.76 (m, 2 H) 7.83 (br d, J = 8.25 Hz, 1 H) 7.94 (br d, J = 10.13 Hz, 1 H) 8.01 (s, 1 H) 8.22 (s, 1 H) 8.54 (s, 1 H) 8.98 (d, J = 2.13 Hz, 1 H).

[0275] Step 2: Preparation of compound 5 [ka]

[0276] THF (0.7 mL) and H 2 Compound 37f (70 mg, 107.07 μmol, 1 equiv.) in LiOH H 2 Degas a mixture of 2H2O (4.94 mg, 117.78 μmol, 1.1 equiv.) and N 2 Purge the mixture three times with N 2The mixture was stirred at 25°C under ambient atmosphere for 16 hours. LC-MS showed that compound 37f was completely consumed with one major peak of the desired compound. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC (neutral condition column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 10% to 50%, 8 min). Compound 5 (15.4 mg, 24.07 μmol, 22.48% yield) was obtained as a white solid. LCMS: RT = 1.918 min, MS calculated: 639.1, [M+H] + =640.1 1 H NMR (400 MHz, DMSO-d 6 ) δ = ppm 1.14 (s, 2 H) 1.23 (s, 1 H) 1.38 (s, 1 H) 1.68 (br d, J = 14.66 Hz, 4 H) 1.72 - 1.75 (m, 1 H) 2.17 (br s, 2 H) 2.89 (br s, 2 H) 3.86 (br d, J = 11.80 Hz, 2 H) 5.88 (s, 2 H) 5.86 - 5.90 (m, 1 H) 5.93 (s, 1 H) 6.84 (br d, J = 8.23 ​​Hz, 1 H) 6.93 (br d, J = 6.91 Hz, 1 H) 7.67 (br d, J = 8.58 Hz, 1 H) 7.72 (br t, J = 7.57 Hz, 1 H) 7.81 (br d, J = 7.75 Hz, 1 H) 7.95 (d, J = 11.44 Hz, 1 H) 8.02 (s, 1 H) 8.18 (s, 1 H) 8.14 - 8.23 ​​(m, 1 H) 8.55 (s, 1 H) 8.98 (s, 1 H) 12.70 - 12.90 (m, 1 H) 12.70 - 12.90 (m, 1 H).

[0277] Example 5: Preparation of Compound 6 [ka]

[0278] Step 1: Preparation of intermediate 39f [ka]

[0279] To a solution of intermediate 38f (5 g, 18.32 mmol, 1 equiv.) in MeOH (50 mL), Pd (1 g, 9.40 mmol, 5.13e-1 equiv.) and sodium acetate (3.01 g, 36.64 mmol, 2 equiv.) were added with N 2 The suspension was degassed under vacuum and H 2 The reaction mixture was purged with H several times. 2 The mixture was stirred at 20° C. for 12 h under reduced pressure, filtered, and the filtrate was concentrated to give intermediate 39f (3.5 g, crude) as a yellow oil. LCMS: RT = 0.227 min, MS calculated: 192.9, [M+H] + =193.8, 195.8 1 H NMR (400 MHz, chloroform-d) δ = 8.65 - 8.78 (1H, m), 4.77 - 4.91 (2H, m), 4.02 (2H, br s), 2.07 (1H, br s).

[0280] Step 2: Preparation of intermediate 40f [ka]

[0281] A mixture of intermediate 39f (14 g, 72.15 mmol, 1 equiv.), DMP (34.72 g, 81.86 mmol, 25.34 mL, 1.13 equiv.) in DCM (300 mL) was degassed and cooled with N 2 The mixture was then stirred under Ar at 20 °C for 5 h. 3 The mixture was basified to pH 8 using aqueous solution, and the residue was then purified with H 2 The reaction mixture was poured into a separatory funnel, separated, and the combined organic layers were washed with brine (10 mL) and Na 2 SO4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 100 / 1 to 92 / 1). Intermediate 40f (11 g, 57.28 mmol, 79.40% yield) was obtained as a white solid. LCMS: RT = 0.646 min, MS calculated: 190.9, [M+H] + =192.8, 194.0 1 H NMR (400 MHz, chloroform-d) δ = 10.05 (1H, d, J = 1.07 Hz) 9.03 (1H, d, J = 0.83 Hz).

[0282] Step 3: Preparation of intermediate 42f [ka]

[0283] To a solution of intermediate 40f (4.3 g, 22.39 mmol, 1 equiv) in DCM (43 mL) was added Cs 2 CO 3 (14.59 g, 44.78 mmol, 2 equiv.) and intermediate 41f (5.43 g, 44.78 mmol, 2 equiv.) were added. The mixture was stirred at 20° C. for 1 h. LC-MS showed that intermediate 40f was completely consumed and one major peak with the desired mass was detected. The mixture was filtered and concentrated under vacuum. Intermediate 42f (9 g, crude) was obtained as a brown solid. LCMS: RT = 0.646 min, MS calculated: 294.0, [M+H] + = 295.0 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.25 - 9.55 (1 H, m) 8.41 - 8.66 (1 H, m) 1.17 (9 H, s).

[0284] Step 3: Preparation of intermediate 43f [ka]

[0285] To a solution of intermediate 42f (9 g, 30.49 mmol, 1 equiv) in THF (50 mL) and MeOH (50 mL) was added NaBH 4 (3.52 g, 93.04 mmol, 3.05 equiv.) was added at 0 °C. The mixture was stirred at 0-20 °C for 1 h and then saturated NH 4 The combined organic phase was washed with brine (50 mL x 2) and anhydrous NaCl solution (200 mL) and extracted with ethyl acetate (50 mL x 3). 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1 / 0 to 0 / 1). Intermediate 43f (4.6 g, 15.48 mmol, 50.76% yield) was obtained as a white solid. LCMS: RT = 0.607 min, MS calculated: 296.0, [M+H] + =296.9, 298.9 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.08 (1 H, s) 6.13 (1 H, t, J=5.71 Hz) 4.23 - 4.39 (2 H, m) 1.14 (9 H, s).

[0286] Step 4: Preparation of intermediate 44f [ka]

[0287] To a solution of intermediate 43f (3.2 g, 10.77 mmol, 1 equiv) in DCM (5 mL) was added HCl / EtOAc (20 mL). The mixture was stirred at 20° C. for 1 h and then concentrated in vacuo to give intermediate 44f (2.5 g, crude) as a white solid. LCMS: RT = 0.130 min, MS calculated: 191.9, [M+H] + =192.8, 194.8 1 H NMR (400 MHz, DMSO-d 6) δ = 9.16 - 9.36 (1 H, m) 8.76 (3 H, br s) 6.62 (3 H, br s) 4.22 (2 H, q, J=5.58 Hz).

[0288] Step 5: Preparation of intermediate 46f [ka]

[0289] To a solution of intermediate 44f (2.5 g, 12.95 mmol, 1 equiv.) and intermediate 45f (2.58 g, 12.95 mmol, 1 equiv.) in THF (30 mL) was added TEA (3.93 g, 38.85 mmol, 5.41 mL, 3 equiv.). The mixture was diluted with N 2 The mixture was stirred at 60° C. for 2 hours under reduced pressure. The residue was poured into water (50 mL). The aqueous phase was extracted with ethyl acetate (30 mL×3). The combined organic phase was washed with brine (30 mL×2) and diluted with anhydrous Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 10 / 1 to 0 / 1). Intermediate 46f (1 g, 2.69 mmol, 20.75% yield) was obtained as a white solid. LCMS: RT = 0.769 min, MS calculated: 371.0, [M+H] + =371.8, 373.8 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.04 - 9.10 (1 H, m) 8.74 - 8.82 (1 H, m) 8.19 - 8.26 (1 H, m) 7.45 - 7.51 (1 H, m) 7.18 - 7.27 (1 H, m) 4.76 - 4.84 (2 H, m) 3.83 - 3.89 (3H, m).

