US20230150998A1 - Compounds as glp-1r agonists - Google Patents

Compounds as glp-1r agonists Download PDF

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US20230150998A1
US20230150998A1 US17/954,047 US202217954047A US2023150998A1 US 20230150998 A1 US20230150998 A1 US 20230150998A1 US 202217954047 A US202217954047 A US 202217954047A US 2023150998 A1 US2023150998 A1 US 2023150998A1
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compound
optionally substituted
alkyl
ring
halo
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Corey REEVES
F. Anthony Romero
Christopher T. Jones
Martijn Fenaux
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Terns Pharmaceuticals Inc
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Terns Inc
Terns Pharmaceuticals Inc
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Application filed by Terns Inc, Terns Pharmaceuticals Inc filed Critical Terns Inc
Publication of US20230150998A1 publication Critical patent/US20230150998A1/en
Assigned to TERNS PHARMACEUTICALS, INC. reassignment TERNS PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: FENAUX, MARTIJN
Assigned to TERNS PHARMACEUTICALS, INC. reassignment TERNS PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: Terns, Inc.
Assigned to Terns, Inc. reassignment Terns, Inc. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: REEVES, Corey, JONES, CHRISTOPHER T., ROMERO, F. ANTHONY
Priority to US18/956,385 priority patent/US20250282772A1/en
Priority to US19/018,788 priority patent/US12378238B2/en
Priority to US19/018,754 priority patent/US12378236B2/en
Priority to US19/018,817 priority patent/US12378239B2/en
Priority to US19/018,773 priority patent/US12378237B2/en
Priority to US19/018,805 priority patent/US12522596B2/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • Type 1 diabetes develops when the body's immune system destroys pancreatic beta cells, the only cells in the body that make the hormone insulin that regulates blood glucose. To survive, people with Type 1 diabetes must have insulin administered by injection or a pump.
  • Type 2 diabetes mellitus usually begins with either insulin resistance or when there is insufficient production of insulin to maintain an acceptable glucose level.
  • GLP-1R glucagon-like peptide-1 receptor
  • GLP-1 is a 30 amino acid long incretin hormone secreted by the L-cells in the intestine in response to ingestion of food. GLP-1 has been shown to stimulate insulin secretion in a physiological and glucose-dependent manner, decrease glucagon secretion, inhibit gastric emptying, decrease appetite, and stimulate proliferation of beta-cells. In non-clinical experiments GLP-1 promotes continued beta-cell competence by stimulating transcription of genes important for glucose-dependent insulin secretion and by promoting beta-cell neogenesis (Meier et al. Biodrugs. 2003; 17 (2): 93-102).
  • GLP-1 plays an important role regulating post-prandial blood glucose levels by stimulating glucose-dependent insulin secretion by the pancreas resulting in increased glucose absorption in the periphery. GLP-1 also suppresses glucagon secretion, leading to reduced hepatic glucose output. In addition, GLP-1 delays gastric emptying and slows small bowel motility delaying food absorption. In people with T2DM, the normal post-prandial rise in GLP-1 is absent or reduced (Vilsboll T, et al. Diabetes. 2001. 50; 609-613).
  • GLP-1 receptor agonists such as liraglutide and exendin-4
  • FPG and PPG fasting and postprandial glucose
  • GLP-1 receptor agonists for an easily-administered prevention and/or treatment for cardiometabolic and associated diseases.
  • GLP-1R glucagon-like peptide-1 receptor
  • composition comprising is a compound of Formula (I), including compounds of Formulae (II)-(VIII), or selected from the group consisting of a compound listed in Table 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • a method of treating a disease or a condition mediated by GLP-1R in a subject in need thereof comprises administering to the subject a therapeutically effective amount of a compound of Formula (I), including compounds of Formulae (II)-(VIII), or selected from the group consisting of compounds listed in Table 1, or a pharmaceutically acceptable salt thereof.
  • the disease or the condition is a cardiometabolic disease.
  • the disease or the condition is diabetes.
  • the disease or the condition is a liver disease.
  • kit comprising a compound of Formula (I), including compounds of Formulae (II)-(VIII), or selected from the group consisting of a compound listed in Table 1, or a pharmaceutically acceptable salt thereof.
  • the kit comprises instructions for use according to a method described herein.
  • a method of making a compound of Formula (I), including compounds of Formulae (II)-(VIII), or selected from the group consisting of a compound listed in Table 1, or a pharmaceutically acceptable salt thereof is also provided.
  • compound intermediates useful in synthesis of a compound of Formula (I), including compounds of Formulae (II)-(VIII), or selected from the group consisting of a compound listed in Table 1, or a pharmaceutically acceptable salt thereof are also provided.
  • the present disclosure provides a compound of Formula (I):
  • X is N or CH
  • Y is N or CR 4 ;
  • n 0 or 1;
  • R is hydrogen;
  • R 1 is —C 1 -C 6 alkylene-R 5 ;
  • R 2 is hydrogen, oxo, or C 1 -C 6 alkyl;
  • R 3 is hydrogen, oxo, or C 1 -C 6 alkyl and
  • R 4 is hydrogen, OH, or C 1 -C 6 alkyl; or
  • R 3 and R 4 are taken together with the carbon atoms to which they are attached to form C 3 -C 6 cycloalkyl optionally substituted by halo or C 1 -C 3 alkyl;
  • R 5 is 5-membered heterocyclyl or 5-membered heteroaryl, each of which comprises 1, 2, or 3 heteroatoms independently selected from O, N, and S, wherein at least one heteroatom of R 5 is S, and further wherein R 5 is optionally substituted by halo, —O—C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkenyl,
  • X is N. In some embodiments, X is CH.
  • Y is N. In some embodiments, Y is CR 4 . In some embodiments, Y is CR 4 , and R 3 and R 4 are taken together with the carbon atoms to which they are attached to form a cyclopropyl group.
  • n is 0. In some embodiments, n is 1.
  • R 1 is —CH 2 —R 5 .
  • R 5 is 5-membered heteroaryl comprising 1, 2, or 3 heteroatoms independently selected from O, N, and S, wherein at least one heteroatom of R 5 is S, and further wherein R 5 is optionally substituted by halo, —O—C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkenyl, or C 1 -C 6 haloalkyl.
  • R 5 is 5-membered heteroaryl comprising 1 or 2 heteroatoms selected from S and N, wherein one heteroatom of R 5 is S, and further wherein R 5 is optionally substituted by halo, —O—C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkenyl, or C 1 -C 6 haloalkyl.
  • R 5 is thiazolyl or isothiazolyl, each optionally substituted by halo, —O—C 1-6 alkyl, C 1 -C 6 alkyl, C 1-6 alkenyl, or C 1 -C 6 haloalkyl.
  • R 5 is thiazol-2-yl or thiazol-5-yl, each optionally substituted by C 1 -C 6 alkyl.
  • R 5 is or
  • R 5 is
  • Ring A is 5- to 6-membered heteroaryl optionally substituted by halo, CN, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkyl optionally substituted by halo or OH. In some embodiments, Ring A is 6-membered heteroaryl optionally substituted by halo, CN, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkyl optionally substituted by halo or OH.
  • Ring A is benzodioxolyl, pyridyl, pyrimidinyl, or pyrazinyl, each of which is optionally substituted by halo, CN, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkyl optionally substituted by halo or OH.
  • Ring A is benzodioxolyl, pyridyl, pyrimidinyl, or pyrazinyl.
  • Ring A is
  • Ring A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • L is *—O—C 1 -C 6 alkylene-** optionally substituted by R L .
  • L is *—O—CH 2 —** or *—O—CD 2 -**.
  • L is —O—.
  • L is a bond.
  • L is *—C(O)—CH 2 —**.
  • Ring B is C 6 -C 14 aryl, which is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 and phenyl.
  • Ring B is phenyl optionally substituted by one to three substituents each independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 and phenyl.
  • Ring B is phenyl optionally substituted by one to three substituents each independently selected from the group consisting of halo, CN, and —CONH 2 .
  • Ring B is
  • Ring B is 4- to 12-membered heterocyclyl, which is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 and phenyl.
  • Ring B is tetrahydroisoquinolinyl optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 and phenyl.
  • Ring B is
  • Ring B is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 and phenyl.
  • Ring B is
  • Ring B is
  • Ring B is a 5- to 12-membered heteroaryl, which is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 and phenyl.
  • Ring B is a 9-membered heteroaryl, which is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 and phenyl.
  • Ring B is 9-membered heteroaryl, which is optionally substituted by one to two substituents independently selected from the group consisting of halo and CN.
  • Ring B is
  • the compound is of Formula VIII:
  • R 7 is hydrogen, chloro, bromo, fluoro, methyl, or vinyl
  • R 7 is hydrogen
  • the compound is a meglumine salt.
  • the present disclosure provides a compound, or pharmaceutically acceptable salt thereof, wherein the compound is selected any one of the compounds in Table 1 other than Reference Compound A.
  • the compound selected from any one of the compounds in Table 1 other than Reference Compound A is a meglumine salt.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of Formula I-VIII or Compound 1-31, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the present disclosure provides a method of treating a disease mediated by glucagon-like peptide-1 receptor (GLP-1R) in an individual in need thereof, comprising administering to the individual any one of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, or any pharmaceutical composition disclosed herein.
  • GLP-1R glucagon-like peptide-1 receptor
  • the disease is a liver disease.
  • the liver disease is primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), drug induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition associated cholestasis (PNAC), bacterial overgrowth or sepsis associated cholestasis, autoimmune hepatitis, viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), graft versus host disease, transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intra- or extrahepatic malignancy, Sjogren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis, or oti-antitrypsin deficiency.
  • PBC primary biliary cir
  • the disease is a cardiometabolic disease. In some embodiments, the disease is obesity.
  • the present disclosure provides the use of any one of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease mediated by GLP-1R.
  • the present disclosure provides a method of decreasing food intake in an individual in need thereof, comprising administering to the individual any one of the compounds, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions disclosed herein.
  • the present disclosure provides a method of increasing glucose tolerance in an individual in need thereof, comprising administering to the individual any one of the compounds, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions disclosed herein.
  • FIG. 1 shows plasma concentrations of Compound 2 and Reference Compound A after oral (PO) administration to rats (3 mg/kg).
  • FIG. 2 shows plasma concentrations of compounds 2, 3, and 4 after oral (PO) administration to rats (0.3 mg/mL, 3 mg/kg).
  • FIG. 3 shows plasma concentrations of compounds 2 and 14 after oral (PO) administration to rats (0.6 mg/mL, 3 mg/kg).
  • FIG. 4 is a timeline that shows the experimental design of the C57BL/6 mouse food intake study.
  • FIG. 5 shows the reduction in food intake caused by Compound 2, Reference Compound A, and liraglutide in C57BL/6 mice that express human GLP-1R.
  • FIG. 6 is a timeline that shows the experimental design of the C57BL/6 mouse glucose tolerance study.
  • FIG. 7 shows the concentration of glucose over time in the blood of C57BL/6 mice that express human GLP-1R following an IP glucose bolus and the administration of Compound 2, Reference Compound A, and liraglutide.
  • FIG. 8 shows the area under the glucose concentration vs time curve shown in FIG. 7 .
  • FIG. 9 shows the concentration of glucose in the blood of C57BL/6 mice expressing wild type mouse GLP-1R (triangles) and humanized GLP-1R (circles) following IP glucose bolus and administration of Compound 2 or liraglutide.
  • FIG. 10 shows the area under the glucose concentration vs. time curve shown in FIG. 9 .
  • FIGS. 11 A and 11 B depicts total ( 11 A) and unbound ( 11 B) Compound 2 in hGLP-1R mice from IPGTT evaluation at various amounts of Compound 2.
  • FIGS. 12 A and 12 B depicts total ( 12 A) and unbound ( 12 B) Reference Compound A in hGLP-1R mice from IPGTT evaluation at various amounts of Reference Compound A.
  • this disclosure relates to compounds that the present inventors have discovered agonize GLP-1R.
  • the present inventors have discovered new GLP-1R agonists that have superior pharmacokinetic properties (e.g., Cmax, AUC 0-last ) relative to alternative GLP-1R agonists, are potent agonists of GLP-1R, and, in humanized animal models, effectuate the improvement of disease-relevant phenotypes such as food intake and glucose tolerance.
  • the benefits of the presently-disclosed compounds could not have been predicted a priori.
  • This disclosure also relates to compositions comprising the GLP-1R agonists disclosed herein and the use of the GLP-1R agonists in treating diseases.
  • compositions and methods include the recited elements, but not exclude others.
