Compounds as GLP-1R agonists

Abstract

The present application provides compounds, or pharma- ceutically acceptable salts thereof, that can be used as glucagon-like peptide-1 receptor (GLP-1R) agonists. Also provided are pharmaceutical compositions containing 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. TIFF2024541920000259.tif45154

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 / 263,003, filed October 25, 2021, the disclosure of which is incorporated herein by reference in its entirety for all purposes. [Background technology]

[0002] Diabetes mellitus is a major public health concern due to its increasing prevalence and associated health risks. The disease is characterized by high levels of blood glucose due to 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 insulin, the hormone that regulates blood sugar. To survive, type 1 diabetes patients must receive insulin by injection or pump. Type 2 diabetes mellitus (T2DM) usually begins with either insulin resistance or insufficient production of insulin to maintain acceptable glucose levels.

[0003] Currently, various pharmacological approaches are available to treat 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 enhance the secretion of insulin by acting on pancreatic beta cells. The commercially available GLP-1R agonists are peptides administered by subcutaneous injection. Liraglutide is also approved for the treatment of obesity.

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

[0005] In healthy individuals, GLP-1 plays an important role in regulating postprandial blood glucose levels by stimulating glucose-dependent insulin secretion by the pancreas, which leads to increased peripheral glucose absorption. GLP-1 also inhibits glucagon secretion and reduces hepatic glucose output. In addition, GLP-1 delays gastric emptying, slows small intestinal motility, and delays food absorption. In people 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) describe that GLP-1 receptor agonists such as liraglutide and exendin-4 have three main pharmacological activities to improve glycemic control in patients with T2DM by reducing fasting and postprandial glucose (FPG and PPG): (i) increasing glucose-dependent insulin secretion (improving phase 1 and 2), (ii) glucagon suppression activity under hyperglycemic conditions, and (iii) slowing the rate of gastric emptying resulting in delayed absorption of meal-derived glucose.

[0007] There remains a need to develop easily administered GLP-1 receptor agonists for the prevention and / or treatment of cardiometabolic and related diseases. 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 for treating diseases and / or conditions mediated by the GLP-1R.

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

[0010] Further provided is a pharmaceutical composition comprising a compound of formula (I) (including subformulas thereof), or a compound selected from 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, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) (including subformulas thereof), or a compound selected from 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 selected from the compounds of formula (I) (including subformulas thereof), as detailed herein, or the compounds listed in Table 1, or a pharma- ceutically acceptable salt thereof, for treatment.

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

[0014] Further provided are kits comprising a compound of Formula (I) (including subformulas thereof), or a compound selected from the compounds listed in Table 1, or a pharma- ceutically acceptable salt thereof. In some embodiments, the kits include instructions for use according to the methods described herein.

[0015] In yet another aspect, there is provided a method of making a compound of formula (I) (including subformulas thereof), or a compound selected from the compounds listed in Table 1, or a pharma- ceutically acceptable salt thereof. Also provided are compound intermediates that are useful in the synthesis of a compound of formula (I) (including subformulas thereof), or a compound selected from 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] [In the formula, X is N or CH; Y is N or CR 4 and; n is 0 or 1; R is hydrogen; R 1 -C1~C6 alkylene-R 5 and; R 2 is hydrogen, oxo, or C1-C6 alkyl; R 3 is hydrogen, oxo, or C1-C6 alkyl; R 4 is hydrogen, OH or C1-C6 alkyl; or R 3 and R 4 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl optionally substituted by halo or C1-C3 alkyl; R 5 is 3- to 6-membered heterocyclyl or 5- to 6-membered heteroaryl, R 5the 3-6 membered heterocyclyl or 5-6 membered heteroaryl is independently optionally substituted by halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkenyl, or C1-C6 haloalkyl; R 7 teeth, [ka] or selected from the group consisting of or R 7 is -C(O)NH-R 8 where R 8 is hydrogen, -OH, -S(O)2-C1-C6 alkyl, or -C1-C6 alkyl optionally substituted by halo; Ring A is a 5- to 12-membered heterocyclyl, a 5- to 12-membered heteroaryl, or a C6-C 14 aryl, each of which is independently optionally substituted with halo, oxo, -CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted with halo or OH; L is a bond, -O-, C1-C6 alkylene, *-O-C1-C6 alkylene-**, *-C1-C6 alkylene-O-**, or *-NR 6 -C1-C6 alkylene-**; * represents the point of attachment to ring A and ** represents the point of attachment to ring B; When L is *-O-C1-C6 alkylene-**, the C1-C6 alkylene is optionally L Each R L are independently C1-C6 alkyl or halo, or two R L together with one or more carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3-6 membered heterocyclyl; When L is C1-C6 alkylene, the C1-C6 alkylene can optionally be R L1 Each R L1are independently halo, OH, oxo, or C1-C6 alkyl, or two R L1 together with one or more carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3-6 membered heterocyclyl; R 6 is hydrogen or C1-C6 alkyl; Ring B is C3~C 10 Cycloalkyl, C6-C 14 aryl, 4-12 membered heterocyclyl, or 5-12 membered heteroaryl, each of which is independently optionally substituted by 1-3 substituents selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -C(O)CH3, -C(O)NH2, -S(O)2CH3, cyclopropyl, and phenyl. or a pharma- ceutically acceptable salt thereof: however, R 7 -C(O)NH-R 8 and R 1 but [ka] X is N, Y is CH, n is 1, and R 2 and R 3 are each hydrogen, ring A is a 6-membered heteroaryl, and L is *-OCH2-**, then ring B is [ka] is a group other than

[0017] In some embodiments, the compound has formula Ia: [ka] or a pharma- ceutically acceptable salt thereof.

[0018] In some embodiments, the compound has formula Ib: [ka] or a pharma- ceutically acceptable salt thereof.

[0019] In some embodiments, n is 1; X is N; R 2 is hydrogen; R 5 is an optionally substituted 5-membered heteroaryl containing 1 or 2 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, or an optionally substituted 4-membered heterocycle containing 1 oxygen atom; R 7 teeth [ka] -C(O)NHCH3, -C(O)NH2, C(O)NHCH2CF3, C(O)NHS(O)2CH3, or C(O)NHOH; Ring A is an optionally substituted 6-9 membered heteroaryl; L is a bond or *-O-CH2-**; Ring B is phenyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo and cyano.

[0020] In some embodiments, R 1 -CH2-R 5 It is.

[0021] In some embodiments, R 5 is a 4-membered heterocyclyl containing one oxygen atom optionally substituted by halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkenyl, or C1-C6 haloalkyl. 5 is optionally substituted by halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkenyl, or C1-C6 haloalkyl. [ka] In some embodiments, R 5 teeth, [ka] It is.

[0022] In some embodiments, R 5 is a 5-membered heteroaryl optionally substituted by halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkenyl, or C1-C6 haloalkyl. 5 is optionally halo, C1-C6 alkyl 、 Substituted by C1-C6 alkoxy, C1-C6 alkenyl, C1-C6 haloalkyl [ka] In some embodiments, R 5 is optionally halo, C1-C6 alkyl 、 Substituted by C1-C6 alkoxy, C1-C6 alkenyl, C1-C6 haloalkyl [ka] In some embodiments, R 5 teeth, [ka] It is.

[0023] In some embodiments, X is N.

[0024] In some embodiments, n is 1.

[0025] In some embodiments, Y is N.

[0026] In some embodiments, Y is CR 4 It is.

[0027] In some embodiments, R 3 and R 4 together with the carbon atom to which they are attached form a cyclopropyl group.

[0028] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] It is.

[0029] In some embodiments, R 7 is -C(O)NH-R 8 In some embodiments, R 8 is hydrogen. In some embodiments, R 8 is -OH. In some embodiments, R 8 is -S(O)2-C1-C6 alkyl. In some embodiments, R 8is -S(O)2CH3. In some embodiments, R 8 is -C1-C6 alkyl optionally substituted with halo. In some embodiments, R 8 is -C1-C2 alkyl, each of which is independently optionally substituted with halo. 8 is -CHCF. In some embodiments, R 8 is -CH3.

[0030] In some embodiments, ring A is a 6-membered heteroaryl. In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] It is.

[0031] In some embodiments, Ring A is a 9-membered heteroaryl. In some embodiments, Ring A is [ka] It is.

[0032] In some embodiments, L is *-O-C1-C6 alkylene-**. In some embodiments, L is *-O-CH2-**.

[0033] In some embodiments, Ring B is a C6 aryl, optionally substituted with 1-3 substituents independently selected from the group consisting of halo and CN. In some embodiments, Ring B is a C6 aryl, which is independently and optionally substituted with 1-3 substituents independently selected from the group consisting of -F, -Cl, -Br, and -CN. In some embodiments, Ring B is [ka] It is.

[0034] In certain aspects, the disclosure provides any one of the compounds in Table 1, or a pharma- ceutically acceptable salt thereof.

[0035] In some embodiments, the present disclosure provides a pharmaceutical composition comprising any one of the compounds disclosed herein, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0036] 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 thereof, comprising administering to the individual a therapeutically effective amount of any one of the compounds disclosed herein, or a pharma- ceutically acceptable salt thereof, or a 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 during pregnancy, parenteral nutrition-associated cholestasis (PNAC), bacterial overgrowth or sepsis-associated cholestasis, autoimmune hepatitis, viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), graft-versus-host disease, transplant liver regeneration, congenital hepatic fibrosis, common bile duct stones, 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.

[0037] In some embodiments, the 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. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0038] 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 ordinarily possessed in the art.

[0039] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly indicates otherwise.

[0040] As used herein, unless otherwise specified, the terms "about" and "approximately," when used in connection with a dose, amount, or weight percentage of a component of a composition or dosage form, refer to a dose, amount, or weight percentage that is recognized by those skilled in the art to produce an equivalent pharmacological effect to that obtained from the specified dose, amount, or weight percentage. Specifically, the terms "about" and "approximately," when used in connection with a value, contemplate a variation within ±15%, ±10%, ±5%, ±4%, ±3%, ±2%, ±1%, or ±0.5% of the specified value. Reference herein to "about" a value or parameter includes (and describes) embodiments that are directed to the value or parameter itself. For example, a statement that refers to "about X" includes a statement of "X."

[0041] "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 that have 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, e.g., other ingredients, and substantial method steps as described. Embodiments defined by each of these transition terms are within the scope of the present invention.

[0042] 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 by 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, lubricants include, for example, magnesium stearate, stearic acid, sodium stearyl fumarate, and the like; chewable tablet materials include, for example, dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), and the like; suspending / gelling agents include, for example, carrageenan, sodium starch glycolate, xanthan gum, and the like; sweeteners include, for example, aspartame, dextrose, fructose dc, sorbitol, sucrose dc, and the like; wet granulating agents include, for example, calcium carbonate, maltodextrin, microcrystalline cellulose, and the like.

[0043] "Pharmaceutically acceptable" refers to safe and non-toxic, preferably for in vivo, and more preferably for human administration.

[0044] "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.

[0045] "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 pharmaceutically acceptable salts include Na, K, Rb, Cs, NH4, Ca, Ba, imidazolium, and ammonium cations based on naturally occurring amino acids. When the compounds used 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 and non-limiting anions useful for pharmaceutically acceptable salts include oxalate, maleate, acetate, propionate, succinate, tartrate, chloride, sulfate, bisulfate, monobasic, dibasic, and tribasic phosphates, mesylate, tosylate, and the like.

[0046] "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.

[0047] 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.

[0048] 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.

[0049] 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 prolongation of survival in a patient. The result may require multiple doses of the compound or composition.

[0050] "Alkyl" refers to monovalent saturated aliphatic hydrocarbyl groups having 1 to 12 carbon atoms, preferably 1 to 10 carbon atoms, and more preferably 1 to 6 carbon atoms. This term includes, by way of example, straight-chain and branched-chain hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), t-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-).x Alkyl refers to an alkyl group having x carbon atoms.

[0051] "Alkylene" refers to a divalent saturated aliphatic hydrocarbyl group having 1 to 12 carbon atoms, preferably 1 to 10 carbon atoms, and more preferably 1 to 6 carbon atoms. This term includes, by way of example, straight-chain and branched-chain hydrocarbyl groups such as methylene (-CH-), ethylene (-CHCH- or -CH(Me)-), propylene (-CHCHCH- or -CH(Me)CH-, or -CH(Et)-).

[0052] "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.

[0053] "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.

[0054] "Cyano" refers to the group -C≡N.

[0055] "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. xCycloalkyl refers to a cycloalkyl group having x ring carbon atoms. Examples of suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl. One or more of the rings can be aryl, heteroaryl, or heterocyclic, provided that the point of attachment is through a non-aromatic, non-heterocyclic saturated carbocyclic ring. "Substituted cycloalkyl" includes oxo, thione, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cyclo "cycloalkyl" refers to a cycloalkyl group having 1 to 5, or preferably 1 to 3, substituents selected from the group consisting of alkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocycle, substituted heterocycle, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein the substituents are defined herein.

[0056] "Halo" or "halogen" refers to fluoro, chloro, bromo, and iodo, preferably fluoro or chloro.

[0057] "Hydroxy" or "hydroxyl" refers to the group --OH.

[0058] "Heteroaryl" refers to an aromatic group of 1-10 carbon atoms and 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur in the ring. Such heteroaryl groups can have a single ring (e.g., pyridinyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl), which may or may not be aromatic and / or contain heteroatoms, provided that the point of attachment is through an atom of the aromatic heteroaryl group. In one embodiment, the nitrogen and / or sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide an N-oxide (N→O), sulfinyl, or sulfonyl moiety. Preferred heteroaryls include 5- or 6-membered heteroaryls such as pyridinyl, pyrrolyl, thiophenyl, and furanyl. Other preferred heteroaryls include 9- or 10-membered heteroaryls such as indolyl, quinolinyl, quinolonyl, isoquinolinyl, and isoquinolonyl.

[0059] "Heterocycle" or "heterocyclic" or "heterocycloalkyl" or "heterocyclyl" refers to a saturated or partially saturated, but not aromatic, group having 1 to 10 ring carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, and 1 to 4 ring heteroatoms, preferably 1 to 3 ring heteroatoms, more preferably 1 to 2 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen. x Heterocycloalkyl refers to a heterocycloalkyl group having x ring atoms, including a ring heteroatom. Heterocycles encompass single or multiple fused rings, including bridged and spiro ring systems. In fused ring systems, one or more of the rings can be cycloalkyl, aryl, or heteroaryl, provided that the point of attachment is through a non-aromatic ring. In one embodiment, the nitrogen and / or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide N-oxide, sulfinyl (S(O)), sulfonyl (S(O)2) moieties.

[0060] 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.

[0061] "Oxo" refers to the atom (=O) or (O).

[0062] 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 does not have to be oxidized, and the description includes cases where the nitrogen atom is not oxidized and cases where the nitrogen atom is oxidized.

[0063] "Optionally substituted" means that, unless otherwise specified, a group may be unsubstituted or substituted with one or more (e.g., 1, 2, 3, 4, or 5) of the substituents recited for that group, and the substituents may be the same or different. In one embodiment, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In another embodiment, an optionally substituted group has four substituents. In some embodiments, an optionally substituted group has 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, or 2-5 substituents. In one embodiment, an optionally substituted group is unsubstituted.

[0064] It is understood that an optionally substituted moiety may be substituted with more than five substituents, if permitted by the valences available for substitution on that moiety. For example, a propyl group may be substituted with seven halogen atoms to provide a perhalopropyl group. The substituents may be the same or different.

[0065] compound In one embodiment, the compound of formula (I): [ka] [In the formula, X is N or CH; Y is N or CR 4 and; n is 0 or 1; R is hydrogen; R 1 -C1~C6 alkylene-R 5 and; R 2 is hydrogen, oxo, or C1-C6 alkyl; R 3 is hydrogen, oxo, or C1-C6 alkyl; R 4 is hydrogen, OH or C1-C6 alkyl; Or, R 3 and R 4 optionally together with the carbon atom to which they are attached form a C3-C6 cycloalkyl optionally substituted by halo or C1-C3 alkyl; R 5 is 3- to 6-membered heterocyclyl or 5- to 6-membered heteroaryl, R 5 the 3-6 membered heterocyclyl or 5-6 membered heteroaryl is independently optionally substituted by halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkenyl, or C1-C6 haloalkyl; R 7 is a 5-12 membered heterocyclyl or a 5-12 membered heteroaryl, where each 5-12 membered heterocyclyl or 5-12 membered heteroaryl is independently optionally substituted by oxo, or R 7 is -C(O)NH-R 8 where R 8 is hydrogen, -OH, -S(O)2-C1-C6 alkyl, or -C1-C6 alkyl optionally substituted by halo; Ring A is a 5- to 12-membered heterocyclyl, a 5- to 12-membered heteroaryl, or a C6-C 14 aryl, each of which is independently optionally substituted by halo, oxo, -CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted by halo or OH; L is a bond, -O-, C1-C6 alkylene, *-O-C1-C6 alkylene-**, *-C1-C6 alkylene-O-**, or *-NR 6 -C1-C6 alkylene-**, * represents the attachment point to ring A, ** represents the attachment point to ring B, When L is -O-C1-C6 alkylene-, the C1-C6 alkylene is optionally L where each R L are independently C1-C6 alkyl or halo, or two RL together with one or more carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3-6 membered heterocyclyl; When L is C1-C6 alkylene, the C1-C6 alkylene is optionally L1 Each R is replaced by L1 are independently halo, OH, oxo, or C1-C6 alkyl, or two R L1 together with one or more carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3-6 membered heterocyclyl; R 6 is hydrogen or C1-C6 alkyl; Ring B is C3~C 10 Cycloalkyl, C6-C 14 aryl, 4-12 membered heterocyclyl, or 5-12 membered heteroaryl, each of which is independently halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C6 alkyl, C1-C6 alkyl, C3-C6 alkyl, C1-C6 alkyl, C2 ... 10 Cycloalkyl, -C(O)C1-C6 alkyl, C(O)NH 2、 -S(O)2 optionally substituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl and phenyl. or a pharma- ceutically acceptable salt thereof, wherein R 7 -C(O)NH-R 8 and R 1 but [ka] X is N, Y is CH, n is 1, and R 2 and R 3 are independently hydrogen, ring A is a 6-membered heteroaryl, and L is *-OCH2-**, then ring B is [ka] is a group other than

[0066] In the description herein, it is to be understood that every description, variation, embodiment or aspect of a moiety / variable may be combined with every description, variation, embodiment or aspect of other moieties / variables as if each and every combination 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, just as if each and every combination were specifically and individually listed.

[0067] It is also understood that the provisos provided herein, insofar as any of them are applicable, may apply to each embodiment of the compounds of formula (I) (and subformulas thereof) described herein.