[0290] Step 6: Preparation of intermediate 47f [ka]

[0291] To a mixture of intermediate 46f (950 mg, 2.55 mmol, 1 equiv) in AcOH (10 mL) was added Fe (1.43 g, 25.52 mmol, 10 equiv) at 0 °C, and the mixture was then cooled to 5 °C with N 2 The mixture was stirred at 60° C. for 20 minutes under atmospheric conditions. The mixture was filtered, and the filtrate was diluted with 1M Na 2 CO 3 The solution was poured into 210 mL of ethyl acetate and stirred for 60 min. The aqueous phase was extracted with DCM (50 mL x 3). The combined organic phase was washed with brine (50 mL x 3) and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo to give intermediate 47f (900 mg, crude) as a white solid. LCMS: RT = 0.522 min, MS calculated: 341.0, [M+H] + =342.0, 343.9 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.02 - 9.15 (1 H, m) 7.18 - 7.30 (1 H, m) 7.01 - 7.11 (1 H, m) 6.61 - 6.67 (1 H, m) 5.47 - 5.68 (3 H, m) 4.49 - 4.58 (2 H, m) 3.74 - 3.78 (3H, m).

[0292] Step 7: Preparation of intermediate 48f [ka]

[0293] To a solution of intermediate 47f (270 mg, 788.99 μmol, 1 equiv) in MeCN (4 mL) was added p-TsOH (54.35 mg, 315.59 μmol, 0.4 equiv) followed by 2-chloroacetyl chloride (106.93 mg, 946.78 μmol, 75.30 μL, 1.2 equiv) at 20° C., and the mixture was then stirred at 60° C. for 4 h. The mixture was concentrated under vacuum. Intermediate 48f (350 mg, crude) was obtained as a yellow solid. LCMS: RT = 0.715 min, MS calculated: 398.9, [M+H] + =399.9, 401.9 1 H NMR (400 MHz, DMSO-d 6 ) δ = 9.12 - 9.16 (1 H, m) 8.29 - 8.31 (1 H, m) 7.84 - 7.88 (1 H, m) 7.51 - 7.58 (1 H, m) 5.96 - 5.99 (2 H, m) 5.19 - 5.24 (2 H, m) 3.93 (3 H, s).

[0294] Step 8: Preparation of intermediate 49f [ka]

[0295] To a solution of intermediate 48f (310 mg, 773.69 μmol, 1 equiv.) and core 3i (373.27 mg, 773.69 μmol, 1 equiv., TFA) in MeCN (4 mL) was added K 2 CO 3 (427.71 mg, 3.09 mmol, 4 equiv) was added. The mixture was stirred at 60° C. for 2 h. The mixture was filtered and the cake was saved. Intermediate 49f (350 mg, 477.72 μmol, 61.75% yield) was obtained as a white solid. LCMS: RT = 2.816 min, MS calculated: 731.1, [M+H] + =732.1, 734.1 1H NMR (400 MHz, chloroform-d) δ = 8.68 - 8.80 (1 H, m) 8.18 - 8.23 ​​(1 H, m) 8.02 - 8.08 (2 H, m) 7.78 - 7.85 (1 H, m) 7.57 - 7.68 (1 H, m) 7.42 - 7.52 (1 H, m) 6.75 - 6.89 (2 H, m) 5.92 (2 H, s) 5.86 (2 H, s) 3.98 (3 H, s) 3.91 (2 H, s) 2.94 - 3.04 (2 H, m) 2.59 - 2.69 (1 H, m) 2.25 - 2.35 (2 H, m) 1.80 - 1.88 (2H, m) 1.68 - 1.80 (2H, m).

[0296] Step 9: Preparation of Compound 6 [ka]

[0297] THF (5 mL) and H 2 A solution of intermediate 49f (150 mg, 204.74 μmol, 1 equiv) in 2.1 mL of LiOH H 2 HO (10.31 mg, 245.69 μmol, 1.2 equiv.) was added. The mixture was stirred at 20° C. for 12 h, adjusted to pH 7 using 1 M citric acid, and then concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (neutral conditions: column: Phenomenex C18 80*40 mm*3 um; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 30% to 60%, 8 min). Compound 6 (15.09 mg, 21.00 μmol, 10.26% yield) was obtained as a white solid. LCMS: Rt = 0.715 min, MS calculated: 717.1, [M+H] + =717.9, 719.9 1H NMR (400 MHz, chloroform-d) δ = 8.74 - 8.78 (1 H, m) 8.23 ​​(1 H, s) 8.06 - 8.11 (1 H, m) 8.00 - 8.04 (1 H, m) 7.79 - 7.86 (1 H, m) 7.55 - 7.63 (1 H, m) 7.40 - 7.47 (1 H, m) 6.71 - 6.84 (2 H, m) 5.88 - 5.91 (2 H, m) 5.85 (2 H, s) 3.88 - 3.94 (2 H, m) 2.92 - 3.01 (2 H, m) 2.58 - 2.69 (2 H, m) 2.24 - 2.34 (3 H, m) 1.68 - 1.87 (17H, m).

[0298] Example 6: Preparation of Compound 7 [ka]

[0299] Step 1: Preparation of intermediate 51f [ka]

[0300] Dioxane (3 mL) and H 2 Intermediate 49f (300 mg, 409.48 μmol, 1 equiv.), intermediate 50f (126.13 mg, 818.95 μmol, 138.91 μL, 2 equiv.), Cs 2 CO 3 (266.83mg, 818.95μmol, 2eq), XPHOS-PD-G 2 A mixture of (32.22 mg, 40.95 μmol, 0.1 equiv.) was degassed and diluted with N 2 Purge the mixture three times with N 2 The mixture was stirred at 80° C. under atmospheric pressure for 1 hour. The residue was poured into water (10 mL). The aqueous phase was extracted with ethyl acetate (5 mL×3). The combined organic phase was washed with brine (5 mL×2) and anhydrous Na 2 SO 4The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 10 / 1 to 0 / 1). Intermediate 51f (150 mg, 220.66 μmol, 53.89% yield) was obtained as a white solid. LCMS: Rt = 2.215 min, MS calculated: 679.2, [M+H] + =680.2, 681.6 1 H NMR (400 MHz, chloroform-d) δ = 8.60 (1 H, s) 8.04 (1 H, s) 7.91 - 7.95 (2 H, m) 7.69 (1 H, d, J=8.53 Hz) 7.53 (1 H, t, J=7.72 Hz) 7.35 (1 H, d, J=9.45 Hz) 6.88 - 6.97 (1 H, m) 6.75 (1 H, d, J=7.28 Hz) 6.68 (1 H, d, J=8.28 Hz) 6.21 (1 H, dd, J=17.00, 1.57 Hz) 5.86 (2 H, s) 5.81 (2 H, s) 5.50 - 5.54 (1 H, m) 3.87 (3 H, s) 3.70 - 3.79 (2 H, m) 2.81 - 2.89 (2 H, m) 2.56 (1 H, br d, J=3.64 Hz) 2.12 - 2.23 (2 H, m) 1.66 - 1.81 (4 H, m).

[0301] Step 2: Preparation of compound 7 [ka]

[0302] THF (4.9 mL) and H 2 A solution of intermediate 51f (140 mg, 205.95 μmol, 1 equiv) in 2.1 mL of LiOH H 2HO (12.96 mg, 308.92 μmol, 1.5 equiv.) was added. The mixture was stirred at 20° C. for 12 h, adjusted to pH 7 using 1 M citric acid, and then concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (neutral conditions: column: Phenomenex C18 80*40 mm*3 um; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 50%-60%, 8 min). LCMS: Rt = 1.771 min, MS calculated: 665.2, [M+H] + =666.3 1 H NMR (400 MHz, chloroform-d) δ = 8.68 - 8.71 (1 H, m) 8.17 - 8.21 (1 H, m) 8.04 - 8.10 (1 H, m) 7.99 - 8.02 (1 H, m) 7.79 - 7.85 (1 H, m) 7.58 - 7.64 (1 H, m) 7.40 - 7.46 (1 H, m) 6.95 - 7.05 (1 H, m) 6.75 - 6.75 (1 H, m) 6.73 - 6.85 (1 H, m) 6.29 (1 H, dd, J=17.05, 1.31 Hz) 5.93 - 6.01 (2 H, m) 5.84 - 5.92 (2 H, m) 5.57 - 5.63 (1 H, m) 3.85 (2 H, s) 2.96 (1 H, br s) 2.91 - 3.00 (1 H, m) 2.60 - 2.69 (1 H, m) 2.24 - 2.32 (2 H, m) 1.75 - 1.90 (4 H, m).