  • Consisting essentially of when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination. For example, a composition consisting essentially of the elements as defined herein would not exclude other elements that do not materially affect the basic and novel characteristic(s) of the claimed invention.
  • Consisting of shall mean excluding more than trace amount of, e.g., other ingredients and substantial method steps recited. Embodiments defined by each of these transition terms are within the scope of this invention.
  • excipient means an inert or inactive substance that may be used in the production of a drug or pharmaceutical, such as a tablet containing a compound of the invention as an active ingredient.
  • a drug or pharmaceutical such as a tablet containing a compound of the invention as an active ingredient.
  • Various substances may be embraced by the term excipient, including without limitation any substance used as a binder, disintegrant, coating, compression/encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspending/gelling agent, or wet granulation agent.
  • “Pharmaceutically acceptable” refers to safe and non-toxic, preferably for in vivo, more preferably, for human administration.
  • “Pharmaceutically acceptable salt” refers to a salt that is pharmaceutically acceptable. A compound described herein may be administered as a pharmaceutically acceptable salt.
  • Salt refers to an ionic compound formed between an acid and a base.
  • such salts include, without limitation, alkali metal, alkaline earth metal, and ammonium salts.
  • ammonium salts include, salts containing protonated nitrogen bases and alkylated nitrogen bases.
  • Exemplary and non-limiting cations useful in pharmaceutically acceptable salts include Na, K, Rb, Cs, NH4, Ca, Ba, imidazolium, and ammonium cations based on naturally occurring amino acids, and ammonium cations that are not based on naturally occurring amino acids, e.g., meglumine.
  • salts include, without limitation, salts of organic acids, such as carboxylic acids and sulfonic acids, and mineral acids, such as hydrogen halides, sulfuric acid, phosphoric acid, and the likes.
  • exemplary and non-limiting anions useful in pharmaceutically acceptable salts include oxalate, maleate, acetate, fumarate, propionate, succinate, tartrate, chloride, sulfate, bisulfate, mono-, di-, and tribasic phosphate, mesylate, tosylate, and the likes.
  • Stereoisomer or “stereoisomers” refers to compounds that differ in the stereogenicity of the constituent atoms such as, without limitation, in the chirality of one or more stereocenters or related to the cis or trans configuration of a carbon-carbon or carbon-nitrogen double bond. Stereoisomers include enantiomers and diastereomers.
  • the term “subject” refers to an animal, including, but are not limited to, a primate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.
  • a primate e.g., human
  • monkey cow, pig, sheep, goat
  • horse dog, cat, rabbit, rat
  • patient are used interchangeably herein in reference, for example, to a mammalian subject, such as a human.
  • treatment is an approach for obtaining beneficial or desired results including clinical results.
  • beneficial or desired results include, but are not limited to, one or more of the following: decreasing one or more symptoms resulting from the disease or disorder, diminishing the extent of the disease or disorder, stabilizing the disease or disorder (e.g., preventing or delaying the worsening of the disease or disorder), delaying the occurrence or recurrence of the disease or disorder, delaying or slowing the progression of the disease or disorder, ameliorating the disease or disorder state, providing a remission (whether partial or total) of the disease or disorder, decreasing the dose of one or more other medications required to treat the disease or disorder, enhancing the effect of another medication used to treat the disease or disorder, delaying the progression of the disease or disorder, increasing the quality of life, and/or prolonging survival of a patient.
  • treatment is a reduction of pathological consequence of the disease or disorder. The methods of this disclosure contemplate any one or more of these aspects of treatment
  • glucose tolerance refers to the ability of a subject to dispose of a glucose load or a subject's glycemic control.
  • “Therapeutically effective amount” or dose of a compound or a composition refers to that amount of the compound or the composition that results in reduction or inhibition of symptoms or a prolongation of survival in a patient. The results may require multiple doses of the compound or the composition.
  • Alkyl refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 12 carbon atoms, preferably from 1 to 10 carbon atoms, and more preferably from 1 to 6 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH 3 —), ethyl (CH 3 CH 2 —), n-propyl (CH 3 CH 2 CH 2 —), isopropyl ((CH 3 ) 2 CH—), n-butyl (CH 3 CH 2 CH 2 CH 2 —), isobutyl ((CH 3 ) 2 CHCH 2 —), sec-butyl ((CH 3 )(CH 3 CH 2 )CH—), t-butyl ((CH 3 ) 3 C—), n-pentyl (CH 3 CH 2 CH 2 CH 2 CH 2 —), and neopentyl ((CH 3 ) 3 CCH 2 —).
  • Cx alkyl refers to an alkyl
  • Alkylene refers to a divalent saturated aliphatic hydrocarbyl group having from 1 to 12 carbon atoms, preferably from 1 to 10 carbon atoms, and more preferably from 1 to 6 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methylene (—CH 2 —), ethylene (—CH 2 CH 2 — or —CH(Me)-), propylene (—CH 2 CH 2 CH 2 — or —CH(Me)CH 2 —, or —CH(Et)-) and the like.
  • Alkoxy refers to the group —O-alkyl wherein alkyl is defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, and n-pentoxy.
  • Aryl refers to a monovalent aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl (Ph)) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-one-7-yl, and the like) provided that the point of attachment is at an aromatic carbon atom.
  • Preferred aryl groups include phenyl and naphthyl.
  • Cyano refers to the group —C—N.
  • Cycloalkyl refers to saturated or unsaturated but nonaromatic cyclic alkyl groups of from 3 to 10 carbon atoms, preferably from 3 to 8 carbon atoms, and more preferably from 3 to 6 carbon atoms, having single or multiple cyclic rings including fused, bridged, and spiro ring systems.
  • Cx cycloalkyl refers to a cycloalkyl group having x number of ring carbon atoms. Examples of suitable cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl.
  • One or more the rings can be aryl, heteroaryl, or heterocyclic provided that the point of attachment is through the non-aromatic, non-heterocyclic ring saturated carbocyclic ring.
  • “Substituted cycloalkyl” refers to a cycloalkyl group having from 1 to 5 or preferably 1 to 3 substituents selected from the group consisting of 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
  • Halo or “halogen” refers to fluoro, chloro, bromo and iodo and preferably is fluoro or chloro.
  • “Hydroxy” or “hydroxyl” refers to the group —OH.
  • Heteroaryl refers to an aromatic group of from 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur within the ring.
  • Such heteroaryl groups can have a single ring (e.g., pyridinyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl) wherein the condensed rings may or may not be aromatic and/or contain a heteroatom provided that the point of attachment is through an atom of the aromatic heteroaryl group.
  • the nitrogen and/or the sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N ⁇ O), sulfinyl, or sulfonyl moieties.
  • Preferred heteroaryls include 5 or 6 membered heteroaryls such as pyridinyl, pyrrolyl, thiophenyl, thiazole, and furanyl.
  • Other preferred heteroaryls include 9 or 10 membered heteroaryls, such as indolyl, quinolinyl, quinolonyl, isoquinolinyl, and isoquinolonyl.
  • Heterocycle or “heterocyclic” or “heterocycloalkyl” or “heterocyclyl” refers to a saturated or partially saturated, but not aromatic, group having from 1 to 10 ring carbon atoms, preferably from 1 to 8 carbon atoms, and more preferably from 1 to 6 carbon atoms, and from 1 to 4 ring heteroatoms, preferably from 1 to 3 heteroatoms, and more preferably from 1 to 2 heteroatoms selected from the group consisting of nitrogen, sulfur, or oxygen.
  • Cx heterocycloalkyl refers to a heterocycloalkyl group having x number of ring atoms including the ring heteroatoms.
  • Heterocycle encompasses single ring or multiple condensed rings, including fused bridged and spiro ring systems.
  • fused ring systems one or more the rings can be cycloalkyl, aryl or heteroaryl provided that the point of attachment is through the non-aromatic ring.
  • the nitrogen and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, sulfinyl (S(O)), sulfonyl (S(O) 2 ) moieties.
  • heterocyclyl and heteroaryl include, but are not limited to, azetidinyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazyl, pyrimidyl, pyridazyl, indolizyl, isoindolyl, indolyl, dihydroindolyl, indazolyl, purinyl, quinolizinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthylpyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, acridinyl, phenanthrolinyl, isothiazolyl, phenazinyl, isoxazolyl, phenoxazinyl, phenothiaziny
  • Oxo refers to the atom ( ⁇ O) or (O).
  • the terms “optional” or “optionally” as used throughout the specification means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
  • “the nitrogen atom is optionally oxidized to provide for the N-oxide (N ⁇ O) moiety” means that the nitrogen atom may but need not be oxidized, and the description includes situations where the nitrogen atom is not oxidized and situations where the nitrogen atom is oxidized.
  • Optionally substituted unless otherwise specified means that a group may be unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4 or 5) of the substituents listed for that group in which the substituents may be the same of different.
  • an optionally substituted group has one substituent.
  • an optionally substituted group has two substituents.
  • an optionally substituted group has three substituents.
  • an optionally substituted group has four substituents.
  • an optionally substituted group has 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, or 2 to 5 substituents.
  • an optionally substituted group is unsubstituted.
  • an optionally substituted moiety can be substituted with more than five substituents, if permitted by the number of valences available for substitution on the moiety.
  • a propyl group can be substituted with seven halogen atoms to provide a perhalopropyl group.
  • the substituents may be the same or different.
  • X is N or CH
  • Y is N or CR 4 ;
  • n 0 or 1;
  • R is hydrogen;
  • R 1 is —C 1 -C 6 alkylene-R 5 ;
  • R 2 is hydrogen, oxo, or C 1 -C 6 alkyl;
  • R 3 is hydrogen, oxo, or C 1 -C 6 alkyl, and
  • R 4 is hydrogen, OH, or C 1 -C 6 alkyl; or
  • R 3 and R 4 are taken together with the carbon atoms to which they are attached to form C 3 -C 6 cycloalkyl optionally substituted by halo or C 1 -C 3 alkyl;
  • R 5 is 5-membered heterocyclyl or 5-membered heteroaryl, each of which comprises 1, 2, or 3 heteroatoms independently selected from O, N, and S, wherein at least one heteroatom of R 5 is S, and further wherein R 5 is optionally substituted by halo, —O—C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkenyl
  • X and Y are each N.
  • X is N and Y is CR 4 .
  • X is N, Y is CR 4 , and R 4 is H, OH, or C 1 -C 6 alkyl.
  • X is N, Y is CR 4 , and R 4 is H, OH, or C 1 -C 3 alkyl.
  • X is N, Y is CR 4 , and R 4 is H or C 1 -C 3 alkyl.
  • X is N, Y is CR 4 , and R 4 is H or OH.
  • X is N, Y is CR 4 , and R 4 is H. In some embodiments, X is N, Y is CR 4 , and R 3 and R 4 are taken together with the carbon atoms to which they are attached to form a cyclopropyl group optionally substituted by halo or C 1 -C 3 alkyl In some embodiments, X is N, Y is CR 4 , and R 3 and R 4 are taken together with the carbon atoms to which they are attached to form a cyclopropyl group optionally substituted by fluoro or methyl.
  • X is N and Y is CR 4 .
  • the compound is of Formula (II-a):
  • n, R 2 , R 3 , R 4 , R 5 , Ring A, L, and Ring B are as defined for Formula (I).
  • X is N
  • Y is CR 4
  • R 3 and R 4 are taken together with the carbon atoms to which they are attached to form a cyclopropyl group optionally substituted by halo or C 1 -C 3 alkyl.
  • the compound is of Formula (II-b), (II-b1), or (II-b2):
  • n, R 2 , R 5 , Ring A, L, and Ring B are as defined for Formula (I).
  • X and Y are each N.
  • the compound is of Formula (II-c):
  • n, R 2 , R 3 , R 5 , Ring A, L, and Ring B are as defined for Formula (I).
  • Ring A is a 6-membered heteroaryl comprising 1, 2, or 3 heteroatoms.
  • the compound is of formula (III):
  • V and W are independently N or CR A , wherein each R A is H, halo, CN, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkyl optionally substituted by halo or OH.
  • V is N and W is CR A .
  • V is CR A and W is N.
  • V and W are each CR A .
  • V and W are each N.
  • V is N and W is CH.
  • V is CH and W is N.
  • V and W are each CH.
  • X is N and Y is CR 4 .
  • the compound is of formula (III-a):
  • n, R 2 , R 3 , R 4 , R 5 , L, and Ring B are as defined for Formula (I), and V and W are as defined for formula (III).
  • X is N
  • Y is CR 4
  • R 3 and R 4 are taken together with the carbon atoms to which they are attached to form a cyclopropyl group optionally substituted by halo or C 1 -C 3 alkyl.
