WO2022040600A1 - Compounds as glp-1r agonists - Google Patents

Compounds as glp-1r agonists Download PDF

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Publication number
WO2022040600A1
WO2022040600A1 PCT/US2021/047015 US2021047015W WO2022040600A1 WO 2022040600 A1 WO2022040600 A1 WO 2022040600A1 US 2021047015 W US2021047015 W US 2021047015W WO 2022040600 A1 WO2022040600 A1 WO 2022040600A1
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WO
WIPO (PCT)
Prior art keywords
optionally substituted
compound
ring
alkyl
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/US2021/047015
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English (en)
French (fr)
Inventor
F. Anthony Romero
Christopher T. Jones
Martijn Fenaux
Corey REEVES
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Terns Pharmaceuticals Inc
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Terns Pharmaceuticals Inc
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Filing date
Publication date
Priority to AU2021327397A priority Critical patent/AU2021327397A1/en
Priority to KR1020237009681A priority patent/KR20230074486A/ko
Priority to EP21859247.5A priority patent/EP4199919A4/en
Priority to US18/042,443 priority patent/US20230322744A1/en
Priority to CN202180071858.5A priority patent/CN116507326A/zh
Priority to MX2023002108A priority patent/MX2023002108A/es
Priority to BR112023003168A priority patent/BR112023003168A2/pt
Priority to CA3192601A priority patent/CA3192601A1/en
Application filed by Terns Pharmaceuticals Inc filed Critical Terns Pharmaceuticals Inc
Priority to JP2023512462A priority patent/JP2023538408A/ja
Priority to PE2023000511A priority patent/PE20231206A1/es
Priority to IL300795A priority patent/IL300795A/en
Publication of WO2022040600A1 publication Critical patent/WO2022040600A1/en
Anticipated expiration legal-status Critical
Priority to CONC2023/0003322A priority patent/CO2023003322A2/es
Ceased legal-status Critical Current

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    • 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
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

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.
  • T2DM Happp, C. et al. Use of Antidiabetic Drugs in the U.S., 2003-2012, Diabetes Care 2014, 37, 1367-1374).
  • GLP-1R glucagon-like peptide- 1 receptor
  • GLP-1R agonists e.g., liraglutide, albiglutide, exenatide, lixisenatide, dulaglutide, semaglutide
  • Marketed GLP-1R agonists are peptides administered by subcutaneous injection. Liraglutide is additionally approved for the treatment of obesity.
  • 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.
  • 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). [0007] Holst (Physiol. Rev.2007, 87, 1409) and Meier (Nat. Rev.
  • GLP-1 receptor agonists such as liraglutide and exendin-4
  • FPG and PPG fasting and postprandial glucose
  • GLP-1R glucagon-like peptide-1 receptor
  • compositions containing these compounds and methods for treating diseases and/or conditions mediated by GLP-1R.
  • GLP-1R glucagon-like peptide-1 receptor
  • a compound of Formula (I) including compounds of Formulae (II)-(IV), or selected from the group consisting of a compound listed in Table 1, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt of any of the foregoing, as detailed herein.
  • a pharmaceutical composition comprising is a compound of Formula (I), including compounds of Formulae (II)-(IV), or selected from the group consisting of a compound listed in Table 1, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt of any of the foregoing, 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)-(IV), or selected from the group consisting of compounds listed in Table 1, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt of any of the foregoing.
  • 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.
  • kits comprising a compound of Formula (I), including compounds of Formulae (II)-(IV), or selected from the group consisting of a compound listed in Table 1, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt of any of the foregoing.
  • the kit comprises instructions for use according to a method described herein.
  • the terms “about” and “approximately,” when used in connection with a value contemplate a variation within ⁇ 15%, within ⁇ 10%, within ⁇ 5%, within ⁇ 4%, within ⁇ 3%, within ⁇ 2%, within ⁇ 1%, or within ⁇ 0.5% of the specified value.
  • references to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”.
  • “Comprising” is intended to mean that the 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.
  • 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.
  • 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. When the compound provided herein contains an acidic functionality, such salts include, without limitation, alkali metal, alkaline earth metal, and ammonium salts. As used herein, ammonium salts include, salts containing protonated nitrogen bases and alkylated nitrogen bases.
  • Exemplary and non-limiting cations useful in pharmaceutically acceptable salts include Na, K, Rb, Cs, NH4, Ca, Ba, imidazolium, and ammonium cations based on naturally occurring amino acids.
  • such 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.
  • anions useful in pharmaceutically acceptable salts include oxalate, maleate, acetate, propionate, succinate, tartrate, chloride, sulfate, bisulfate, mono-, di-, and tribasic phosphate, mesylate, tosylate, and the likes.
  • “Stereoisomer” or “stereoisomers” refer 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 is used interchangeably herein in reference, for example, to a mammalian subject, such as a human.
  • “treatment” or “treating” 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.
  • “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 (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), t-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-).
  • Cx alkyl refers to an alkyl group having x number of carbon atoms.
  • Alkylene refers to a divalent saturated aliphatic hydrocarbyl group having from 1to 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 (-CH2-), ethylene (-CH2CH2- or –CH(Me)-), propylene (- CH2CH2CH2- or –CH(Me)CH2-, or –CH(Et)-) and the likes.
  • 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.
  • 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.
  • 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, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy,
  • Halo or “halogen” refers to fluoro, chloro, bromo and iodo and preferably is fluoro or chloro.
  • 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.
  • 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, 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, pheno
  • 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.
  • Ring B is C 3 -C 10 cycloalkyl, C 6 -C 14 aryl, 4- to 12-membered heterocyclyl, or 5- to 12-membered heteroaryl, each of which is independently optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, –COCH3, –CONH2, –S(O)2CH3, and phenyl.
  • X is N and Y is CR 4 .
  • X is CH and Y is N.
  • X and Y are each N.
  • 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; and 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, C1-C6 alkyl, –COCH3, –CONH2, –S(O)2CH3, 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, C1-C6 alkyl, –COCH3, –CONH2, – S(O)2CH3, 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, C1-C6 alkyl, –COCH3, – 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, –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 C3-C10 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, –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, –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 C3-C10 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, –COCH 3 , – CONH2, –S(O)2CH3, 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, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted by halo or OH.