[0303] Example 7: Preparation of Compound 14 [ka]

[0304] Step 1: Preparation of intermediate 53f [ka]

[0305] Toluene (5 mL) 2 Intermediate 52f (100 mg, 325.61 μmol, 1 equiv.), core 4i (165.18 mg, 488.41 μmol, 1.5 equiv., K + ), Cs 2 CO 3 (318.27mg, 976.82μmol, 3eq), CatacXium A Pd G 3 A mixture of (11.86 mg, 16.28 μmol, 0.05 equiv.) was degassed and diluted with N 2 Purge the mixture three times with N 2 The mixture was stirred at 120° C. for 4 hours under atmospheric pressure. 2 The reaction mixture was poured into a separatory funnel and separated. The combined organic layers were washed with brine (10 mL) and diluted with Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 100 / 1 to 0 / 1, TLC-petroleum ether / ethyl acetate = 10 / 1, product R f =0.6). Intermediate 53f (200 mg, 437.16 μmol, 67.13% yield) was obtained as a yellow oil. LCMS: RT = 1.049 min, MS calculated: 457.50, [M+H] + = 458.2 1H NMR (400 MHz, chloroform-d) δ = ppm 7.55 (dt, J = 17.79, 7.67 Hz, 2 H) 7.29 - 7.47 (m, 7 H) 6.78 - 6.87 (m, 1 H) 6.62 (d, J = 8.32 Hz, 1 H) 5.45 (d, J = 3.22 Hz, 2 H) 5.31 (s, 1 H) 5.15 (s, 2 H) 3.74 - 3.88 (m, 2 H) 3.50 - 3.65 (m, 1 H) 3.30 (br s, 1 H) 2.41 - 2.51 (m, 1 H) 2.02 - 2.18 (m, 1H) 1.69 (br s, 1 H) 1.20 - 1.31 (m, 2 H) 0.83 - 0.97 (m, 2 H).

[0306] Step 2: Preparation of intermediate 54f [ka] A mixture of intermediate 53f (15 mg, 32.79 μmol, 1 equiv.) in TFA (32.79 μmol, 1.00 equiv.) was degassed and diluted with N 2 Purge the mixture three times with N 2 The mixture was stirred at 50° C. under atmospheric pressure for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated. Intermediate 54f (14 mg, crude, TFA) was obtained as a yellow oil. LCMS: RT = 0.735 min, MS calculated: 323.36, [M+H] + = 324.2 1H NMR (400 MHz, chloroform-d) δ = ppm 7.72 (t, J = 7.88 Hz, 1 H) 7.62 (t, J = 7.50 Hz, 1 H) 7.48 (br d, J = 8.00 Hz, 1 H) 7.37 - 7.43 (m, 2 H) 6.96 (d, J = 7.50 Hz, 1 H) 6.80 (d, J=8.25 Hz, 1 H) 5.39 - 5.53 (m, 2 H) 4.58 (br s, 16 H) 3.76 - 3.86 (m, 1 H) 3.26 - 3.43 (m, 2 H) 2.95 (br d, J=9.26 Hz, 1H) 2.69 - 2.79 (m, 1 H) 2.31 - 2.39 (m, 1 H) 1.79 - 1.88 (m, 1 H) 1.49 (dd, J=9.26, 5.63 Hz, 1 H) 1.46 - 1.53 (m, 1 H) 1.26 (s, 1 H) 1.08 (t, J = 5.75 Hz, 1H)

[0307] Step 3: Preparation of intermediate 55f [ka]

[0308] Intermediate 54f (241.18 mg, 745.85 μmol, 1 equiv.), 26f (240 mg, 745.85 μmol, 1 equiv.), K 2 CO 3 A mixture of (309.24 mg, 2.24 mmol, 3 equiv.) was degassed and diluted with N 2 Purge the mixture three times with N 2 The mixture was stirred at 50° C. for 3 hours under atmospheric pressure. 2 The reaction mixture was poured into a separatory funnel and separated. The combined organic layers were washed with brine (10 mL) and diluted with 20 mL of NaCl. 2 SO 4 The residue was purified by column chromatography (SiO 2, petroleum ether / ethyl acetate = 100 / 1 to 30 / 1, TLC-dichloromethane / methanol = 10 / 1, product R f =0.6) to give intermediate 55f (300 mg, crude) as a yellow oil. LCMS: RT = 0.807 min, MS calculated: 608.69, [M+H] + = 609.3 1 H NMR (400 MHz, DMSO-d 6 ) δ = ppm 9.03 (s, 1 H) 8.91 (s, 1 H) 8.89 - 8.92 (m, 1 H) 8.29 (d, J = 1.25 Hz, 1 H) 8.19 (d, J = 1.00 Hz, 1 H) 8.04 (s, 1 H) 7.95 (s, 1 H) 7.82 - 7.92 (m, 2 H) 7.77 (d, J = 8.50 Hz, 1 H) 7.60 - 7.74 (m, 4 H) 7.31 - 7.38 (m, 1 H) 6.90 - 6.95 (m, 1 H) 6.66 (d, J = 8.13 Hz, 1 H) 6.02 (s, 1H) 5.96 (s, 1 H) 5.38 - 5.47 (m, 2 H) 5.19 (s, 1 H) 3.90 (br s, 1 H) 3.88 (d, J = 6.75 Hz, 5 H) 2.68 - 2.90 (m, 2 H) 2.32 - 2.43 (m, 2 H) 1.84 - 1.97 (m, 1 H) 1.84 - 1.97 (m, 1 H) 1.61 - 1.73 (m, 1 H) 1.01 - 1.09 (m, 1 H) 0.78 (dd, J = 5.88, 3.50 Hz, 1 H).

[0309] Step 4: Preparation of compound 14 [ka]

[0310] THF (2.1 mL) and H 2 Intermediate 55f (150 mg, 246.43 μmol, 1 equiv.) in LiOH H 2Degas a mixture of O (20.68 mg, 492.87 μmol, 2 equiv.) and N 2 Purge the mixture three times with N 2 The mixture was stirred at 20° C. under atmospheric conditions for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated. The crude product was purified by reverse phase HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 15%-45%, 8 min). Intermediate 14 (26.73 mg, 43.93 μmol, 17.83% yield, 97.74% purity) was obtained as a white solid. LCMS: RT = 2.647 min, MS calculated: 594.66, [M+H] + = 595.3 1 H NMR (400 MHz, DMSO-d 6 ) δ = ppm 8.91 (d, J = 0.63 Hz, 1 H) 8.13 (s, 1 H) 7.95 (s, 1 H) 7.89 (dd, J = 10.01, 1.25 Hz, 1 H) 7.82 (dd, J = 8.38, 1.50 Hz, 1 H) 7.68 - 7.71 (m, 1 H) 7.60 - 7.66 (m, 3 H) 6.92 (d, J = 7.63 Hz, 1 H) 6.66 (d, J = 8.13 Hz, 1 H) 5.93 (s, 2 H) 5.42 (d, J = 3.00 Hz, 2 H) 3.87 (d, J = 13.63Hz, 1H) 3.75 (d, J = 13.63 Hz, 1 H) 2.81 - 2.85 (m, 1 H) 2.76 (br d, J = 10.38 Hz, 2 H) 2.38 - 2.46 (m, 2 H) 1.86 - 1.94 (m, 1 H) 1.86 - 1.94 (m, 1 H) 1.62 - 1.70 (m, 1 H) 1.04 (dd, J = 9.13, 3.13 Hz, 1 H) 0.80 (dd, J = 5.94, 3.56 Hz, 1 H).