  • the compound is of Formula (III-b), (III-b1), or (III-b2):
  • n, R 2 , R 5 , L, and Ring B are as defined for Formula (I), and V and W are as defined for formula (III).
  • the compound is of formula (III-b-3):
  • n, R 2 , R 5 , L, and Ring B are as defined for Formula (I).
  • X and Y are each N.
  • the compound is of Formula (III-c):
  • n, R 2 , R 3 , R 5 , L, and Ring B are as defined for Formula (I), and V and W are as defined for formula (III).
  • L is *—O—C 1 -C 6 alkylene-**, optionally substituted by R L as described for Formula (I). In some embodiments, L is *—O—CH 2 —**. In some embodiments, the compound is of Formula (IV):
  • n, R 2 , R 3 , R 5 , and Ring B are as defined for Formula (I), and V and W are as defined for formula (III).
  • X is N and Y is CR 4 .
  • the compound is of formula (IV-a):
  • n, R 2 , R 3 , R 4 , R 5 , and Ring B are as defined for Formula (I), and V and W are as defined for formula (III).
  • X is N
  • Y is CR 4
  • R 3 and R 4 are taken together with the carbon atoms to which they are attached to form a cyclopropyl group optionally substituted by halo or C 1 -C 3 alkyl.
  • the compound is of Formula (IV-b), (IV-b1), or (IV-b2):
  • n, R 2 , R 5 , and Ring B are as defined for Formula (I), and V and W are as defined for formula (III).
  • the compound is of formula (IV-b-3):
  • n, R 2 , R 5 , L, and Ring B are as defined for Formula (I).
  • L is —O—.
  • the compound is of Formula (V):
  • n, R 2 , R 3 , R 5 , and Ring B are as defined for Formula (I), and V and W are as defined for formula (III).
  • X is N and Y is CR 4 .
  • the compound is of formula (V-a):
  • n, R 2 , R 3 , R 4 , R 5 , and Ring B are as defined for Formula (I), and V and W are as defined for formula (III).
  • X is N
  • Y is CR 4
  • R 3 and R 4 are taken together with the carbon atoms to which they are attached to form a cyclopropyl group optionally substituted by halo or C 1 -C 3 alkyl.
  • the compound is of Formula (V-b), (V-b1), or (V-b2):
  • n, R 2 , R 5 , and Ring B are as defined for Formula (I), and V and W are as defined for formula (III).
  • the compound is of formula (V-b3):
  • n, R 2 , R 5 , L, and Ring B are as defined for Formula (I).
  • X is N
  • Y is CR 4
  • R 3 and R 4 are taken together with the carbon atoms to which they are attached to form a C 3 -C 6 cycloalkyl
  • n, R 2 , Ring A, and Ring B are as detailed herein for Formula (I).
  • Y is CR 4 ; R 3 and R 4 are taken together with the carbon atoms to which they are attached to form a C 3 -C 6 cycloalkyl; Ring B is optionally substituted phenyl; and X, n, R 2 , and Ring A are as detailed herein for Formula (I).
  • R 3 and R 4 are taken together with the carbon atoms to which they are attached to form a C 3 cycloalkyl.
  • X is N.
  • n is 1.
  • R 2 is H.
  • Ring A is pyridinyl.
  • X is N, n is 1, and R 2 is H.
  • X is N; Y is CR 4 ; R 4 is H; and n, R 2 , R 3 , Ring A, and Ring B are as detailed herein for Formula (I).
  • X is N; Y is CR 4 ; R 4 is H; Ring B is C 3 -C 10 cycloalkyl, 4- to 12-membered heterocyclyl, or 5- to 12-membered heteroaryl, each of which is independently optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 , and phenyl; and n, R 2 , R 3 , and Ring A are as detailed herein for Formula (I).
  • X is N; Y is CR 4 ; R 4 is H; Ring B is 4- to 12-membered heterocyclyl, or 5- to 12-membered heteroaryl, each of which is independently optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 , and phenyl; and n, R 2 , R 3 , and Ring A are as detailed herein for Formula (I).
  • X is N; Y is CR 4 ; R 4 is H; n is 1; R 2 and R 3 are each H; Ring A is pyridyl; Ring B is 4- to 12-membered heterocyclyl, or 5- to 12-membered heteroaryl, each of which is independently optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 , and phenyl.
  • X and Y are each N;
  • Ring B is C 3 -C 10 cycloalkyl, 4- to 12-membered heterocyclyl, or 5- to 12-membered heteroaryl, each of which is independently optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 , and phenyl; and n, R 2 , R 3 , and Ring A are as detailed herein for Formula (I).
  • X and Y are each N;
  • Ring B is C 3 -C 10 cycloalkyl, 4- to 12-membered heterocyclyl, or 5- to 12-membered heteroaryl, each of which is independently optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 , and phenyl; n is 1; R 2 and R 3 are each H; and Ring A is as detailed herein for Formula (I).
  • X and Y are each N;
  • Ring B is 4- to 12-membered heterocyclyl, or 5- to 12-membered heteroaryl, each of which is independently optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 , and phenyl; n is 1; R 2 and R 3 are each H; and Ring A is as detailed herein for Formula (I).
  • X and Y are each N;
  • Ring B is C 3 -C 10 cycloalkyl, 4- to 12-membered heterocyclyl, or 5- to 12-membered heteroaryl, each of which is independently optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 , and phenyl; n is 1; R 2 and R 3 are each H; and Ring A is pyrazolyl or pyridyl, each of which is optionally substituted by halo, CN, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkyl optionally substituted by halo or OH.
  • X is N
  • Y is CH
  • n is 1
  • both R 2 and R 3 are hydrogen
  • Ring A is pyridinyl
  • Ring B is 5- to 12-membered heteroaryl, each of which is independently optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 , and phenyl.
  • R 1 is —C 1 -C 3 alkylene-R 5 . In some embodiments, R 1 is —CH 2 —R 5 .
  • R 5 is 5-membered heterocyclyl comprising 1, 2, or 3 heteroatoms independently selected from O, N, and S, wherein at least one heteroatom of R 5 is S, and wherein R 5 is optionally substituted by halo, —O—C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkenyl, or C 1 -C 6 haloalkyl.
  • R 5 is 5-membered heteroaryl comprising 1, 2, or 3 heteroatoms independently selected from O, N, and S, wherein at least one heteroatom of R 5 is S, and wherein R 5 is optionally substituted by by halo, —O—C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkenyl, or C 1 -C 6 haloalkyl.
  • R 5 is 5-membered heterocyclyl or 5-membered heteroaryl, each of which comprises 1 or 2 heteroatoms independently selected from N and S, wherein at least one heteroatom of R 5 is S, and wherein R 5 is optionally substituted by halo, —O—C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkenyl, or C 1 -C 6 haloalkyl.
  • R 5 is 5-membered heterocyclyl or 5-membered heteroaryl, each of which comprises 1 or 2 heteroatoms selected from N or S, wherein one heteroatom of R 5 is S, and wherein R 5 is optionally substituted by halo, —O—C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkenyl, or C 1 -C 6 haloalkyl.
  • R 5 is thiazolyl, isothiazolyl, or thiophenyl, each of which is optionally substituted by halo, —O—C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkenyl, or C 1 -C 6 haloalkyl. In some embodiments, R 5 is
  • R 5 is
  • R 5 is
  • R 5 is
  • R 5 is unsubstituted
  • R 5 is thiazole optionally substituted by methyl, bromo, vinyl, ethyl, methoxy, chloro, or fluoro. In some embodiments, R 5 is
  • X is N. In other embodiments, X is CH.
  • n is 0. In other embodiments, n is 1.
  • Y is N.
  • Y is CR 4 , wherein R 4 is hydrogen, OH or C 1 -C 6 alkyl.
  • R 3 and R 4 are optionally taken together with the carbon atoms to which they are attached to form C 3 -C 6 cycloalkyl optionally substituted by halo or C 1 -C 3 alkyl.
  • the C 3 -C 6 cycloalkyl can be cyclopropyl optionally substituted by halo, such as fluoro, or C 1 -C 3 alkyl, such as methyl.
  • R 2 and R 3 are independently hydrogen, oxo, or C 1 -C 6 alkyl. In some embodiments, R 2 and R 3 are hydrogen. In some embodiments, R 2 and R 3 are oxo. In some embodiments, R 2 and R 3 are methyl.
  • Ring A is 5- to 12-membered heterocyclyl, which is optionally substituted by halo, CN, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkyl optionally substituted by halo or OH. In some embodiments, Ring A is
  • Ring A is 5- to 12-membered heteroaryl, which is optionally substituted by halo, CN, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkyl optionally substituted by halo or OH.
  • Exemplary Ring A include, but are not limited to,
  • Ring A is independently optionally substituted by halo, CN, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkyl optionally substituted by halo or OH.
  • Ring A is
  • Ring A is benzodioxolyl, pyridyl, pyrimidinyl, or pyrazinyl. In some embodiments, Ring A is
  • L is a bond.
  • L is —O—.
  • L is C 1 -C 6 alkylene.
  • L is unsubstituted C 1 -C 6 alkylene.
  • L is C 1 -C 6 alkylene optionally substituted by R L , wherein each R L1 is independently halo, OH, oxo, or C 1 -C 6 alkyl, or two R L1 are taken together with the carbon atom or atoms to which they are attached to form C 3 -C 6 cycloalkyl or 3- to 6-membered heterocyclyl.
  • L is unsubstituted C 1 -C 2 alkylene.
  • L is C 1 -C 2 alkylene optionally substituted by RY, wherein each R L1 is independently halo, OH, oxo, or C 1 -C 6 alkyl.
  • L is unsubstituted C 2 alkylene. In some embodiments, L is C 2 alkylene optionally substituted by R L1 , wherein each R L1 is independently halo, OH, oxo, or C 1 -C 6 alkyl. In some such embodiments, L is
  • L is *—O—C 1 -C 6 alkylene-**, wherein * represents the point of attachment to ring A and ** represents the point of attachment to ring B.
  • L can be *—OCH 2 —**.
  • the C 1 -C 6 alkylene of L is substituted by R L , wherein each R L is independently C 1 -C 6 alkyl or halo, or two R L are taken together with the carbon atom or atoms to which they are attached to form C 3 -C 6 cycloalkyl or 3- to 6-membered heterocyclyl.
  • the C 1 -C 6 alkylene is substituted by R L , wherein each R L is independently C 1 -C 6 alkyl or two R L are taken together with the carbon atom or atoms to which they are attached to form C 3 -C 6 cycloalkyl or 3- to 6-membered heterocyclyl.
  • R L is *—OC(R L ) 2 —**
  • two R L can be taken together with the carbon atom or atoms to which they are attached to form C 3 -C 6 cycloalkyl or 3- to 6-membered heterocyclyl.
  • L is *—C 1 -C 6 alkylene-O—**. In some embodiments, L is *—NR 6 —C 1 -C 6 alkylene-**, wherein R 6 is hydrogen or C 1 -C 6 alkyl. In some embodiments, L comprises an isotope of hydrogen, e.g., deuterium. In some embodiments, L is *—O—CH 2 —** or *—O—CD 2 -**. In some embodiments, L is *—O—CD 2 -**. In some embodiments, L comprises an oxo group. In some embodiments, L is *—C(O)—CH 2 —**.
  • Ring B is C 3 -C 10 cycloalkyl, which is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 and phenyl.
  • substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 and phenyl.
  • Exemplary C 3 -C 10 cycloalkyl include, but are not limited to,
  • Ring B is C 6 -C 14 aryl, which is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 and phenyl.
  • Ring B is C 6 -C 14 aryl, which is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 and phenyl.
  • the C 6 -C 14 aryl can be
  • each of which is independently optionally substituted by one to three substituents each independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 and phenyl.
  • Ring B is 4- to 12-membered heterocyclyl, which is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 and phenyl.
  • substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 and phenyl.
  • Exemplary 4- to 12-membered heterocyclyl include, but are not limited to,
  • Ring B is 5- to 12-membered heteroaryl, which is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 and phenyl.
  • Ring B is 5- to 12-membered heteroaryl, which is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 and phenyl.
  • Exemplary 5- to 12-membered heteroaryl include, but are not limited to,
  • Ring B is phenyl optionally substituted by one to three substituents each independently selected from the group consisting of halo, CN, and —CONH 2 .
  • Ring B is
  • Ring B is
  • Ring B is
  • Ring B is a 9-membered heteroaryl, which is optionally substituted by one to two substituents independently selected from the group consisting of halo and CN. In some embodiments, Ring B is
  • X, n, R, R 1 , R 2 , Ring A, and L are as described for Formula (I), and Ring B is C 3 -C 10 cycloalkyl optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 , and phenyl.