  • a compound of Formula (IV) [0053] or a stereoisomer, tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein X, Y, n, R 2 , R 3 , Ring A, and Ring B are as detailed herein for Formula (I) with the provisos if applicable.
  • both X and Y are N
  • n is 1
  • both R 2 and R 3 are oxo
  • the compound is of Formula (III-a) or (IV-a), or a stereoisomer, tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A, and Ring B are as detailed herein for Formula (I).
  • Ring A is pyridinyl.
  • X is N
  • Y is CR 4
  • n is 1
  • R 2 is H
  • R 3 and R 4 taken together with the carbon atoms to which they are attached to form cyclopropyl
  • the compound is of Formula (III-b) or (IV-b), or a stereoisomer, tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A, and Ring B are as detailed herein for Formula (I).
  • Ring A is pyridinyl.
  • Ring A is pyrazolyl. In certain embodiments of Formula (III-b) or (IV-b), Ring B is optionally substituted phenyl. In certain embodiments of Formula (III-b) or (IV-b), Ring A is pyridinyl and Ring B is as detailed herein for Formula (I). In certain embodiments of Formula (III-b) or (IV-b), Ring A is pyrazolyl and Ring B is as detailed herein for Formula (I). In certain embodiments of Formula (III-b) or (IV-b), Ring A is pyridinyl and Ring B is optionally substituted phenyl.
  • Ring A is pyrazolyl and Ring B is optionally substituted phenyl.
  • X is N
  • Y is CH
  • n is 1
  • both R 2 and R 3 are hydrogen
  • 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, C1-C6 alkyl, –COCH3, –CONH2, – S(O) 2 CH 3 , and phenyl.
  • both X and Y are N, n is 1, both R 2 and R 3 are oxo, and the compound is of Formula (IV’-a) or (IV”-a), or a pharmaceutically acceptable salt thereof, wherein Ring A, and Ring B are as detailed herein for Formula (I).
  • Ring A is pyridinyl.
  • X is N
  • Y is CR 4
  • n is 1
  • R 2 is H
  • R 3 and R 4 taken together with the carbon atoms to which they are attached to form cyclopropyl
  • the compound is of Formula (IV’-b) or (IV”-b), or a pharmaceutically acceptable salt thereof, wherein Ring A, and Ring B are as detailed herein for Formula (I).
  • Ring A is pyridinyl.
  • Ring A is pyrazolyl.
  • Ring B is optionally substituted phenyl.
  • Ring A is pyridinyl and Ring B is as detailed herein for Formula (I).
  • Ring A is pyrazolyl and Ring B is as detailed herein for Formula (I).
  • Ring A is pyridinyl and Ring B is optionally substituted phenyl.
  • Ring A is pyrazolyl and Ring B is optionally substituted phenyl.
  • X is N, Y is CH, n is 1, both R 2 and R 3 are hydrogen, and Ring [0062]
  • X is N, Y is CH, n is 1, both R 2 and R 3 are hydrogen, Ring A is pyridinyl, and 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, C1-C6 alkyl, –COCH3, –CONH2, – S(O)2CH3, and phenyl.
  • a compound of Formula (I) (including compounds of Formulae (II)-(IV) if applicable), or a stereoisomer, tautomer, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is -C 1 -C 6 alkylene-R 5 , wherein R 5 is 3- to 6-membered heterocyclyl or 5- to 6-membered heteroaryl, each of which is independently optionally substituted by C 1 -C 6 alkyl. In some embodiments, R 1 is –CH 2 -R 5 .
  • R 1 is taken together with R and the intervening atoms to form a Ring C, wherein Ring C is a 5- to 7-membered heterocyclyl optionally substituted by C1-C6 alkyl.
  • Exemplary Ring C include, but are not limited to, , each of which is independently optionally substituted by C 1 -C 6 alkyl.
  • R 5 is 3- to 6-membered heterocyclyl, optionally substituted by C1-C6 alkyl.
  • R 5 is each of which is independently optionally substituted by C1-C6 alkyl. In some embodiments, R 5 is , each of which is independently optionally substituted by C1-C6 alkyl. In some embodiments, R 5 is independently optionally substituted by C 1 -C 6 alkyl. In some embodiments, R 5 is 5- to 6- membered heteroaryl, optionally substituted by C1-C6 alkyl. In some embodiments, R 5 is 5- membered heteroaryl, optionally substituted by C1-C6 alkyl. In some embodiments, R 5 is pyrrolyl, oxazolyl, imidazolyl, or triazolyl.
  • R 5 is , each of which is optionally substituted by C1- C 6 alkyl. In some embodiments, R 5 is , which is optionally substituted by C 1 -C 6 [0065] In some embodiments of a compound of Formula (I) (including compounds of Formulae (II)-(IV)), or a stereoisomer, tautomer, or a pharmaceutically acceptable salt of any of the foregoing, X is N. In other embodiments, X is CH. [0066] In some embodiments of a compound of Formula (I) (including compounds of Formulae (II)-(IV)), or a stereoisomer, tautomer, or a pharmaceutically acceptable salt of any of the foregoing, n is 0.
  • n is 1.
  • Y is N.
  • Y is CR 4 , wherein R 4 is hydrogen, OH or C1-C6 alkyl.
  • R 3 and R 4 are optionally taken together with the carbon atoms to which they are attached to form C3-C6 cycloalkyl.
  • the C 3 -C 6 cycloalkyl can be cyclopropyl.
  • R 2 and R 3 are independently hydrogen, oxo, or C1-C6 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, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted by halo or OH.
  • Ring A can , which is optionally substituted by halo, CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted by halo or OH.
  • Ring which is optionally substituted by halo, CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted by halo or OH.
  • Ring C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted by halo or OH.
  • Ring A is 5- to 12-membered heteroaryl, which is optionally substituted by halo, CN, C3-C6 cycloalkyl, or C 1 -C 6 alkyl optionally substituted by halo or OH.