[0068] In some embodiments, the present disclosure provides a compound of formula I, 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 -C1-C6 alkylene-R 5 and; R 2 is hydrogen, oxo, or C1-C6 alkyl; R 3 is hydrogen, oxo, or C1-C6 alkyl; R 4 is hydrogen, OH or C1-C6 alkyl; or R 3 and R 4 optionally together with the carbon atom to which they are attached form a C3-C6 cycloalkyl optionally substituted by halo or C1-C3 alkyl; R 5 is 3- to 6-membered heterocyclyl or 5- to 6-membered heteroaryl, where R 5the 3-6 membered heterocyclyl or 5-6 membered heteroaryl is independently optionally substituted by halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkenyl, or C1-C6 haloalkyl; R 7 teeth, [ka] or selected from the group consisting of; or R 7 is -C(O)NH-R 8 where R 8 is hydrogen, -OH, -S(O)2-C1-C6 alkyl, or -C1-C6 alkyl optionally substituted with halo; Ring A is a 5- to 12-membered heterocyclyl, a 5- to 12-membered heteroaryl, or a C6-C 14 aryl, each of which is independently optionally substituted by halo, oxo, -CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted by halo or OH; L is a bond, -O-, C1-C6 alkylene, *-O-C1-C6 alkylene-**, *-C1-C6 alkylene-O-**, or *-NR 6 -C1-C6 alkylene-**, * represents the point of attachment to ring A and ** represents the point of attachment to ring B; When L is -O-C1-C6 alkylene-, the C1-C6 alkylene is optionally L Each R is replaced by L are independently C1-C6 alkyl or halo, or two R L together with one or more carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3-6 membered heterocyclyl; When L is C1-C6 alkylene, the C1-C6 alkylene is optionally L1 Each R is replaced by L1 are independently halo, OH, oxo, or C1-C6 alkyl, or two RL1 together with one or more carbon atoms to which they are attached form a C3-C6 cycloalkyl or a 3-6 membered heterocyclyl; R 6 is hydrogen or C1-C6 alkyl; Ring B is C3~C 10 Cycloalkyl, C6-C 14 aryl, 4-12 membered heterocyclyl, or 5-12 membered heteroaryl, each of which is independently optionally substituted by 1-3 substituents independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, -C(O)CH3, -C(O)NH2, -S(O)2CH3, cyclopropyl, and phenyl; however, R 7 -C(O)NH-R 8 and R 1 but [ka] X is N, Y is CH, n is 1, and R 2 and R 3 are each hydrogen, ring A is a 6-membered heteroaryl, and L is *-OCH2-**, then ring B is [ka] is a group other than

[0069] In some embodiments of Formula (I), the compound of Formula (Ia): [ka] [where X, Y, n, R 2 , R 3 , R 5 , R 7 , ring A, L, and ring B are as defined in formula (I). or a pharma- ceutically acceptable salt thereof.

[0070] In some embodiments of formula (Ia), X is N and Y is N. In some embodiments, the compound has formula (Ib): [ka] [where n, R 2 , R 3 , R 5 , R 7 , ring A, L, and ring B are as defined in formula (I). or a pharma- ceutically acceptable salt thereof.

[0071] In some embodiments of Formula (Ia), X is N and Y is CR 4 In some embodiments, the compound has formula (Ic): [ka] [where n, R 2 , R 3 , R 4 , R 5 , R 7 , ring A, L, and ring B are as defined in formula (I). or a pharma- ceutically acceptable salt thereof.

[0072] In some embodiments of formula (Ic), 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. In some embodiments, the compound has formula (Id-1), (Id-2), or (Id-3): [ka] [where n, R 2 , R 5 , R 7 , ring A, L, and ring B are as defined in formula (I). or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is of formula (Id-1). In some embodiments, the compound is of formula (Id-2). In some embodiments, the compound is of formula (Id-3).

[0073] In some embodiments of formula (Ia), ring A is a 6-membered heteroaryl containing 1, 2, or 3 heteroatoms. In some embodiments, the compound has formula (Ie): [ka] [where X, Y, n, R 2 , R 3 , R 5 , R 7 , L, and ring B are as defined in formula (I), and V and W are independently N or CR A And each R A is optionally H, halo, CN, C3-C6 cycloalkyl, or C1-C6 alkyl substituted by halo or OH. 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 CR A 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.

[0074] In some embodiments of Formula (Ie), L is *-O-C1-C6 alkylene-**, optionally with R L In some embodiments, L is *-O-CH2-**. In some embodiments, the compound has the formula (If): [ka]

[0075] [where n, X, Y, R 2 , R 3 , R 5 , R 7 and ring B is as defined in formula (I), and V and W are as defined in formula (Ie). It is a compound represented by the formula:

[0076] In some embodiments of formula (If), ring B optionally contains one or more R B and each R B are independently halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C 10 In some embodiments, the compound has the formula (Ig): [ka]

[0077] [where n, X, Y, R 2 , R 3 , R 5 , and R 7 is as defined in formula (I), and V and W are as defined in formula (Ie). It is a compound represented by the formula:

[0078] In some embodiments of formula (Ie), 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. In some embodiments, the compounds have the formula (Ih-1), (Ih-2), (Ih-3): [ka]

[0079] [where n, R 2 , R 5 , R 7 , L, and ring B are as defined in formula (I), and V and W are as defined in formula (Ie). In some embodiments, the compound is of formula (Ih-1). In some embodiments, the compound is of formula (Ih-2). In some embodiments, the compound is of formula (Ih-3).

[0080] In some embodiments of formula (Ie), 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, and ring B optionally contains one or more R B and each R B are independently halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C 10 In some embodiments, the compound is selected from the group consisting of cycloalkyl, -C(O)C1-C6 alkyl, -C(O)NH2, -S(O)2C1-C6 alkyl, and phenyl. In some embodiments, the compound is represented by formula (Ii): [ka] [where n, R 5 , and R 7 is as defined in formula (I), and V and W are as defined in formula (Ie). or a pharma- ceutically acceptable salt thereof.

[0081] In some embodiments of Formula (Ia), Ring A is pyridine and L is *-O-C1-C6 alkylene-**, optionally R LIn some embodiments, ring A is pyridine and L is -O-CH2-. In some embodiments, the compound has formula (Ij): [ka] [where n, X, Y, R 5 , R 7 and Ring B is as defined in formula (I). or a pharma- ceutically acceptable salt thereof.

[0082] In some embodiments of formula (Ij), X is N, Y is N, and R 2 is H and R 3 is H and n is 1. In some embodiments, the compound has the formula (Ik): [ka] [In the formula, R 5 , R 7 and Ring B is as defined in formula (I). or a pharma- ceutically acceptable salt thereof.

[0083] In some embodiments of formula (Ij), X is N, Y is CH, and R 2 is H and R 3 is H and n is 1. In some embodiments, the compound has formula (II): [ka] [In the formula, R 5 , R 7 and Ring B is as defined in formula (I). or a pharma- ceutically acceptable salt thereof.

[0084] In some embodiments of Formula (Ij), R 2 is H, n is 1, and ring B optionally contains one or more R X where each RX is independently selected from the group consisting of halo and -CN. In some embodiments, the compound has formula (Im): [ka] [where X, Y, R 3 , R 5 , and R 7 is as defined in formula (I), R X is as defined above] or a pharma- ceutically acceptable salt thereof.

[0085] In some embodiments of Formula (Ia), 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, and ring B is 2-fluoro-4-cyanophenyl. In some embodiments, the formula (In): [ka] [where n, R 2 , R 5 , R 7 , ring A, and L are as defined in formula (I). or a pharma- ceutically acceptable salt thereof.

[0086] In some embodiments of formula (I), L is -O-. In some embodiments, formula (Io): [ka] [where n, X, Y, R, R 1 , R 2 , R 3 , R 7 , ring A, and ring B are as defined in formula (I). or a pharma- ceutically acceptable salt thereof.

[0087] In some embodiments of Formula (I), L is *-NR6 -C1-C6 alkylene-**, where R 6 is hydrogen or C1-C6 alkyl. In some embodiments, L is *-NR 6 -CH2-**, where R 6 is hydrogen or C1-C6 alkyl. In some embodiments, formula (Ip): [ka] [where n, X, Y, R, R 1 , R 2 , R 3 , R 6 , R 7 , ring A, and ring B are as defined in formula (I). or a pharma- ceutically acceptable salt thereof.

[0088] In some embodiments of formula (I), the compound of formula (Iq-1), (Iq-2), (Iq-3), (Iq-4), (Iq-5), (Iq-6), or (Iq-7): [ka] [ka] [where X, Y, n, R, R 1 , R 2 , R 3 , ring A, L, and ring B are as defined in formula (I). or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is of formula (Iq-1). In some embodiments, the compound is of formula (Iq-2). In some embodiments, the compound is of formula (Iq-3). In some embodiments, the compound is of formula (Iq-4). In some embodiments, the compound is of formula (Iq-5). In some embodiments, the compound is of formula (Iq-6). In some embodiments, the compound is of formula (Iq-7).

[0089] In some embodiments, the present disclosure provides that the compound of formula I has formula Is: [ka] or a pharma- ceutically acceptable salt thereof.

[0090] In some embodiments, the present disclosure provides that the compound of formula I has the formula It: [ka] or a pharma- ceutically acceptable salt thereof.

[0091] In some embodiments, a compound of formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, n is 1; X is N; R 2 is hydrogen; R 5 is an optionally substituted 5-membered heteroaryl containing 1 or 2 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, or an optionally substituted 4-membered heterocycle containing 1 oxygen atom; R 7 but, [ka] -C(O)NHCH3, -C(O)NH2, C(O)NHCH2CF3, C(O)NHS(O)2CH3, or C(O)NHOH; Ring A is an optionally substituted 6-9 membered heteroaryl; L is a bond or *-O-CH2-**; Ring B is optionally phenyl substituted with 1 to 3 substituents independently selected from the group consisting of halo and cyano.

[0092] In some embodiments of the compounds of Formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, R 1 -CH2-R 5 It is.

[0093] In some embodiments of the compounds of Formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, R 1 -CH2-R 5 and R 5 is a 4-membered heterocyclyl optionally substituted by halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkenyl, or C1-C6 haloalkyl. In some such embodiments, R 5 is optionally replaced by halo [ka] In some such embodiments, R is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkenyl, or C1-C6 haloalkyl. 5 teeth, [ka] It is.

[0094] In some embodiments of the compounds of Formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, R 1 is -CH2-R 5 and R 5 is a 5-membered heteroaryl optionally substituted by halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkenyl, or C1-C6 haloalkyl. In some such embodiments, R 5 is optionally substituted by halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkenyl, or C1-C6 haloalkyl; [ka] In some such embodiments, R 5 is optionally substituted by halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkenyl, or C1-C6 haloalkyl; [ka] In some embodiments, R 5 teeth, [ka] It is.

[0095] In some embodiments of the compounds of Formula (I) (including subformulas thereof, where applicable), or a pharma- ceutically acceptable salt thereof, X is N.

[0096] In some embodiments of the compounds of Formula (I) (including subformulas thereof, where applicable), or a pharma- ceutically acceptable salt thereof, n is 1.

[0097] In some embodiments of the compounds of formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, Y is N. In other embodiments, Y is CR 4 In some such embodiments, R 3 and R 4 together with the carbon atom to which they are attached form a cyclopropyl, optionally substituted with halo or C1-C3 alkyl.

[0098] In some embodiments of the compounds of Formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, R 7 teeth, [ka] It is.

[0099] In some embodiments of the compounds of Formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, R7 teeth, [ka] It is.

[0100] In some embodiments of the compounds of Formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, R 7 teeth, [ka] It is.

[0101] In some embodiments of the compounds of Formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, R 7 teeth, [ka] It is.

[0102] In some embodiments of the compounds of Formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, R 7 teeth, [ka] It is.

[0103] In some embodiments of the compounds of Formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, R 7 teeth, [ka] It is.

[0104] In some embodiments of the compounds of Formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, R 7 is -C(O)NH-R 8 In some such embodiments, R 8 is hydrogen. In other such embodiments, R8 is -OH.

[0105] In some embodiments of the compounds of Formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, R 7 is -C(O)NH-R 8 and R 8 is -S(O)2-C1-C6 alkyl. In some such embodiments, R 8 is -S(O)2CH3.

[0106] In some embodiments of the compounds of Formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, R 7 is -C(O)NH-R 8 and R 8 is -C1-C6 alkyl optionally substituted with halo. In some such embodiments, R 8 is -C1-C2 alkyl, each of which is independently optionally substituted with halo. In some such embodiments, R 8 is -CHCF. In other such embodiments, R 8 is -CH3.

[0107] In some embodiments of a compound of Formula (I) (including subformulas thereof, where applicable), or a pharma- ceutically acceptable salt thereof, Ring A is a 6-membered heteroaryl optionally substituted by halo, oxo, -CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted by halo or OH. In some such embodiments, Ring A is [ka] In some such embodiments, ring A is: [ka] In some embodiments, ring A is a 9-membered heteroaryl. In some embodiments, ring A is [ka] It is.

[0108] In some embodiments of the compound of formula (I) (including subformulas thereof, where applicable), or a pharma- ceutically acceptable salt thereof, L is *-O-C1-C6 alkylene-**. In some such embodiments, L is *-O-CH2-**.

[0109] In some embodiments of a compound of Formula (I) (including subformulas thereof, where applicable), or a pharma- ceutically acceptable salt thereof, Ring B is C6 aryl, optionally substituted with 1-3 substituents independently selected from the group consisting of halo and CN. In some such embodiments, Ring B is optionally substituted with 1-3 substituents independently selected from the group consisting of -F, -Cl, -Br, and -CN. [ka] In some such embodiments, ring B is: [ka] It is.

[0110] In some embodiments of the compounds of Formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, R 1 is -C1~C6 alkylene-R 5 In some such embodiments, R 1 is -CH2CH2-R 5 In other such embodiments, R 1 is -CH2-R 5 It is.

[0111] In some embodiments of the compounds of Formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, R 5 In some such embodiments, R 5 is -OCH3. In another embodiment, R 5 is -C(O)C1-C6 alkyl optionally substituted by -CN. In some such embodiments, R 5 is -C(O)C alkyl optionally substituted by -CN. In other embodiments, R 5 is a 3-6 membered heterocyclyl optionally substituted by halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkenyl, or C1-C6 haloalkyl. In some such embodiments, R 5 is a 3-6 membered heterocyclyl optionally substituted by -CH, -CHCH, -OCH, -CH=CH, or -Br. 5 is a 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkenyl, or halo. In some such embodiments, R 5 is a 5-6 membered heteroaryl optionally substituted by -CH3, -CH2CH3, -OCH3, -CH=CH2, or -Br.

[0112] In some embodiments of the compounds of Formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, R 5 is a 4-membered heterocyclyl optionally substituted by halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkenyl, or C1-C6 haloalkyl. In some such embodiments, R 5 is a 4-membered heterocyclyl optionally substituted by -CH, -CHCH, -OCH, -CH=CH, or -Br. 5 is optionally C1-C6 alkyl 、In some such embodiments, R is a 5-membered heterocyclyl substituted by C1-C6 alkoxy, C1-C6 alkenyl, or halo. 5 is a 5-membered heterocyclyl optionally substituted by -CH3, -CH2CH3, -OCH3, -CH=CH2, or -Br.

[0113] In some embodiments of the compounds of Formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, R 5 is a 4-membered heterocyclyl optionally substituted by halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkenyl, or C1-C6 haloalkyl. In some such embodiments, R 5 is a 4-membered heterocyclyl optionally substituted by -CH, -CHCH, -OCH, -CH=CH, or -Br. In other such embodiments, R 5 teeth, [ka] each of which is independently optionally substituted with C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkenyl, or halo. In some such embodiments, R 5 teeth, [ka] each of which is independently optionally substituted by -CH, -CHCH, -OCH, -CH=CH, or -Br. In other such embodiments, R 5 teeth, [ka] each of which is independently optionally substituted with C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkenyl, or halo. In some such embodiments, R 5 teeth, [ka] each of which is independently optionally substituted by -CH, -CHCH, -OCH, -CH=CH, or -Br. In some such embodiments, R 5 teeth, [ka] It is.

[0114] In some embodiments of the compounds of Formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, R 5 is a 5-membered heterocyclyl optionally substituted by halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkenyl, or C1-C6 haloalkyl. In some such embodiments, R 5 is a 5-membered heterocyclyl optionally substituted by -CH, -CHCH, -OCH, -CH=CH, or -Br. In other such embodiments, R 5 is optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkenyl, or halo. [ka] In some such embodiments, R 5 is optionally substituted by -CH3, -CH2CH3, -OCH3, -CH=CH2, or -Br [ka] In other such embodiments, R 5 is optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkenyl, or halo. [ka] In some such embodiments, R 5 is optionally substituted by -CH3, -CH2CH3, -OCH3, -CH=CH2, or -Br [ka] In some such embodiments, R 5 teeth, [ka] It is.

[0115] In some embodiments of the compounds of Formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, R 5 is a 5-membered heteroaryl optionally substituted by halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkenyl, or C1-C6 haloalkyl. In some such embodiments, R 5 is a 5-membered heteroaryl optionally substituted by -CH, -CHCH, -OCH, -CH=CH, or -Br. In other such embodiments, R 5 teeth, [ka] each of which is independently optionally substituted with C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkenyl, or halo. In some such embodiments, R 5 teeth, [ka] each of which is independently optionally substituted by -CH, -CHCH, -OCH, -CH=CH, or -Br. In other such embodiments, R 5 teeth, [ka] each of which is independently optionally substituted with C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkenyl, or halo. In some such embodiments, R 5 teeth, [ka] each of which is independently optionally substituted by -CH, -CHCH, -OCH, -CH=CH, or -Br. In some such embodiments, R 5 teeth, [ka] It is.

[0116] In some embodiments of the compound of Formula (I), or a pharma- ceutically acceptable salt thereof, R 5 is a 5-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from O, N, and S; R 5 At least one heteroatom in is S, and R 5 is optionally substituted by halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkenyl, or C1-C6 haloalkyl. In some such 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 furthermore, R 5 is optionally substituted by -CH, -CHCH, -OCH, -CH=CH, or -Br. In other such embodiments, R 5 teeth, [ka] each of which is independently optionally substituted with C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkenyl, or halo. In some such embodiments, R 5 teeth, [ka] each of which is independently optionally substituted by -CH, -CHCH, -OCH, -CH=CH, or -Br. In other such embodiments, R 5 teeth, [ka] each of which is independently optionally substituted with C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkenyl, or halo. In some such embodiments, R 5 teeth, [ka] each of which is independently optionally substituted by -CH, -CHCH, -OCH, -CH=CH, or -Br. In some such embodiments, R 5 teeth, [ka] It is.

[0117] In some embodiments of the compounds of Formula (I) (including subformulas thereof, where applicable), or a pharma- ceutically acceptable salt thereof, X is N. In other embodiments, X is CH.

[0118] In some embodiments of the compounds of Formula (I) (including subformulas thereof, where applicable), or a pharma- ceutically acceptable salt thereof, n is 0. In other embodiments, n is 1.