[0311] Example 8: Preparation of Compound 16 [ka]

[0312] Step 1: Preparation of intermediate 58f [ka]

[0313] Intermediate 56f (27.57 mg, 189.95 μmol, 2 equiv.), intermediate 57f (50 mg, 94.98 μmol, 1 equiv.), K 3 PO 4 (60.48 mg, 284.93 μmol, 3 equiv.), Xantphos (43.96 mg, 75.98 μmol, 0.8 equiv.) and Pd(OAc). 2 A mixture of (8.53 mg, 37.99 μmol, 0.4 equiv.) was degassed and diluted with N 2 Purge the mixture three times with N 2 The mixture was stirred at 90° C. for 4 hours under atmospheric pressure. 2 The reaction mixture was poured into a separatory funnel and separated. The combined organic layers were washed with brine (2 mL) and diluted with 1,2-dichloromethane (1 mL) and extracted with EtOAc (4 mL×2). 2 SO 4 The residue was purified by preparative TLC (SiO 2 , petroleum ether: ethyl acetate = 0:1, product R f =0.5) to give intermediate 58f (10 mg, 16.93 μmol, 17.82% yield) as a yellow solid. LCMS: RT = 0.574 min, MS calculated: 590.69, [M+H] + = 591.4 1H NMR (400 MHz, chloroform-d) δ = ppm 8.77 (d, J = 0.63 Hz, 1 H) 8.14 (d, J = 1.50 Hz, 1 H) 7.98 - 8.02 (m, 1 H) 7.88 - 7.94 (m, 3 H) 7.76 - 7.79 (m, 1 H) 7.68 - 7.72 (m, 2 H) 7.62 (t, J = 7.82 Hz, 1 H) 7.26 (s, 4 H) 6.92 - 7.01 (m, 2 H) 6.15 (s, 1 H) 5.89 (s, 2 H) 3.95 (s, 3 H) 3.92 (s, 2 H) 3.06 (br d, J = 11.63 Hz, 2 H) 2.73 - 2.82 (m, 1 H) 2.73 - 2.82 (m, 1 H) 2.32 - 2.41 (m, 2 H) 1.89 - 2.03 (m, 5 H) 1.35 - 1.35 (m, 1 H) 0.75 - 0.93 (m, 7H).

[0314] Step 2: Preparation of intermediate 59f [ka]

[0315] Intermediate 58f (90 mg, 152.36 μmol, 1 equiv.) in MeOH (5 mL), NaBH 4 A mixture of (28.82 mg, 761.82 μmol, 5 equiv.) was degassed and diluted with N 2 Purge the mixture three times with N 2 The mixture was stirred at 20°C for 2 hours under atmospheric pressure. The residue was dissolved in saturated NH 4 The mixture was diluted with Cl (1 mL) (0° C.) and extracted with DCM (2 mL×2). The reaction mixture was poured into a separatory funnel and separated. The combined organic layers were washed with brine (1 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give a residue, which gave intermediate 59f (80 mg, crude) as a yellow solid. LCMS: RT = 0.616 min, MS calculated: 592.71, [M+H] + = 593.31 H NMR (400 MHz, chloroform-d) δ = ppm 8.78 (s, 1 H) 8.14 (s, 1 H) 8.01 (d, J = 8.50 Hz, 1 H) 7.88 (s, 1 H) 7.77 (d, J = 8.50 Hz, 1 H) 7.64 (d, J = 8.13 Hz, 2 H) 7.50 - 7.60 (m, 3 H) 7.08 (d, J = 7.75 Hz, 1 H) 6.94 (d, J = 7.63 Hz, 1 H) 5.88 (s, 2 H) 5.31 (s, 2 H) 5.23 (dd, J = 8.50, 2.63 Hz, 1 H) 3.95 (s, 3 H) 3.90 (s, 2 H) 3.01 - 3.18 (m, 4 H) 2.75 (br t, J = 11.76 Hz, 1 H) 2.30 - 2.40 (m, 2 H) 1.84 - 1.98 (m, 3 H).

[0316] Example 3: Preparation of Compound 16 [ka]

[0317] THF (1.4 mL) and H 2 Intermediate 59f (80 mg, 134.97 μmol, 1 equiv.) in LiOH H 2 Degas a mixture of 2O (11.33 mg, 269.95 μmol, 2 equiv.) and N 2 Purge the mixture three times with N 2 The mixture was stirred at 20° C. for 12 hours under atmospheric conditions. The reaction mixture was filtered, and the filtrate was concentrated. The crude product was purified by reverse phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (NH 4 HCO 3)-ACN]; B%: 12%-42%, 8 min). Compound 16 (26.98 mg, 46.32 μmol, 34.31% yield, 99.34% purity) was obtained as a white solid. LCMS: RT = 2.284 min, MS calculated: 578.68, [M+H] + = 579.3 1 H NMR (400 MHz, methanol-d 4 ) δ = ppm 8.96 (d, J = 0.75 Hz, 1 H) 8.23 ​​(d, J = 1.00 Hz, 1 H) 7.96 - 8.01 (m, 2 H) 7.70 (d, J = 8.50 Hz, 1 H) 7.58 - 7.66 (m, 3 H) 7.50 (d, J = 8.13 Hz, 2 H) 7.10 (d, J = 7.75 Hz, 1 H) 7.02 (d, J = 7.25 Hz, 1 H) 6.01 (s, 2 H) 5.16 (dd, J = 7.38, 5.75 Hz, 1 H) 3.96 (s, 2 H) 3.09 - 3.15 (m, 2H) 3.05 (br d, J = 11.38 Hz, 2 H) 2.64 - 2.77 (m, 1 H) 2.28 - 2.40 (m, 2 H) 1.69 - 1.89 (m, 4 H).

[0318] Example 9: Preparation of Compound 20 [ka]

[0319] Step 1: Preparation of intermediate 62f [ka]

[0320] To a solution of intermediate 60f (3.18 g, 21.02 mmol, 1 equiv) in DMF (40 mL) was added Cs 2 CO 3(13.70 g, 42.04 mmol, 2 equiv.) and intermediate 61f (5 g, 21.02 mmol, 1 equiv.) were added. The mixture was stirred at 20° C. for 2 h. The residue was dissolved in H 2 The mixture was diluted with 20 mL of EtOAc (30 mL × 3) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with Na 2 SO 4 The residue was purified by column chromatography (SiO 2 The mixture was purified with petroleum ether / ethyl acetate=50 / 1 to 5 / 1) to give intermediate 62f (2 g, 6.49 mmol, 30.88% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ = 3.32 (s, 1 H) 5.53 (s, 2 H) 7.10 - 7.20 (m, 1 H) 7.53 (s, 1 H) 7.77 (d, J = 3.42 Hz, 2 H) 7.94 (d, J = 9.90 Hz, 1 H) 8.45 (d, J = 5.75 Hz, 1H).

[0321] Step 2: Preparation of intermediate 63f [ka]

[0322] Dioxane (10 mL) and H 2 Intermediate 62f (1.5 g, 4.87 mmol, 1 equiv.), Intermediate 6f (1.51 g, 4.87 mmol, 1 equiv.), Pd(dppf)Cl in O (2 mL) 2 (178.11mg, 243.42μmol, 0.05eq), K 2 CO 3 A mixture of (2.02 g, 14.61 mmol, 3 equiv.) was degassed and diluted with N 2 Purge the mixture three times with N 2 The mixture was stirred at 90° C. for 2 hours under atmospheric pressure. 2 The mixture was diluted with 200 mL of 2H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with aqueous NaCl (30 mL) and 2 SO4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 10 / 1 to 0 / 1). Intermediate 63f (1.2 g, 2.92 mmol, 60.05% yield) was obtained as a white solid. LCMS: Rt = 0.971 min, MS calculated: 410.2, [M+H] + =411.2 1 H NMR (400 MHz, chloroform-d) δ = 1.25 (s, 3 H) 1.50 (s, 10 H) 1.95 (s, 1 H) 2.68 (br s, 2 H) 3.63 (br t, J = 5.38 Hz, 2 H) 4.17 (br d, J = 2.00 Hz, 2 H) 5.58 (s, 2 H) 6.66 (d, J = 5.75 Hz, 1 H) 7.17 (br s, 1 H) 7.42 (dd, J = 9.26, 1.25 Hz, 1 H) 7.48 (dd, J = 8.00, 1.00 Hz, 1 H) 7.57 - 7.65 (m, 1H) 8.45 - 8.49 (m, 1 H).