  • X, n, R, R 1 , R 2 , Ring A, and L are as described for Formula (I), and Ring B is C 6 -C 14 aryl optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 , and phenyl.
  • X, n, R, R 1 , R 2 , Ring A, and L are as described for Formula (I), and Ring B is C 6 aryl optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 , and phenyl.
  • X, n, R, R 1 , R 2 , Ring A, and L are as described for Formula (I), L is *—OCH 2 —**, and Ring B is C 6 aryl optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 , and phenyl.
  • X, n, R, R 1 , R 2 , Ring A, and L are as described for Formula (I), and Ring B is 4- to 12-membered heterocyclyl optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 , and phenyl.
  • X, n, R, R 1 , R 2 , Ring A, and L are as described for Formula (I), and Ring B is 5- to 12-membered heteroaryl optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 , and phenyl.
  • X is N, n is 1, Ring A is 9- to 10-membered heterocyclyl, which is optionally substituted by halo, CN, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkyl optionally substituted by halo or OH; and R, R 1 , R 2 , L, and Ring B is as described for Formula (I).
  • Formula (I) (including compounds of Formulae (II)-(V), and subformulae thereof, if applicable), X is N, n is 1, Ring A is 5- to 12-membered heteroaryl, which is optionally substituted by halo, CN, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkyl optionally substituted by halo or OH; and R, R 2 , L, and Ring B are as described for Formula (I). In some such embodiments, Ring A is 5- to 6-membered heteroaryl.
  • Ring A is 6-membered heteroaryl, which is optionally substituted by halo, CN, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkyl optionally substituted by halo or OH. In some such embodiments, Ring A is
  • Ring A is
  • X is N, n is 1, Ring B is C 3 -C 10 cycloalkyl, which is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 and phenyl; and R, R 1 , R 2 , Ring A, and L are as described for Formula (I).
  • Ring A is 5- to 6-membered heteroaryl, which is optionally substituted by halo, CN, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkyl optionally substituted by halo or OH;
  • Ring B is C 3 -C 10 cycloalkyl, which is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 and phenyl; and R, R 1 , R 2 , and L are as described for Formula (I).
  • Ring A is
  • Ring A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Ring A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is as described for Formula (I).
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is 5-membered heteroaryl comprising one S heteroatom and one N heteroatom, optionally substituted by halo, —O—C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkenyl, or C 1 -C 6 haloalkyl.
  • Ring A is 5- to 6-membered heteroaryl, which is optionally substituted by halo, CN, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkyl optionally substituted by halo or OH;
  • L is *—O—C 1 -C 6 alkylene-** optionally substituted by R L as described for Formula (I);
  • Ring B is C 3 -C 10 cycloalkyl, which is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 and phenyl; and R and R 2 are as described for Formula (I).
  • L is *—O—CH
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is as described for Formula (I).
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is 5-membered heteroaryl comprising one S heteroatom and one N heteroatom, optionally substituted by halo, —O—C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkenyl, or C 1 -C 6 haloalkyl.
  • Ring A is 5- to 6-membered heteroaryl, which is optionally substituted by halo, CN, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkyl optionally substituted by halo or OH; L is a bond; Ring B is C 3 -C 10 cycloalkyl, which is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 and phenyl; and R and R 2 are as described for Formula (I).
  • R and R 2 are as described for Formula (I).
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is as described for Formula (I).
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is 5-membered heteroaryl comprising one S heteroatom and one N heteroatom, optionally substituted by halo, —O—C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkenyl, or C 1 -C 6 haloalkyl.
  • R and R 2 are as described for Formula (I).
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is as described for Formula (I).
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is 5-membered heteroaryl comprising one S heteroatom and one N heteroatom, optionally substituted by halo, —O—C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkenyl, or C 1 -C 6 haloalkyl.
  • Ring B is C 6 -C 14 aryl, which is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 and phenyl; and R, R 2 , Ring A, and L are as described for Formula (I).
  • X is N, n is 1, Ring B is C 6 -C 14 aryl, which is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 and phenyl; and R, R 2 , Ring A, and L are as described for Formula (I).
  • X is N, n is 1, Ring B is C 6 aryl, which is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 and phenyl; and R, R 2 , Ring A, and L are as described for Formula (I).
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is as described for Formula (I).
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is 5-membered heteroaryl comprising one S heteroatom and one N heteroatom, optionally substituted by halo, —O—C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkenyl, or C 1 -C 6 haloalkyl.
  • Ring A is 5- to 6-membered heteroaryl, which is optionally substituted by halo, CN, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkyl optionally substituted by halo or OH;
  • Ring B is C 6 aryl, which is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 and phenyl; and R, R 1 , R 2 , and L are as described for Formula (I).
  • Ring A is
  • Ring A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Ring A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Ring A is 5- to 6-membered heteroaryl, which is optionally substituted by halo, CN, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkyl optionally substituted by halo or OH;
  • L is *—O—C 1 -C 6 alkylene-** optionally substituted by R L as described for Formula (I);
  • Ring B is C 6 aryl, which is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 and phenyl; and R and R 2 are as described for Formula (I).
  • L is *—O—CH 2 —**
  • R and R 2 are as described for Formula (I).
  • L is *—O—CH 2 —**
  • R and R 2 are as described for
  • Ring A, L, and Ring B optionally substituted as described for Ring A, L, and Ring B herein.
  • Ring A, L, and Ring B optionally substituted as described for Ring A, L, and Ring B herein.
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is as described for Formula (I).
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is 5-membered heteroaryl comprising one S heteroatom and one N heteroatom, optionally substituted by halo, —O—C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkenyl, or C 1 -C 6 haloalkyl.
  • Ring A is 5- to 6-membered heteroaryl, which is optionally substituted by halo, CN, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkyl optionally substituted by halo or OH;
  • L is a bond;
  • Ring B is C 6 aryl, which is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 and phenyl; and R and R 2 are as described for Formula (I).
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is as described for Formula (I).
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is 5-membered heteroaryl comprising one S heteroatom and one N heteroatom, optionally substituted by halo, —O—C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkenyl, or C 1 -C 6 haloalkyl.
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is as described for Formula (I).
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is 5-membered heteroaryl comprising one S heteroatom and one N heteroatom, optionally substituted by halo, —O—C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkenyl, or C 1 -C 6 haloalkyl.
  • Ring B is 4- to 12-membered heterocyclyl, which is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 and phenyl; and R, R 2 , Ring A, and L are as described for Formula (I).
  • Ring A is
  • Ring A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Ring A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • X is N, n is 1, R 1 is —CH 2 —R 5 , R 5 is as described for Formula (I). In some embodiments of any of the foregoing, X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is 5-membered heteroaryl comprising one S heteroatom and one N heteroatom, optionally substituted by halo, —O—C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkenyl, or C 1 -C 6 haloalkyl.
  • Ring B is 4- to 12-membered heterocyclyl, which is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 and phenyl; and R, R 2 , Ring A, and L are as described for Formula (I).
  • Ring B is 9- to 12-membered heterocyclyl, which is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 and phenyl; and R, R 2 , Ring A, and L are as described for Formula (I).
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is as described for Formula (I).
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is 5-membered heteroaryl comprising one S heteroatom and one N heteroatom, optionally substituted by halo, —O—C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkenyl, or C 1 -C 6 haloalkyl.
  • Ring A is 5- to 6-membered heteroaryl, which is optionally substituted by halo, CN, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkyl optionally substituted by halo or OH;
  • Ring B is 4- to 12-membered heterocyclyl, which is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 and phenyl; and R, R 2 , and L are as described for Formula (I).
  • Ring A is
  • Ring A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Ring A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is as described for Formula (I).
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is 5-membered heteroaryl comprising one S heteroatom and one N heteroatom, optionally substituted by halo, —O—C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkenyl, or C 1 -C 6 haloalkyl.
  • Ring A is 5- to 6-membered heteroaryl, which is optionally substituted by halo, CN, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkyl optionally substituted by halo or OH;
  • L is *—O—C 1 -C 6 alkylene-** optionally substituted by R L as described for Formula (I);
  • Ring B is 4- to 12-membered heterocyclyl, which is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 and phenyl; and R and R 2 are as described for Formula (I).
  • L is *—O—CH 2
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is as described for Formula (I).
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is 5-membered heteroaryl comprising one S heteroatom and one N heteroatom, optionally substituted by halo, —O—C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkenyl, or C 1 -C 6 haloalkyl.
  • Ring A is 5- to 6-membered heteroaryl, which is optionally substituted by halo, CN, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkyl optionally substituted by halo or OH; L is a bond; Ring B is 9- to 12-membered heterocyclyl, which is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 and phenyl; and R and R 2 are as described for Formula (I).
  • R and R 2 are as described for Formula (I).
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is as described for Formula (I).
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is 5-membered heteroaryl comprising one S heteroatom and one N heteroatom, optionally substituted by halo, —O—C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkenyl, or C 1 -C 6 haloalkyl.
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is as described for Formula (I).
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is 5-membered heteroaryl comprising one S heteroatom and one N heteroatom, optionally substituted by halo, —O—C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkenyl, or C 1 -C 6 haloalkyl.
  • Ring B is 5- to 12-membered heteroaryl, which is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 and phenyl; and R, R 2 , Ring A, and L are as described for Formula (I).
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is as described for Formula (I).
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is 5-membered heteroaryl comprising one S heteroatom and one N heteroatom, optionally substituted by halo, —O—C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkenyl, or C 1 -C 6 haloalkyl.
  • Ring A is 5- to 6-membered heteroaryl, which is optionally substituted by halo, CN, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkyl optionally substituted by halo or OH;
  • Ring B is 5- to 12-membered heteroaryl, which is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 and phenyl; and R, R 2 , and L are as described for Formula (I).
  • Ring A is
  • Ring A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Ring A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is as described for Formula (I).
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is 5-membered heteroaryl comprising one S heteroatom and one N heteroatom, optionally substituted by halo, —O—C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkenyl, or C 1 -C 6 haloalkyl.
  • Ring A is 5- to 6-membered heteroaryl, which is optionally substituted by halo, CN, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkyl optionally substituted by halo or OH;
  • L is *—O—C 1 -C 6 alkylene-** optionally substituted by R L as described for Formula (I);
  • Ring B is 5- to 12-membered heteroaryl, which is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 and phenyl; and R and R 2 are as described for Formula (I).
  • L is *—O—CH 2 —
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is as described for Formula (I).
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is 5-membered heteroaryl comprising one S heteroatom and one N heteroatom, optionally substituted by halo, —O—C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkenyl, or C 1 -C 6 haloalkyl.
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is as described for Formula (I).
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is 5-membered heteroaryl comprising one S heteroatom and one N heteroatom, optionally substituted by halo, —O—C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkenyl, or C 1 -C 6 haloalkyl.
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is as described for Formula (I).
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is 5-membered heteroaryl comprising one S heteroatom and one N heteroatom, optionally substituted by halo, —O—C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkenyl, or C 1 -C 6 haloalkyl.
  • Ring B is a fused bicyclic ring system comprising fused rings Ring C and Ring D.
  • Ring C is a fused bicyclic ring system comprising fused rings Ring C and Ring D.
  • Ring C is C 5 -C 6 cycloalkyl, 5- to 7-membered heterocyclyl, or 5- to 6-membered heteroaryl;
  • Ring D is C 6 cycloalkyl, C 6 aryl or 6-membered heteroaryl
  • Ring C and Ring D are optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 , and phenyl.
  • Ring D is C 6 aryl
  • Ring C is C 5 -C 6 cycloalkyl, 5- to 7-membered heterocyclyl, or 5- to 6-membered heteroaryl
  • Ring C and Ring D are optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 , and phenyl.
  • Ring A is 5- to 6-membered heteroaryl, which is optionally substituted by halo, CN, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkyl optionally substituted by halo or OH.
  • Ring D is C 6 aryl
  • Ring C is C 5 -C 6 cycloalkyl. In some such embodiments, Ring C and Ring D form
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is 5- to 6-membered heteroaryl optionally substituted by C 1 -C 6 alkyl.
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is as described for Formula (I).
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is 5-membered heteroaryl comprising one S heteroatom and one N heteroatom, optionally substituted by halo, —O—C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkenyl, or C 1 -C 6 haloalkyl.
  • Ring D is C 6 aryl and Ring C is 5- to 7-membered heterocyclyl. In some such embodiments, Ring C and Ring D form
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is 5- to 6-membered heteroaryl optionally substituted by C 1 -C 6 alkyl.
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is as described for Formula (I).