[0119] In some embodiments of the compounds of formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, Y is N. In other embodiments, Y is CR 4 In some such embodiments, R 3 and R 4together with the carbon atom to which they are attached form a C-C cycloalkyl. In some such embodiments, R 3 and R 4 together with the carbon atom to which they are attached form a cyclopropyl.

[0120] In some embodiments of the compounds of Formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, R 7 is -C(O)NH-R 8 In some such embodiments, R 8 is hydrogen. In other such embodiments, R 8 In other such embodiments, R 8 is -S(O)2-C1-C6 alkyl. In other such embodiments, R 8 is -C1-C6 alkyl optionally substituted with halo. In some such embodiments, R 8 is C alkyl or C alkyl, each of which is independently optionally substituted with halo. In some such embodiments, R 8 is -CHCF. In other such embodiments, R 8 is -CH3.

[0121] In some embodiments of the compounds of Formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, R 7 is a 5- to 12-membered heterocyclyl or a 5- to 12-membered heteroaryl, each of which is independently optionally substituted by oxo.

[0122] In some embodiments of the compounds of Formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, R 7 is a 5-membered heterocyclyl or a 5-membered heteroaryl, each of which is independently optionally substituted by oxo. In some such embodiments, R 7 teeth [ka] and each of which is independently optionally substituted by oxo. In some such embodiments, R 7 teeth [ka] and each of which is independently optionally substituted by oxo. In some such embodiments, R 7 teeth, [ka] It is.

[0123] In some embodiments of the compounds of Formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, R 7 is a 6-membered heteroaryl optionally substituted by oxo. In some such embodiments, R 7 teeth, [ka] and optionally substituted by oxo. In some such embodiments, R 7 teeth, [ka] and optionally substituted by oxo. In some such embodiments, R 7 teeth, [ka] It is.

[0124] In some embodiments of a compound of formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, ring A is a 5-12 membered heterocyclyl optionally substituted with halo, oxo, -CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted with halo or OH. In some such embodiments, ring A is a 5-12 membered heterocyclyl optionally substituted with -Cl, -F, oxo, -CN, cyclopropyl, or C1-C3 alkyl optionally substituted with halo or OH. In other embodiments, ring A is a 5-12 membered heteroaryl optionally substituted with halo, oxo, -CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted with halo or OH. In some such embodiments, ring A is a 5-12 membered heteroaryl optionally substituted with -Cl, -F, oxo, -CN, cyclopropyl, or C1-C3 alkyl optionally substituted with halo or OH. In other embodiments, ring A is a C6-C6 alkyl optionally substituted with halo, oxo, -CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted with halo or OH. 14 In some such embodiments, Ring A is a C6-C alkyl optionally substituted by -Cl, -F, oxo, -CN, cyclopropyl, or C1-C3 alkyl optionally substituted by halo or OH. 14 It is aryl.

[0125] In some embodiments of a compound of Formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, ring A is a 9-membered heterocyclyl optionally substituted by halo, oxo, -CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted by halo or OH. In some such embodiments, ring A is a 9-membered heterocyclyl optionally substituted by -Cl, -F, oxo, -CN, cyclopropyl, or C1-C3 alkyl optionally substituted by halo or OH. In other such embodiments, ring A is [ka] each of which is independently optionally substituted by halo, oxo, -CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted by halo or OH. In some such embodiments, ring A is [ka] and each of which is independently optionally substituted by -Cl, -F, oxo, -CN, cyclopropyl, or C1-C3 alkyl optionally substituted by halo or OH. [ka] each of which is independently optionally substituted by halo, oxo, -CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted by halo or OH. In some such embodiments, ring A is [ka] each of which is independently optionally substituted by -Cl, -F, oxo, -CN, cyclopropyl, or C1-C3 alkyl optionally substituted by halo or OH. In some such embodiments, ring A is [ka] It is.

[0126] In some embodiments of a compound of Formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, ring A is a 10-membered heterocyclyl optionally substituted by halo, oxo, -CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted by halo or OH. In some such embodiments, ring A is a 10-membered heterocyclyl optionally substituted by -Cl, -F, oxo, -CN, cyclopropyl, or C1-C3 alkyl optionally substituted by halo or OH. In other such embodiments, ring A is [ka] each of which is independently optionally substituted by halo, oxo, -CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted by halo or OH. In some such embodiments, ring A is [ka] and each of which is independently optionally substituted by -Cl, -F, oxo, -CN, cyclopropyl, or C1-C3 alkyl optionally substituted by halo or OH. [ka] each of which is independently optionally substituted by halo, oxo, -CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted by halo or OH. In some such embodiments, ring A is [ka] each of which is independently optionally substituted by -Cl, -F, oxo, -CN, cyclopropyl, or C1-C3 alkyl optionally substituted by halo or OH. In some such embodiments, ring A is [ka] It is.

[0127] In some embodiments of a compound of Formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, ring A is a 5-membered heteroaryl optionally substituted with halo, oxo, -CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted with halo or OH. In some such embodiments, ring A is a 5-membered heteroaryl optionally substituted with -Cl, -F, oxo, -CN, cyclopropyl, or C1-C3 alkyl optionally substituted with halo or OH. In other such embodiments, ring A is [ka] each of which is independently optionally substituted by halo, oxo, -CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted by halo or OH. In some such embodiments, ring A is [ka] and each of which is independently optionally substituted by -Cl, -F, oxo, -CN, cyclopropyl, or C1-C3 alkyl optionally substituted by halo or OH. [ka] each of which is independently optionally substituted by halo, oxo, -CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted by halo or OH. In some such embodiments, ring A is [ka] each of which is independently optionally substituted by -Cl, -F, oxo, -CN, cyclopropyl, or C1-C3 alkyl optionally substituted by halo or OH. In some such embodiments, ring A is [ka] It is.

[0128] In some embodiments of a compound of Formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, ring A is a 6-membered heteroaryl optionally substituted with halo, oxo, -CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted with halo or OH. In some such embodiments, ring A is a 6-membered heteroaryl optionally substituted with -Cl, -F, oxo, -CN, cyclopropyl, or C1-C3 alkyl optionally substituted with halo or OH. In other such embodiments, ring A is [ka] each of which is independently optionally substituted by halo, oxo, -CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted by halo or OH. In some such embodiments, ring A is [ka] In other such embodiments, ring A is: [ka] each of which is independently optionally substituted by halo, oxo, -CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted by halo or OH. In some such embodiments, ring A is [ka] each of which is independently optionally substituted by -Cl, -F, oxo, -CN, cyclopropyl, or C1-C3 alkyl optionally substituted by halo or OH. In some such embodiments, ring A is [ka] It is.

[0129] In some embodiments of a compound of Formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, ring A is a 9-membered heteroaryl optionally substituted with halo, oxo, -CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted with halo or OH. In some such embodiments, ring A is a 9-membered heteroaryl optionally substituted with -Cl, -F, oxo, -CN, cyclopropyl, or C1-C3 alkyl optionally substituted with halo or OH. In other such embodiments, ring A is [ka] each of which is independently optionally substituted by halo, oxo, -CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted by halo or OH. In some such embodiments, ring A is [ka] each of which is independently optionally substituted by -Cl, -F, oxo, -CN, cyclopropyl, or C1-C3 alkyl substituted by halo or OH. In other such embodiments, Ring A is [ka] each of which is independently optionally substituted by halo, oxo, -CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted by halo or OH. In some such embodiments, ring A is [ka] each of which is independently optionally substituted by -Cl, -F, oxo, -CN, cyclopropyl, or C1-C3 alkyl optionally substituted by halo or OH. In some such embodiments, ring A is [ka] It is.

[0130] In some embodiments of a compound of Formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, ring A is a 10-membered heteroaryl optionally substituted with halo, oxo, -CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted with halo or OH. In some such embodiments, ring A is a 10-membered heteroaryl optionally substituted with -Cl, -F, oxo, -CN, cyclopropyl, or C1-C3 alkyl optionally substituted with halo or OH. In other such embodiments, ring A is [ka] and optionally substituted by halo, oxo, -CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted by halo or OH. In some such embodiments, Ring A is [ka] and optionally substituted by -Cl, -F, oxo, -CN, cyclopropyl, or C1-C3 alkyl optionally substituted by halo or OH. In other such embodiments, Ring A is [ka] and optionally substituted by halo, oxo, -CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted by halo or OH. In some such embodiments, Ring A is [ka] and optionally substituted by -Cl, -F, oxo, -CN, cyclopropyl, or C1-C3 alkyl optionally substituted by halo or OH. In some such embodiments, Ring A is [ka] It is.

[0131] In some embodiments of a compound of Formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, ring A is phenylene, which is optionally substituted with halo, oxo, -CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted with halo or OH. In some such embodiments, ring A is phenylene, which is optionally substituted with -Cl, -F, oxo, -CN, cyclopropyl, or C1-C3 alkyl optionally substituted with halo or OH. In other such embodiments, ring A is [ka] and optionally substituted by halo, oxo, -CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted by halo or OH. In some such embodiments, Ring A is [ka] and optionally substituted by -Cl, -F, oxo, -CN, cyclopropyl, or C1-C3 alkyl optionally substituted by halo or OH. In some such embodiments, Ring A is [ka] It is.

[0132] In some embodiments of a compound of Formula (I) (including subformulas thereof, where applicable), or a pharma- ceutically acceptable salt thereof, L is a bond. In other embodiments, L is -O-. In other embodiments, L is C1-C6 alkylene. In some such embodiments, L is -CH2- or -CH2CH2-. In other embodiments, L is *-O-C1-C6 alkylene-**, where * represents the point of attachment to ring A and ** represents the point of attachment to ring B. In some such embodiments, L is *-O-CH2-**, *-O-CH(CH3)-**, or *-O-CH2CH2-**. In other embodiments, L is *-C1-C6 alkylene-O-**. In some such embodiments, L is *-CH2-O-**. In other embodiments, L is *-NR 6 In some such embodiments, L is -C1-C6 alkylene-**. In some such embodiments, L is *-N(CH3)-CH2-**.

[0133] In some embodiments of the compound of Formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, Ring B is optionally selected from the group consisting of halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C6 alkyl, -CN ... 10 C3-C substituted by cycloalkyl, -C(O)C1-C6 alkyl, -C(O)NH2, -S(O)2C1-C6 alkyl, or phenyl 10In some such embodiments, Ring B is a C-C alkyl optionally substituted with -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted with halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. 10 In other embodiments, Ring B is optionally substituted with halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C 10 C6-C substituted by cycloalkyl, -C(O)C1-C6 alkyl, -C(O)NH2, -S(O)2C1-C6 alkyl, or phenyl 14 In some such embodiments, Ring B is a C-C alkyl optionally substituted with -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted with halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. 14 In other embodiments, Ring B is optionally halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C 10 In some such embodiments, Ring B is a 4-12 membered heterocyclyl optionally substituted with halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C6 alkyl, -C(O)NH2, -S(O)2C1-C6 alkyl, or phenyl. 10 In other embodiments, Ring B is a 4-12 membered heterocyclyl optionally substituted with halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C6 alkyl, -C(O)NH2, -S(O)2C1-C6 alkyl, or phenyl. 10In some such embodiments, Ring B is a 5-12 membered heteroaryl optionally substituted with -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted with halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl.

[0134] In some embodiments of the compound of Formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, Ring B is optionally selected from the group consisting of halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C6 alkyl, -C1-C6 alkyl, -C ... 10 In some such embodiments, Ring B is a C4 cycloalkyl optionally substituted with -Br, -Cl, -F, -CN, oxo, C1 alkyl optionally substituted with halo, cyclopropyl, -C(O)CH3, -C(O)NH2, -S(O)2CH3, or phenyl. In other such embodiments, Ring B is a C4 cycloalkyl optionally substituted with -Br, -Cl, -F, -CN, oxo, C1 alkyl optionally substituted with halo, cyclopropyl, -C(O)CH3, -C(O)NH2, -S(O)2CH3, or phenyl. [ka] and optionally halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C 10 In some such embodiments, Ring B is substituted with: [ka] and optionally substituted by -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted by halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. In some such embodiments, Ring B is [ka] It is.

[0135] In some embodiments of a compound of formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, ring B is C6 cycloalkyl optionally substituted with halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C10 cycloalkyl, -C(O)C1-C6 alkyl, -C(O)NH2, -S(O)2C1-C6 alkyl, or phenyl. In some such embodiments, ring B is C6 cycloalkyl optionally substituted with -Br, -Cl, -F, -CN, oxo, C1 alkyl optionally substituted with halo, cyclopropyl, -C(O)CH3, -C(O)NH2, -S(O)2CH3, or phenyl. In other such embodiments, ring B is [ka] and optionally halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C 10 In some such embodiments, Ring B is substituted with: [ka] and optionally substituted by -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted by halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. In some such embodiments, Ring B is [ka] It is.

[0136] In some embodiments of the compound of Formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, Ring B is optionally selected from halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C6 alkyl, -C1-C6 alkyl, -C ... 10 In some such embodiments, Ring B is a C9 cycloalkyl optionally substituted with -Br, -Cl, -F, -CN, oxo, C1 alkyl optionally substituted with halo, cyclopropyl, -C(O)CH3, -C(O)NH2, -S(O)2CH3, or phenyl. In other such embodiments, Ring B is a C9 cycloalkyl optionally substituted with -Br, -Cl, -F, -CN, oxo, C1 alkyl optionally substituted with halo, cyclopropyl, -C(O)CH3, -C(O)NH2, -S(O)2CH3, or phenyl. [ka] each of which is independently selected from halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C 10 In some such embodiments, Ring B is substituted by: [ka] each of which is independently optionally substituted by -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted by halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. In other such embodiments, Ring B is [ka] each of which is independently selected from halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C 10 In some such embodiments, Ring B is substituted by: [ka] each of which is independently optionally substituted by -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted by halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. In some such embodiments, Ring B is [ka] It is.

[0137] In some embodiments of the compound of Formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, Ring B is optionally selected from the group consisting of halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C6 alkyl, -C1 ... 10 C substituted by cycloalkyl, -C(O)C1-C6 alkyl, -C(O)NH2, -S(O)2C1-C6 alkyl, or phenyl 10In some such embodiments, Ring B is a C alkyl optionally substituted with -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted with halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. 10 In other such embodiments, Ring B is: [ka] and optionally halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C 10 In some such embodiments, Ring B is substituted with: [ka] and optionally substituted by -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted by halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. In other such embodiments, Ring B is [ka] each of which is independently selected from halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C 10 In some such embodiments, Ring B is substituted by: [ka] each of which is independently optionally substituted by -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted by halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. In some such embodiments, Ring B is [ka] It is.

[0138] In some embodiments of the compounds of Formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, Ring B is [ka] each of which is independently selected from halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C 10 In some such embodiments, Ring B is substituted by: [ka] each of which is independently optionally substituted by -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted by halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. In other such embodiments, Ring B is [ka] each of which is independently selected from halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C 10 In some such embodiments, Ring B is substituted by: [ka] each of which is independently optionally substituted by -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted by halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. In some such embodiments, Ring B is [ka] It is.

[0139] In some embodiments of the compound of Formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, Ring B is optionally selected from the group consisting of halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C6 alkyl, -C1 ... 10 In some such embodiments, Ring B is a 4-membered heterocyclyl optionally substituted with -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted with halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. In other such embodiments, Ring B is a 4-membered heterocyclyl optionally substituted with -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted with halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. [ka] each of which is independently selected from halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C 10 In some such embodiments, Ring B is substituted by: [ka] each of which is independently optionally substituted by -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted by halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. In other such embodiments, Ring B is [ka] each of which is independently selected from halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C 10 In some such embodiments, Ring B is substituted with: [ka] each of which is independently optionally substituted by -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted by halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. In some such embodiments, Ring B is [ka] It is.

[0140] In some embodiments of the compound of Formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, Ring B is optionally selected from the group consisting of halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C6 alkyl, -C1 ... 10In some such embodiments, Ring B is a 6-membered heterocyclyl optionally substituted with -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted with halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. In other such embodiments, Ring B is a 6-membered heterocyclyl optionally substituted with -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted with halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. [ka] each of which is independently selected from halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C 10 In some such embodiments, Ring B is substituted by: [ka] each of which is independently optionally substituted by -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted by halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. In other such embodiments, Ring B is [ka] each of which is independently selected from halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C 10 In some such embodiments, Ring B is substituted by: [ka] each of which is independently optionally substituted with halo, -CN, oxo, C1-C6 alkyl optionally substituted with -Br, -Cl, -F, -CN, oxo, C1 alkyl optionally substituted with halo, cyclopropyl, -C(O)CH3, -C(O)NH2, -S(O)2CH3, or phenyl. In some such embodiments, Ring B is [ka] It is.

[0141] In some embodiments of the compound of Formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, Ring B is selected from the group consisting of halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C 10 In some such embodiments, Ring B is a 7-membered heterocyclyl optionally substituted with -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted with halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. In other such embodiments, Ring B is a 7-membered heterocyclyl optionally substituted with -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted with halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. [ka] and optionally halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C 10 In some such embodiments, Ring B is substituted by: [ka] and optionally substituted with halo, -CN, oxo, C1-C6 alkyl optionally substituted with -Br, -Cl, -F, -CN, oxo, C1 alkyl optionally substituted with halo, cyclopropyl, -C(O)CH3, -C(O)NH2, -S(O)2CH3, or phenyl. In other such embodiments, Ring B is [ka] and optionally halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C 10 In some such embodiments, Ring B is substituted with: [ka] and optionally substituted with halo, -CN, oxo, C1-C6 alkyl optionally substituted with -Br, -Cl, -F, -CN, oxo, C1 alkyl optionally substituted with halo, cyclopropyl, -C(O)CH3, -C(O)NH2, -S(O)2CH3, or phenyl. In some such embodiments, Ring B is [ka] It is.

[0142] In some embodiments of the compound of Formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, Ring B is optionally selected from the group consisting of halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C6 alkyl, -C1 ... 10In some such embodiments, Ring B is a 9-membered heterocyclyl optionally substituted with -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted with halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. In other such embodiments, Ring B is a 9-membered heterocyclyl optionally substituted with -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted with halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. [ka] each of which is independently selected from halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C 10 In some such embodiments, Ring B is substituted by: [ka] each of which is independently optionally substituted by -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted by halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. In other such embodiments, Ring B is [ka] each of which is independently selected from halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C 10 In some such embodiments, Ring B is substituted by: [ka] each of which is independently optionally substituted by -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted by halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. In some such embodiments, Ring B is [ka] It is.