[0323] Step 3: Preparation of intermediate 64f [ka]

[0324] To a solution of intermediate 63f (500 mg, 1.22 mmol, 1 equiv) in MeOH (8 mL), 2 Pd / C (200 mg, 1.22 mmol, 10% purity, 1 equiv.) was added under atmospheric pressure. The suspension was degassed and diluted with H 2 The mixture was purged with H 2 (15 Psi) at 20° C. for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2, petroleum ether / ethyl acetate = 20 / 1 to 1 / 1). Intermediate 64f (330 mg, 1.18 mmol, 96.98% yield) was obtained as a white solid. LCMS: Rt = 0.681 min, MS calculated: 279.16, [M-55] + =224.2 1 H NMR (400 MHz, chloroform-d) δ = 1.48 (s, 9 H) 1.70 - 1.88 (m, 2 H) 1.89 - 2.00 (m, 2 H) 2.69 - 2.82 (m, 1 H) 2.82 - 2.95 (m, 2 H) 4.16 - 4.33 (m, 2 H) 6.35 (d, J = 6.60 Hz, 1 H) 7.97 - 8.02 (m, 1 H)

[0325] Step 3: Preparation of intermediate 65f [ka]

[0326] To a solution of intermediate 64f (0.3 g, 1.07 mmol, 1 equiv) in toluene (5 mL) was added Ag 2 CO 3 (592.29 mg, 2.15 mmol, 2 equiv.) and intermediate 65f (252.86 mg, 1.18 mmol, 1.1 equiv.) were added. The mixture was stirred at 100° C. for 2 h. The reaction mixture was stirred at 100° C. for 2 h. 2 The mixture was diluted with 20 mL of O and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with Na 2 SO 4 The residue was purified by column chromatography (SiO 2 The mixture was purified with petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give intermediate 66f (330 mg, 800.08 μmol, 74.50% yield) as a white solid. 1H NMR (400 MHz, chloroform-d) δ = 1.49 (s, 10 H) 1.77 (qd, J = 12.41, 4.34 Hz, 2 H) 1.95 (br d, J = 12.23 Hz, 2 H) 2.81 - 2.99 (m, 3 H) 4.20 (br d, J = 2.20 Hz, 2 H) 5.55 (s, 2 H) 6.66 (d, J = 5.75 Hz, 1 H) 7.41 (dd, J = 9.17, 1.47 Hz, 1 H) 7.48 (dd, J = 7.83, 1.34 Hz, 1 H) 7.58 - 7.64 (m, 1 H) 8.40 - 8.44 (m, 1 H).

[0327] Step 3: Preparation of intermediate 67f [ka]

[0328] To a solution of intermediate 66f (0.3 g, 727.35 μmol, 1 equiv) in DCM (5 mL) was added TFA (3.08 g, 27.01 mmol, 2 mL, 37.14 equiv). The mixture was stirred at 20° C. for 1 h. The reaction was clean by TLC. The reaction mixture was concentrated under reduced pressure to remove the solvent. Intermediate 67f (220 mg, 704.36 μmol, 96.84% yield) was obtained as a yellow oil.

[0329] Step 4: Preparation of intermediate 68f [ka]

[0330] To a solution of intermediate 67f (220 mg, 683.69 μmol, 1 equiv) in ACN (10 mL), 2 CO 3 (283.47 mg, 2.05 mmol, 3 equiv.) and intermediate 26f (213.55 mg, 683.69 μmol, 1 equiv.) were added. The mixture was stirred at 60° C. for 1 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by H2 The mixture was diluted with 20 mL of 2H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with aqueous NaCl (20 mL) and 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 10 / 1 to 0 / 1). Intermediate 68f (200 mg, 334.64 μmol, 48.95% yield) was obtained as a white solid. LCMS: Rt = 1.230 min, MS calculated: 597.2, [M+H] + =598.4 1 H NMR (400 MHz, chloroform-d) δ = 1.90 (br d, J = 11.26 Hz, 2 H) 1.97 - 2.14 (m, 6 H) 2.35 (br d, J = 8.25 Hz, 2 H) 2.78 - 2.90 (m, 1 H) 3.01 (br d, J = 9.51 Hz, 2 H) 3.91 (s, 2 H) 3.96 (s, 3 H) 5.56 (s, 2 H) 5.94 (s, 2 H) 6.66 (d, J = 5.75 Hz, 1 H) 7.35 - 7.45 (m, 1 H) 7.48 (d, J = 8.00 Hz, 1 H) 7.60 - 7.68 (m, 1 H) 7.77 (d, J = 8.50 Hz, 1 H) 7.87 (s, 1 H) 8.01 (dd, J = 8.57, 1.06 Hz, 1 H) 8.14 (s, 1 H) 8.39 - 8.45 (m, 1 H) 8.73 - 8.76 (m, 1H).

[0331] Example 5: Preparation of Compound 20 [ka]

[0332] To a solution of intermediate 68f (0.1 g, 167.32 μmol, 1 equiv) in THF (1.5 mL) was added H 2 LiOH H in O (0.5 mL) 2A solution of 10.53 mg, 250.98 μmol, 1.5 equiv. was added. The mixture was stirred at 20° C. for 12 h. The reaction was adjusted to pH=8 by adding citric acid, and then the mixture was directly purified. The residue was purified by preparative HPLC (neutral condition column: Waters Xbridge BEH C18 100*30 mm*10 um; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 30% to 50%, 8 min). Compound 20 (43.79 mg, 75.03 μmol, 44.84% yield) was obtained as a white solid. LCMS: Rt = 2.003 min, MS calculated: 583.1, [M+H] + =584.1 1 H NMR (400 MHz, methanol-d 4 ) δ = 1.82 - 1.96 (m, 4 H) 2.33 (td, J = 11.07, 4.03 Hz, 2 H) 2.80 (dt, J = 10.30, 5.18 Hz, 1 H) 3.02 (br d, J = 11.37 Hz, 2 H) 3.94 (s, 2 H) 5.60 (s, 2 H) 6.01 (s, 2 H) 6.78 (d, J = 5.87 Hz, 1 H) 7.55 - 7.62 (m, 2 H) 7.67 - 7.72 (m, 2 H) 7.96 - 8.01 (m, 2 H) 8.22 (d, J = 0.98 Hz, 1H) 8.40 (d, J = 5.87 Hz, 1 H) 8.91 - 8.93 (m, 1 H).

[0333] Compound 31 can be prepared according to the synthetic methods described herein, optionally following the guidance of WO 2019 / 239319.

[0334] Biological assays Example B1: GLP-1R Cellular Assay Stable cell lines expressing high and low GLP-1R surface expression were generated by cloning a puromycin-selectable DNA plasmid encoding the human GLP-1R receptor under the control of the EF1A promoter (accession number: NM 002062.5) were generated in transfected CHO-K1 cells (Fugene6). 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 to detect cAMP (LANCE Ultra cAMP assay, Perkin Elmer). 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 determine EC as a measure of responsiveness to the GLP-1R control peptide. 50 To ensure stability, the responsiveness of selected cell lines was monitored over multiple passages. CHO-K1 hGLP-1Rhigh Clone 16 and CHO-K1 hGLP-1Rlow Clone10 showed consistently high and low responsiveness to GLP-1R control peptide, respectively, and was 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, washed three times with PBS+0.5% BSA, and then 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 Clone 16 cells are CHO-K1-hGLP-1low The MFI level was significantly higher than that of clone 10 cells.

[0335] CHO-K1 hGLP-1Rlow For compound testing in the 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, and 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 50Values ​​were determined by fitting the percent activation as a function of compound concentration using the Hill equation (XLfit).

[0336] EC of exemplary compounds in low expression assay 50 The values ​​are shown below in Table 2. The compounds tested were compound samples prepared according to the general procedures described in the Examples section. [Table 2]

[0337] Example B2: 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.

[0338] 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 at a dose of 3 mg / kg by oral gavage to male 7-11 week old Sprague-Dawley rats.

[0339] 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.

[0340] 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 C 0 , 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.