  • exemplary Ring A include,
  • Ring A is which is independently optionally substituted by halo, CN, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkyl optionally substituted by halo or OH.
  • L is bond.
  • L is -O-.
  • L is C 1 -C 6 alkylene.
  • L is unsubstituted C 1 -C 6 alkylene.
  • L is C1-C6 alkylene optionally substituted by R L1 , wherein each R L1 is independently halo, OH, or C1-C6 alkyl, or two R L1 are taken together with the carbon atom or atoms to which they are attached to form C3-C6 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 R L1 , wherein each R L1 is independently halo, OH, or C1-C6 alkyl.
  • L is unsubstituted C2 alkylene.
  • L is C2 alkylene optionally substituted by R L1 , wherein each R L1 is independently halo, OH, or C1-C6 alkyl.
  • L is , some embodiments, L is *-O-C1-C6 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 C1-C6 alkylene is substituted by R L , wherein each R L is independently C1-C6 alkyl or halo, or two R L are taken together with the carbon atom or atoms to which they are attached to form C3-C6 cycloalkyl or 3- to 6-membered heterocyclyl.
  • L when L is *-O-C 1 -C 6 alkylene-**, the C1-C6 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 C3-C6 cycloalkyl or 3- to 6- membered heterocyclyl.
  • R L when L is *-OC(RL)2-**, two RL can be taken together with the carbon atom or atoms to which they are attached to form C3-C6 cycloalkyl or 3- to 6-membered heterocyclyl.
  • L is *-C 1 -C 6 alkylene- O-**.
  • L is *–NR 6 -C 1 -C 6 alkylene-**, wherein R 6 is hydrogen or C 1 - C 6 alkyl.
  • R 6 is hydrogen or C 1 - C 6 alkyl.
  • 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 - C6 alkyl, –COCH3, –CONH2, –S(O)2CH3 and phenyl.
  • Exemplary C3-C10 cycloalkyl include, but are not limited to, , each of which is independently optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, –COCH3, –CONH2, –S(O)2CH3 and phenyl.
  • Ring each of which is independently optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, –COCH3, –CONH2, – S(O) 2 CH 3 and phenyl.
  • Ring B is , , , 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, –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, C1-C6 alkyl, –COCH3, –CONH2, –S(O)2CH3 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, C1-C6 alkyl, –COCH3, –CONH2, –S(O)2CH3 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, –COCH 3 , –CONH 2 , –S(O) 2 CH 3 and phenyl.
  • Exemplary 4- to 12-membered heterocyclyl include, but are not limited to, , , , , , , , , , 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, –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, –COCH 3 , –CONH 2 , –S(O) 2 CH 3 and phenyl.
  • Ring B is C 3 - C 10 cycloalkyl, C 6 -C 14 aryl, 4- to 12-membered heterocyclyl, or 5- to 12-membered heteroaryl, each of which is independently optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, –COCH3, – CONH 2 , –S(O) 2 CH 3 , and phenyl.
  • the compound is of Formula (Va) or (Vb): or a pharmaceutically acceptable salt thereof, wherein X, n, R, R 1 , R 2 , Ring A, L, and Ring B are as described for Formula (I).
  • Ring B is C3-C10 cycloalkyl, C6-C14 aryl, 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, C1-C6 alkyl, –COCH3, – CONH 2 , –S(O) 2 CH 3 , and phenyl.
  • X is N, n is 1, and R, R 1 , R 2 , Ring A, L, and Ring B are as described for Formula (I).
  • X is N, n is 1, R 1 is –CH2-R 5 , and R, R 5 , R 2 , Ring A, L, and Ring B are as described for Formula (I).
  • R 5 is 3- to 6-membered heterocyclyl, optionally substituted by C 1 -C 6 alkyl.
  • R 5 is 5- to 6- membered heteroaryl optionally substituted by C 1 -C 6 alkyl, preferably wherein R 5 is 5- membered heteroaryl, optionally substituted by C 1 -C 6 alkyl.
  • X is N, n is 1, R 1 is – CH2-R 5 , R 5 is 3- to 6-membered heterocyclyl optionally substituted by C1-C6 alkyl, Ring A is 5- to 12-membered heterocyclyl, which is optionally substituted by halo, CN, C3-C6 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).
  • X is N, n is 1, R 1 is –CH2-R 5 , R 5 is 3- to 6-membered heterocyclyl optionally substituted by C1-C6 alkyl, 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 2 , L, and Ring B are as described for Formula (I).
  • R 5 is 4- to 5-membered heterocyclyl optionally substituted by C1-C6 alkyl.
  • X is N, n is 1, R 1 is – CH2-R 5 , R 5 is 3- to 6-membered heterocyclyl optionally substituted by C1-C6 alkyl, 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).
  • X is N, n is 1, R 1 is –CH2-R 5 , R 5 is 3- to 6-membered heterocyclyl optionally substituted by C1-C6 alkyl, 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; and R, R 2 , L, and Ring B are as described for Formula (I).
  • Ring A is 5- to 6-membered heteroaryl, which is optionally substituted by halo, CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted by halo or OH.
  • 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.
  • Ring A is unsubstituted 6- membered heteroaryl such as .
  • Ring A is embodiments of any of the foregoing, R 5 is 4- to 5-membered heterocyclyl optionally substituted by C 1 -C 6 alkyl.
  • X is N, n is 1, R 1 is –CH2-R 5 , R 5 is 5- to 6-membered heteroaryl optionally substituted by C1-C6 alkyl, 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; and R, R 2 , L, and Ring B is as described for Formula (I).
  • X is N, n is 1, R 1 is –CH2-R 5 , R 5 is 5- to 6-membered heteroaryl optionally substituted by C1-C6 alkyl, 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 2 , L, and Ring B is as described for Formula (I).
  • X is N, n is 1, R 1 is – CH2-R 5 , R 5 is 5-membered heteroaryl optionally substituted by C1-C6 alkyl, 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 2 , L, and Ring B is as described for Formula (I).