[0143] In some embodiments of the compound of Formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, Ring B is optionally selected from the group consisting of halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C6 alkyl, -CN ... 10 In some such embodiments, Ring B is a 10-membered heterocyclyl optionally substituted with -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted with halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. In other such embodiments, Ring B is a 10-membered heterocyclyl optionally substituted with -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted with halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. [ka] each of which is independently selected from halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C 10 In some such embodiments, Ring B is substituted by: [ka] each of which is independently optionally substituted by -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted by halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. In other such embodiments, Ring B is [ka] each of which is independently selected from halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C 10 In some such embodiments, Ring B is substituted by: [ka] each of which is independently optionally substituted by -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted by halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. In some such embodiments, Ring B is [ka] It is.

[0144] In some embodiments of the compound of Formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, Ring B is optionally selected from the group consisting of halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C6 alkyl, -C1-C6 alkyl, -C ... 10In some such embodiments, Ring B is an 11-membered heterocyclyl optionally substituted with -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted with halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. In other such embodiments, Ring B is an 11-membered heterocyclyl optionally substituted with -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted with halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. [ka] each of which is independently selected from halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C 10 In some such embodiments, Ring B is substituted by: [ka] each of which is independently optionally substituted by -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted by halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. In other such embodiments, Ring B is [ka] each of which is independently selected from halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C 10 In some such embodiments, Ring B is substituted by: [ka] each of which is independently optionally substituted by -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted by halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. In some such embodiments, Ring B is [ka] It is.

[0145] In some embodiments of the compound of Formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, Ring B is optionally selected from the group consisting of halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C6 alkyl, -C1-C6 alkyl, -C ... 10 In some such embodiments, Ring B is a 5-membered heteroaryl optionally substituted with -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted with halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. In other such embodiments, Ring B is a 5-membered heteroaryl optionally substituted with -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted with halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. [ka] each of which is independently selected from halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C 10In some such embodiments, Ring B is substituted by: [ka] each of which is independently optionally substituted by -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted by halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. In other such embodiments, Ring B is [ka] each of which is independently selected from halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C 10 In some such embodiments, Ring B is substituted by: [ka] each of which is independently optionally substituted by -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted by halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. In some such embodiments, Ring B is [ka] It is.

[0146] In some embodiments of the compound of Formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, Ring B is optionally selected from the group consisting of halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C6 alkyl, -C1-C6 alkyl, -C ... 10In some such embodiments, Ring B is a 6-membered heteroaryl optionally substituted with -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted with halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. In other such embodiments, Ring B is a 6-membered heteroaryl optionally substituted with -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted with halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. [ka] each of which is independently selected from halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C 10 In some such embodiments, Ring B is substituted by: [ka] each of which is independently optionally substituted by -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted by halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. In other such embodiments, Ring B is [ka] each of which is independently selected from halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C 10 In some such embodiments, Ring B is substituted by: [ka] each of which is independently optionally substituted by -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted by halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. In some such embodiments, Ring B is [ka] It is.

[0147] In some embodiments of the compound of Formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, Ring B is optionally selected from the group consisting of halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C6 alkyl, -CN ... 10 In some such embodiments, Ring B is a 9-membered heteroaryl optionally substituted with -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted with halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. In other such embodiments, Ring B is a 9-membered heteroaryl optionally substituted with -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted with halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. [ka] each of which is independently selected from halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C 10 In some such embodiments, ring B is substituted with cycloalkyl, -C(O)C1-C6 alkyl, -C(O)NH2, -S(O)2C1-C6 alkyl, or phenyl. [ka] each of which is independently optionally substituted by -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted by halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. In other such embodiments, Ring B is [ka] each of which is independently selected from halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C 10 In some such embodiments, Ring B is substituted by: [ka] each of which is independently optionally substituted by -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted by halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. In some such embodiments, Ring B is [ka] It is.

[0148] In some embodiments of the compound of Formula (I) (including subformulas thereof, if applicable), or a pharma- ceutically acceptable salt thereof, Ring B is optionally selected from the group consisting of halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C6 alkyl, -C1 ... 10 In some such embodiments, Ring B is a 10-membered heteroaryl optionally substituted with -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted with halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. In other such embodiments, Ring B is a 10-membered heteroaryl optionally substituted with -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted with halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. [ka] each of which is independently selected from halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C 10 In some such embodiments, Ring B is substituted by: [ka] each of which is independently optionally substituted by -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted by halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. In other such embodiments, Ring B is [ka] each of which is independently selected from halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C 10In some such embodiments, Ring B is substituted by: [ka] each of which is independently optionally substituted by -Br, -Cl, -F, -CN, oxo, C alkyl optionally substituted by halo, cyclopropyl, -C(O)CH, -C(O)NH, -S(O)CH, or phenyl. In some such embodiments, Ring B is [ka] It is.

[0149] In some embodiments of formula (I) (including subformulas thereof, if applicable), ring A is a 5-12 membered heterocyclyl optionally substituted with halo, oxo, -CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted with halo or OH; ring B is a 5-12 membered heterocyclyl optionally substituted with halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C6 alkyl, -CN, -C6 alkyl, -C1- ... 10 C3-C substituted by cycloalkyl, -C(O)C1-C6 alkyl, -C(O)NH2, -S(O)2C1-C6 alkyl, or phenyl 10 In some such embodiments, L is a bond. In other such embodiments, L is -O-. In other such embodiments, L is C1-C6 alkylene. In other such embodiments, L is *-O-C1-C6 alkylene-**, where * represents the point of attachment to ring A and ** represents the point of attachment to ring B. In other such embodiments, L is *-C1-C6 alkylene-O-**. In other such embodiments, L is *-NR 6 -C1~C6 alkylene-**.

[0150] In some embodiments of formula (I) (including subformulas thereof, if applicable), ring A is a 5-12 membered heterocyclyl optionally substituted with halo, oxo, -CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted with halo or OH; ring B is a 5-12 membered heterocyclyl optionally substituted with halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C6 alkyl, -CN, -C6 alkyl, -C1- ... 10 C6-C substituted by cycloalkyl, -C(O)C1-C6 alkyl, -C(O)NH2, -S(O)2C1-C6 alkyl, or phenyl 14 In some such embodiments, L is a bond. In other such embodiments, L is -O-. In other such embodiments, L is C1-C6 alkylene. In other such embodiments, L is *-O-C1-C6 alkylene-**, where * represents the point of attachment to ring A and ** represents the point of attachment to ring B. In other such embodiments, L is *-C1-C6 alkylene-O-**. In other such embodiments, L is *-NR 6 -C1~C6 alkylene-**.

[0151] In some embodiments of formula (I) (including subformulas thereof, if applicable), ring A is a 5-12 membered heterocyclyl optionally substituted with halo, oxo, -CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted with halo or OH; ring B is a 5-12 membered heterocyclyl optionally substituted with halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C6 alkyl, -CN, -C6 alkyl, -C1- ... 10In some such embodiments, L is a bond. In other such embodiments, L is -O-. In other such embodiments, L is C1-C6 alkylene. In other such embodiments, L is *-O-C1-C6 alkylene-**, where * represents the point of attachment to ring A and ** represents the point of attachment to ring B. In other such embodiments, L is *-C1-C6 alkylene-O-**. In other such embodiments, L is *-NR 6 -C1~C6 alkylene-**.

[0152] In some embodiments of formula (I) (including subformulas thereof, if applicable), ring A is a 5-12 membered heterocyclyl optionally substituted by halo, oxo, -CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted by halo or OH; ring B is a 5-12 membered heterocyclyl optionally substituted by halo, -CN, oxo, C1-C6 alkyl optionally substituted by halo, C3-C6 alkyl, -CN, -C6 alkyl, -C1- ... 10 In some such embodiments, L is a bond. In other such embodiments, L is -O-. In other such embodiments, L is C1-C6 alkylene. In other such embodiments, L is *-O-C1-C6 alkylene-**, where * represents the point of attachment to ring A and ** represents the point of attachment to ring B. In other such embodiments, L is *-C1-C6 alkylene-O-**. In other such embodiments, L is *-NR 6 -C1~C6 alkylene-**.

[0153] In some embodiments of formula (I) (including subformulas thereof, if applicable), ring A is a 5-12 membered heteroaryl optionally substituted with halo, oxo, -CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted with halo or OH; ring B is a 5-12 membered heteroaryl optionally substituted with halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted with halo or OH; 10 C3-C substituted by cycloalkyl, -C(O)C1-C6 alkyl, -C(O)NH2, -S(O)2C1-C6 alkyl, or phenyl 10 In some such embodiments, L is a bond. In other such embodiments, L is -O-. In other such embodiments, L is C1-C6 alkylene. In other such embodiments, L is *-O-C1-C6 alkylene-**, where * represents the point of attachment to ring A and ** represents the point of attachment to ring B. In other such embodiments, L is *-C1-C6 alkylene-O-**. In other such embodiments, L is *-NR 6 -C1~C6 alkylene-**.

[0154] In some embodiments of formula (I) (including subformulas thereof, if applicable), ring A is a 5-12 membered heteroaryl optionally substituted with halo, oxo, -CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted with halo or OH; ring B is a 5-12 membered heteroaryl optionally substituted with halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted with halo or OH; 10 C6-C substituted by cycloalkyl, -C(O)C1-C6 alkyl, -C(O)NH2, -S(O)2C1-C6 alkyl, or phenyl 14In some such embodiments, L is a bond. In other such embodiments, L is -O-. In other such embodiments, L is C1-C6 alkylene. In other such embodiments, L is *-O-C1-C6 alkylene-**, where * represents the point of attachment to ring A and ** represents the point of attachment to ring B. In other such embodiments, L is *-C1-C6 alkylene-O-**. In other such embodiments, L is *-NR 6 -C1~C6 alkylene-**.

[0155] In some embodiments of formula (I) (including subformulas thereof, if applicable), ring A is a 5-12 membered heteroaryl optionally substituted with halo, oxo, -CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted with halo or OH; ring B is optionally substituted with halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted with halo or OH; 10 In some such embodiments, L is a bond. In other such embodiments, L is -O-. In other such embodiments, L is C1-C6 alkylene. In other such embodiments, L is *-O-C1-C6 alkylene-**, where * represents the point of attachment to ring A and ** represents the point of attachment to ring B. In other such embodiments, L is *-C1-C6 alkylene-O-**. In other such embodiments, L is *-NR 6 -C1~C6 alkylene-**.

[0156] In some embodiments of Formula (I) (including subformulas thereof, if applicable), Ring A is a 5-12 membered heteroaryl optionally substituted with halo, oxo, -CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted with halo or OH; and Ring B is a C5-C6 alkyl optionally substituted with halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C10 cycloalkyl, -C(O)C1-C6 alkyl, -C(O)NH2, -S(O)2C1-C6 alkyl, or phenyl. 12 In some such embodiments, L is a bond. In other such embodiments, L is -O-. In other such embodiments, L is C1-C6 alkylene. In other such embodiments, L is *-O-C1-C6 alkylene-**, where * represents the point of attachment to ring A and ** represents the point of attachment to ring B. In other such embodiments, L is *-C1-C6 alkylene-O-**. In other such embodiments, L is *-NR6-C1-C6 alkylene-**.

[0157] In some embodiments of formula (I) (including subformulas thereof, if applicable), ring A is optionally a C6-C cycloalkyl substituted by halo, oxo, -CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted by halo or OH. 14 aryl, and Ring B is optionally halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C 10 C3-C substituted by cycloalkyl, -C(O)C1-C6 alkyl, -C(O)NH2, -S(O)2C1-C6 alkyl, or phenyl 10In some such embodiments, L is a bond. In other such embodiments, L is -O-. In other such embodiments, L is C1-C6 alkylene. In other such embodiments, L is *-O-C1-C6 alkylene-**, where * represents the point of attachment to ring A and ** represents the point of attachment to ring B. In other such embodiments, L is *-C1-C6 alkylene-O-**. In other such embodiments, L is *-NR 6 -C1~C6 alkylene-**.

[0158] In some embodiments of formula (I) (including subformulas thereof, if applicable), ring A is optionally a C6-C cycloalkyl substituted by halo, oxo, -CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted by halo or OH. 14 aryl, and Ring B is optionally halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C 10 C6-C substituted by cycloalkyl, -C(O)C1-C6 alkyl, -C(O)NH2, -S(O)2C1-C6 alkyl, or phenyl 14 In some such embodiments, L is a bond. In other such embodiments, L is -O-. In other such embodiments, L is C1-C6 alkylene. In other such embodiments, L is *-O-C1-C6 alkylene-**, where * represents the point of attachment to ring A and ** represents the point of attachment to ring B. In other such embodiments, L is *-C1-C6 alkylene-O-**. In other such embodiments, L is *-NR 6 -C1~C6 alkylene-**.

[0159] In some embodiments of formula (I) (including subformulas thereof, if applicable), ring A is optionally a C6-C cycloalkyl substituted by halo, oxo, -CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted by halo or OH. 14aryl, and Ring B is optionally halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C 10 In some such embodiments, L is a bond. In other such embodiments, L is -O-. In other such embodiments, L is C1-C6 alkylene. In other such embodiments, L is *-O-C1-C6 alkylene-**, where * represents the point of attachment to ring A and ** represents the point of attachment to ring B. In other such embodiments, L is *-C1-C6 alkylene-O-**. In other such embodiments, L is *-NR 6 -C1~C6 alkylene-**.

[0160] In some embodiments of formula (I) (including subformulas thereof, if applicable), ring A is optionally a C6-C cycloalkyl substituted by halo, oxo, -CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted by halo or OH. 14 aryl, and Ring B is optionally halo, -CN, oxo, C1-C6 alkyl optionally substituted with halo, C3-C 10 In some such embodiments, L is a bond. In other such embodiments, L is -O-. In other such embodiments, L is C1-C6 alkylene. In other such embodiments, L is *-O-C1-C6 alkylene-**, where * represents the point of attachment to ring A and ** represents the point of attachment to ring B. In other such embodiments, L is *-C1-C6 alkylene-O-**. In other such embodiments, L is *-NR 6 -C1~C6 alkylene-**.

[0161] In some embodiments, a compound selected from compound numbers 1 to 18 in Table 1 below, or a pharma- ceutically acceptable salt thereof, is provided. [Table 1-1] [Table 1-2] [Table 1-3]

[0162] In another aspect, there is provided a method for preparing a compound selected from the group consisting of a compound of formula (I) (including subformulas thereof), or the compounds listed in Table 1, and pharma- ceutically acceptable salts thereof. The compounds described herein may be prepared according to general schemes, as illustrated by the general procedures and examples. When following the general procedures, slight variations in temperature, concentration, reaction time, and other parameters may occur, which do not substantially affect the outcome of the procedure.

[0163] Also provided are compound intermediates useful in the synthesis of compounds of formula (I), including subformulas thereof, or compounds selected from the group listed in Table 1, and pharma-ceutically acceptable salts thereof. The synthesis of representative compounds and intermediates is illustrated in the Examples below.

[0164] The compounds provided herein may exist as salts, even if no salts are provided, and the present disclosure is understood to encompass all salts and solvates of the compounds provided herein, as well as non-salt and non-solvate forms of the compounds, as will be well understood by those skilled in the art.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.

[0165] Where tautomeric forms may exist for any of the compounds described herein, each tautomeric form is intended, even though only one or some of the tautomeric forms may be explicitly depicted. The tautomeric form specifically depicted may or may not be the predominant form in solution or when used in accordance with the methods described herein.

[0166] 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 shown herein may have asymmetric centers and therefore exist in different enantiomeric or diastereomeric forms. All optical isomers and stereoisomers of 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 shown herein is intended to represent the 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 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 enantiomers of the compound in which that stereocenter is in the "R" stereochemical configuration are 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.

[0167] 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 in one or more atoms that constitute such compounds. In some embodiments, the compounds are isotopically labeled, such as the isotopically labeled compounds of formula (I) or variations thereof described herein, in which a proportion of one or more atoms is 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 and 14 C) is useful in compound or substrate tissue distribution studies. 2 Incorporation of heavier isotopes, such as H), can offer certain therapeutic advantages due to greater metabolic stability, e.g., increased in vivo half-life, or reduced dosage requirements, and therefore may be preferred in some instances.

[0168] Isotopically labeled compounds of the present invention can generally be prepared by standard methods and techniques known to those skilled in the art, or by procedures similar to those described in the accompanying examples substituting the appropriate isotopically labeled reagent for the corresponding unlabeled reagent.

[0169] The invention also includes any or all metabolic products of any of the described compounds, including any chemical species produced by in vivo transformation of any of the described compounds, such as those produced in vivo following administration to humans, including intermediates and metabolites of the compounds that would be produced in vivo following administration to humans.

[0170] 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 subformulas thereof, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier or excipient.

[0171] 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.

[0172] 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 compounds of different stereochemical forms.

[0173] 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 or forms thereof detailed herein.

[0174] 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.

[0175] 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.

[0176] The compounds described herein can be administered to individuals (e.g., humans) in the form of generally acceptable oral compositions, such as tablets, coated tablets, and hard or soft shell gel capsules, emulsions or suspensions. Examples of carriers that can be used to prepare such compositions include lactose, corn starch or its derivatives, talc, stearates or their 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.

[0177] A composition comprising two compounds utilized herein is 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 subformulas thereof) described herein, or a pharma- ceutically acceptable salt thereof. In some embodiments, the present disclosure provides a dosage form comprising a therapeutically effective amount of a compound of formula (I) (including subformulas thereof), or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is selected from compound numbers 1-18 in Table 1.

[0178] Method and use The compounds and compositions described herein may, in some aspects, be used to treat the diseases and / or conditions described herein, e.g., diseases and / or conditions mediated by GLP-1R. In some embodiments, a method of treating a disease or condition in a subject in need thereof comprises administering to the subject a therapeutically effective amount of a compound of formula (I) (including subformulas thereof, if applicable), or a pharmaceutically acceptable salt thereof. In some embodiments, a method of treating a disease or condition in a subject in need thereof comprises administering to the subject a therapeutically effective amount of a compound selected from compound numbers 1-14 of Table 1, or a pharmaceutically acceptable salt thereof.

[0179] According to the present application, the diseases or conditions to be treated and / or prevented include cardiometabolic and diabetes (T1D and / or T2DM, including prediabetes), idiopathic T1D (type 1b), latent autoimmune diabetes in adults (LADA), early onset T2DM (EOD), early onset atypical diabetes mellitus (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, renal disease (e.g., acute kidney injury, renal tubular dysfunction, inflammation-induced changes in the proximal tubule), diabetes Other conditions that may be causing this include: chronic 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 disorder, bulimia nervosa, and syndromic obesity such as Prader-Willi and Bardet-Biedl syndromes), weight gain due to use of other medications (e.g., due to use of steroids and antipsychotics), excessive sugar cravings, dyslipidemia (including hyperlipidemia, hypertriglyceridemia, increased total cholesterol, high LDL cholesterol, and low HDL cholesterol), hyperinsulinemia, and hypercalcemia. Phosphatemia, NAFLD, steatosis, NASH, liver disease such as fibrosis, cirrhosis, and hepatocellular carcinoma, cardiovascular disease, atherosclerosis (including coronary artery disease), peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction (e.g., necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataracts, glomerulosclerosis , chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina, thrombosis, atherosclerosis, transient ischemic attacks, vascular restenosis, glucose metabolism disorders, impaired fasting plasma glucose states, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, 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 treatment of addiction (e.g., alcohol and / or drug abuse).