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is 5-membered heteroaryl comprising one S heteroatom and one N heteroatom, optionally substituted by halo, —O—C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkenyl, or C 1 -C 6 haloalkyl.
  • Ring D is C 6 aryl and Ring C is 5- to 6-membered heteroaryl. In some such embodiments, Ring C and Ring D form
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is 5- to 6-membered heteroaryl optionally substituted by C 1 -C 6 alkyl.
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is as described for Formula (I).
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is 5-membered heteroaryl comprising one S heteroatom and one N heteroatom, optionally substituted by halo, —O—C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkenyl, or C 1 -C 6 haloalkyl.
  • Ring D is 6-membered heteroaryl and Ring C is C 5 -C 6 cycloalkyl, 5- to 7-membered heterocyclyl, or 5- to 6-membered heteroaryl, wherein Ring C and Ring D are optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 , and phenyl.
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is as described for Formula (I).
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is 5-membered heteroaryl comprising one S heteroatom and one N heteroatom, optionally substituted by halo, —O—C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkenyl, or C 1 -C 6 haloalkyl.
  • Ring D is 6-membered heteroaryl and Ring C is C 5 -C 6 cycloalkyl, wherein Ring C and Ring D are optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 , and phenyl.
  • X is N
  • n is 1
  • R 1 is —CH 2 —R 5
  • R 5 is as described for Formula (I).
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is 5-membered heteroaryl comprising one S heteroatom and one N heteroatom, optionally substituted by halo, —O—C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkenyl, or C 1 -C 6 haloalkyl.
  • Ring D is 6-membered heteroaryl and Ring C is 5- to 7-membered heterocyclyl, wherein Ring C and Ring D are optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 , and phenyl.
  • X is N
  • n is 1
  • R 1 is —CH 2 —R 5
  • R 5 is as described for Formula (I).
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is 5-membered heteroaryl comprising one S heteroatom and one N heteroatom, optionally substituted by halo, —O—C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkenyl, or C 1 -C 6 haloalkyl.
  • Ring D is 6-membered heteroaryl and Ring C is 5- to 6-membered heteroaryl. In some embodiments, Ring C and Ring D are
  • X is N
  • n is 1
  • R 1 is —CH 2 —R 5
  • R 5 is as described for Formula (I).
  • X is N, n is 1, R 1 is —CH 2 —R 5 , and R 5 is 5-membered heteroaryl comprising one S heteroatom and one N heteroatom, optionally substituted by halo, —O—C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkenyl, or C 1 -C 6 haloalkyl.
  • R 5a is H, halo, —O—C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkenyl, or C 1 -C 6 haloalkyl.
  • R 5a is H or —CH 3 .
  • X is N and Y is CR 4 .
  • the compound is of Formula (VII-a):
  • n, R 2 , R 3 , R 4 , Ring A, L, and Ring B are as described for Formula (I), and R 5a is as described for Formula (VII).
  • X is N
  • Y is CR 4
  • R 3 and R 4 are taken together with the carbon atoms to which they are attached to form a cyclopropyl group optionally substituted by halo or C 1 -C 3 alkyl.
  • the compound is of Formula (VII-b), (VII-b1), or (VII-b2):
  • n, R 2 , R 3 , R 4 , Ring A, L, and Ring B are as described for Formula (I), and R 5a is as described for Formula (VII).
  • Ring B is C 6 aryl, which is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 and phenyl.
  • Ring B is C 6 aryl, which is optionally substituted by one to two substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 and phenyl.
  • Ring B is C 6 aryl, which is optionally substituted by one to two substituents independently selected from the group consisting of halo and CN.
  • L is *—O—CH 2 —**.
  • the compound is of Formula (VII-c):
  • R B1 and R B2 are independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 and phenyl.
  • R B1 and R B2 are independently selected from the group consisting of halo and CN.
  • X is N
  • Y is CR 4
  • R 3 and R 4 are taken together with the carbon atoms to which they are attached to form a cyclopropyl group optionally substituted by halo or C 1 -C 3 alkyl.
  • the compound is of Formula (VII-d), (VII-d1), or (VII-d2):
  • R 2 and Ring A are as described for Formula (I), R 5a is as described for Formula (VII), and R B1 and R B2 are as described for Formula (VII-c).
  • the compound of Formula VII is of Formula VII-e:
  • X 2 is N or CH
  • R 10 is Cl or CN.
  • the compound of Formula VII-e is of Formula VII-ei
  • the compound of Formula VII-e is of Formula VII-eii:
  • the compound of Formula I is of Formula VIII
  • R 7 is hydrogen chloro, bromo, fluoro, methyl, or vinyl
  • the compound of Formula I is of Formula VIII-a:
  • X 1 is N or CH; and R 9 is H or —OCH 3 .
  • a method of making a compound of Formula (I), including compounds of Formulae (II)-(V), (VI), (VII), (VIII) and subformulae thereof), or selected from the group consisting of a compound listed in Table 1, or a pharmaceutically acceptable salt of any of the foregoing.
  • Compounds described herein may be prepared according to general schemes, as exemplified by the general procedures and examples. Minor variations in starting materials, temperatures, concentrations, reaction times, and other parameters can be made when following the general procedures, which do not substantially affect the results of the procedures.
  • the compounds depicted herein may be present as salts even if salts are not depicted and it is understood that the present disclosure embraces all salts and solvates of the compounds depicted here, as well as the non-salt and non-solvate form of the compound, as is well understood by the skilled artisan.
  • the salts of the compounds provided herein are pharmaceutically acceptable salts. Where one or more tertiary amine moiety is present in the compound, the N-oxides are also provided and described.
  • tautomeric forms may be present for any of the compounds described herein, each and every tautomeric form is intended even though only one or some of the tautomeric forms may be explicitly depicted.
  • the tautomeric forms specifically depicted may or may not be the predominant forms in solution or when used according to the methods described herein.
  • 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 given herein may have asymmetric centers and therefore exist in different enantiomeric or diastereomeric forms. All optical isomers and stereoisomers of the compounds of the general formula, and mixtures thereof in any ratio, are considered within the scope of the formula.
  • any formula given herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof in any ratio, unless a specific stereochemistry is otherwise indicated.
  • a compound of Table 1 is depicted with a particular stereochemical configuration, also provided herein is any alternative stereochemical configuration of the compound, as well as a mixture of stereoisomers of the compound in any ratio.
  • a compound of Table 1 has a stereocenter that is in an “S” stereochemical configuration
  • the enantiomer of the compound wherein that stereocenter is in an “R” stereochemical configuration is in an “R” stereochemical configuration.
  • a compound of Table 1 has a stereocenter that is in an “R” configuration
  • enantiomer of the compound in an “S” stereochemical configuration also provided are mixtures of the compound with both the “S” and the “R” stereochemical configuration.
  • the invention also intends isotopically-labeled and/or isotopically-enriched forms of compounds described herein.
  • the compounds herein may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compound is isotopically-labeled, such as an isotopically-labeled compound of the formula (I) or variations thereof described herein, where a fraction of one or more atoms are replaced by an isotope of the same element.
  • Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 O, 17 O, 32 P, 35 S, 18 F, 36 Cl.
  • Certain isotope labeled compounds e.g., 3 H and 14 C
  • Incorporation of heavier isotopes such as deuterium ( 2 H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, or reduced dosage requirements and, hence may be preferred in some instances.
  • 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 appropriate isotopically-labeled reagents in place of the corresponding non-labeled reagent.
  • the invention also includes any or all metabolites of any of the compounds described.
  • the metabolites may include any chemical species generated by a biotransformation of any of the compounds described, such as intermediates and products of metabolism of the compound, such as would be generated in vivo following administration to a human.
  • the present disclosure also includes salts, e.g., pharmaceutically acceptable salts, of any of the compounds disclosed herein.
  • the present disclosure provides a meglumine salt of any one of the compounds disclosed herein, e.g., a 1:1 compound:meglumine salt, a 2:1 compound:meglumine salt, a 1:2 compound:meglumine salt.
  • compositions or simply “pharmaceutical compositions” of any of the compounds detailed herein are embraced by this invention.
  • the invention includes pharmaceutical compositions comprising a compound of Formula (I) (including compounds of Formulae (II)-(VIII)), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid.
  • Pharmaceutical compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation.
  • compositions comprising a compound as detailed herein are provided, such as compositions of substantially pure compounds.
  • a composition containing a compound as detailed herein or a salt thereof is in substantially pure form.
  • substantially pure intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than the compound comprising the majority of the composition or a salt thereof.
  • a composition of a substantially pure compound intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than the compound or a salt thereof.
  • a composition of substantially pure compound or a salt thereof is provided wherein the composition contains no more than 25% impurity.
  • a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 20% impurity.
  • a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 10% impurity.
  • a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 5% impurity.
  • a composition of substantially pure compound or a salt thereof wherein the composition contains or no more than 3% impurity. In still another variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 1% impurity. In a further variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 0.5% impurity. In yet other variations, a composition of substantially pure compound means that the composition contains no more than 15% or preferably no more than 10% or more preferably no more than 5% or even more preferably no more than 3% and most preferably no more than 1% impurity, which impurity may be the compound in a different stereochemical form.
  • the compounds herein are synthetic compounds prepared for administration to an individual such as a human.
  • compositions are provided containing a compound in substantially pure form.
  • the invention embraces pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier or excipient.
  • methods of administering a compound are provided. The purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein.
  • the compounds may be formulated for any available delivery route, including an oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular, subcutaneous or intravenous), topical or transdermal delivery form.
  • oral e.g., nasal, sublingual, vaginal, buccal or rectal
  • parenteral e.g., intramuscular, subcutaneous or intravenous
  • topical or transdermal delivery form e.g., topical or transdermal delivery form.
  • a compound may be formulated with suitable carriers to provide delivery forms that include, but are 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 spray 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.
  • suitable carriers include, but are 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),
  • compositions described herein can be used in the preparation of a formulation, such as a pharmaceutical formulation, by combining the compounds as active ingredients with a pharmaceutically acceptable carrier, such as those mentioned above.
  • a pharmaceutically acceptable carrier such as those mentioned above.
  • the carrier may be in various forms.
  • pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.
  • Formulations comprising the compound may also contain other substances which have valuable therapeutic properties.
  • Pharmaceutical formulations may be prepared by known pharmaceutical methods. Suitable formulations can be found, e.g., in Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21st ed. (2005), which is incorporated herein by reference.
  • Compounds as described herein may be administered to individuals (e.g., a human) in a form of generally accepted oral compositions, such as tablets, coated tablets, and gel capsules in a hard or in soft shell, emulsions or suspensions.
  • oral compositions such as tablets, coated tablets, and gel capsules in a hard or in soft shell, emulsions or suspensions.
  • carriers which may be used for the preparation of such compositions, are lactose, corn starch or its derivatives, talc, stearate or its salts, etc.
  • Acceptable carriers for gel capsules with soft shell are, for instance, plant oils, wax, fats, semisolid and liquid polyols, and so on.
  • pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.
  • compositions comprising two compounds utilized herein are described. Any of the compounds described herein can be formulated in a tablet in any dosage form described herein.
  • the composition comprises a compound of Formula (I) (including compounds of Formulae (II)-(VIII)), or a pharmaceutically acceptable salt thereof, as described herein.
  • a dosage form comprises a therapeutically effective amount of a compound of Formula (I) (including compounds of Formulae (II)-(VIII)), or a pharmaceutically acceptable salt thereof.
  • the compound or a pharmaceutically acceptable salt thereof is selected from Compound Nos. 1-11 in Table 1.
  • the compound or a pharmaceutically acceptable salt thereof is selected from Compound Nos. 1-31 in Table 1
  • the 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 compounds of Formulae (II)-(VI)), or a pharmaceutically acceptable salt thereof.
  • the 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 any one of the compounds in Table 1, or a pharmaceutically acceptable salt thereof.
  • the method of treating a disease or condition in a subject in need thereof comprises administering to the subject an effective amount of a compound of Formula (I) (including compounds of Formulae (II)-(VIII)), or a pharmaceutically acceptable salt thereof. In some embodiments, the method of treating a disease or condition in a subject in need thereof comprises administering to the subject an effective amount of a compound selected from any one of the compounds in Table 1, or a pharmaceutically acceptable salt thereof.