  • X is N, n is 1, R 1 is – CH2-R 5 , R 5 is 5- to 6-membered heteroaryl optionally substituted by C1-C6 alkyl, 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 is as described for Formula (I).
  • X is N, n is 1, R 1 is –CH2-R 5 , R 5 is 5- to 6-membered heteroaryl optionally substituted by C1-C6 alkyl, 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; and R, R 2 , L, and Ring B are is as described for Formula (I).
  • X is N, n is 1, R 1 is – CH 2 -R 5 , R 5 is 5-membered heteroaryl optionally substituted by C 1 -C 6 alkyl, 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; and R, R 2 , L, and Ring B are is as described for Formula (I).
  • 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.
  • Ring A is , , , [0081]
  • X is N, n is 1, R 1 is – CH 2 -R 5 , R 5 is 3- to 6-membered heterocyclyl optionally substituted by C 1 -C 6 alkyl, 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, C1-C6 alkyl, C1-C6 haloalkyl, –COCH3, –CONH2, –S(O)2CH3 and phenyl; and R, R 2 , Ring A, and L are as described for Formula (I).
  • 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, –COCH3, –CONH2, –S(O)2CH3 and phenyl.
  • X is N, n is 1, R 1 is – CH 2 -R 5 , R 5 is 4- to 5-membered heterocyclyl optionally substituted by C 1 -C 6 alkyl, 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, C1-C6 alkyl, C1-C6 haloalkyl, –COCH3, –CONH2, –S(O)2CH3 and phenyl; and R, R 2 , Ring A, and L are as described for Formula (I).
  • Ring B is cyclobutyl, cyclohexyl, or tetrahydronaphthalenyl, each of 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 , – CONH2, –S(O)2CH3 and phenyl.
  • 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, –COCH 3 , –CONH 2 , –S(O) 2 CH 3 and phenyl.
  • X is N, n is 1, R 1 is – CH2-R 5 , R 5 is 3- to 6-membered heterocyclyl optionally substituted by C1-C6 alkyl, Ring B is C6-C14 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).
  • Ring B is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, –COCH 3 , –CONH 2 , –S(O) 2 CH 3 and phenyl.
  • X is N, n is 1, R 1 is – CH2-R 5 , R 5 is 4- to 5-membered heterocyclyl optionally substituted by C1-C6 alkyl, Ring B is C6-C14 aryl, which is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, C1-C6 haloalkyl, –COCH3, –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 phenyl or naphthalenyl, each of 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 optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, –COCH3, –CONH2, –S(O)2CH3 and phenyl.
  • X is N, n is 1, R 1 is – CH 2 -R 5 , R 5 is 3- to 6-membered heterocyclyl optionally substituted by C 1 -C 6 alkyl, 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, C1-C6 alkyl, C1-C6 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 optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, –COCH3, –CONH2, –S(O)2CH3 and phenyl.
  • X is N, n is 1, R 1 is – CH 2 -R 5 , R 5 is 4- to 5-membered heterocyclyl optionally substituted by C 1 -C 6 alkyl, Ring B is 9- to 10-membered heterocyclyl, which is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, C1-C6 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 three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C1-C6 haloalkyl, –COCH3, –CONH2, –S(O)2CH3 and phenyl.
  • 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, –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 3- to 6-membered heterocyclyl optionally substituted by C 1 -C 6 alkyl, 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, C1-C6 alkyl, C1-C6 haloalkyl, –COCH3, –CONH2, –S(O)2CH3 and phenyl; and R, R 2 , Ring A, and L are as described for Formula (I).
  • Ring B is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, –COCH3, –CONH2, –S(O)2CH3 and phenyl.
  • X is N, n is 1, R 1 is – CH 2 -R 5 , R 5 is 4- to 5-membered heterocyclyl optionally substituted by C 1 -C 6 alkyl, 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, C1-C6 alkyl, C1-C6 haloalkyl, –COCH3, –CONH2, –S(O)2CH3 and phenyl; and R, R 2 , Ring A, and L are as described for Formula (I).
  • 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, –COCH 3 , –CONH 2 , –S(O) 2 CH 3 and phenyl.
  • X is N, n is 1, R 1 is – CH2-R 5 , R 5 is 4- to 5-membered heterocyclyl optionally substituted by C1-C6 alkyl, Ring B is 9- to 10-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, –COCH3, –CONH2, –S(O)2CH3 and phenyl; and R, R 2 , Ring A, and L are as described for Formula (I).
  • 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, –COCH 3 , –CONH 2 , –S(O) 2 CH 3 and phenyl.
  • X is N, n is 1, R 1 is – CH2-R 5 , R 5 is 5- to 6-membered heteroaryl optionally substituted by C1-C6 alkyl, 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 , –CONH2, –S(O)2CH3 and phenyl; and R, R 2 , Ring A, and L are as described for Formula (I).
  • Ring B is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, –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 5-membered heteroaryl optionally substituted by C 1 -C 6 alkyl, 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, C1-C6 alkyl, C1-C6 haloalkyl, –COCH3, – CONH2, –S(O)2CH3 and phenyl; and R, R 2 , Ring A, and L are as described for Formula (I).
  • 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, –COCH3, –CONH2, –S(O)2CH3 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 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, C1-C6 alkyl, C1-C6 haloalkyl, –COCH3, –CONH2, –S(O)2CH3 and phenyl; and R, R 2 , and L are as described for Formula (I).
  • Ring A is . In other such embodiments, Ring A is . In still other such embodiments, Ring A is In some embodiments of the foregoing, 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, –COCH 3 , –CONH 2 , –S(O) 2 CH 3 and phenyl.
  • X is N, n is 1, R 1 is –CH2-R 5 , R 5 is 5-membered heteroaryl optionally substituted by C1-C6 alkyl.
  • 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-C1-C6 alkylene-**;
  • Ring B is C3-C10 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-CH2-**.
  • Ring B is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, –COCH3, –CONH2, –S(O)2CH3 and phenyl.
  • X is N, n is 1, R 1 is –CH 2 -R 5 , R 5 is 5-membered heteroaryl optionally substituted by C 1 -C 6 alkyl.