[0341] Results: Plasma PK parameters after intravenous administration are shown in Table 3. Plasma PK parameters after oral administration are shown in Tables 4 and 5. Plasma concentrations of compound 2 and reference compound A after oral administration of 3 mg / kg are shown in Figure 1. Plasma concentrations of compounds 2, 3, and 4 after oral administration of 0.3 mg / mL and 3 mg / kg are shown in Figure 2. Plasma concentrations of compounds 2 and 14 after oral administration of 0.6 mg / mL and 3 mg / kg are shown in Figure 3. [Table 3] [Table 4] [Table 5]

[0342] Under various routes and methods of administration, Compound 2 and compounds similar thereto (i.e., Compound 14) consistently show improved in vivo pharmacokinetic performance compared to Reference Compound A. After intravenous administration, Compound 2 exhibits greater exposure and approximately 2-fold longer t 1 / 2 , and 30% lower clearance (Table 3). Compound 2 also showed significantly enhanced PK properties after oral administration compared to reference Compound A (Tables 4, 5), with t 1 / 2Compounds 14, 25, 27, and 29 showed similarly improved PK properties compared to reference compound A when administered orally under identical conditions.

[0343] Example B3. Food intake in a humanized mouse model The ability of the compounds disclosed herein to alter food intake in C57BL / 6 mice expressing human GLP-1R (hGLP-1R) was evaluated.

[0344] Vehicle: 5% polyethylene glycol 400:95% (12% (w / v) sulfobutyl-β-cyclodextrin in water), (v / v).

[0345] Vehicle preparation: Sulfobutyl-β-cyclodextrin (12,000.0 mg) was added to a 100 mL volumetric flask, made up to 100 mL with water and vortexed until completely dissolved. 95 mL was transferred to a new 100 mL flask / cylinder and 5 mL of polyethylene glycol 400 was added and the mixture was vortexed until completely dissolved to obtain a clear solution.

[0346] Preparation of Formulations: Formulations were used within 24 hours of preparation. If a suspension occurred, the formulations were stirred continuously at room temperature.

[0347] Preparation of Reference Compound A (30 mg / kg, 10 mL / kg) PO administration: Reference Compound A (11.70 mg) was dissolved in 3.900 mL of vehicle and vortexed until completely dissolved to give a clear solution with a final concentration of 3.0000 mg / mL.

[0348] Preparation of Reference Compound A (10 mg / kg, 10 mL / kg) PO administration: Reference Compound A (12.000.0 mg) was dissolved in 2.600 mL of vehicle (30 mg / kg) and vortexed until completely dissolved to give a clear solution with a final concentration of 1.0000 mg / mL.

[0349] Preparation of liraglutide (0.3 mg / kg, 2 mL / kg) SC administration: (0.05 mL) liraglutide solution (6 mg / mL) was diluted with 1.950 mL of saline and vortexed to obtain a clear solution with a final concentration of 0.150 mg / mL.

[0350] Preparation of Compound 2 (60 mg / kg, 10 mL / kg) PO administration: Compound 2 (32.76 mg) as the meglumine salt was dissolved in 3.900 mL of vehicle and vortexed until completely dissolved to give a final concentration of 8.4000 mg / mL suspension (approximately 6.0 mg / mL active pharmaceutical ingredient [API]).

[0351] Preparation of Compound 2 (30 mg / kg, 10 mL / kg) PO administration: Compound 2 (2.600 mL) (60 mg / kg) was diluted with 2.600 mL of vehicle and vortexed until completely dissolved to give a final concentration of 4.2000 mg / mL suspension (approximately 3.0 mg / mL API).

[0352] Preparation of Compound 2 (10 mg / kg, 10 mL / kg) PO administration: Compound 2 (1.300 mL) (30 mg / kg) was diluted with 2.600 mL of vehicle and vortexed until completely dissolved to give a final concentration of 1.4000 mg / mL suspension (approximately 1.0 mg / mL API).

[0353] Animal room: The animal room environment was controlled for temperature (21-25°C) and relative humidity (40-70%). Temperature and relative humidity were monitored and recorded twice daily. An electronic time-controlled lighting system was used to provide a 12-h light / 12-h dark cycle with lights off from 7 pm to 7 am. Mice were fed regular chow and fresh water during acclimation, and animals were allowed to acclimate to the testing facility for 1 week before the start of the study.

[0354] The dosing protocol used in this study is shown in Table 6. [Table 6]

[0355] Food Intake Study Procedure: Acclimatization and Grouping: Mice were acclimated to vehicle QD PO administration for 4 days and baseline body weight and food intake were measured for 4 consecutive days. Animals were assigned to 8 groups based on body weight and food intake on day 3.

[0356] Dose weight and food intake measurements: All animals were housed in clean cages with sawdust bedding, fasted overnight, and mice were dosed with vehicle or test compound in the morning. Food for all groups was added 15 minutes after dosing, and remaining food was recorded at 2, 4, 6, 8, 10, and 24 hours after dosing. (Figure 4) Body weight was measured daily during the study.

[0357] The time protocol for this study is shown in Table 7. [Table 7]

[0358] Compound 2 significantly suppressed food intake in humanized mice compared to vehicle controls (Figure 5).

[0359] Data processing and analysis: Manual data were transferred to an Excel spreadsheet. All values ​​were expressed as mean ± SEM. The significance of inter- and intragroup differences was assessed by one- or two-way ANOVA using Graph Pad statistical software. A P value <0.05 was considered statistically significant.

[0360] Example B4: Glucose tolerance The ability of compounds disclosed herein to alter glucose tolerance in C57BL / 6 mice expressing human GLP-1R (hGLP-1R) was evaluated.

[0361] Vehicle: 5% polyethylene glycol 400:95% (12% (w / v) sulfobutyl-β-cyclodextrin in water), (v / v).

[0362] Vehicle preparation: Sulfobutyl-β-cyclodextrin (12,000.0 mg) was added to a 100 mL volumetric flask, made up to 100 mL with water, vortexed until completely dissolved, and 95 mL was transferred to a new 100 mL flask / cylinder. 5 mL of polyethylene glycol 400 was added to the mixture and vortexed until the mixture was completely dissolved to obtain a clear solution.

[0363] Preparation of Formulations: Formulations were used within 24 hours of preparation. If a suspension occurred, the formulations were stirred continuously at room temperature.

[0364] Preparation of liraglutide (0.3 mg / kg, 2 mL / kg) SC administration: 0.05 mL of liraglutide solution (6 mg / mL) was diluted with 1.950 mL of saline and vortexed to obtain a clear solution with a final concentration of 0.150 mg / mL.

[0365] Preparation of Reference Compound A (1 mg / kg, 10 mL / kg) PO administration: 1 mg of Reference Compound A was dissolved in 10.000 mL of vehicle and vortexed until completely dissolved to give a clear solution with a final concentration of 0.1000 mg / mL.

[0366] Preparation of Reference Compound A (0.3 mg / kg, 10 mL / kg) PO administration: 1.050 mL of Reference Compound A was diluted with 2.450 mL of vehicle and vortexed until completely dissolved to give a clear solution with a final concentration of 0.0300 mg / mL.

[0367] Preparation of Compound 2 (3 mg / kg, 10 mL / kg) PO administration: 2 mg of Compound 2 as the meglumine salt was dissolved in 4.762 mL of vehicle and vortexed until completely dissolved to give a final concentration of 0.4200 mg / mL suspension (approximately 0.3 mg / mL active pharmaceutical ingredient [API]).

[0368] Preparation of Compound 2 (1 mg / kg, 10 mL / kg) PO administration: 1.520 mL of Compound 2 (3 mg / kg) as the meglumine salt was diluted with 3.040 mL of vehicle and vortexed until completely dissolved to give a clear solution with a final concentration of 0.1400 mg / mL (approximately 0.1 mg / mL API).

[0369] Preparation of Compound 2 (0.3 mg / kg, 10 mL / kg) PO administration: 1.050 mL of Compound 2 (1 mg / kg) as the meglumine salt was diluted with 2.450 mL of vehicle and vortexed until completely dissolved to give a clear solution with a final concentration of 0.0420 mg / mL (approximately 0.03 mg / mL API).

[0370] Animal room: The animal room environment was controlled for temperature (21-25°C) and relative humidity (40-70%). Temperature and relative humidity were monitored and recorded twice daily. An electronic time-controlled lighting system was used to provide a 12-h light / 12-h dark cycle with lights off from 7 am to 7 pm. Mice were fed regular chow and fresh water during acclimation, and animals were allowed to acclimate to the testing facility for 1 week before the start of the study.