[0180] In some embodiments, provided herein is a method of treating a cardiometabolic disease in a subject (e.g., a human patient) in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof.

[0181] In some embodiments, provided herein is a method of treating diabetes in a subject (e.g., a human patient) in need thereof, the method 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.

[0182] In some embodiments, provided herein is a method of treating liver disorders 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 liver disorders include, but are not limited to, hepatitis, fibrosis, and steatohepatitis. In some embodiments, the liver disorder is selected from the list consisting of primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), drug-induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition-associated cholestasis (PNAC), bacterial overgrowth or sepsis-associated cholestasis, autoimmune hepatitis, viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), graft-versus-host disease, transplant liver regeneration, congenital hepatic fibrosis, common bile duct stones, granulomatous liver disease, intrahepatic or extrahepatic malignancies, Sjogren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis, and Othi-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 method of treatment provided herein delays or delays the progression of NAFLD to NASH. In one embodiment, the methods of treatment provided herein slow or delay the progression of NASH, which can progress to, for example, one or more of cirrhosis, 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.

[0183] According to the present application, the compounds described herein, or pharma- ceutically acceptable salts thereof, may be administered by any suitable route in the form of a pharmaceutical composition adapted to the route and in a dose effective for the intended treatment. In some embodiments, it is a compound of any of the embodiments of formula (I) or is selected from the compounds of Table 1, or pharma- ceutically acceptable salts thereof. The compounds and / or compositions described herein may be administered orally, rectally, vaginally, parenterally, or topically.

[0184] 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 buccal or sublingual administration may be used to allow the compound to enter the blood stream directly from the mouth.

[0185] In some embodiments, the compound and / or composition can be administered directly into the bloodstream, muscle, or 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.

[0186] 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.

[0187] Dosing 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, dosing 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 compound per kg 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. It is not uncommon for the administration of the compounds of the present application to be repeated multiple times (typically up to 4 times) per day. If necessary, the total daily dose may be increased, typically using multiple doses per day.

[0188] 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 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, the dose may range from about 0.01 to about 10 mg / kg / min during a constant rate infusion.

[0189] The compounds and / or compositions described herein may be used alone or in combination with other therapeutic agents. Administration of two or more agents "in combination" means that all agents are administered close enough in time that each can produce a biological effect within the same time frame. The presence of one agent may alter the biological effect of the other agent. Two or more agents may be administered simultaneously, concurrently, or sequentially. In addition, simultaneous administration may be performed by mixing the agents prior to administration, or by administering the compounds as separate dosage forms at the same time but at the same or different administration sites.

[0190] The present application provides any of the uses, methods, or compositions defined herein, in which a compound of any embodiment 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, including pharmaceutical compositions selected from a compound of any embodiment of formula (I), or a compound selected from Table 1, or a pharma- ceutically acceptable salt thereof, in admixture with at least one pharma- ceutically acceptable excipient and one or more other therapeutic agents, as defined in any of the embodiments described herein.

[0191] In some embodiments, the one or more other therapeutic agents are selected from the group consisting of biguanides (e.g., metformin), sulfonylureas (e.g., tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, or glipizide), thiazolidinediones (e.g., pioglitazone, rosiglitazone, or lobeglitazone), glitazars (e.g., saroglitazar, aleglitazapine, or rivaroxaban), and the like. meglitinides (e.g., nateglinide, repaglinide), dipeptidyl peptidase-4 (DPP-4) inhibitors (e.g., sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, dutogliptin, or omarigliptin), glitazones (e.g., pioglitazone, rociglitazone, glitazones, balaglitazone, rivoglitazone, or lobeglitazone), sodium-glucose-coupled transporter type 2 (SGLT2) inhibitors (e.g., empagliflozin, canagliflozin, dapagliflozin, ipragliflozin, ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, or ertugliflozin), SGLTL1 inhibitors, GPR40 agonists (FFAR1 / FFA1 agonists, e.g., 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 and pharmaceutically acceptable solvates of the agents and salts.

[0192] 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 (CB1 R) antagonist, a lipase inhibitor (e.g., orlistat), a human proaylet peptide (HIP), a melanocortin receptor 4 agonist (e.g., cetamelanotide), a melanin concentrating hormone receptor 1 antagonist, a farnesoid X receptor (FXR) agonist (e.g., obeticholic acid), zonisamide, phentermine (alone or in combination with topiramic acid), a norepinephrine / dopamine reuptake inhibitor (e.g., bupropion), an opioid receptor antagonist ( These include but are not limited to: naltrexone), norepinephrine / dopamine reuptake inhibitors and opioid receptor antagonist combinations (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), serotonergic agents (e.g., lorcaserin), methionine aminopeptidase 2 (MetAP2) inhibitors (e.g., beloranib or ZGN-1061), phendimetrazine, diethylpropion, benzphetamine, SGLT2 inhibitors (e.g., empagliflozin, canagliflozin, dapagliflozin, ipragliflozin, ipragliflozin, tofoglifozin, serglifozin etabonate, remoliflozin etabonate, or ertuglifozin), SGLTL1 inhibitors, dual SGLT2 / SGLT1 inhibitors, fibroblast growth factor receptor (FGFR) 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 pharmaceutical and pharmaceutical acceptable salts of the specifically named agents and pharmaceutical acceptable solvates of the above agents and salts).

[0193] 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), PPAR a / d agonists (e.g., elafibranor), synthetic fatty acid-bile acid conjugates (e.g., aramchol), caspase inhibitors (e.g., emricasan), anti-lysyl oxidase homolog 2 (LOXL2) monoclonal antibodies (e.g., simtuzumab), galectin 3 inhibitors (e.g., GR-MD-02), MAPK5 inhibitors (e.g., GS-4997), dual antagonists of chemokine receptor 2 (CCR2) and CCR5 (e.g., cenicrivirosi), fibroblast growth factor 21 (FGF21) agonists (e.g., BMS-986036), leukotriene D4 (LTD4) receptor antagonists (e.g., tiperukast), 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-CB1 R antibodies, or apoptosis signal-regulating kinase 1 (ASK1) inhibitors (including pharmacologic acceptable salts of the specifically named agents and pharmacologic acceptable solvates of such agents and salts).

[0194] Products and Kits The present disclosure further provides a product comprising the compound of the present application, or a pharma- ceutically acceptable salt thereof, the 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.

[0195] 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, or a pharma- ceutically acceptable salt thereof, a composition described herein, and / or one or more other therapeutic agents useful for a disease detailed herein, in accordance with the present application, to provide effective treatment of an individual for an extended period of time, e.g., 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 more. The kit may also include multiple unit doses of the compounds / compositions described herein and instructions for use, and may be packaged in an amount sufficient for storage and use in a pharmacy (e.g., a hospital pharmacy and a compounding pharmacy).

[0196] 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.

[0197] Method of synthesis In some aspects, the disclosure provides methods of preparing the disclosed compounds.

[0198] In some aspects, the disclosure provides methods of preparing the compounds comprising one or more of the steps described herein.

[0199] 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.

[0200] In some aspects, the disclosure provides intermediates described herein that are suitable for use in the methods of preparing the compounds described herein.

[0201] The compounds of the present disclosure can be prepared by any suitable technique known in the art. Particular processes for the preparation of these compounds are further described in the accompanying Examples.

[0202] In the descriptions of synthetic methods described herein, and in any mentioned synthetic methods used to prepare starting materials, it should be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment, and work-up procedures, can be selected by one of ordinary skill in the art.

[0203] 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.

[0204] 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. Those skilled in the art will understand when such protection is necessary and how such protecting groups can be 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 method described in the literature or known to those skilled in the art as appropriate for the removal of the protecting group in question, and such methods are selected to result in the removal of the protecting group with minimal disturbance of groups elsewhere in the molecule. Thus, when a reactant contains a group such as, for example, amino, carboxy, or hydroxy, it may be desirable to protect the group in some of the reactions described herein.

[0205] For example, suitable protecting groups for amino or alkylamino are, for example, acyl groups, such as alkanoyl groups, for example acetyl, alkoxycarbonyl groups, for example methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl groups, arylmethoxycarbonyl groups, for example benzyloxycarbonyl, or aroyl groups, for example benzoyl. The deprotection conditions of the above-mentioned protecting groups necessarily vary according to the selection of protecting groups. Thus, for example, acyl groups or aroyl groups, such as alkanoyl or alkoxycarbonyl groups, can be removed by hydrolysis using a suitable base, for example an alkali metal hydroxide, for example lithium hydroxide or sodium hydroxide. Alternatively, acyl groups such as the tert-butoxycarbonyl group may be removed by treatment with a suitable acid, for example hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid, and arylmethoxycarbonyl groups such as the benzyloxycarbonyl group may be removed by hydrogenation, for example over a catalyst such as palladium on carbon, or by treatment with a Lewis acid, for example boron tris(trifluoroacetate).A suitable alternative protecting group for a primary amino group is, for example, the phthaloyl group, which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or hydrazine.

[0206] Suitable protecting groups for hydroxyl groups are, for example, acyl groups, such as alkanoyl groups, for example acetyl, aroyl groups, for example benzoyl, or arylmethyl groups, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, acyl groups, such as alkanoyl or aroyl groups, can be removed by hydrolysis using a suitable base, for example an alkali metal hydroxide, for example lithium hydroxide, sodium hydroxide, or ammonia. Alternatively, arylmethyl groups, such as benzyl groups, can be removed by hydrogenation, for example, over a catalyst, such as palladium on carbon.

[0207] A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or ethyl group which may be removed by hydrolysis with a base such as sodium hydroxide, or for example a tert-butyl group which may be removed by treatment with an acid, for example an organic acid, such as trifluoroacetic acid, or for example a benzyl group which may be removed by hydrogenation over a catalyst such as palladium on carbon.

[0208] 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) to another compound of formula (I), (iii) forming a pharma- ceutically acceptable salt, hydrate or solvate thereof, and / or (iv) forming a prodrug thereof.

[0209] The resulting compound of formula (I) can be isolated and purified using techniques well known in the art.

[0210] In some embodiments, the reaction of the compounds is preferably carried out in the presence of a suitable solvent, which is 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; diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentyl methyl ether (CPME), methyl tert-butyl ether (MTBE) or dioxane; ethylene glycol monomethyl ether (DMBE) or ... Examples of suitable solvents include, but are not limited to, glycol ethers, such as monoethyl ether or monoethylene glycol dimethyl ether (diglyme); ketones, such as acetone, methionine, methyl butyl ketone (MIBK) or butanone; amides, such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N-methylpyrrolidone (NMP); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate or methyl acetate; or mixtures of such solvents or with water.

[0211] The reaction temperature is preferably about -100°C to 300°C, depending on the reaction step and conditions used.

[0212] 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. A suitable reaction time can be easily determined by methods known in the art, such as reaction monitoring. Based on the above reaction temperature, a suitable reaction time generally ranges from 10 minutes to 48 hours.

[0213] Moreover, by utilizing the procedures described herein, in combination with ordinary skill in the art, additional compounds of the present disclosure can be readily prepared. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.

[0214] 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 any particular instance, whenever necessary or useful. In addition, some of the compounds of the present disclosure can be easily synthesized by reacting other compounds of the present disclosure under appropriate conditions, for example by applying standard synthetic methods such as reduction, oxidation, addition or substitution reactions, to convert one specific functional group present in the compounds of the present disclosure or in a suitable precursor molecule to another functional group. These methods 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 and 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).

[0215] General routes for the preparation of the compounds of the present application are depicted in Schemes 1-10 herein. [ka] [ka] [ka] [ka] [ka]

[0216] Biological assays Once produced, the compounds designed, selected, and / or optimized by the above-described methods 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 expected activity, binding activity, and / or binding specificity.

[0217] Furthermore, high throughput screening can be used to speed up 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 performing 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.

[0218] A variety of in vitro or in vivo biological assays may be suitable for detecting the effects of the disclosed compounds, including, but not limited to, enzyme activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and assays described herein.

[0219] In some embodiments, the biological assays are described in the Examples herein.

[0220] GLP-1R Cellular Assay Stable cell lines expressing high and low GLP-1R surface expression were generated in CHO-K1 cells transfected with a puromycin-selectable DNA plasmid encoding the human GLP-1R receptor (accession number: NM_002062.5) under the EF1A promoter (Figure 6). 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 before being 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, placed in 384-well plates (1,000 cells / well) and combined with GLP-1R control peptide (10 nL) that was serially diluted using an acoustic dispenser (ECHO). Plates were incubated for 30 min at 25°C before EU-cAMP tracer (5 μL) and Ulight-anti-cAMP (5 μL) reagents were added to each well, followed by a 15 min incubation at 25°C. TR-FRET signals were detected using an EnVision multimode plate reader (excitation = 320 nm; emission = 615 and 655 nm). Dose-response curves were used to measure EC as a measure of responsiveness to the GLP-1R control peptide. 50Values ​​were generated. Selected cell lines were monitored for responsiveness over multiple passages to ensure stability. CHO-K1_hGLP-1Rhigh_clone16 and CHO-K1_hGLP-1Rlow_clone10 showed consistently high and low responsiveness to the GLP-1R control peptide, respectively, and were selected for further analysis to determine the relative levels of GLP-1R surface expression. Briefly, GLP-1R expression was analyzed by flow cytometry using a fluorescein-labeled exendin-4 peptide fluorescent probe (FLEX). Cells were harvested in Versene solution and washed three times with PBS+0.5% BSA before being incubated with FLEX reagent (10 μM) for 2 h at room temperature. After incubation, cells were washed three times in PBS+0.5% BSA before a final resuspension in PBS before analysis by flow cytometry to measure FLEX mean fluorescence intensity (MFI), as a measure of GLP-1R expression on the cell surface. Both cell lines showed high MFI values ​​compared to control CHO-K1 cells, confirming GLP-1R surface expression; CHO-K1_hGLP-1Rhigh_clone16 cells showed significantly higher MFI levels compared to CHO-K1-hGLP-1low_clone10 cells.

[0221] For compound testing in the CHO-K1_hGLP-1Rlow_clone10 cell line, cells were seeded in 384-well plates (1,000 cells / well). Test compounds were serially diluted in DMSO (10-point, 3-fold dilutions) and added to the wells using an echo dispenser (10 nL / well), 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 against a control GLP-1 peptide agonist run in parallel. EC was calculated by fitting the percent activation as a function of compound concentration using the Hill equation (XLfit). 50 value was determined.

[0222] Hepatic clearance Hepatic clearance, or the liver's ability to extract and metabolize drugs as they pass through the liver, is controlled by liver blood flow (Q), protein binding (fu), and the intrinsic ability of liver enzymes to metabolize drugs (CLint). CLint is a measure of the theoretical unlimited maximum clearance of unbound drug by the clearing organ in the absence of blood flow or plasma protein binding limitations. This term relates to the functional reserves 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.

[0223] Route of Administration The compounds of the present disclosure, or pharma- ceutically acceptable salts thereof, may be administered alone as monotherapy or in addition to one or more other substances and / or treatments. Such combination treatment may be achieved by way of simultaneous, sequential or separate administration of the individual components of the treatment.

[0224] For example, therapeutic efficacy may be enhanced by administration of an adjuvant (i.e., the adjuvant itself may have minimal therapeutic benefit, but when combined with another therapeutic agent, the overall therapeutic benefit to the individual is enhanced). Alternatively, by way of example only, the benefit experienced by an individual may be increased by administering a compound of formula (I) together with another therapeutic agent (including a treatment regimen) that also has therapeutic benefit.

[0225] When the compound of the present disclosure is administered in combination with other therapeutic agents, the compound of the present disclosure does not need to be administered by the same route as the other therapeutic agents, and may be administered by different routes due to different physical and chemical properties.For example, the compound of the present disclosure may be administered orally to generate and maintain good blood levels, and the other therapeutic agents may be administered intravenously.The initial administration may be performed according to established protocols known in the art, and then, based on the observed effects, the dosage, mode of administration, and administration time may be modified by those skilled in the art.

[0226] The particular choice of other therapeutic agent will depend on the attending physician's diagnosis and judgment of the individual's condition and appropriate treatment protocol. According to this aspect of the disclosure, there is provided a combination for use in treating a disease in which GLP-1R activity is implicated, the combination comprising a compound of the disclosure as defined herein, or a pharma- ceutically acceptable salt thereof, and another suitable agent.

[0227] According to a further aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, in combination with a suitable pharma- ceutically acceptable diluent or carrier.

[0228] In addition to their use in therapeutic agents, the compounds of formula (I) and pharma- ceutically acceptable salts thereof are also useful as pharmacological tools in the development and standardization of in vitro and in vivo test systems for the evaluation of the effects of modulators of GLP-1R activity in laboratory animals such as dogs, rabbits, monkeys, minipigs, rats, and mice as part of the search for new therapeutic agents.

[0229] In any of the above pharmaceutical composition, process, method, use, medicament, and manufacture features of the present disclosure, any of the alternative embodiments of the macromolecules of the present disclosure described herein also apply.

[0230] The compounds of the present disclosure or pharmaceutical compositions containing these compounds may be administered to a subject by any route of administration, whether systemic / peripheral or local (ie, to the desired site of action).