  • a disease or condition to be treated and/or prevented is selected from the group consisting of cardiometabolic and associated diseases including diabetes (T1 D and/or T2DM, including pre-diabetes), idiopathic T1 D (Type 1 b), latent autoimmune diabetes in adults (LADA), early-onset T2DM (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease (e.g., acute kidney disorder, tubular dysfunction, proinflammatory changes to the proximal tubules), diabetic retinopathy, adipocyte dysfunction, visceral adipose deposition, sleep apnea, obesity (including hypothalamic obesity and monogenic obesity) and related comorbidities (e.g., osteoarthritis and urine in
  • necrosis and apoptosis stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, post-prandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's Disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attacks, vascular restenosis, impaired glucose metabolism, conditions of impaired fasting plasma glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcerations, ulcerative colitis, hyper apo B lipoproteinemia, Alzheimer's Disease, schizophrenia, impaired cognition, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, Polycy
  • provided herein is a method of treating a cardiometabolic disease in a subject (e.g., a human patient) in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.
  • a method of treating diabetes in a subject comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.
  • exemplary diabetes include, but are not limited to, T1 D, T2DM, pre-diabetes, idiopathic T1 D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, and gestational diabetes.
  • liver disorders include, without limitation, liver inflammation, fibrosis, and steatohepatitis.
  • the liver disorder is selected from the list consisting of primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), drug induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition associated cholestasis (PNAC), bacterial overgrowth or sepsis associated cholestasis, autoimmune hepatitis, viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), graft versus host disease, transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intra- or extrahepatic malignancy, Sjogren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis, and oti-antitrypsin deficiency.
  • PBC primary biliary cirrhosis
  • 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).
  • the liver disorder is selected from the group consisting of liver fibrosis, alcohol induced fibrosis, steatosis, alcoholic steatosis, NAFLD, and NASH.
  • the liver disorder is NASH.
  • the liver disorder is liver inflammation.
  • the liver disorder is liver fibrosis. In another embodiment, the liver disorder is alcohol induced fibrosis. In another embodiment, the liver disorder is steatosis. In another embodiment, the liver disorder is alcoholic steatosis. In another embodiment, the liver disorder is NAFLD. In one embodiment, the treatment methods provided herein impedes or slows the progression of NAFLD to NASH. In one embodiment, the treatment methods provided herein impedes or slows the progression of NASH. NASH can progress, e.g., to one or more of liver cirrhosis, hepatic cancer, etc. In some embodiments, the liver disorder is NASH. In some embodiments, the patient has had a liver biopsy. In some embodiments, the method further comprising obtaining the results of a liver biopsy.
  • the present disclosure provides a method of decreasing food intake in a subject in need thereof, the method comprising administering an effective amount of any one of the compounds or pharmaceutical compositions disclosed herein to the subject.
  • administration of a compound disclosed herein causes the subject's food intake to be reduced at least 10%, e.g., at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% relative to the subject's food intake in the absence of a compound disclosed herein.
  • the subject's food intake is reduced, e.g., reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%, for at least 1 hour following administration, e.g., at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 12 hours, at least 1 day, or at least 2 days following administration.
  • the present disclosure provides a method of improving glucose tolerance in a subject in need thereof.
  • concentration of glucose in the blood of a subject is lower, e.g., 10% lower, 20% lower, 30% lower, 40% lower, 50% lower, 60% lower, 70% lower, 80% lower, 90% lower, 100% lower, 200% lower, 500% lower, 1000% lower, than the blood glucose concentration would have been had the subject not been administered the compound disclosed herein.
  • a compound described herein, or a pharmaceutically acceptable salt thereof can be administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.
  • it is a compound of any embodiment of Formula (I) or selected from the compounds of Table 1, or a pharmaceutically acceptable salt thereof.
  • the compounds and/or compositions described herein may be administered orally, rectally, vaginally, parenterally, or topically.
  • the compounds and/or compositions may be administered orally.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the bloodstream directly from the mouth.
  • the compounds and/or compositions may be administered directly into the bloodstream, into muscle, or into an internal organ.
  • Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous.
  • Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • the compounds and/or compositions may be administered topically to the skin or mucosa, that is, dermally or transdermally. In some embodiments, the compounds and/or compositions may be administered intranasally or by inhalation. In some embodiments, the compounds and/or compositions may be administered rectally or vaginally. In some embodiments, the compounds and/or compositions may be administered directly to the eye or ear.
  • the dosage regimen for the compounds and/or compositions described herein is 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 employed. Thus, the dosage regimen may vary widely.
  • the total daily dose of the compounds of the present application is typically from 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.
  • total daily dose of the compounds of the present application is from about 0.01 to about 30 mg/kg, and in another embodiment, from about 0.03 to about 10 mg/kg, and in yet another embodiment, from about 0.1 to about 3. It is not uncommon that the administration of the compounds of the present application will be repeated a plurality of times in a day (typically no greater than 4 times). Multiple doses per day typically may be used to increase the total daily dose, if desired.
  • 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 the active ingredient for the symptomatic adjustment of the dosage to the patient.
  • a medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, or in another embodiment, from about 1 mg to about 100 mg of active ingredient.
  • doses may range from about 0.01 to about 10 mg/kg/minute during a constant rate infusion.
  • the compounds and/or compositions described herein can be used alone, or in combination with other therapeutic agents.
  • the administration of two or more agents “in combination” means that all of the agents are administered closely enough in time that each may generate a biological effect in the same time frame. The presence of one agent may alter the biological effects of the other agent(s).
  • the two or more agents may be administered simultaneously, concurrently or sequentially. Additionally, simultaneous administration may be carried out by mixing the agents prior to administration or by administering the compounds at the same point in time but as separate dosage forms at the same or different site of administration.
  • the present application provides any of the uses, methods or compositions as defined herein wherein a compound of any embodiment of Formula (I) or selected from the compounds of Table 1 as described herein, or a pharmaceutically acceptable salt thereof, is used in combination with one or more other therapeutic agent.
  • This would include a pharmaceutical composition comprising a compound of any embodiment of Formula (I) or selected from the compounds of Table 1, or a pharmaceutically acceptable salt thereof, as defined in any of the embodiments described herein, in admixture with at least one pharmaceutically acceptable excipient and one or more other therapeutic agent.
  • the one or more other therapeutic agent is an anti-diabetic agent including but not limited to a biguanide (e.g., metformin), a sulfonylurea (e.g., tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, or glipizide), a thiazolidinedione (e.g., pioglitazone, rosiglitazone, or lobeglitazone), a glitazar (e.g., saroglitazar, aleglitazar, muraglitazar or tesaglitazar), a meglitinide (e.g., nateglinide, repaglinide), a dipeptidyl peptidase 4 (DPP-4) inhibitor (e.g., sitagliptin, vilda
  • glucose-dependent insulinotropic peptide GIP
  • an alpha glucosidase inhibitor e.g. voglibose, acarbose, or miglitol
  • an insulin or an insulin analogue including the pharmaceutically acceptable salts of the specifically named agents and the pharmaceutically acceptable solvates of said agents and salts.
  • the one or more other therapeutic agent is an antiobesity agent including but not limited to peptide YY or an analogue thereof, a neuropeptide Y receptor type 2 (NPYR2) agonist, a NPYR1 or NPYR5 antagonist, a cannabinoid receptor type 1 (CB1 R) antagonist, a lipase inhibitor (e.g., orlistat), a human proislet peptide (HIP), a melanocortin receptor 4 agonist (e.g., setmelanotide), a melanin concentrating hormone receptor 1 antagonist, a farnesoid X receptor (FXR) agonist (e.g.
  • obeticholic acid zonisamide
  • phentermine alone or in combination with topiramate
  • a norepinephrine/dopamine reuptake inhibitor e.g., buproprion
  • an opioid receptor antagonist e.g., naltrexone
  • a combination of norepinephrine/dopamine reuptake inhibitor and opioid receptor antagonist e.g., a combination of bupropion and naltrexone
  • a GDF-15 analog sibutramine, a cholecystokinin agonist, amylin and analogues therof (e.g., pramlintide), leptin and analogues thereof (e.g., metroleptin)
  • a serotonergic agent e.g., lorcaserin
  • a methionine aminopeptidase 2 (MetAP2) inhibitor e.g., beloranib or ZGN-1061
  • the one or more other therapeutic agent is an agent to treat NASH including but not limited to PF-05221304, an FXR agonist (e.g., obeticholic acid), a PPAR u/6 agonist (e.g., elafibranor), a synthetic fatty acid-bile acid conjugate (e.g., aramchol), a caspase inhibitor (e.g., emricasan), an anti-lysyl oxidase homologue 2 (LOXL2) monoclonal antibody (e.g., sizumab), a galectin 3 inhibitor (e.g., GR-MD-02), a MAPK5 inhibitor (e.g., GS-4997), a dual antagonist of chemokine receptor 2 (CCR2) and CCR5 (e.g., cenicriviroc), a fibroblast growth factor21 (FGF21) agonist (e.g., BMS-986036), a levothacil
  • the present disclosure further provides articles of manufacture comprising a compound, or a pharmaceutically acceptable salt thereof in accordance with the present application, a composition described herein, or one or more unit dosages described herein in suitable packaging.
  • the article of manufacture is for use in any of the methods described herein.
  • suitable packaging e.g., containers
  • An article of manufacture may further be sterilized and/or sealed.
  • kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub-unit doses.
  • kits may be provided that contain sufficient dosages of a compound, or a pharmaceutically acceptable salt thereof in accordance with the present application, a composition described herein, and/or one or more other therapeutic agent useful for a disease detailed herein to provide effective treatment of an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more.
  • Kits may also include multiple unit doses of the compounds/compositions described herein and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).
  • kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component(s) of the methods of the present disclosure.
  • the instructions included with the kit generally include information as to the components and their administration to an individual.
  • the present disclosure provides a method of preparing a compound of the present disclosure.
  • the present disclosure provides a method of a compound, comprising one or more steps as described herein.
  • the present disclosure provides a compound obtainable by, or obtained by, or directly obtained by a method for preparing a compound as described herein.
  • the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein.
  • the compounds of the present disclosure can be prepared by any suitable technique known in the art. Particular processes for the preparation of these compounds are described further in the accompanying examples.
  • a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl.
  • the deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate).
  • a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
  • a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl.
  • the deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia.
  • an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.
  • a suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a tert-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.
  • a base such as sodium hydroxide
  • a tert-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.
  • the processes may then further comprise the additional steps of: (i) removing any protecting groups present; (ii) converting the compound Formula (I) into another compound of Formula (I); (iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and/or (iv) forming a prodrug thereof.
  • the resultant compounds of Formula (I) can be isolated and purified using techniques well known in the art.
  • the reaction of the compounds is carried out in the presence of a suitable solvent, which is preferably inert under the respective reaction conditions.
  • suitable solvents comprise but are not limited to hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichlorethylene, 1,2-dichloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentylmethyl ether (CPME), methyl tert-butyl ether (MTBE) or dioxane; glycol ethers, such as
  • the reaction temperature is suitably between about ⁇ 100° C. and 300° C., depending on the reaction step and the conditions used.
  • Reaction times are generally in the range between a fraction of a minute and several days, depending on the reactivity of the respective compounds and the respective reaction conditions. Suitable reaction times are readily determinable by methods known in the art, for example reaction monitoring. Based on the reaction temperatures given above, suitable reaction times generally lie in the range between 10 minutes and 48 hours.
  • compounds of the present disclosure are readily accessible by various synthetic routes, some of which are exemplified in the accompanying examples.
  • the skilled person will easily recognise which kind of reagents and reactions conditions are to be used and how they are to be applied and adapted in any particular instance—wherever necessary or useful—in order to obtain the compounds of the present disclosure.
  • some of the compounds of the present disclosure can readily be synthesized by reacting other compounds of the present disclosure under suitable conditions, for instance, by converting one particular functional group being present in a compound of the present disclosure, or a suitable precursor molecule thereof, into another one by applying standard synthetic methods, like reduction, oxidation, addition or substitution reactions; those methods are well known to the skilled person.
  • Compounds designed, selected and/or optimized by methods described above, once produced, can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity.
  • the molecules can be characterized by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and/or binding specificity.
  • high-throughput screening can be used to speed up analysis using such assays.
  • it can 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. Pat. No. 5,763,263.
  • High-throughput assays can use one or more different assay techniques including, but not limited to, those described below.
  • in vitro or in vivo biological assays may be suitable for detecting the effect of the compounds of the present disclosure.
  • These in vitro or in vivo biological assays can include, but are not limited to, enzymatic activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein.
  • the biological assays are described in the Examples herein.
  • Stable cell lines expressing high and low GLP-1R surface expression were generated in CHO-K1 cells transfected (Fugene 6) with a puromycin selectable DNA plasmid encoding human GLP-1R receptor (accession number: NM_002062.5) under control of an EF1A promoter.