[0371] Study Procedure: Intraperitoneal glucose tolerance test:

[0372] The group design used in this study is shown in Table 8. [Table 8]

[0373] Acclimatization and Grouping: Following a 1-week washout period following completion of the lifetime food intake study, mice were utilized to perform an intraperitoneal glucose tolerance test (IPGTT). Mice remained in treatment groups from the food intake study. Baseline fasting glucose levels were used to balance treatment groups (final n=7 per treatment group). Outlier mice (n=3) based on abnormal fasting glucose levels and body weight were used for PK evaluation.

[0374] Intraperitoneal glucose tolerance test (IPGTT): Mice were placed in clean cages with sawdust flooring and fasted overnight. Basal fasting blood glucose levels were measured by tail vein notch before dosing in the morning, and 3 mice per group with abnormal fasting blood glucose levels and body weight were used for PK evaluation. Mice were dosed with vehicle or test compound at 9:30 AM according to the dose protocol (Table 8). Glucose was injected intraperitoneally at 2 g / kg, 10 mL / kg dose volume, at 10 AM, 0.5 hours after vehicle or test compound dosing. Blood glucose levels were measured at 0 min (pre-dose), 15 min, 30 min, 60 min, and 120 min after glucose dosing. (Figure 6) Additionally, after glucose measurements at 0 min and 15 min, approximately 30 μL of blood was collected via the tail vein into pre-chilled EDTA-2K tubes and placed on ice. Blood samples were processed for plasma as soon as possible by centrifugation at 3200×g for 10 min at 4° C., and plasma was stored at −80° C. for insulin assay.

[0375] IPGTT (120 min)-PK bleed: 40 μL blood samples (all treatment groups) were collected under the chin of mice at IPGTT-120 min after blood glucose measurement into pre-chilled EDTA-2K tubes. Blood samples were processed for plasma by centrifugation at 3200×g for 10 min at 4°C. 15 μL plasma was stored at -80°C for PK analysis. Whole brains were collected from 4 mice in group 7 of the PD cohort after blood collection at 120 min post-dose, rinsed with saline, patted dry, placed in pre-weighed tubes, and collected for PK analysis and stored at -80°C.

[0376] The design of the PK bleeding group is shown in Table 9. [Table 9]

[0377] PK Bleeding: 30 μL of blood was collected at 0.25, 0.5, 1, 2, 4, and 8 hours. Blood samples were processed for plasma by centrifugation at 3200×g for 10 minutes at 4° C. 12 μL of plasma was collected at −80° C. for further analysis. Whole brains were collected from 3 mice in group 7 of the PK cohort after 8 hours post-dose blood collection, rinsed with saline, patted dry, placed in pre-weighed tubes, and collected for PK analysis and stored at −80° C. PK time points are summarized in Table 10. [Table 10]

[0378] Data processing and analysis: Manual data were transferred to an Excel spreadsheet. All values ​​are expressed as mean ± SEM. The significance of inter- and intragroup differences was assessed by one- or two-way ANOVA using Graph Pad statistical software. A P value <0.05 was considered statistically significant.

[0379] Compound 2 significantly enhanced glucose tolerance in mice compared to vehicle controls (Figures 7 and 8).

[0380] Glucose tolerance in mice expressing wild-type (WT) mouse GLP-1R was also evaluated using the same method as above after administration of Compound 2. Glucose tolerance in mice expressing WT mouse GLP-1R was not affected by Compound 2, whereas glucose tolerance in mice expressing human GLP-1R was improved by Compound 2 (Figures 9 and 10).

[0381] The results of the PK experiments are shown in Figures 11A, 11B, 12A, and 12B and summarized in Tables 11 and 12. [Table 11] [Table 12]

[0382] As shown above, Compound 2 achieved higher plasma concentrations than reference Compound A. For example, when administered at 0.3 mg / kg, Compound 2 achieved approximately 3-fold higher C than reference Compound A. max and 4-fold higher AUC last When administered at 1.0 mg / kg, Compound 2 produced approximately 5.7-fold higher C than the reference Compound A. max , and AUC about 4.6-fold higher than that of reference compound A. last This resulted in...

[0383] Sample processing For plasma: 3 μL aliquots of samples were protein precipitated with 60 μL of internal standards (100 ng / mL labetalol and 100 ng / mL dexamethasone and 100 ng / mL tolbutamide and 100 ng / mL verapamil and 100 ng / mL glyburide and 100 ng / mL celecoxib in ACN), the mixture was vortex mixed at 800 rpm for 10 min and centrifuged at 3220×g and 4° C. for 15 min. An aliquot of 55 μL of the supernatant was transferred to another clean 96-well plate, centrifuged at 3220×g and 4° C. for 5 min, and 4 μL (reference compound A) or 6 μL (compound 2 and retest) samples were injected for LC-MS / MS analysis.

[0384] Description of dilution procedure: (for retest) Dilution factor 10: 2 μL aliquot of sample was mixed with 18 μL of blank matrix.

[0385] Data processing: Integration and calculation of retention times, chromatogram plots, and peak areas were performed using Analyst® 1.6.3 software (SCIEX, MA, USA).

[0386] Study samples Sample storage: During analysis, study samples were stored at a temperature of -20°C. After analysis, study samples were stored in a freezer with a nominal temperature of -80°C.

[0387] Pharmacokinetic data analysis: Individual plasma concentrations of reference compound A and compound 2 in study animals were subjected to non-compartmental pharmacokinetic analysis using Phoenix WinNonlin software (version 6.3 or later, Certara) with extravascular input and uniform weighting. A linear / logarithmic trapezoidal rule was applied to obtain PK parameters. Individual plasma concentration values ​​below the lower limit of quantification (LOQ) were excluded from the calculation of PK parameters. Nominal dose levels and nominal sampling times were used for the calculation of all pharmacokinetic parameters.

[0388] Analysis results Linearity: Calibration curves for reference compound A and compound 2 were constructed using eight non-zero standards ranging from 1.00 to 3000 ng / mL for plasma. Regression analysis for reference compound A and compound 2 was performed by plotting the peak area ratios (Y) of reference compound A and compound 2 to IS versus their concentrations (X) in ng / mL, respectively. The calibration curve fit equation for reference compound A was a linear regression with 1 / x2 as the weighting factor. The calibration curve fit equation for compound 2 was a quadratic regression with 1 / x2 as the weighting factor for plasma. The correlation coefficient (R) of the linear regression for reference compound A in plasma is 0.9875 or greater. The correlation coefficient (R) of the quadratic regression for compound 2 in plasma is 0.996 or greater.

[0389] Calibration Standards: Working backwards, at least 75% of the calibration standards, or at least six calibration standards, should be within ±20% of the nominal value for plasma.

[0390] QC Samples: For plasma samples, at least two-thirds of all QC samples and 50% of the QC samples at each concentration level should be back-calculated within ±20% of the nominal value for the plasma sample.

[0391] Study Sample Concentrations:All bioanalytical runs were completed successfully and accepted.

[0392] The concentrations of Reference Compound A were measured in male C57BL / 6J hGLP-1R mouse plasma following administration of Reference Compound A PO (0.300 and 1.00 mg / kg). Bioanalytical concentrations of Reference Compound A in male C57BL / 6J hGLP-1R mouse plasma are listed in Tables 13 and 14.

[0393] The concentrations of Compound 2 in male C57BL / 6J hGLP-1R mouse plasma were measured following administration of Compound 2 PO (0.300, 1.00 and 3.00 mg / kg). Bioanalytical concentrations of Compound 2 in male C57BL / 6J hGLP-1R mouse plasma are listed in Tables 15 and 16.

[0394] Pharmacokinetic Analysis Results: In general, after oral administration to C57BL / 6 hGLP-1R mice, all animals were exposed to either reference compound A or compound 2. The PK parameters of reference compound A are shown in Tables 17 and 18, and the PK parameters of compound 2 are shown in Tables 19, 20, and 21.