  • Ring A is 5- to 6- membered heteroaryl, which is optionally substituted by halo, CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted by halo or OH; L is a bond; Ring B is C3-C10 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).
  • 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, –COCH 3 , –CONH 2 , – S(O)2CH3 and phenyl.
  • X is N, n is 1, R 1 is – CH2-R 5 , R 5 is 5-membered heteroaryl optionally substituted by C1-C6 alkyl.
  • 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-; Ring B is C3-C10 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).
  • Ring B is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, –COCH3, –CONH2, – S(O) 2 CH 3 and phenyl.
  • X is N, n is 1, R 1 is – CH 2 -R 5 , R 5 is 5-membered heteroaryl optionally substituted by C 1 -C 6 alkyl.
  • 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, C1-C6 alkyl, C1-C6 haloalkyl, –COCH3, –CONH2, – 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 , R 5 is 5- membered heteroaryl optionally substituted by C1-C6 alkyl, Ring B is C6-C14 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 –CH2-R 5 , R 5 is 5-membered heteroaryl optionally substituted by C1-C6 alkyl, Ring B is C6 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).
  • Ring B is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, –COCH3, –CONH2, –S(O)2CH3 and phenyl.
  • X is N, n is 1, R 1 is –CH 2 -R 5 , R 5 is 5-membered heteroaryl optionally substituted by C 1 -C 6 alkyl.
  • Ring A is 5- to 6- membered heteroaryl, which is optionally substituted by halo, CN, C3-C6 cycloalkyl, or C1-C6 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, C1-C6 alkyl, C1-C6 haloalkyl, –COCH3, –CONH2, –S(O)2CH3 and phenyl; and R, R 2 , and L are as described for Formula (I).
  • Ring A is . In other such embodiments, Ring A is . In still other such embodiments, Ring A 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, –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 5-membered heteroaryl optionally substituted by C 1 -C 6 alkyl.
  • Ring A is 5- to 6- membered heteroaryl, which is optionally substituted by halo, CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted by halo or OH;
  • L is *-O-C 1 -C 6 alkylene-**;
  • 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, C1-C6 alkyl, C1-C6 haloalkyl, –COCH3, –CONH2, – S(O)2CH3 and phenyl; and R and R 2 are as described for Formula (I).
  • Ring A, L, and Ring B herein.
  • B is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, –COCH3, –CONH2, –S(O)2CH3 and phenyl.
  • X is N, n is 1, R 1 is –CH2-R 5 , R 5 is 5-membered heteroaryl optionally substituted by C 1 -C 6 alkyl.
  • Ring A is 5- to 6- membered heteroaryl, which is optionally substituted by halo, CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted by halo or OH; L is a bond; Ring B is C6 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).
  • 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, C1-C6 alkyl, –COCH3, –CONH2, – S(O)2CH3 and phenyl.
  • X is N, n is 1, R 1 is – CH 2 -R 5 , R 5 is 5-membered heteroaryl optionally substituted by C 1 -C 6 alkyl.
  • Ring A is 5- to 6- membered heteroaryl, which is optionally substituted by halo, CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted by halo or OH; L is -O-; Ring B is C6 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).
  • Ring B is C3-C10 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, –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 5-membered heteroaryl optionally substituted by C 1 -C 6 alkyl.
  • 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 .
  • Ring A is .
  • Ring A is .
  • Ring A is .
  • Ring B is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, –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 5-membered heteroaryl optionally substituted by C 1 -C 6 alkyl.
  • 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, C1-C6 alkyl, C1-C6 haloalkyl, –COCH3, –CONH2, –S(O)2CH3 and phenyl; and R, R 2 , Ring A, and L are as described for Formula (I).
  • Ring B is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, –COCH3, –CONH2, –S(O)2CH3 and phenyl.
  • X is N, n is 1, R 1 is –CH2-R 5 , R 5 is 5-membered heteroaryl optionally substituted by C 1 -C 6 alkyl.
  • Ring A is 5- to 6- membered heteroaryl, which is optionally substituted by halo, CN, C3-C6 cycloalkyl, or C1-C6 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 . In other such embodiments, Ring A is . In still other such embodiments, Ring A is .
  • Ring B is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, –COCH3, –CONH2, –S(O)2CH3 and phenyl.
  • X is N, n is 1, R 1 is –CH 2 -R 5 , R 5 is 5-membered heteroaryl optionally substituted by C 1 -C 6 alkyl.
  • Ring A is 5- to 6- membered heteroaryl, which is optionally substituted by halo, CN, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted by halo or OH;
  • L is *-O-C 1 -C 6 alkylene-**;
  • 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, –COCH3, –CONH2, –S(O)2CH3 and phenyl; and R and R 2 are as described for Formula (I).
  • L is *-O-CH2-**.
  • Ring B is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, –COCH3, –CONH2, –S(O)2CH3 and phenyl.
  • X is N, n is 1, R 1 is –CH 2 -R 5 , R 5 is 5-membered heteroaryl optionally substituted by C 1 -C 6 alkyl.
  • Ring A is 5- to 6- membered heteroaryl, which is optionally substituted by halo, CN, C3-C6 cycloalkyl, or C1-C6 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, C1-C6 alkyl, C1-C6 haloalkyl, –COCH3, –CONH2, –S(O)2CH3 and phenyl; and R and R 2 are as described for Formula (I).
  • Ring B is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, –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 5-membered heteroaryl optionally substituted by C1-C6 alkyl.
  • 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-; 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, C1-C6 alkyl, C1-C6 haloalkyl, –COCH3, –CONH2, –S(O)2CH3 and phenyl; and R and R 2 are as described for Formula (I).
  • 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, –COCH 3 , – CONH 2 , –S(O) 2 CH 3 and phenyl.
  • X is N, n is 1, R 1 is –CH2-R 5 , R 5 is 5-membered heteroaryl optionally substituted by C1-C6 alkyl.
  • 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, –COCH3, –CONH2, –S(O)2CH3 and phenyl; and R, R 2 , Ring A, and L are 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, –COCH3, –CONH2, –S(O)2CH3 and phenyl; and R, R 2 , Ring A, and L are as described for Formula (I).