  • Transfected cells were seeded into 24-well plates (9,000 cells/well) containing complete medium and incubated in a humidified incubator at 37° C. with 5% carbon dioxide. After overnight incubation, medium was replaced with complete medium supplemented with puromycin (6 ⁇ g/mL) and refreshed every 2-3 days to select for stably transfected cells.
  • GLP-1R expression was analyzed by flow cytometry using a fluorescein-labeled Exendin-4 peptide fluorescent probe (FLEX).
  • FLEX fluorescein-labeled Exendin-4 peptide fluorescent probe
  • CHO-K1_hGLP-1Rhigh_clone16 cells showed significantly higher MFI levels relative to CHO-K1-hGLP-1low_clone10 cells.
  • test compounds were serially diluted in DMSO (10-point, 3-fold dilution), added to wells using an ECHO dispenser (10 nL/well) and plates were centrifuged for 1 min and agitated for 2 min at room temperature prior to 30-minute incubation at 25° C. After incubation, Eu-cAMP (5 ⁇ L) and Ulight-anti-cAMP (5 ⁇ L) reagents were added to each well, followed by centrifugation for 1 minute, agitation for 2 minutes at room temperature, and final incubation of the plates at 25° C. for 15 minutes.
  • Hepatic clearance or the ability of the liver to extract and metabolize a drug as it passes through the liver, is controlled by hepatic blood flow (Q), protein binding (fu) and the intrinsic ability of the liver enzymes to metabolize a drug (CLint).
  • CLint is a measure of theoretical unrestricted maximum clearance of unbound drug by an eliminating organ, in absence of blood flow or plasma protein binding limitations. This term relates to the functional reserve of the organ.
  • the CLint may be determined in vitro using enzyme kinetics.
  • An in vitro hepatocyte stability assay can be conducted to determine the unrestricted maximum liver clearance of unbound test agents as compared to clearance of reference standard.
  • Step 3 A mixture of intermediate 3f (2 g, 6.74 mmol, 1 eq), intermediate 4f (1.42 g, 8.09 mmol, 1.2 eq), BINAP (839.20 mg, 1.35 mmol, 0.2 eq), Cs 2 CO 3 (4.39 g, 13.48 mmol, 2 eq) and Pd 2 (dba) 3 (617.08 mg, 673.87 ⁇ mol, 0.1 eq) in toluene (80 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100° C. for 3 hrs under N2 atmosphere. LC-MS showed intermediate 3f was consumed and one main peak with desired mass was detected.
  • Step 1 A mixture of intermediate 5f (50 g, 161.70 mmol, 1 eq), intermediate 6f (38.31 g, 161.70 mmol, 1 eq), Pd(dppf)Cl 2 .CH 2 Cl 2 (13.21 g, 16.17 mmol, 0.1 eq), K 2 CO 3 (44.70 g, 323.41 mmol, 2 eq) and in dioxane (800 mL) H 2 O (160 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 90° C. for 2 hr under N2 atmosphere.
  • Step 2 To a mixture of intermediate 7f (15 g, 44.22 mmol, 1 eq) in EtOAc (200 mL) was added PtO 2 (3.13 g, 13.76 mmol) under N2. The suspension was degassed under vacuum and purged with H 2 several times. The mixture was stirred under H 2 (15 psi) at 20° C. for 8 hrs. LC-MS showed intermediate 7f was consumed completely and one main peak with desired mass was detected. The reaction mixture was filtered, and the filtrate was concentrated.
  • Step 3 A mixture of intermediate 8f (10 g, 29.30 mmol, 1 eq), intermediate 9f (5.31 g, 35.17 mmol, 1.2 eq), t-BuONa (8.45 g, 87.91 mmol, 3 eq), Xphos Pd G4 (2.52 g, 2.93 mmol, 0.1 eq) in toluene (100 mL) was degassed and purged with N 2 3 times, and then the mixture was stirred at 100° C. for 2 hrs under N2 atmosphere. LC-MS showed intermediate 8f was consumed completely and one main peak with desired mass was detected.
  • Step 2 A mixture of intermediate 11f (1.3 g, 6.63 mmol, 1 eq), Lawesson's reagent (1.61 g, 3.98 mmol, 0.6 eq) in toluene (20 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 120° C. for 3 hr under N2 atmosphere.
  • the crude product was used without purification directly in the next step.
  • Crude Intermediate 12f (2.81 g, 13.24 mmol, 100.00% yield) was obtained as a yellow liquid.
  • Step 3 A mixture of intermediate 13f (600 mg, 3.12 mmol, 1 eq), NBS (833.38 mg, 4.68 mmol, 1.5 eq), AIBN (51.26 mg, 312.15 ⁇ mol, 0.1 eq) in CCl 4 (6 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 80° C. for 12 hr under N2 atmosphere.
  • the reaction mixture was diluted with H 2 O (30 mL) and extracted with DCM (30 mL*3). The combined organic layers were washed with NaCl a.q. (10 mL*3), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a residue.
  • Step 4 A mixture of intermediate 6f (2.8 g, 9.06 mmol, 1 eq), intermediate 15f (2.63 g, 9.96 mmol, 1.1 eq), Pd(dppf)Cl 2 ′CH 2 Cl 2 (369.75 mg, 452.77 ⁇ mol, 0.05 eq), K 2 CO 3 (3.75 g, 27.17 mmol, 3 eq) in DMSO (15 mL) and H 2 O (1.5 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 80° C. for 2 hr under N 2 atmosphere. The reaction mixture was diluted with H 2 O 10 mL and extracted with EtOAc (10 mL*3).
  • Step 6 A mixture of intermediate 17f (410 mg, 1.47 mmol, 1 eq), intermediate 14f (399.34 mg, 1.47 mmol, 1 eq), Ag 2 CO 3 (812.34 mg, 2.95 mmol, 2 eq), in toluene (7 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 100° C. for 3 hr under N 2 atmosphere. LC-MS showed intermediate 17f was consumed completely and one main peak with desired. The reaction mixture was diluted with H 2 O (20 mL) and extracted with EtOAc (20 mL*3).
  • Step 7 A mixture of intermediate 18f (190 mg, 405.51 ⁇ mol, 1 eq), HCl/EtOAc (4 M, 2.85 mL, 28.11 eq), in EtOAc (2 mL) was degassed and purged with N 2 3 times, and then the mixture was stirred at 25° C. for 0.5 hr under N 2 atmosphere. LC-MS showed intermediate 18f was consumed completely and one main peak with desired. The reaction mixture was concentrated under reduced pressure. Core 3i (150 mg, 370.47 ⁇ mol, 91.36% yield, as HCl salt) was obtained as a white solid.
  • Step 1 To a solution of diethylzinc (1 M, 303.01 mL, 8 eq) in DCM (50 mL) was added TFA (34.55 g, 303.01 mmol, 22.44 mL, 8 eq) in DCM (50 mL) slowly at ⁇ 15° C. and the mixture was stirred at ⁇ 15° C. for 1 hour.
  • CH 2 I 2 (162.31 g, 606.02 mmol, 48.89 mL, 16 eq) in DCM (50 mL) was added to the mixture at ⁇ 15° C. and the mixture was stirred at ⁇ 15° C. for 1 hour.
  • Compound 31 can be prepared according to synthetic methods described herein, optionally with guidance from WO2019/239319.
  • Stable cell lines expressing high and low GLP-1R surface expression were generated in CHO-K1 cells transfected (Fugene 6) with a puromycin selectable DNA plasmid encoding human GLP-1R receptor (accession number: NM_002062.5) under control of an EF1A promoter.
  • Transfected cells were seeded into 24-well plates (9,000 cells/well) containing complete medium and incubated in a humidified incubator at 37° C. with 5% carbon dioxide. After overnight incubation, medium was replaced with complete medium supplemented with puromycin (6 ⁇ g/mL) and refreshed every 2-3 days to select for stably transfected cells.
  • GLP-1R expression was analyzed by flow cytometry using a fluorescein-labeled Exendin-4 peptide fluorescent probe (FLEX).
  • FLEX fluorescein-labeled Exendin-4 peptide fluorescent probe
  • CHO-K1_hGLP-1Rhigh_clone16 cells showed significantly higher MFI levels relative to CHO-K1-hGLP-1low_clone10 cells.
  • test compounds were serially diluted in DMSO (10-point, 3-fold dilution), added to wells using an ECHO dispenser (10 nL/well) and plates were centrifuged for 1 min and agitated for 2 min at room temperature prior to 30-minute incubation at 25° C. After incubation, Eu-cAMP (5 ⁇ L) and Ulight-anti-cAMP (5 ⁇ L) reagents were added to each well, followed by centrifugation for 1 minute, agitation for 2 minutes at room temperature, and final incubation of the plates at 25° C. for 15 minutes.
  • the EC 50 values of exemplary compounds in the low expression assay are shown in Table 2 below.
  • the compounds tested were compound samples prepared according to the General Procedures described in the Examples section.
  • Intravenous dosing Compounds were formulated at 0.5 mg/mL in a solution comprising 5% polyethylene glycol 400 and 95% (12% (w/v) sulfobutyl- ⁇ -cyclodextrin in water) (v/v). Formulated compounds were sterile filtered through a 0.22 micron filter before dosing. Compounds were administered to male, 7-11-week-old Sprague-Dawley rats by jugular vein cannula infusion over 30 minutes at a dose of 1 mg/kg.
  • Oral dosing Compounds were formulated at 0.3 mg/mL or 0.6 mg/mL in a solution comprising 5% polyethylene glycol 400 and 95% (12% (w/v) sulfobutyl- ⁇ -cyclodextrin in water) (v/v). Formulated compounds were administered to male, 7-11 week old Sprague-Dawley rats by oral gavage at a dose of 3 mg/kg.
  • Plasma samples Blood collections of about 0.2 mL per time point were performed from jugular vein or other suitable site of each animal, into pre-chilled commercial EDTA-K2 tubes and placed on wet ice until centrifugation. Blood samples were processed for plasma by centrifugation at approximately 4° C., 3,200 g for 10 min. Plasma was collected and transferred into pre-labeled 96 well plate or polypropylene tubes, quick frozen over dry ice and kept at ⁇ 60° C. or lower until LC-MS/MS analysis.
  • Plasma concentration versus time data was plotted in graph and analyzed by non-compartmental approaches using the Phoenix WinNonlin 6.3 software program.
  • PK parameters were calculated according to dosing route, e.g., CL, V dss and C 0 for intravenous administration, C max , T max or % F for extravascular administration, and T 1/2 , AUC (0-t) , AUC (0-inf) , MRT (0-t) , MRT (0-inf) for all routes.
  • PK parameters in plasma after intravenous dosing are shown in Table 3.
  • PK parameters in plasma after oral dosing are shown in Tables 4 and 5.
  • Plasma concentrations of Compound 2 and Reference Compound A after oral dosing with 3 mg/kg are shown in FIG. 1 .
  • Plasma concentrations of Compounds 2, 3, and 4 after oral dosing with 0.3 mg/mL, 3 mg/kg are shown in FIG. 2 .
  • Plasma concentrations for compounds 2 and 14 after oral dosing with 0.6 mg/mL, 3 mg/kg are shown in FIG. 3 .
  • Compound 2 Under various routes and methods of administration, Compound 2, and compounds similar to it (i.e., Compound 14) exhibit consistently improved in vivo pharmacokinetic performance as compared with Reference Compound A. After intravenous administration, Compound 2 exhibited greater exposure, ⁇ 2-fold longer t 1/2 , and 30% lower clearance as compared with Reference Compound A (Table 3). Compound 2 also exhibited significantly enhanced PK properties relative to Reference Compound A after oral administration (Table 4, Table 5), with improved t 1/2 , and 4-6-fold higher AUC. Compounds 14, 25, 27, and 29 exhibited similarly improved PK properties relative to Reference Compound A when dosed orally under identical conditions.
  • polyethylene glycol 400 95% (12% (w/v) sulfobutyl- ⁇ -cyclodextrin in water), (v/v).
  • Sulfobutyl- ⁇ -cyclodextrin (12,000.0 mg) was added to a 100 mL volumetric flask and QC with water to 100 mL, and vortexed until fully dissolved; 95 mL was transferred to anew 100 mL flask/cylinder and 5 mL polyethylene glycol 400 was added, the mixture was vortexed until fully dissolved to achieve a clear solution.
  • the formulation was used within 24 hours after preparation.
  • the formulation was stirred continuously at room temperature if a suspension resulted.
  • Reference Compound A (11.70 mg) was dissolved in 3.900 mL vehicle, vortex until fully dissolved to achieve a final concentration of 3.0000 mg/mL clear solution.
  • Reference Compound A (12.000.0 mg) was dissolved (30 mg/kg) in 2.600 mL vehicle, vortexed until fully dissolved to achieve a final concentration of 1.0000 mg/mL, clear solution.