[0231] Routes of administration include, but are not limited to, oral (e.g., by ingestion), buccal, sublingual, transdermal (e.g., by patch, plaster, etc.), transmucosal (e.g., by patch, plaster, etc.), intranasal (e.g., by nose spray or powder), intraocular (e.g., by eye drops), pulmonary (e.g., by inhalation or insufflation therapy, e.g., via an aerosol, e.g., using through the mouth or nose), rectal (e.g., by suppository or enema), intravaginal (e.g., by pessary), parenteral, including injection, e.g., subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, subarachnoid, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal, and the like, depot or reservoir implant, e.g., subcutaneous or intramuscular. EXAMPLES

[0232] For illustrative purposes, neutral compounds of formula (I) are synthesized and tested in the Examples. It is understood that neutral compounds of formula (I) can be converted to pharma- ceutically acceptable salts of the corresponding compounds using techniques in the art (e.g., by saponifying an ester to a carboxylate, or by hydrolyzing an amide to form the corresponding carboxylic acid, and then converting the carboxylic acid to a carboxylate). [Table 2-1] [Table 2-2]

[0233] Example 1. Preparation of Compound 1 [ka] To a solution of the indicated precursor (50 mg, 88.09 umol, 1 equiv) in DMF (5 mL) was added HATU (40.20 mg, 105.71 umol, 1.2 equiv) and DIPEA (34.16 mg, 264.28 umol, 46.03 uL, 3 equiv) at 20°C. After the mixture was stirred at 20°C for 0.5 h, methylamine (7.14 mg, 105.71 umol, 1.2 equiv, HCl) was added to the mixture at 20°C and the reaction was stirred at 20°C for 7.5 h. TLC (petroleum ether:ethyl acetate=1:2, product Rf=0.25) showed the starting material had disappeared and a new main spot was detected. LCMS (MS m / z 581.3 (M+H)) showed the desired product MS. The mixture was poured into water (15 mL) and extracted with ethyl acetate (10 mL*3). The combined ethyl acetate was washed with brine (15 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (ethyl acetate:petroleum ether=2:1). Compound 1 (24.40 mg, 39.17 umol, 44.46% yield, 93.2% purity) was obtained as a white solid. LCMS (Rt=3.004 min, MS m / z 581.2 (M+H)). 1H NMR(400 MHz, methanol-d4)δ ppm 8.07(s,1 H),7.87(s,1 H),7.81-7.76(m,1 H),7.75-7.68(m,1 H),7.65-7.51(m,3 H),7.43(t,J=8.0 Hz,1 H),7.11(s,1 H),6.23(d,J=8.0 Hz,1 H),6.13(d,J=7.6 Hz,1 H),5.89(s,2 H),5.41(s,2 H),3.94(s,2 H),3.29(m,4 H),2.95(s,3 H),2.50(t,J=4.8 Hz,4 H).

[0234] Example 2. Preparation of Compound 2 [ka] To a solution of the indicated precursor (40 mg, 70.48 umol, 1 equiv) in DMF (1 mL) was added HATU (32.16 mg, 84.57 umol, 1.2 equiv) and DIPEA (27.32 mg, 211.43 umol, 36.83 uL, 3 equiv) at 20°C. After the mixture was stirred at 20°C for 0.5 h, NH4Cl (15.08 mg, 281.90 umol, 4 equiv) was added to the mixture at 20°C and the reaction was stirred at 20°C for 7.5 h. TLC (ethyl acetate:methanol=10:1, product Rf=0.33) showed that the starting material had disappeared and a new main spot was detected. The mixture was poured into water (15 mL) and extracted with ethyl acetate (10 mL*3). The combined ethyl acetate was washed with brine (15 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (ethyl acetate:methanol=10:1). Compound 2 (28.05 mg, 46.69 umol, yield 66.25%, purity 96.65%) was obtained as a white solid and checked by HPLC. 1H NMR(400 MHz,DMSO-d6)δ ppm 8.17(s,1 H),8.04(s,1 H),7.92(br s,1 H),7.88-7.86(d,J=10.0 Hz,1 H),7.79(d,J=8.4 Hz,1 H),7.72-7.60(m,3 H),7.44(t,J=8.0 Hz,1 H),7.32(br s,1 H),7.13(s,1 H),6.28(d,J=8.0 Hz,1 H),6.10(d,J=8.0 Hz,1 H),5.84(s,2 H),5.37(s,2 H),3.86(s,2 H),3.19(m,4 H),2.40(m,4 H).LCMS: RT=2.270 min, MS calculated value: 566.5, [M+H]+=567.2

[0235] Example 3. Preparation of Compound 3 [ka] To a solution of the indicated precursor (50 mg, 88.09 umol, 1 equiv) in DMF (3 mL) was added HATU (40.20 mg, 105.71 umol, 1.2 equiv) and DIPEA (34.16 mg, 264.28 umol, 46.03 uL, 3 equiv) at 20°C. After the mixture was stirred at 20°C for 0.5 h, 2,2,2-trifluoroethanamine (43.63 mg, 440.47 umol, 34.63 uL, 5 equiv) was added to the mixture at 20°C and the reaction was stirred at 20°C for 7.5 h. The mixture was poured into water (15 mL) and extracted with ethyl acetate (20 mL*3). The combined ethyl acetate was washed with brine (15 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (ethyl acetate:methanol=10:1). Compound 3 was obtained as a white solid. LCMS (MS m / z 649.3 (M+H)). 1H NMR (400 MHz, methanol-d4) δ ppm 8.14(s,1 H),7.87(s,2 H),7.85-7.83(d,J=7.6 Hz,1 H),7.75-7.73(d,J=7.6 Hz,1 H),7.52-7.62(m,3 H),7.43(t,J=8.0 Hz,1 H),7.12(s,1 H),6.23(d,J=8.07 Hz,1 H),6.13(d,J=7.82 Hz,1 H),5.91(s,2 H),5.41(s,2 H),4.12(q,J=9.2 Hz,2 H),3.95(s,2 H),3.30-3.26(m,4 H),2.51(m,4 H).

[0236] Example 4. Preparation of Compound 4 [ka] To a solution of the indicated precursor (70 mg, 123.33 umol, 1 equiv) in DCM (3 mL) was added 2-chloro-1-methyl-pyridin-1-ium iodine (37.81 mg, 148.00 umol, 1.2 equiv), methanesulfonamide (23.46 mg, 246.67 umol, 2 equiv), and DMAP (1.51 mg, 12.33 umol, 0.1 equiv) at 20° C. The reaction was stirred at 20° C. for 10 min, after which TEA (37.44 mg, 370.00 umol, 51.50 uL, 3 equiv) was added to the mixture at 20° C. The reaction was stirred at 20° C. for 16 h. TLC (dichloromethane:methanol=10:1, product Rf=0.60) showed that SM had disappeared and a new main spot was detected. The mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL*3). The combined ethyl acetate was washed with brine (15 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (dichloromethane:methanol=10:1). Compound 4 (26.45 mg, 38.65 umol, 31.34% yield, 94.20% purity) was obtained as a white solid. 1H NMR(400 MHz,CDCl3-d)δ ppm 1H NMR(400 MHz,CDCl3)δ ppm 8.14(s,1H),7.81(d,J=8.4 Hz,1H),7.74-7.68(m,1H),7.62-7.55(m,2H),7.43(m,2H),7.34(d,J=9.6 Hz,1H),7.04(s,1H),6.12-6.21(m,2H),5.79(s,2H),5.42(s,2H),3.98(s,2 H),3.39(m,7H),2.61(m,4H).LCMS: RT=2.229 min, MS calculated value: 644.7, [M+H]+=645.2.

[0237] Example 5. Preparation of Compound 5 [ka] To intermediate 1 (500 mg, 3.01 mmol, 1 equiv) and intermediate 2 (314.68 mg, 3.61 mmol, 1.2 equiv) in a solution of THF (30 mL) and DMF (4 mL) was added TEA (609.18 mg, 6.02 mmol, 837.93 uL, 2 equiv). The mixture was stirred at 60 °C for 16 h. TLC (petroleum ether:ethyl acetate = 3:1, Rf = 0.3) showed that a new spot was formed. The mixture was quenched with water (40 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic phase was washed with brine (20 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:1). Intermediate 3 (740 mg, crude) was obtained as a yellow solid. 1 H NMR(400MHz,chloroform-d)δ 8.42(br s,1H),8.28(d,J=8.8 Hz,1H),7.29(d,J=1.1 Hz,1H),6.91(dd,J=1.4,8.7 Hz,1H),5.17(dt,J=3.7,7.6 Hz,1H),4.83-4.73(m,1H),4.62(td,J=6.1,9.2 Hz,1H),3.57(t,J=5.0 Hz,2H),2.88-2.75(m,1H),2.69-2.57(m,1H).

[0238] [ka] To a solution of intermediate 3 (0.49 g, 2.10 mmol, 1 equiv.) in EtOH (20 mL), TEA (425.20 mg, 4.20 mmol, 584.87 uL, 2 equiv.) and NH2OH.HCl (292.00 mg, 4.20 mmol, 2 equiv.) were added. The mixture was stirred at 85° C. for 2 h. TLC (petroleum ether:ethyl acetate=0:1, R f =0.42) indicated that a new spot was formed. The reaction mixture was concentrated. H2O (30 mL) was added and the aqueous phase was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 0:1). Intermediate 4 (0.48 g, 1.80 mmol, 85.81% yield) was obtained as a yellow solid. 1 H NMR(400MHz, methanol-d4)δ 8.42(br s,1H),8.15(d,J=9.0 Hz,1H),7.34(d,J=1.5 Hz,1H),6.98(dd,J=1.8,9.0 Hz,1H),5.22-5.10(m,1H),4.77-4.69(m,1H),4.65-4.57(m,1H),3.78-3.61(m,2H),2.84-2.72(m,1H),2.68-2.55(m,1H).

[0239] [ka] To a solution of intermediate 4 (0.6 g, 2.25 mmol, 1 equiv) in THF (30 mL) was added CDI (730.80 mg, 4.51 mmol, 2 equiv) and TEA (456.06 mg, 4.51 mmol, 627.32 uL, 2 equiv). The mixture was stirred at 40 °C for 16 h. Another batch of CDI (365.40 mg, 2.25 mmol, 1 equiv) and TEA (228.03 mg, 2.25 mmol, 313.66 uL, 1 equiv) was added. The mixture was stirred at 40 °C for 4 h. The reaction mixture was concentrated. NH4Cl (50 mL) was added and the aqueous phase was extracted with ethyl acetate (50 mL x 3) and DCM: i-PrOH = 10:1 (50 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was stirred in ethyl acetate (5 mL) for 10 minutes and then filtered. The filter cake was washed with MeCN (3 mL×2). Intermediate 5 (0.6 g, 2.05 mmol, 91.11% yield) was obtained as a yellow solid. 1 H NMR(400MHz, methanol-d4)δ 8.25(d,J=8.8 Hz,1H),7.53(d,J=1.7 Hz,1H),7.38(s,1H),7.12(dd,J=1.7,8.9 Hz,1H),5.23-5.11(m,1H),4.77-4.69(m,1H),4.60(td,J=6.0,9.2 Hz,1H),3.78-3.63(m,2H),2.85-2.73(m,1H),2.63(tdd,J=7.2,9.1,11.3 Hz,1H).

[0240] [ka] To a solution of intermediate 5 (0.55 g, 1.88 mmol, 1 equiv) in EtOH (20 mL) was added Na2S2O3 (2.62 g, 15.06 mmol, 3.28 mL, 8 equiv) in H2O (16 mL). The mixture was stirred at 25 °C for 5 min. The mixture was concentrated to remove EtOH. H2O (50 mL) was added and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The product was used in the next step without purification. Intermediate 6 (410 mg, 1.56 mmol, 83.07% yield) was obtained as a yellow solid. 1 H NMR (400MHz, methanol-d4)δ 7.03-6.99(m,2H),6.74(d,J=8.4 Hz,1H),5.11(dq,J=4.2,6.9 Hz,1H),4.73(dt,J=5.9,8.0 Hz,1H),4.62(td,J=6.0,9.1 Hz,1H),3.52-3.36(m,2H),2.80-2.71(m,1H),2.60(tdd,J=7.2,9.1,11.1 Hz,1H).

[0241] [ka] To a solution of intermediate 7 (0.5 g, 1.61 mmol, 1 equiv) and ethyl 2-bromoacetate (295.00 mg, 1.77 mmol, 195.37 uL, 1.1 equiv) in MeCN (20 mL) was added K2CO3 (1.11 g, 8.03 mmol, 5 equiv) at 20 °C. The mixture was stirred at 60 °C for 3 h. The reaction mixture was filtered and the cake was washed with ethyl acetate (20 mL). The filtrate was concentrated and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1 to 5: 1). Intermediate 8 (430 mg, 1.08 mmol, 67.37% yield) was obtained as a yellow oil. 1H NMR(400MHz,chloroform-d)δ 7.64(t,J=7.5 Hz,1H),7.54(t,J=7.8 Hz,1H),7.45(d,J=7.9 Hz,1H),7.38(d,J=9.3 Hz,1H),6.78(d,J=7.3 Hz,1H),6.65(d,J=8.2 Hz,1H),5.57-5.49(m,2H),4.22(q,J=7.1 Hz,2H),3.27(s,2H),3.07(br d,J=11.5 Hz,2H),2.66-2.52(m,1H),2.39-2.27(m,2H),1.96(dq,J=3.6,12.3 Hz,2H),1.89-1.80(m,2H),1.30(t,J=7.2 Hz,3H).

[0242] [ka] To a solution of intermediate 8 (450 mg, 1.13 mmol, 1 equiv) in MeOH (2 mL) and THF (5 mL) was added dropwise a solution of NaOH (67.93 mg, 1.70 mmol, 1.5 equiv) in H2O (5 mL). The mixture was stirred at 25 °C for 2 h. The mixture was concentrated to remove THF and MeOH. Then 1M HCl was added dropwise until pH 5. H2O (30 mL) was added and the aqueous phase was extracted with ethyl acetate (30 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The product was used in the next step without purification. Intermediate 9 (0.7 g, crude) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 7.91(dd,J=1.3,10.0 Hz,1H),7.80-7.66(m,4H),6.93(d,J=7.2 Hz,1H),6.78(d,J=8.2 Hz,1H),5.53-5.48(m,2H),4.06(s,2H),3.94-3.85(m,1H),3.55(br d,J=12.2 Hz,1H),3.16(br s,1H),2.92-2.83(m,1H),2.76(br s,1H),2.07-1.96(m,3H).

[0243] [ka] To a solution of intermediate 9 (507.05 mg, 1.37 mmol, 1.8 equiv) and intermediate 6 (200 mg, 762.59 umol, 1 equiv) in DMF (5 mL) was added HATU (434.94 mg, 1.14 mmol, 1.5 equiv) and DIEA (197.12 mg, 1.53 mmol, 265.66 uL, 2 equiv). The mixture was stirred at 25° C. for 16 h. The mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL×3). The combined organic phase was washed with brine (20 mL×3), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was identified by preparative TLC (ethyl acetate:methanol=5:1, R f =0.32) to give intermediate 10 (180 mg, 293.33 umol, 38.47% yield) as a yellow solid. 1 H NMR(400MHz,chloroform-d)δ 9.38(br s,1H),8.03(s,1H),7.65-7.52(m,3H),7.43(br d,J=7.7 Hz,1H),7.33(br d,J=9.5 Hz,1H),7.15(br s,2H),6.80(d,J=7.1 Hz,1H),6.67(d,J=8.2 Hz,1H),5.50(s,2H),5.02(br s,1H),4.64(br d,J=6.8 Hz,1H),4.58-4.49(m,2H),4.31(br s,1H),3.92(s,1H),3.29(br s,2H),3.08(br d,J=9.0 Hz,2H),2.65(br d,J=7.3 Hz,2H),2.49(br s,3H),1.94(br s,3H).

[0244] [ka] To a solution of intermediate 10 (170 mg, 277.04 umol, 1 eq.) in toluene (6 mL), PTSA (23.85 mg, 138.52 umol, 0.5 eq.) was added. The mixture was stirred at 120°C for 4 h. The mixture was concentrated. The crude product was purified by preparative HPLC (NH4HCO3). Column: Waters Xbridge Prep OBD C18 150*40mm*10um; Mobile phase: [Water (10 mM NH4HCO3)-ACN]; B%: 25%~40%, 8 min, compound 5 (12.01 mg, 19.55 umol, 7.06% yield, 96.96% purity) was obtained as a white solid. 1 H NMR (400MHz, methanol-d4)δ 8.10(s,1H),7.79-7.65(m,3H),7.65-7.49(m,3H),6.85(d,J=7.2 Hz,1H),6.70(d,J=8.0 Hz,1H),5.52(s,2H),5.29(m,1H),4.74(m,1H),4.66(m,2H),4.50(m,1H),4.17-4.09(d,J=13.6 Hz,1H),4.05-3.98(d,J=13.6 Hz,1H),3.16(m,1H),3.05(m,1H),2.87-2.78(m,1H),2.73-2.63(m,1H),2.60-2.52(m,1H),2.50-2.37(m,2H),1.94-1.82(m,4H).LCMS:[M+H] + =596.3.

[0245] Example 6. Preparation of Compound 6 [ka] To a solution of intermediate 5A (300 mg, 1.08 mmol, 1 equiv.) and 1-(bromomethyl)-4-chloro-2-fluoro-benzene (289.03 mg, 1.29 mmol, 1.2 equiv.) in toluene (1 mL) at 20°C, Ag2CO3 (594.39 mg, 2.16 mmol, 97.76 uL, 2 equiv.) was added. The mixture was stirred at 80°C for 16 h. The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=80:1 to 20:1). Intermediate 5B (390 mg, 926.58 umol, 85.97% yield) was obtained as a colorless oil. 1 H NMR(400 MHz, methanol-d4)δ ppm 7.58(t,J=7.8 Hz,1H),7.48(t,J=8.3 Hz,1H),7.23-7.15(m,2H),6.82(d,J=7.3 Hz,1H),6.64(d,J=8.3 Hz,1H),5.40(s,2H),4.16(br d,J=13.2 Hz,2H),2.94-2.72(m,3H),1.85-1.76(m,2H),1.73-1.61(m,2H),1.49(s,9H).

[0246] [ka] A solution of Intermediate 5B (370 mg, 879.06 umol, 1 equiv) in HCl / dioxane (15 mL) was stirred at 20° C. for 0.5 h. The solution was concentrated to remove the solvent. Intermediate 5 was obtained as a white solid. 1 H NMR(400 MHz, methanol-d4)δ ppm 8.07(t,J=8.0 Hz,1H),7.58(t,J=8.1 Hz,1H),7.34-7.25(m,2H),7.19(dd,J=5.0,7.9 Hz,2H),5.53(s,2H),3.53(br d,J=12.8 Hz,2H),3.23-3.07(m,3H),2.22-2.00(m,4H).

[0247] [ka] To a solution of intermediate 1 (0.8 g, 3.00 mmol, 1 equiv.) and [(2S)-oxetan-2-yl]methanamine (391.56 mg, 4.49 mmol, 1.5 equiv.) in DMF (14 mL) and THF (7 mL) was added TEA (606.39 mg, 5.99 mmol, 834.10 uL, 2 equiv.) at 20° C. The solution was stirred at 25° C. for 16 h. The mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL*3). The combined ethyl acetate was washed with H2O (20 mL*3), brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=80:1 to 20:1). Intermediate 2 (681 mg, 2.04 mmol, 68.03% yield) was obtained as a yellow solid. 1 H NMR (400 MHz, methanol-d4) δ ppm 8.34(br s,1H),7.84(d,J=8.9 Hz,1H),7.53(d,J=1.6 Hz,1H),7.04(dd,J=1.7,8.9 Hz,1H),5.15-5.07(m,1H),4.72(dt,J=6.1,8.0 Hz,1H),4.58(td,J=6.0,9.2 Hz,1H),3.68-3.53(m,2H),2.81-2.71(m,1H),2.61(tdd,J=7.2,9.1,11.3 Hz,1H).