  • 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, –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 5-membered heteroaryl optionally substituted by C1-C6 alkyl.
  • 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, C1-C6 alkyl, C1-C6 haloalkyl, –COCH3, –CONH2, –S(O)2CH3 and phenyl; and R, R 2 , and L are as described for Formula (I).
  • Ring A is . In other such embodiments, Ring A is . In still other such embodiments, Ring A 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, –COCH 3 , –CONH 2 , –S(O) 2 CH 3 and phenyl.
  • X is N, n is 1, R 1 is –CH2-R 5 , R 5 is 5-membered heteroaryl optionally substituted by C1-C6 alkyl.
  • 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-**;
  • 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, C1-C6 alkyl, C1-C6 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 -**.
  • 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, –COCH 3 , –CONH 2 , – S(O)2CH3 and phenyl.
  • X is N, n is 1, R 1 is – CH2-R 5 , R 5 is 5-membered heteroaryl optionally substituted by C1-C6 alkyl.
  • 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 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).
  • Ring B is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, –COCH3, – CONH2, –S(O)2CH3 and phenyl.
  • X is N, n is 1, R 1 is –CH 2 -R 5 , R 5 is 5-membered heteroaryl optionally substituted by C 1 -C 6 alkyl.
  • 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-; 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, C1-C6 alkyl, C1-C6 haloalkyl, –COCH3, –CONH2, – S(O) 2 CH 3 and phenyl; and R and R 2 are as described for Formula (I).
  • Ring B is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, –COCH3, –CONH2, – S(O)2CH3 and phenyl.
  • X is N, n is 1, R 1 is – CH 2 -R 5 , R 5 is 5-membered heteroaryl optionally substituted by C 1 -C 6 alkyl.
  • the compound is of Formula (Vb-1): or a pharmaceutically acceptable salt thereof, wherein X, n, R, R 1 , R 2 , L, and Ring B are as described for Formula (I).
  • Ring B is C3-C10 cycloalkyl, C6-C14 aryl, 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, –COCH 3 , – CONH2, –S(O)2CH3, and phenyl.
  • X is N, n is 1, and R, R 1 , R 2 , L, and Ring B are as described for Formula (I).
  • X is N, n is 1, R 1 is –CH 2 -R 5 , and R, R 5 , R 2 , L, and Ring B are as described for Formula (I).
  • R 5 is 3- to 6-membered heterocyclyl, optionally substituted by C1-C6 alkyl.
  • R 5 is 5- to 6-membered heteroaryl optionally substituted by C 1 -C 6 alkyl, preferably wherein R 5 is 5-membered heteroaryl, optionally substituted by C 1 -C 6 alkyl.
  • X is N, n is 1, R 1 is –CH 2 -R 5 , R 5 is 5- membered heteroaryl optionally substituted by C1-C6 alkyl, Ring B is C3-C10 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 2 , and L are as described for Formula (I).
  • L is *-O-C 1 -C 6 alkylene-**, preferably wherein L is *-O-CH 2 -**. In other such embodiments, L is a bond. In other such embodiments, L is -O-.
  • X is N, n is 1, R 1 is –CH2-R 5 , R 5 is 5- membered heteroaryl optionally substituted by C 1 -C 6 alkyl, 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, C1-C6 alkyl, –COCH3, –CONH2, –S(O)2CH3 and phenyl; and R, R 2 , and L are as described for Formula (I).
  • L is *-O-C1-C6 alkylene-**, preferably wherein L is *-O-CH 2 -**. In other such embodiments, L is a bond. In other such embodiments, L is -O-.
  • X is N, n is 1, R 1 is –CH2-R 5 , R 5 is 5- membered heteroaryl optionally substituted by C1-C6 alkyl, Ring B is C6-C14 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 , and L are as described for Formula (I).
  • L is *-O-C1-C6 alkylene-**, preferably wherein L is *-O-CH2-**. In other such embodiments, L is a bond. In other such embodiments, L is -O-.
  • X is N, n is 1, R 1 is –CH 2 -R 5 , R 5 is 5- membered heteroaryl optionally substituted by C 1 -C 6 alkyl, 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, C1-C6 alkyl, –COCH3, –CONH2, –S(O)2CH3 and phenyl; and R, R 2 , and L are as described for Formula (I).
  • L is *-O-C 1 -C 6 alkylene-**, preferably wherein L is *-O-CH 2 -**. In other such embodiments, L is a bond. In other such embodiments, L is -O-.
  • X is N, n is 1, R 1 is –CH2-R 5 , R 5 is 5- membered heteroaryl optionally substituted by C 1 -C 6 alkyl, 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, C1-C6 alkyl, C1-C6 haloalkyl, –COCH3, –CONH2, –S(O)2CH3 and phenyl; and R, R 2 , and L are as described for Formula (I).
  • L is *-O-C1-C6 alkylene-**, preferably wherein L is *-O-CH2-**. In other such embodiments, L is a bond. In other such embodiments, L is -O-.
  • X is N, n is 1, R 1 is –CH 2 -R 5 , R 5 is 5- membered heteroaryl optionally substituted by C 1 -C 6 alkyl, 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, C1-C6 alkyl, –COCH3, –CONH2, – S(O)2CH3 and phenyl; and R, R 2 , and L are as described for Formula (I).
  • L is *-O-C 1 -C 6 alkylene-**, preferably wherein L is *-O-CH 2 -**. In other such embodiments, L is a bond. In other such embodiments, L is -O-.
  • X is N, n is 1, R 1 is –CH2-R 5 , R 5 is 5- membered heteroaryl optionally substituted by C1-C6 alkyl, 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 , – CONH2, –S(O)2CH3 and phenyl; and R, R 2 , and L are as described for Formula (I).
  • L is *-O-C1-C6 alkylene-**, preferably wherein L is *-O-CH2-**. In other such embodiments, L is a bond. In other such embodiments, L is -O-.
  • X is N, n is 1, R 1 is –CH 2 -R 5 , R 5 is 5- membered heteroaryl optionally substituted by C 1 -C 6 alkyl, 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, C1-C6 alkyl, –COCH3, –CONH2, –S(O)2CH3 and phenyl; and R, R 2 , and L are as described for Formula (I).