  • Liraglutide solution (0.05 mL) was diluted (6 mg/mL) in 1.950 mL saline and vortexed to achieve a final concentration of 0.150 mg/mL, clear solution.
  • Compound 2 (2.600 mL) (60 mg/kg) was diluted in 2.600 mL of vehicle, vortex until fully dissolved to achieve a final concentration at 4.2000 mg/mL, suspension ( ⁇ 3.0 mg/mL API).
  • Compound 2 (1.300 mL) (30 mg/kg) was diluted in 2.600 mL of vehicle, vortex until fully dissolved to achieve a final concentration of 1.4000 mg/mL, suspension ( ⁇ 1.0 mg/mL API).
  • the animal room environment was controlled for temperature (21-25° C.) and relative humidity (40-70%). Temperature and relative humidity were monitored and recorded twice daily.
  • An electronic time-controlled lighting system was used to provide a 12 h light/12 h dark cycle, 7:00 pm-7:00 am, lights out.
  • the mice were fed normal diet and fresh water during acclimation, animals were acclimated in the testing facility for one week prior to study start.
  • mice were acclimated for QD PO dosing with vehicle for 4 days, baseline body weight and food intake were measured for 4 consecutive days. Animals were allocated into 8 groups based on body weight and 3 rd day's food intake.
  • Compound 2 significantly suppressed food intake in humanized mice relative to vehicle control ( FIG. 5 ).
  • polyethylene glycol 400 95% (12% (w/v) sulfobutyl- ⁇ -cyclodextrin in water), (v/v)
  • Sulfobutyl- ⁇ -cyclodextrin (12,000.0 mg) was added to a 100 mL volumetric flask and QC with water to 100 mL, vortexed until fully dissolved, transferred 95 mL to anew 100 mL flask/cylinder. 5 mL polyethylene glycol 400 was added to the mixture and vortexed until fully dissolved to achieve a clear solution.
  • the formulation was used within 24 hours after preparation.
  • the formulation was stirred continuously at room temperature if a suspension resulted.
  • Liraglutide solution (6 mg/mL) was diluted in 1.950 mL saline and vortexed to achieve a final concentration of 0.150 mg/mL, clear solution.
  • Reference Compound A 1 mg was dissolved in in 10.000 mL vehicle and vortexed until fully dissolved to achieve a final concentration of 0.1000 mg/mL, clear solution.
  • Reference Compound A (1 mg/kg) was diluted in 2.450 mL of vehicle and vortexed until fully dissolved to achieve a final concentration of 0.0300 mg/mL, clear solution.
  • the animal room environment was controlled for temperature (21-25° C.) and relative humidity (40-70%). Temperature and relative humidity were monitored and recorded twice daily.
  • An electronic time-controlled lighting system was used to provide a 12 h light/12 h dark cycle, 7:00 am-7:00 pm, lights out.
  • the mice were fed normal diet and fresh water during acclimation, animals were acclimated in the testing facility for one week prior to study start.
  • IPGTT intraperitoneal Glucose Tolerance Test
  • IPGTT Intraperitoneal Glucose Tolerance Test
  • mice were placed clean cages with sawdust bedding and fasted overnight. Basal fasting glucose was measured by tail vein nick before dosing in the morning, 3 mice per group of abnormal fasting blood glucose and body weight were used for PK assessment. Mice were administered with vehicle or test compounds according to dose protocol (Table 8) at 9:30 am. 0.5 h later after vehicle or test compounds dosing, glucose was intraperitoneal injected with 2 g/kg at a dose volume of 10 mL/kg at 10:00 am. Blood glucose levels were measured at 0 (pre-dose), 15-, 30-, 60-, and 120-min post glucose dosing. ( FIG.
  • blood samples 40 ⁇ L blood samples (all treatment groups) were collected from mice under the jaw at IPGTT-120 min after blood glucose measurement into pre-chilled EDTA-2K tubes. Blood samples were processed for plasma by centrifugation at 4° C., 3200 ⁇ g for 10 min. 15 ⁇ L plasma was stored at ⁇ 80° C. for PK analysis. From 4 mice in Group 7 of the PD cohort, whole brain was collected after blood is harvested at 120 min post dose, rinsed with saline and patted dry and placed into a pre-weighed tube and stored at ⁇ 80° C. collected for PK analysis.
  • Compound 2 significantly enhanced the glucose tolerance of the mice relative to the vehicle control ( FIGS. 7 and 8 ).
  • mice expressing wildtype (WT) mouse GLP-1R was also evaluated after the administration of compound 2 using methods analogous to those described above.
  • the glucose tolerance of mice expressing WT mouse GLP-1R was not affected by Compound 2, whereas the glucose tolerance of mice expressing human GLP-1R was improved by Compound 2 ( FIGS. 9 and 10 ).
  • Compound 2 achieved higher plasma concentrations than Reference Compound A. For example, when administered at 0.3 mg/kg, Compound 2 effectuated approximately a three-fold higher C max and a four-fold higher AUC last than Reference Compound A. When administered at 1.0 mg/kg, Compound 2 effectuated an approximately 5.7-fold higher C max than Reference Compound A and an approximately 4.6-fold higher AUC last than Reference Compound A.
  • the study samples were stored at temperature of ⁇ 20° C. After analysis, the study samples were stored in a freezer at a nominal temperature of ⁇ 80° C.
  • the individual plasma concentrations of Reference Compound A and Compound 2 in study animals was subjected to non-compartmental pharmacokinetic analysis using the Phoenix WinNonlin software (version 6.3 or above, Certara) with extravascular input and uniform weighting.
  • the linear/log trapezoidal rule was applied in obtaining the PK parameters.
  • Individual plasma concentration values that were below the lower limit of quantitation (LOQ) were excluded from the PK parameter calculation.
  • the nominal dose levels and nominal sampling times were used in the calculation of all pharmacokinetic parameters.
  • the calibration curve of Reference Compound A and Compound 2 was constructed using eight non-zero standards ranging from 1.00 to 3000 ng/mL for plasma.
  • the regression analysis of Reference Compound A and Compound 2 was performed by plotting the peak area ratio of Reference Compound A and Compound 2 over IS (Y) against their concentration (X) in ng/mL, respectively.
  • the fit equation of calibration curve Reference Compound A was linear regression with 1/ ⁇ 2 as weighting factor.
  • the fit equation of calibration curve Compound 2 was quadratic regression with 1/ ⁇ 2 as weighting factor for plasma.
  • the correlation coefficient (R) of the linear regression of Reference Compound A in plasma is ⁇ 0.9875.
  • the correlation coefficient (R) of the quadratic regression of Compound 2 in plasma is ⁇ 0.996.
  • compositions of Compound 2 in male C57BL/6J hGLP-1R mouse plasma after PO (0.300, 1.00 and 3.00 mg/kg) administrations of compound 2 were determined.
  • Bioanalytical concentration of Compound 2 in male C57BL/6J hGLP-1R mouse plasma are listed in Table 15 and Table 16.
  • PK parameters for Reference Compound A are shown in Table 17 and Table 18, and PK parameters for Compound 2 are shown in Table 19, Table 20, and Table 21.
  • Reference Compound A Following oral administration of Reference Compound A at 0.3 and 1 mg/kg in mice, the observed maximum plasma concentrations were reach by a median Tmax of 0.5 hours post administration and then declined with a terminal elimination t1 ⁇ 2 of 0.604 hours following 0.3 mg/kg, and 1.99 hours following 1 mg/kg.
  • All concentrations were below the limit of quantitation ( ⁇ 1 ng/mL), resulting in mean AUC0 ⁇ last of 24.5 ng ⁇ h/mL.
  • plasma concentrations were measurable out to 8 hours post administration at 1 mg/kg, resulting in mean AUC0 ⁇ last of 85.5 ng ⁇ h/mL.
  • exposure to Reference Compound A increased with dose in an approximately proportional manner.
  • Test compounds were incubated in rat and human hepatocytes and stability was assessed from the substrate depilation approach.
  • Test compounds were dissolved in dimethyl sulfoxide (DMSO) to create a 10 mM Stock, and then further diluted to create a 1000 ⁇ Working Stock of 1 mM with DMSO in 96-well plates for test compounds and the positive control (midazolam).
  • DMSO dimethyl sulfoxide
  • Vials containing cryopreserved hepatocytes were removed from the liquid nitrogen tank and immediately immersed in a 37° C. water bath. The vials were shaken gently until the contents had thawed and were then immediately emptied into 48 mL of pre-warmed HT Medium in a 50 mL conical tube.
  • DMEM Dulbecco's Modified Eagle medium
  • Test Compounds were incubated at 1 ⁇ M with 1 ⁇ 10 6 cells/mL hepatocytes in DMEM for 0, 30, 60, 120 and 240 minutes. The incubation was carried out with gentle shaking at 37° C. under a humid atmosphere of 95% air/5% CO 2 . The volume of the incubation mixture was 37 ⁇ L with a final 0.1% DMSO. At each of the time points, the incubation was stopped by adding 150 ⁇ L quenching solution (100% acetonitrile, 0.1% formic acid containing bucetin as an internal standard for positive ESI mode). Subsequently, the mixtures were vortexed for 20 min and centrifuged at 4,000 RPM at 10° C.
  • quenching solution 100% acetonitrile, 0.1% formic acid containing bucetin as an internal standard for positive ESI mode
  • the supernatant (80 ⁇ L) was transferred to a clean 96-well plate and analyzed by LC-MS/MS. Midazolam at 1 ⁇ M with a final 0.1% DMSO was included as a positive control to verify assay performance. The percent parent remaining, intrinsic and predicted hepatic clearance and ti/2 were calculated. All samples were analyzed by LC-MS/MS using an AB Sciex API 4000 instrument, coupled to a Shimadzu LC-20AD LC Pump system. Separation was achieved using a Waters Atlantis T3 dC18 reverse phase HPLC column (20 mm ⁇ 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). Elution conditions are detailed below.
  • the ion optics of each test compound were optimized for their declustering potential (DP), collection energy (CE), collision-cell exit potential (CXP) and used in a selected ion monitoring experiment in the positive ion mode.
  • the peak area ratio of each test compound to internal standard was then evaluated for stability.
  • the extent of metabolism was calculated based on the disappearance of the test compound, compared to its initial concentration.
  • the initial rates of clearance of the test compound were calculated using the linear regression plot of semi-log % remaining of the compound versus time.
  • the elimination rate constant (k) of the linear regression plot was then used to determine t 1/2 and the intrinsic clearance (CLint) using the following formula, where C hepatocyte (million cells/mL) is the cell density of the incubation:
  • CL hep predicted ( CL int(in vivo) ⁇ Q liver )/( CL int(in vivo) +Q liver )
  • liver weight The relevant physiological parameters of liver weight, blood flow, and hepatocellularity for various species are listed below:
  • Liver Weight Hepatocellularity Liver Blood (g liver/kg body (106 cells/g Flow (Q liver , Species weight) liver) mL/min/kg) Human 25.7 135 20.7 Rat 40 120 55.2
  • Rat Human Clint Clint Cmpd # (mL/min/kg) t1/2 (min) (mL/min/kg) t1/2 (min)
  • 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 certification are shown below.
  • the permeability assay buffer was Hanks' balanced salt solution containing 10 mM HEPES and 15 mM glucose at a pH of 7.4.
  • the buffer in the receiver chamber also contained 1% bovine serum albumin.
  • the dosing solution concentration was 5 ⁇ M of test article in the assay buffer.
  • Cell monolayers were dosed on the apical side (A-to-B) or basolateral side (B-to-A) and incubated at 37° C.
  • dC r /dt is the slope of the cumulative receiver concentration versus time in ⁇ M s ⁇ 1 ;
  • V r is the volume of the receiver compartment in cm 3 ;
  • V d is the volume of the donor compartment in cm 3 ;
  • A is the area of the insert (1.13 cm 2 for 12-well);
  • C A is the average of the nominal dosing concentration and the measured 120-minute donor concentration in ⁇ M;
  • CN is the nominal concentration of the dosing solution in ⁇ M;
  • C r final is the cumulative receiver concentration in ⁇ M at the end of the incubation period;
  • C d final is the concentration of the donor in ⁇ M at the end of the incubation period.
  • Efflux ratio (ER) is defined as P app (B-to-A)/P app (A-to-B).
  • Passive permeability and efflux ratio are meant to serve as a proxies to evaluate the potential of molecules' oral bioavailability.
  • high passive permeability (Papp) and low efflux ratio (ER) are preferable and indicate a higher likelihood of orally bioavailable compound.

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