[0248] [ka] A solution of Na2S2O3 (1.16g, 6.66mmol, 1.45mL, 8eq) in H2O (10mL) was added to a solution of intermediate 2 (278mg, 832.06umol, 1eq) in THF (10mL) at 0℃, and the solution was stirred at 50℃ for 16h. The solution was concentrated to remove most of the THF. The mixture was extracted with ethyl acetate (10mL*3). The combined ethyl acetate was washed with brine (15mL), dried over Na2SO4, filtered and concentrated. Intermediate 3 (197mg, crude) was obtained as a yellow oil. 1H NMR(400 MHz, methanol-d4)δ ppm 6.90-6.82(m,2H),6.48(d,J=8.1 Hz,1H),5.05(dq,J=4.2,6.9 Hz,1H),4.75-4.67(m,1H),4.60(td,J=6.0,9.1 Hz,1H),3.41-3.32(m,1H),2.78-2.68(m,1H),2.64-2.52(m,1H).

[0249] [ka] To a solution of intermediate 3 (197 mg, 647.76 umol, 1 equiv) in EtOH (10 mL), 2-chloro-1,1,1-trimethoxy-ethane (600.83 mg, 3.89 mmol, 522.46 uL, 6 equiv) was added at 20 °C, and the mixture was stirred at 70 °C for 16 h. The mixture was concentrated to remove most of the solvent. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 80:1 to 20:1). Intermediate 4 (180 mg, 496.42 umol, 76.64% yield) was obtained as a yellow solid. 1 H NMR (400 MHz, methanol-d4) δ ppm 8.05(d,J=1.3 Hz,1H),7.60(dd,J=1.5,8.5 Hz,1H),7.45(d,J=8.6 Hz,1H),5.17(dq,J=2.4,7.1 Hz,1H),5.08-4.96(m,2H),4.70-4.49(m,3H),4.38(td,J=6.0,9.2 Hz,1H),2.76(dtd,J=6.1,8.1,11.5 Hz,1H),2.44(tdd,J=7.3,9.1,11.4 Hz,1H).

[0250] [ka] K2CO3 (411.65 mg, 2.98 mmol, 6 equiv) was added to a solution of intermediate 4 (180 mg, 496.42 umol, 1 equiv) and intermediate 5 (283.76 mg, 794.28 umol, 1.6 equiv, HCl) in CH3CN (1 mL) at 20°C, and the mixture was stirred at 50°C for 16 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified by preparative TLC (petroleum ether / ethyl acetate=3:1). Intermediate 6 (280 mg, 389.54 umol, 78.47% yield, 90% purity) was obtained as a yellow solid. 1 H NMR (400 MHz, methanol-d4) δ ppm8.03(d,J=1.2 Hz,1H),7.60-7.53(m,2H),7.49(s,1H),7.41(d,J=8.6 Hz,1H),7.24-7.14(m,2H),6.82(d,J=7.2 Hz,1H),6.63(d,J=8.1 Hz,1H),5.42(s,2H),5.24(dq,J=2.5,7.2 Hz,1H),4.78(s,2H),4.67-4.59(m,2H),4.45(s,1H),4.00-3.93(m,1H),3.87-3.80(m,1H),3.08-3.00(m,1H),2.91(br d,J=12.2 Hz,1H),2.85-2.74(m,1H),2.69-2.58(m,1H),2.56-2.45(m,1H),2.36-2.19(m,2H),1.91-1.78(m,4H).

[0251] [ka] Xphos Pd G2 (29.43 mg, 37.41 umol, 0.1 equiv.) and N-cyclohexyl-N-methyl-cyclohexanamine (219.22 mg, 1.12 mmol, 238.03 uL, 3 equiv.) were added to CH 3 Intermediate 6 (242 mg, 374.08 umol, 1 equiv) and ethyl prop-2-ynoate (110.09 mg, 1.12 mmol, 110.09 uL, 3The mixture was added to a solution of 1000 ml of ethyl acetate (10 mL*3) at 20°C and the mixture was stirred at 80°C for 4 hours. The mixture was poured into water (15 mL) and extracted with ethyl acetate (10 mL*3). The combined ethyl acetate was washed with brine (15 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=80:1-20:1) and TLC (petroleum ether:ethyl acetate=1:1). Intermediate 7 (110 mg, 160.43 umol, 42.89% yield, 90% purity) was obtained as a yellow solid. 1 H NMR(400 MHz, methanol-d4)δ ppm 8.00-7.97(m,1H),7.66(d,J=8.4 Hz,1H),7.57(t,J=7.8 Hz,1H),7.48(d,J=8.3 Hz,2H),7.20(s,2H),6.82(d,J=7.3 Hz,1H),6.63(d,J=8.2 Hz,1H),5.42(s,2H),5.30-5.21(m,1H),4.70-4.60(m,2H),4.57(s,1H),4.49(td,J=5.9,9.1 Hz,1H),4.28(q,J=7.1 Hz,2H),4.03-3.97(m,1H),3.88(d,J=13.8 Hz,1H),3.04(br d,J=8.9 Hz,1H),2.92(br d,J=11.0 Hz,1H),2.86-2.74(m,1H),2.71-2.60(m,1H),2.57-2.47(m,1H),2.38-2.20(m,2H),1.92-1.78(m,5H),1.33(t,J=7.1 Hz,3H).

[0252] [ka] NH2OH.HCl (51.24 mg, 737.31 umol, 3.5 eq) and KOH (94.55 mg, 1.69 mmol, 8 eq) were added to a solution of intermediate 7 (130 mg, 210.66 umol, 1 eq) in MeOH (6 mL) at 20°C. The solution was stirred at 20°C for 16 h. The mixture was poured into water (15 mL) and extracted with ethyl acetate (10 mL*3). The combined ethyl acetate was washed with brine (15 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (ethyl acetate:methanol=10:1). Compound 6 (30.46 mg, 48.76 umol, 23.14% yield, 96.69% purity) was obtained as a white solid. 1 H NMR(400 MHz, methanol-d4)δ ppm 8.07(s,1H),7.73-7.65(m,2H),7.57(t,J=7.6 Hz,1H),7.49(t,J=8.0 Hz,1H),7.23-7.15(m,2H),6.82(d,J=7.2 Hz,1H),6.63(d,J=8.2 Hz,1H),6.33(s,1H),5.41(s,2H),5.32-5.24(m,1H),4.91(m,1H),4.73(d,J=15.4 Hz,1H),4.67-4.61(m,1H),4.48(m,1H),4.08-4.01(d,J=13.6 Hz,1H),3.95-3.89(d,J=13.6 Hz,1H),3.09(m,1H),2.97(m,1H),2.87-2.76(m,1H),2.70-2.61(m,1H),2.59-2.49(m,1 H),2.41-2.26(m,2H),1.94-1.82(m,4H).LCMS: RT=2.395 min, MS calculated value: 604.0, [M+H]+=604.3.

[0253] Example 7. Preparation of Compound 7 Compound 7 was prepared in a similar manner to compound 1. 1H NMR(400MHz,CDCl3)δ ppm 7.99(s,1H),7.84(d,J=8.4 Hz,1H),7.68(d,J=8.4 Hz,1H),7.42(t,J=8.0 Hz,1H),7.38-7.32(m,1H),7.26-7.21(m,2H),6.16(m,2H),5.35(s,2H)5.25(m,1H),4.81-4.63(m,3H),4.48(m,1H), 4.05-3.94(s,2H),3.57-3.43(m,4H),2.86-2.71(m,1H),2.65(m,4H),2.58-2.43(m,1H).LCMS:[M+H]+=650.2, 652.2.

[0254] Example 8. Preparation of Compound 8 [ka] Compound 8 was prepared according to the scheme depicted herein. 1 H NMR(400 MHz,DMSO-d6)δ 8.35(s,1 H),7.92-7.84(m,2 H),7.80-7.76(d,J=8.4 Hz,1 H),7.73-7.70(m,2 H),7.68-7.64(t,J=8.0 Hz,1 H),6.90(d,J=8.0 Hz,1 H),6.74(d,J=8.0 Hz,1 H),5.48(s,2 H),5.20-5.12(m,1 H),4.86-4.77(m,1 H),4.72-4.65(m,1 H),4.55-4.47(m,1 H),4.43(m,1 H),4.07-4.00(d,J=13.6 Hz,1 H),3.91-3.84(d,J=13.6 Hz,1 H),3.06(m,1 H),2.98-2.89(m,1 H),2.76-2.67(m,2 H),2.44(m,1 H),2.34-2.21(m,2 H),1.82-1.69(m,4 H).LCMS:[M+H] + =580.2

[0255] Example 9. Preparation of Compound 9 Compound 9 was prepared according to the methods disclosed herein. 1H NMR(400 MHz,MeOD)δ ppm 8.93(s,1 H),7.84(s,1 H),7.71-7.64(t,J=7.2 Hz,1 H),7.62-7.52(m,3 H),7.45(s,1 H),7.40-7.37(s,1 H),6.80(d,J=7.2 Hz,1 H),6.67(d,J=8.0 Hz,1 H),5.87(s,2 H),5.51(s,2 H),3.75(s,2 H),3.53-3.46(d,J=2.0 Hz,2 H),2.98-2.90(m,2 H),2.66-2.53(m,1 H),2.25-2.16(m,2 H),1.80-1.62(m,4 H).LCMS:[M+H] + =598.2

[0256] Example 10. Preparation of Compound 10 Compound 10 was made in a similar manner to compound 8. WO2022 / 040600, incorporated herein by reference, is also useful in the preparation of compound 10. 1 H NMR(400 MHz,DMSO-d6)δ ppm 8.90(s,1 H),8.19(s,1 H),7.98(s,1 H),7.88(m,2 H),7.75(d,J=8.4 Hz,1 H),7.71-7.59(m,4 H),6.92(d,J=7.2 Hz,1 H),6.65(d,J=8.0 Hz,1 H),5.91(s,2 H),5.41(s,2 H),3.88(d,J=13.6 Hz,1 H),3.77(d,J=13.6 Hz,1 H),2.89-2.65(m,2 H),2.43-2.33(m,3 H),1.94-1.85(m,1 H),1.65(m,1 H),1.04(m,1 H),0.79(m,1 H).LCMS:[M+H] + =619.1

[0257] Example 11. Preparation of Compound 11 Compound 11 was made in a similar manner to compound 8. 1H NMR(400 MHz,MeOD)δ ppm 8.94(s,1 H),8.25(s,1 H),8.05(s,1 H),8.03-8.00(dd,J=8.4,1.2 Hz,1 H),7.80(d,J=8.4 Hz,1 H),7.70(t,J=8.0 Hz,1 H),7.65-7.54(m,3 H),6.85(d,J=7.2 Hz,1 H),6.70(d,J=8.0 Hz,1 H),6.05(s,2 H),5.54(s,2 H),4.03(s,2 H),3.17-3.09(m,2 H),2.74-2.62(m,1 H),2.47-2.35(m,2 H),1.90-1.79(m,4 H).LCMS:[M+H] + =607.4

[0258] Example 12. Preparation of Compound 12 [ka] Compound 12 was prepared according to the scheme depicted herein. 1 H NMR(400 MHz,DMSO-d6)δ ppm 10.75(br s,1 H),8.97(s,1 H),8.04(s,1 H),7.88(d,J=10.0 Hz,1 H),7.72-7.69(m,2 H),7.67(s,2 H),7.64-7.60(t,J=17.30,8.86 Hz,3 H),7.45(s,1 H),7.39(d,J=8.4 Hz,1 H),6.86(d,J=7.2 Hz,1 H),6.71(d,J=8.0 Hz,1 H),5.90(s,2 H),5.47(s,2 H),3.83(s,2 H),3.29(s,1 H),2.94(m,2 LCMS [M+H] + =622.1.

[0259] Example 13. Preparation of Compound 13 Compound 13 was made in a similar manner to compound 5. 1H NMR(400 MHz,DMSO-d6)δ ppm 8.98(s,1 H),8.08(s,1 H),8.03(s,1 H),7.91-7.86(d,J=6.4 Hz,1 H),7.78-7.74(d,J=8.4 Hz,1 H),7.73-7.69(m,3 H),7.68-7.63(t,J=8.0 Hz,1 H),6.87(d,J=7.2 Hz,1 H),6.72(d,J=8.0 Hz,1 H),5.98(s,2 H),5.48(s,2 H),3.88(s,2 H),2.97(m,2 H),2.65-2.54(m,1 H),2.26-2.15(m,2 H),1.79-1.62(m,4 H).LCMS:[M+H] + =623.4.

[0260] Example 14. Preparation of Compound 14 Compound 14 was made in a similar manner to compound 1. 1 H NMR(400 MHz,MeOD)δ ppm 8.07(s,1 H),7.71-7.65(m,3 H),7.63-7.52(m,3 H),6.84(d,J=7.2 Hz,1 H),6.69(d,J=8.0 Hz,1 H),5.52(s,2 H),5.32-5.25(m,1 H),4.91(m,1 H),4.71(m,1 H),4.68-4.62(m,1 H),4.49(m,1 H),4.11-4.06(d,J=13.6 Hz,1 H),3.98-3.92(d,J=13.6 Hz,1 H),3.11(,1 H),2.98(m,1 H),2.87-2.77(m,1 LCMS:[M+H] + =571.1.

[0261] Example 15. Preparation of Compound 15 [ka] Compound 15 was prepared according to the scheme depicted herein. 1H NMR(400 MHz,DMSO-d6)δ ppm 8.96(s,1 H),8.01(s,1 H),7.88(d,J=9.6 Hz,1 H),7.77(s,1 H),7.72-7.68(m,2 H),7.67-7.60(m,2 H),7.46(dd,J=8.4,1.6 Hz,1 H),6.86(d,J=7.2 Hz,1 H),6.71(d,J=8.0 Hz,1 H),6.37(br s,1 H),5.90(s,2 H),5.47(s,2 H),4.81-4.78(d,J=6.4 Hz,2 H),4.74(d,J=6.4 Hz,2 H),3.84(s,2 H),2.94(m,2 H),2.62-2.54(m,1 H),2.22-2.14(m,2 H),1.76-1.61(m,4 H).LCMS:[M+H] + =611.20.

[0262] Example 16. Preparation of Compound 16 [ka] Separately from this intermediate, compound 16 was prepared in a similar manner to compound 8. 1 H NMR(400 MHz,MeOD)δ ppm 8.12(s,1 H),7.86(d,J=8.4 Hz,1 H),7.70-7.62(m,2 H),7.52(d,J=10.4 Hz,1 H),7.44(dd,J=8.0,1.2 Hz,1 H),6.73-6.66(t,J=8.0 Hz,1 H),6.65-6.59(m,2 H),5.22-5.12(m,1 H),4.57-4.51(m,2 H),4.40-4.35(m,1 H),4.30-4.25(m,2 H),3.42-3.26(m,2 H),2.81-2.65(m,4 H),2.52-2.38(m,1 H),1.98(s,3 H),1.91-1.83(m,4 H).LCMS [M+H] + =607.2.

[0263] Example B1. Biological activity of compounds of the present disclosure The biological activity of the compounds of the present disclosure was determined utilizing the assays described herein.

[0264] EC of exemplary compounds in low expression assay 50 The values ​​are shown in Table B1 below. The compounds tested were compound samples prepared according to the general procedures described in the Examples section. [Table 3]

[0265] Example B2: Pharmacokinetics in rats Intravenous dosing: 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 dosing. Compounds were administered to male 7-11 week old Sprague-Dawley rats at a dose of 1 mg / kg via jugular vein cannula infusion over 30 minutes.

[0266] Oral dosing: 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). The formulated compounds were administered by gavage to male 7-11 week old Sprague-Dawley rats at a dose of 10 mL / kg.

[0267] Sample collection: Approximately 0.2 mL of blood was collected per time point from the jugular vein or other suitable site of each animal into pre-chilled commercial EDTA-K2 tubes and placed on wet ice until centrifugation. Blood samples were processed for plasma by centrifugation at 3,200 g for 10 min at approximately 4° C. Plasma was collected and transferred to pre-labeled 96-well plates or polypropylene tubes, quickly frozen on dry ice, and kept at −60° C. or below until LC-MS / MS analysis.

[0268] Data Analysis: Plasma concentration versus time data were plotted on graphs and analyzed by a non-compartmental analysis approach using the Phoenix WinNonlin 6.3 software program, or higher builds. Relevant PK parameters were analyzed according to the route of administration, e.g., CL for intravenous administration, V dss and C0, C for extravascular administration. max , T max or F%, as well as T for all routes 1 / 2 , AUC (0-t) , AUC (0-inf) , MRT (0-t) , MRT (0-inf) was calculated. [Table 4]

[0269] Example B3: Metabolic stability in hepatocytes Test compounds were incubated in rat and human hepatocytes to assess stability from a substrate decay approach. Test compounds were dissolved in dimethyl sulfoxide (DMSO) to make 10 mM stocks and then further diluted to make 1000x working stocks of 1 mM 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 emptied 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 shaking the tube as if spinning it in a centrifuge tube and resuspended in 4 mL of warm Dulbecco's Modified Eagle Medium (DMEM). Cell density was determined by cell counter by Nexcelom and DMEM medium was added to obtain a target density of 1×106 cells / mL. The assay was performed in 96-well microtiter plates. Test compounds were added at a concentration of 1 μM at 1×106 cells / mL in DMEM. 6 The mixtures were incubated with 1000 cells / mL of hepatocytes for 0, 30, 60, 120, and 240 min. Incubations were performed at 37 °C under a humidified atmosphere of 95% air / 5% CO2 with gentle shaking. The volume of the incubation mixture was 37 μL with a final 0.1% DMSO. At each time point, the incubation was stopped by adding 150 μL of quenching solution (100% acetonitrile, 0.1% bucetin with formic acid as internal standard for positive ESI mode). The mixtures were then vortexed for 20 min and centrifuged at 4,000 rpm at 10 °C. The supernatants (80 μL) were transferred to a clean 96-well plate and analyzed by LC-MS / MS. 1 μM midazolam with a final 0.1% DMSO was included as a positive control to verify the assay performance. Percent parent remaining, intrinsic and predicted hepatic clearance, and t 1 / 2was calculated. All samples were analyzed by LC-MS / MS using an AB Sciex API4000 instrument coupled to a Shimadzu LC-20AD LC pump system. Separation was achieved using a Waters Atlantis T3 dC18 reversed-phase HPLC column (20 mm x 2.1 mm) at a flow rate of 0.5 mL / min. The mobile phase consisted of 0.1% formic acid in water (solvent A) and 0.1% formic acid in 100% acetonitrile (solvent B). The elution conditions are detailed below. [Table 5]

[0270] The ion optics for each test compound were optimized for their declustering potential (DP), collection energy (CE), collision cell exit potential (CXP) and used in 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 its initial concentration. The initial rate of clearance of the test compound was calculated using a linear regression plot of the semi-log% of the compound remaining versus time. The elimination rate constant (k) from the linear regression plot was then used to calculate the t 1 / 2 and inherent clearance (CL int ) was determined (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

[0271] This method of intrinsic clearance determination assumes that the test compound concentration is well below the compound's Michaelis-Menten constant for its metabolic enzyme.