  • L is *- O-C 1 -C 6 alkylene-**, preferably wherein L is *-O-CH 2 -**. In other such embodiments, L is a bond. In other such embodiments, L is -O-.
  • Ring B1 is C3-C10 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, –COCH3, –CONH2, –S(O)2CH3, and phenyl.
  • X is N.
  • X is N
  • R 1 is –CH 2 -R 5
  • Y, n, R, R 5 , R 2 , R 3 , and L are as described for Formula (I)
  • Ring A 1 and Ring B 1 are as described for Formula (I’).
  • X is N
  • R 1 is –CH2-R 5
  • R 5 is 3- to 6- membered heterocyclyl optionally substituted by C1-C6 alkyl
  • Ring B1 is C3-C10 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
  • Y, n, R, R 2 , and R 3 are as described for Formula (I)
  • Ring A 1 is as described for Formula (I’).
  • X is N; R 1 is –CH2-R 5 ; R 5 is 3- to 6-membered heterocyclyl optionally substituted by C1-C6 alkyl; Ring B1 is C3-C10 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,–COCH 3 , –CONH 2 , –S(O) 2 CH 3 and phenyl; Y, n, R, R 2 , and R 3 are as described for Formula (I); and Ring A1 is as described for Formula (I’).
  • X is N; R 1 is –CH 2 -R 5 ; R 5 is 3- to 6- membered heterocyclyl optionally substituted by C 1 -C 6 alkyl; Ring B 1 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, C1-C6 alkyl, C1-C6 haloalkyl, –COCH3, –CONH 2 , –S(O) 2 CH 3 and phenyl; Y, n, R, R2, and R3 are as described for Formula (I); and Ring A 1 is as described for Formula (I’).
  • X is N; R 1 is –CH2-R 5 ; R 5 is 3- to 6-membered heterocyclyl optionally substituted by C1-C6 alkyl; Ring B1 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, C1-C6 alkyl,– COCH 3 , –CONH 2 , –S(O) 2 CH 3 and phenyl; Y, n, R, R 2 , and R 3 are as described for Formula (I); and Ring A 1 is as described for Formula (I’).
  • X is N; R 1 is –CH 2 -R 5 ; R 5 is 3- to 6- membered heterocyclyl optionally substituted by C 1 -C 6 alkyl; Ring B 1 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, C1-C6 alkyl, C1-C6 haloalkyl, –COCH3, – CONH2, –S(O)2CH3 and phenyl; Y, n, R, R 2 , and R 3 are as described for Formula (I); and Ring A 1 is as described for Formula (I’).
  • X is N; R 1 is –CH 2 -R 5 ; R 5 is 3- to 6-membered heterocyclyl optionally substituted by C 1 -C 6 alkyl; Ring B 1 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, C1-C6 alkyl,–COCH3, – CONH 2 , –S(O) 2 CH 3 and phenyl; Y, n, R, R 2 , and R 3 are as described for Formula (I); and Ring A 1 is as described for Formula (I’).
  • X is N; R 1 is –CH2-R 5 ; R 5 is 5- to 6- membered heteroaryl optionally substituted by C1-C6 alkyl; Ring B1 is C3-C10 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; Y, n, R, R 2 , and R 3 are as described for Formula (I); and Ring A 1 is as described for Formula (I’).
  • X is N; R 1 is –CH2-R 5 ; R 5 is 5- to 6-membered heteroaryl optionally substituted by C1-C6 alkyl; Ring B1 is C3-C10 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,–COCH 3 , –CONH 2 , –S(O) 2 CH 3 and phenyl; Y, n, R, R 2 , and R 3 are as described for Formula (I); and Ring A1 is as described for Formula (I’).
  • X is N; R 1 is –CH 2 -R 5 ; R 5 is 5- to 6- membered heteroaryl optionally substituted by C 1 -C 6 alkyl; Ring B 1 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, C1-C6 alkyl, C1-C6 haloalkyl, –COCH3, –CONH 2 , –S(O) 2 CH 3 and phenyl; Y, n, R, R 2 , and R 3 are as described for Formula (I); and Ring A 1 is as described for Formula (I’).
  • X is N; R 1 is –CH2-R 5 ; R 5 is 5- to 6-membered heteroaryl optionally substituted by C1-C6 alkyl; Ring B1 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,–COCH 3 , – CONH 2 , –S(O) 2 CH 3 and phenyl; Y, n, R, R 2 , and R 3 are as described for Formula (I); and Ring A 1 is as described for Formula (I’).
  • X is N; R 1 is –CH 2 -R 5 ; 5- to 6-membered heteroaryl optionally substituted by C 1 -C 6 alkyl; Ring B 1 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, C1-C6 alkyl, C1-C6 haloalkyl, –COCH3, –CONH2, – S(O)2CH3 and phenyl; Y, n, R, R 2 , and R 3 are as described for Formula (I); and Ring A1 is as described for Formula (I’).
  • X is N
  • R 1 is –CH 2 -R 5
  • R 5 is 5- to 6-membered heteroaryl optionally substituted by C 1 -C 6 alkyl
  • Ring B 1 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, C1-C6 alkyl,–COCH3, – CONH 2 , –S(O) 2 CH 3 and phenyl
  • Y, n, R, R 2 , and R 3 are as described for Formula (I)
  • Ring A 1 is as described for Formula (I’).
  • a compound of Formula (I”) or a pharmaceutically acceptable salt thereof, wherein X, Y, n, R, R 2 , R 3 , Ring A, and L are as described for Formula (I);
  • R 1 is -C 1 -C 6 alkylene-R 5a , wherein R 5a is 5- to 6-membered heteroaryl optionally substituted by C 1 -C 6 alkyl;
  • Ring B1 is C3-C10 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.
  • Ring B1 is C3-C10 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, –COCH 3 , –CONH 2 , –S(O) 2 CH 3 , and phenyl.
  • X is N.