[0395] After oral administration of Reference Compound A to mice at 0.3 mg / kg and 1 mg / kg, the maximum plasma concentrations observed were reached with a median Tmax of 0.5 hours post-dose and then declined, with a final elimination t1 / 2 of 0.604 hours post-dose at 0.3 mg / kg and 1.99 hours post-dose at 1 mg / kg. By 4 hours post-dose at 0.3 mg / kg, all concentrations were below the limit of quantification (<1 ng / mL), with a mean AUC0-last of 24.5 ng.h / mL. In general, plasma concentrations were measurable up to 8 hours post-dose at 1 mg / kg, with a mean AUC0-last of 85.5 ng.h / mL. Overall, exposure to Reference Compound A increased approximately proportionally with dose.

[0396] After oral administration of compound 2 to mice at 0.3, 1, and 3 mg / kg, the maximum plasma concentrations observed were reached with a median Tmax of 0.5 hours post-dose and then declined, with final elimination t1 / 2 of 1.40, 1.42, and 2.03 hours after administration of 0.3, 1, and 3 mg / kg, respectively. In general, plasma concentrations were measurable up to 8 hours post-dose at all doses, with mean AUC0-lasts of 107 ng.h / mL at 0.3 mg / kg, 390 ng.h / mL at 1 mg / kg, and 2441 ng.h / mL at 3 mg / kg.

[0397] Overall, exposure to Compound 2 increased more than proportionally with dose, with a 10-fold increase in dose resulting in a 22-fold increase in exposure. In comparison, exposure to Compound 2 in plasma was approximately 4-fold greater than exposure to the reference Compound A at 0.3 and 1 mg / kg in mice.

[0398] Absorption in C57BL / 6 hGLP-1R male mice was rapid, with a median Tmax of 0.5 hours for both reference Compound A and Compound 2, after which plasma concentrations declined with a final T1 / 2 of less than 2 hours for both test articles. Exposure to reference Compound A increased approximately dose-proportionally from 0.3 mg / kg to 1 mg / kg, whereas exposure to Compound 2 increased more than proportionally from 0.3 mg / kg to 3 mg / kg. In comparison, plasma exposure to Compound 2 was 4-fold greater than exposure to reference Compound A at both 0.3 mg / kg and 1 mg / kg. [Table 13] [Table 14] [Table 15-1] [Table 15-2] [Table 16] [Table 17] [Table 18] [Table 19] [Table 20] [Table 21]

[0399] Example B5: Metabolic stability of hepatocytes Test compounds were incubated with rat and human hepatocytes to assess stability from a matrix 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 minutes 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 cells were incubated with 1000 cells / mL hepatocytes for 0, 30, 60, 120 and 240 min. The incubation was carried out in 95% air / 5% CO 2The incubations were carried out at 37°C in a humidified atmosphere 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 mixture was then vortexed for 20 minutes and centrifuged at 4,000 RPM at 10°C. The supernatant (80 μL) was transferred to a clean 96-well plate and analyzed by LC-MS / MS. To validate the assay performance, 1 μM midazolam with 0.1% DMSO final was included as a positive control. 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 API 4000 instrument connected to a Shimadzu LC-20AD LC pump system. Separation was achieved using a Waters Atlantis T3 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 22]

[0400] 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

[0401] 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.

[0402] 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

[0403] Physiological parameters related to liver weight, blood flow, and hepatocellularity in various species are presented below. [Table 23]

[0404] The results are shown in the table below for intrinsic clearance (mL / min / kg) and half-life (t1 / 2). [Table 24]

[0405] Compounds 12, 14 and 23 significantly increased CLint values ​​in rat hepatocytes compared to the reference standard, whereas the remaining compounds 4, 20, 26, 27, 29, 30 and 31 had values ​​significantly lower than the reference. The CLint of compound 2 was not significantly different from the reference.

[0406] The half-lives of compounds 4, 20, 26, 27, 29, 30, 31 in rat hepatocytes were significantly longer compared to the reference, whereas the values ​​obtained for 12, 13, and 23 were significantly lower. The compounds did not show significant differences from the reference.

[0407] CLint values ​​calculated for humans were higher than the reference for all compounds except compound 30, which showed no significant difference.

[0408] The calculated half-lives of all compounds were significantly shorter compared to the standards, except for compound 30, which showed no significant difference compared to the reference.

[0409] All compounds, except compound 30, showed improved CLint and half-life in humans compared to the reference standard.

[0410] Example B6. 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: 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 test substance in assay buffer. Cell monolayers were dosed apically (A-to-B) or basolaterally (B-to-A) and incubated at 37 °C for 24 h at 4 °C in a humidified incubator with 5% CO. 2The cells were incubated at 37 °C containing 0.1% NaCl. Samples were taken from the donor and receiver chambers at 120 min. Each measurement was performed in duplicate. To ensure that the cell monolayer was not damaged 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. The 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 (μM s -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 25]

[0411] Passive permeability and efflux ratio are intended to serve as proxies to assess the oral bioavailability potential of a molecule, where a high passive permeability (Papp) and low efflux ratio (ER) are favorable and indicate a high likelihood of an orally bioavailable compound. These data indicate superior Papp and ER compared to benchmark molecules.

[0412] All publications, including patents, patent applications, and scientific articles, referred to in this specification are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, including a patent, patent application, or scientific article, was specifically and individually indicated to be incorporated by reference.

[0413] Although the foregoing invention has been described in some detail by way of illustration and example for clarity of understanding, it will be apparent to those skilled in the art that certain minor changes and modifications may be implemented in light of the above teachings. Accordingly, the descriptions and examples should not be construed as limiting the scope of the invention.

Claims

1. The following compound: 【Chemical 1】 、 【Chemistry 2】 、 【Chemistry 3】 、 【Chemistry 4】 、 【change】 、 【Chemistry 5】 、 【Chemistry 6】 ,or 【Chemistry 7】 or a pharmaceutically acceptable salt thereof.

2. The compound is 【Chemistry 8】 2. The compound of claim 1, wherein:

3. The compound of claim 2 , wherein the compound is a meglumine salt.

4. A pharmaceutical combination for treating a disease mediated by the glucagon-like peptide-1 receptor (GLP-1R), comprising a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, and a further therapeutic agent.

5. 5. The pharmaceutical combination of claim 4, wherein the additional therapeutic agent is an antidiabetic agent, an antiobesity agent, or an agent for treating NASH.

6. The pharmaceutical combination according to claim 4, wherein the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof and the additional therapeutic agent are administered simultaneously, concurrently, or sequentially.

7. 5. The pharmaceutical combination of claim 4, wherein the disease mediated by the glucagon-like peptide-1 receptor (GLP-1R) is a liver disease.

8. 5. The pharmaceutical combination of claim 4, 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 malignancy, Sjogren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis, or alpha 1-antitrypsin deficiency.

9. 5. The pharmaceutical combination of claim 4, wherein the liver disease is diabetes.

10. 5. The pharmaceutical combination of claim 4, wherein the liver disease is a cardiometabolic disease.

11. 5. The pharmaceutical combination of claim 4, wherein the liver disease is obesity.

12. 5. The pharmaceutical combination of claim 4 for reducing food intake in an individual in need thereof.

13. 5. The pharmaceutical combination of claim 4 for increasing glucose tolerance in an individual in need thereof.

14. A pharmaceutical composition for treating a disease mediated by the glucagon-like peptide-1 receptor (GLP-1R), comprising the compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

15. 15. The pharmaceutical composition of claim 14, further comprising another therapeutic agent.

16. 15. The pharmaceutical composition of claim 14, wherein the disease mediated by the glucagon-like peptide-1 receptor (GLP-1R) is a liver disease.

17. 15. The pharmaceutical composition of claim 14, 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 malignancy, Sjogren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis, or alpha-1-antitrypsin deficiency.

18. The pharmaceutical composition of claim 14, wherein the liver disease is diabetes.

19. The pharmaceutical composition of claim 14, wherein the liver disease is a cardiometabolic disease.

20. The pharmaceutical composition of claim 14, wherein the liver disease is obesity.

21. 4. A pharmaceutical composition for reducing food intake in an individual in need thereof, comprising a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

22. A pharmaceutical composition for increasing glucose tolerance in an individual in need thereof, comprising a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

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