[0272] Predicted hepatic clearance (CL hep ) is the normalized CL based on liver weight int(インビボ)was used and calculated using the well-stirred method using the following formula: CL int(インビボ) =CL int x Liver cellularity x Liver weight CL hep予測 =(CL int(インビボ) ×Q 肝臓 ) / (CL int(インビボ) +Q 肝臓 ) In the formula, Q 肝臓 ((ml / min / kg) is the hepatic blood flow

[0273] The relevant physiological parameters of liver weight, blood flow, and liver cellularity for various species are listed below. [Table 6]

[0274] The results are presented in Table B3 below for intrinsic clearance (mL / min / kg) and half-life (t1 / 2). [Table 7]

[0275] Example B4. Passive permeability and flux ratio Caco-2 cells (clone C2BBe1) were obtained from American Type Culture Collection (Manassas, VA). Cell monolayers were grown to confluence on collagen-coated microporous membranes in 12-well assay plates. Details of the plates and their authentication are given below. The permeability assay buffer was Hanks' balanced salt solution containing 10 mM HEPES and 15 mM glucose at pH 7.4. The buffer in the receiver chamber also contained 1% bovine serum albumin. The dosing solution concentration was 5 μM of test article in assay buffer. Cell monolayers were dosed apically (A to B) or basolaterally (B to A) and incubated at 37°C with 5% CO2 in a humidified incubator. Samples were taken from the donor and receiver chambers at 120 min. Each measurement was performed in duplicate. Lucifer Yellow flux was also measured after the experiment for each monolayer to ensure that no damage was done to the cell monolayer during the flux period. All samples were assayed by LC-MS / MS using electrospray ionization. Apparent permeability (P app ) and percent recovery was calculated as follows: P app =(dC r / dt) × V r / (A×C A )(1) Percent recovery = 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 (units: μM s -1 ) and V r is the volume of the receiver compartment in cm 3 ) and V d is the volume of the donor compartment (unit: cm 3 ), and A is the area of ​​the insert (1.13 cm 2, 12 wells) and C A is the average of the nominal dose concentration and the measured 120 min donor concentration (in μM), and C N is the nominal concentration of the dosing solution (unit: μM), and C r 最終 is the cumulative receiver concentration at the end of the incubation period (unit: μM), and C d 最終 is the concentration of donor at the end of the incubation period (in μM). The efflux ratio (ER) is the ratio of P app (B to A) / P app It is defined as (A to B). [Table 8]

[0276] Equivalent The details of one or more embodiments of the present disclosure are described in the accompanying description above. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred methods and materials are described herein. Other features, objects, and advantages of the present disclosure will be apparent from the description and claims. In this specification and the appended claims, the singular form includes the plural reference unless the context clearly dictates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. All patents and publications cited herein are incorporated by reference.

[0277] The foregoing description has been presented for illustrative purposes only and is not intended to limit the disclosure to the precise form disclosed, but rather to be limited by the scope of the claims appended hereto.

Claims

1. Formula (I): 【Chemistry 1】 [In the formula: X is N or CH; Y is N or CR ４ and n is 0 or 1; R is hydrogen; R １ Ha-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 alkyl, and R ４ is hydrogen, OH or C １ ~C ６ Is it alkyl? Or, R ３ and R ４ together with the carbon atom to which they are attached, optionally halo or C １ ~C ３ C substituted by alkyl ３ ~C ６ Forming a cycloalkyl; R ５ is a 5-6 membered heteroaryl (optionally halo, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ alkenyl, or C １ ~C ６ substituted by haloalkyl; R ７ teeth, 【Chemistry 2】 or selected from the group consisting of or R ７ is -C(O)NH-R ８ where R ８ is hydrogen, -OH, -S(O) ２ -C １ ~C ６ alkyl, or —C optionally substituted by halo １ ~C ６ is alkyl; Ring A is a 5- to 12-membered heterocyclyl, a 5- to 12-membered heteroaryl, or C ６ ~C １４ aryl, each of which independently is optionally selected from halo, oxo, —CN, C ３ ~C ６ cycloalkyl, or C optionally substituted by halo or OH １ ~C ６ substituted by alkyl; L is a bond, —O—, C １ ~C ６ Alkylene, *—O—C １ ~C ６ Alkylene-**, *-C １ ~C ６ Alkylene-O-**, or *-NR ６ -C １ ~C ６ alkylene-**, where: * represents the point of attachment to ring A, and ** represents the point of attachment to ring B; L is *-O-C １ ~C ６ When alkylene-** is C １ ~C ６ The alkylene may optionally be R Ｌ where each R Ｌ are independently １ ~C ６ alkyl or halo, or two R Ｌ together with one or more carbon atoms to which they are attached, C ３ ~C ６ forming a cycloalkyl or a 3- to 6-membered heterocyclyl; L is C １ ~C ６ When C is alkylene, １ ~C ６ The alkylene may optionally be R Ｌ１ where each R Ｌ１ are independently halo, OH, oxo, or C １ ~C ６ alkyl or two R Ｌ１ together with one or more carbon atoms to which they are attached, C ３ ~C ６ forming a cycloalkyl or a 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 optionally selected from halo, CN, oxo, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, —C(O)CH ３ , —C(O)NH ２ , -S(O) ２ CH ３ , cyclopropyl, and phenyl. or a pharmaceutically acceptable salt thereof.

2. n is 1; X is N; R ２ is hydrogen; R ５ is an optionally substituted 5-membered heteroaryl containing 1 or 2 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; R ７ but, 【Transformation 7】 -C(O)NHCH ３ , —C(O)NH ２ , C(O)NHCH ２ CF ３ ,C(O)NHS(O) ２ CH ３ or C(O)NHOH; Ring A is an optionally substituted 6-9 membered heteroaryl; L is a bond or *-O-CH ２ -**; Ring B is phenyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo and cyano; 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

3. R ５ Optionally, halo, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ alkenyl, or C １ ~C ６ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, which is a 5-membered heteroaryl substituted by haloalkyl.

4. R ５ but, 【Chemistry 12】 3. The compound of claim 1 or 2, wherein:

5. R ７ but, 【Chemistry 13】 3. The compound of claim 1 or 2, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

6. R ７ is-C(O)NH-R ８ 3. The compound of claim 1 or 2, wherein:

7. R ８ is hydrogen, -OH, -S(O) ２ CH ３ , -CH ２ CF ３ , or -CH ３ 3. The compound of claim 1 or 2, wherein:

8. 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein ring A is a 6-membered heteroaryl.

9. Ring A is 【Chemistry 20】 3. The compound of claim 1 or 2, wherein:

10. 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein ring A is a 9-membered heterocyclyl.

11. Ring A is 【Chemistry 21】 3. The compound of claim 1 or 2, wherein

12. Formula (I): 【Chemistry 1】 [In the formula: X is N or CH; Y is N or CR ４ and n is 0 or 1; R is hydrogen; R １ Ha-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 alkyl, and R ４ is hydrogen, OH or C １ ~C ６ Is it alkyl? Or, R ３ and R ４ together with the carbon atom to which they are attached, optionally halo or C １ ~C ３ C substituted by alkyl ３ ~C ６ Forming a cycloalkyl; R ５ is a 3- to 6-membered heterocyclyl or a 5- to 6-membered heteroaryl, where R ５ The 3- to 6-membered heterocyclyl or 5- to 6-membered heteroaryl may independently optionally be selected from halo, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ alkenyl, or C １ ~C ６ substituted by haloalkyl; R ７ teeth, 【Chemistry 2】 or selected from the group consisting of or R ７ is -C(O)NH-R ８ where R ８ is hydrogen, -OH, -S(O) ２ -C １ ~C ６ alkyl, or —C optionally substituted by halo １ ~C ６ is alkyl; Ring A is a 6-membered heteroaryl (optionally halo, oxo, -CN, C ３ ~C ６ cycloalkyl or —C optionally substituted by halo or OH １ ~C ６ substituted by alkyl; L is a bond, —O—, C １ ~C ６ Alkylene, *—O—C １ ~C ６ Alkylene-**, *-C １ ~C ６ Alkylene-O-**, or *-NR ６ -C １ ~C ６ alkylene-**, where: * represents the point of attachment to ring A, and ** represents the point of attachment to ring B; L is *-O-C １ ~C ６ When alkylene-** is C １ ~C ６ The alkylene may optionally be R Ｌ where each R Ｌ are independently １ ~C ６ alkyl or halo, or two R Ｌ together with one or more carbon atoms to which they are attached, C ３ ~C ６ forming a cycloalkyl or a 3- to 6-membered heterocyclyl; L is C １ ~C ６ When C is alkylene, １ ~C ６ The alkylene may optionally be R Ｌ１ where each R Ｌ１ are independently halo, OH, oxo, or C １ ~C ６ alkyl or two R Ｌ１ together with one or more carbon atoms to which they are attached, C ３ ~C ６ forming a cycloalkyl or a 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 optionally selected from halo, CN, oxo, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, —C(O)CH ３ , —C(O)NH ２ , -S(O) ２ CH ３ , cyclopropyl, and phenyl. or a pharmaceutically acceptable salt thereof: however, R ７ is-C(O)NH-R ８ and R １ but 【Transformation 3】 X is N, Y is CH, n is 1, and R ２ and R ３ are each hydrogen, ring A is a 6-membered heteroaryl, and L is *-OCH ２ When -**, ring B is 【Chemistry 4】 or a pharmaceutically acceptable salt thereof.

13. n is 1; X is N; R ２ is hydrogen; R ５ is an optionally substituted 5-membered heteroaryl containing 1 or 2 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, or an optionally substituted 4-membered heterocyclyl containing 1 oxygen atom; R ７ but, 【Transformation 7】 -C(O)NHCH ３ , —C(O)NH ２ , C(O)NHCH ２ CF ３ ,C(O)NHS(O) ２ CH ３ or C(O)NHOH; Ring A is an optionally substituted 6-membered heteroaryl; L is a bond or *-O-CH ２ -**; Ring B is phenyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo and cyano; 13. The compound of claim 12, or a pharmaceutically acceptable salt thereof.

14. R ５ But, Halo, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ alkenyl, or C １ ~C ６ 14. The compound of claim 12 or 13, or a pharmaceutically acceptable salt thereof, which is a 4-membered heterocyclyl containing one oxygen atom optionally substituted by haloalkyl.

15. R ５ but, 【Chemistry 9】 14. The compound of claim 12 or 13, wherein:

16. R ５ Optionally, halo, C １ ~C ６ Alkyl, C1-C6 alkoxy, C １ ~C ６ alkenyl, or C １ ~C ６ 14. The compound of claim 12 or 13, or a pharmaceutically acceptable salt thereof, which is a 5-membered heteroaryl substituted by haloalkyl.

17. R ５ but, 【Chemistry 11】 14. The compound of claim 12 or 13, wherein:

18. R ７ but, 【Chemistry 13】 14. The compound of claim 12 or 13, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

19. R ７ is -C(O)NH-R ８ 14. The compound of claim 12 or 13, wherein:

20. R ８ is hydrogen, -OH, -S(O) ２ CH ３ , -CH ２ CF ３ , or -CH ３ 14. The compound of claim 12 or 13, wherein:

21. Ring A is 【Chemistry 20】 14. The compound of claim 12 or 13, wherein:

22. Formula (I): 【Chemistry 1】 [In the formula, X is N or CH; Y is N or CR ４ and n is 0 or 1; R is hydrogen; R １ Ha-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 alkyl, and R ４ is hydrogen, OH or C １ ~C ６ Is it alkyl? or R ３ and R ４ together with the carbon atom to which they are attached, optionally represent halo or C １ ~C ３ C substituted by alkyl ３ ~C ６ Forming a cycloalkyl; R ５ is a 3- to 6-membered heterocyclyl or a 5- to 6-membered heteroaryl, and R ５ The 3- to 6-membered heterocyclyl or 5- to 6-membered heteroaryl independently optionally includes halo, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ alkenyl, or C １ ~C ６ substituted by haloalkyl; R ７ teeth, 【Chemistry 2】 or selected from the group consisting of or R ７ is -C(O)NH-R ８ where R ８ is -OH, -S(O) ２ -C １ ~C ６ alkyl, or —C optionally substituted by halo １ ~C ６ is alkyl; Ring A is a 5- to 12-membered heterocyclyl, a 5- to 12-membered heteroaryl, or C ６ ~C １４ aryl, each of which independently is optionally selected from halo, oxo, —CN, C ３ ~C ６ cycloalkyl, or C optionally substituted by halo or OH １ ~C ６ substituted by alkyl; L is a bond, —O—, C １ ~C ６ Alkylene, *—O—C １ ~C ６ Alkylene-**, *-C １ ~C ６ Alkylene-O-**, or *-NR ６ -C １ ~C ６ alkylene-**; * represents the point of attachment to ring A, and ** represents the point of attachment to ring B; L is *-O-C １ ~C ６ When alkylene-**, C １ ~C ６ The alkylene may optionally be R Ｌ and each R Ｌ are independently １ ~C ６ alkyl or halo, or two R Ｌ together with one or more carbon atoms to which they are attached, C ３ ~C ６ forming a cycloalkyl or a 3- to 6-membered heterocyclyl; L is C １ ~C ６ When it is alkylene, C １ ~C ６ The alkylene may optionally be R Ｌ１ and each R Ｌ１ are independently halo, OH, oxo, or C １ ~C ６ alkyl or two R Ｌ１ together with one or more carbon atoms to which they are attached, C ３ ~C ６ forming a cycloalkyl or a 3- to 6-membered heterocyclyl; R ６ is hydrogen or C １ ~C ６ alkyl; Ring B is C ３ ~C １０ Cycloalkyl, C ６ ~C １４ aryl, 4- to 12-membered heterocyclyl, or 5- to 12-membered heteroaryl, each of which is independently optionally selected from halo, CN, oxo, C1-C ６ Alkyl, C １ ~C ６ Haloalkyl, —C(O)CH ３ , —C(O)NH ２ , -S(O) ２ CH ３ , cyclopropyl, and phenyl. or a pharmaceutically acceptable salt thereof: however, R ７ is-C(O)NH-R ８ and R １ but 【Transformation 3】 X is N, Y is CH, n is 1, and R ２ and R ３ are each hydrogen, ring A is a 6-membered heteroaryl, and L is *-OCH ２ When -**, ring B is 【Chemistry 4】 is a group other than or a pharmaceutically acceptable salt thereof.

23. n is 1; X is N; R ２ is hydrogen; R ５ is an optionally substituted 5-membered heteroaryl containing 1 or 2 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, or an optionally substituted 4-membered heterocycle containing 1 oxygen atom; R ７ but 【Transformation 7】 -C(O)NHCH ３ , C(O)NHCH ２ CF ３ ,C(O)NHS(O) ２ CH ３ or C(O)NHOH; Ring A is an optionally substituted 6-9 membered heteroaryl; L is a bond or *—O—CH ２ -**; Ring B is phenyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo and cyano; 23. The compound of claim 22, or a pharmaceutically acceptable salt thereof.

24. R ５ Optionally, halo, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ alkenyl, or C １ ~C ６ 24. The compound of claim 22 or 23, or a pharmaceutically acceptable salt thereof, which is a 4-membered heterocyclyl containing one oxygen atom substituted by haloalkyl.

25. R ５ but, 【Chemistry 9】 24. The compound of claim 22 or 23, wherein:

26. R ５ Optionally, halo, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ alkenyl, or C １ ~C ６ 24. The compound of claim 22 or 23, or a pharmaceutically acceptable salt thereof, which is a 5-membered heteroaryl substituted by haloalkyl.

27. R ５ but, 【Chemistry 11】 24. The compound of claim 22 or 23, wherein:

28. R ７ but 【Chemistry 11】 24. The compound of claim 22 or 23, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

29. R ７ is-C(O)NH-R ８ 24. The compound of claim 22 or 23, wherein:

30. R ８ But -OH, -S(O) ２ CH ３ , -CH ２ CF ３ , or -CH ３ 24. The compound of claim 22 or 23, wherein:

31. 24. The compound of claim 22 or 23, or a pharmaceutically acceptable salt thereof, wherein Ring A is a 6-membered heteroaryl.

32. Ring A is 【Chemistry 11】 24. The compound of claim 22 or 23, wherein:

33. 24. The compound of claim 22 or 23, or a pharmaceutically acceptable salt thereof, wherein Ring A is a 9-membered heterocyclyl.

34. Ring A is 【Chemistry 11】 24. The compound of claim 22 or 23, wherein:

35. Formula Is: 【Transformation 5】 24. The compound of claim 1, 2, 12, 13, 22 or 23, or a pharmaceutically acceptable salt thereof, wherein:

36. Formula It: 【Transformation 6】 24. The compound of claim 1, 2, 12, 13, 22 or 23, or a pharmaceutically acceptable salt thereof, wherein:

37. R １ Ga-CH ２ -R ５ 24. The compound of any one of claims 1, 2, 12, 13, 22 or 23, or a pharmaceutically acceptable salt thereof.

38. X is N; n is 1; and / or Y is N or CR ４ That is, 24. A compound according to any one of claims 1, 2, 12, 13, 22 or 23, or a pharmaceutically acceptable salt thereof.

39. R ３ and R ４ 24. The compound of any one of claims 1, 2, 12, 13, 22 or 23, or a pharmaceutically acceptable salt thereof, wherein: together with the carbon atom to which they are attached form a cyclopropyl group.

40. L is *-O-CH ２ 24. The compound of any one of claims 1, 2, 12, 13, 22, or 23, or a pharmaceutically acceptable salt thereof, wherein -**.

41. Ring B is optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, and -CN. ６ 24. The compound of any one of claims 1, 2, 12, 13, 22 or 23, or a pharmaceutically acceptable salt thereof, which is aryl.

42. Ring B is 【Chemistry 22】 24. The compound of any one of claims 1, 2, 12, 13, 22 or 23, or a pharmaceutically acceptable salt thereof.

43. Table 1: Table 1 Table 2 Table 3 or a pharmaceutically acceptable salt thereof.

44. A pharmaceutical composition comprising a compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

45. 45. A medicament for treating a disease mediated by the glucagon-like peptide-1 receptor (GLP-1R) in an individual in need thereof, the medicament comprising a compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 44.

46. 46. ​​The method of claim 45, wherein the disease is a liver disease.

47. The pharmaceutical composition of claim 46, wherein the liver disease is primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), drug-induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition-associated cholestasis (PNAC), bacterial overgrowth or sepsis-associated cholestasis, autoimmune hepatitis, viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), graft-versus-host disease, transplant liver regeneration, congenital hepatic fibrosis, common bile duct stones, granulomatous liver disease, intrahepatic or extrahepatic malignancy, Sjogren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis, or Othie-antitrypsin deficiency.

48. 46. ​​The method of claim 45, wherein the disease is diabetes.

49. 46. ​​The method of claim 45, wherein the disease is a cardiometabolic disease.

50. 46. ​​The method of claim 45, wherein the disease is obesity.

Images