  • X is N
  • R 1 is –CH 2 -R 5a
  • Y, n, R, R 2 , R 3 , Ring A, and L are as described for Formula (I)
  • R 5a and Ring B 1 are as described for Formula (I”).
  • a compound of Formula (VI), or a pharmaceutically acceptable salt thereof wherein X, Y, n, R, R 1 , R 2 , R 3 , Ring A, and L are as described for Formula (I); is a fused bicyclic ring system comprising fused rings Ring C and Ring D, wherein Ring C is C5-C6 cycloalkyl, 5- to 7-membered heterocyclyl, or 5- to 6-membered heteroaryl; and Ring D is C6 cycloalkyl, C6 aryl or 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, –COCH3, –CONH2, –S(O)2CH3, and phenyl.
  • 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, –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 C and Ring D are optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, –COCH3, –CONH2, –S(O)2CH3, 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.
  • Ring C and Ring D form , 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)2CH3, and phenyl.
  • 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, –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 5- to 6-membered heteroaryl optionally substituted by C1-C6 alkyl. In some embodiments of any of the foregoing, X is N, n is 1, R 1 is –CH2-R 5 , and R 5 is 5- membered heteroaryl optionally substituted by C1-C6 alkyl. [0135] In some embodiments of Formula (VI), Ring D is C 6 aryl and Ring C is 5- to 7- membered heterocyclyl.
  • Ring C and Ring D form , 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 C and Ring D are optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, –COCH3, –CONH2, –S(O)2CH3, and phenyl.
  • 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 –CH2-R 5 , and R 5 is 5- membered heteroaryl optionally substituted by C1-C6 alkyl.
  • Ring D is C 6 aryl and Ring C is 5- to 6- membered heteroaryl.
  • Ring C and Ring D form , , 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 , – CONH2, –S(O)2CH3, and phenyl.
  • 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, –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 5- to 6- membered heteroaryl optionally substituted by C1-C6 alkyl. In some embodiments of any of the foregoing, X is N, n is 1, R 1 is –CH2-R 5 , and R 5 is 5- membered heteroaryl optionally substituted by C 1 -C 6 alkyl.
  • 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, C1-C6 alkyl, C1-C6 haloalkyl, –COCH 3 , –CONH 2 , –S(O) 2 CH 3 , and phenyl.
  • Ring C and Ring D are optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, –COCH3, –CONH2, –S(O)2CH3, and phenyl.
  • X is N
  • n is 1
  • R 1 is –CH2-R 5
  • 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 5- membered heteroaryl optionally substituted by C1-C6 alkyl.
  • Ring D is 6-membered heteroaryl and Ring C is C5-C6 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, –COCH3, –CONH2, –S(O)2CH3, and phenyl.
  • X is N, n is 1, R 1 is –CH2-R 5 , and R 5 is 5- to 6-membered heteroaryl optionally substituted by C1-C6 alkyl. 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 optionally substituted by C 1 -C 6 alkyl.
  • 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, C1-C6 alkyl, –COCH3, –CONH2, –S(O)2CH3, and phenyl.
  • X is N
  • n is 1
  • R 1 is –CH2-R 5
  • 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 5- membered heteroaryl optionally substituted by C1-C6 alkyl.
  • Ring D is 6-membered heteroaryl and Ring C is 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, C1-C6 alkyl, –COCH3, – CONH2, –S(O)2CH3, and phenyl.
  • 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. 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 optionally substituted by C 1 -C 6 alkyl.
  • Representative compounds are listed in Table 1 below. In some embodiments, provided is a compound, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt of any of the foregoing, which is selected from Compound Nos.1-142 in Table 1.
  • Compounds were prepared as described in the Examples.
  • Compounds described herein may be prepared according to general schemes, as exemplified by the general procedures and examples. Minor variations in 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 salts of the compounds provided herein are pharmaceutically acceptable salts.
  • 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.
  • 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.
  • 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 is also provided herein.
  • mixtures of the compound with both the “S” and the “R” stereochemical configuration are 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.
  • 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 are useful in compound or substrate tissue distribution study.
  • 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.
  • compositions and Formulations 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.
  • Pharmaceutically Acceptable Compositions and Formulations [0150] Pharmaceutically acceptable 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)-(IV)), or a stereoisomer, tautomer, or a pharmaceutically acceptable salt of any of the foregoing, 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.
  • a compound as detailed herein may in one aspect be in a purified form and compositions comprising a compound in purified forms are detailed herein.
  • Compositions comprising a compound as detailed herein or a salt thereof 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 wherein the composition contains or no more than 10% 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 5% impurity. In another variation, a composition of substantially pure compound or a salt thereof is provided 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.
  • 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.
  • 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),
  • Compounds 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.
  • 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)-(IV)), or a stereoisomer, tautomer, or a pharmaceutically acceptable salt of any of the foregoing, as described herein.
  • a dosage form comprises a therapeutically effective amount of a compound of Formula (I) (including compounds of Formulae (II)-(IV)), or a stereoisomer, tautomer, or a pharmaceutically acceptable salt of any of the foregoing.
  • the compound or a stereoisomer, tautomer, or a pharmaceutically acceptable salt of any of the foregoing is selected from Compound Nos.1-142 in Table 1.
  • the compound or a stereoisomer, tautomer, or a pharmaceutically acceptable salt of any of the foregoing is selected from Compound Nos.143-187 in Table 1. In some embodiments, the compound or a stereoisomer, tautomer, or a pharmaceutically acceptable salt of any of the foregoing is selected from Compound Nos.1-187 in Table 1. Methods of Use and Uses [0158] Compounds and compositions described herein may in some aspects be used in treatment of diseases and/or conditions described herein, for example, diseases and/or conditions mediated by GLP-1R.
  • the method of treating a desease 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)-(IV)), or a stereoisomer, tautomer, or a pharmaceutically acceptable salt of any of the foregoing.
  • the method of treating a desease or condition in a subject in need thereof comprises administering to the subject a therapeutically effective amount of a compound selected from Compound Nos.1-142 in Table 1, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt of any of the foregoing.
  • the method of treating a desease or condition in a subject in need thereof comprises administering to the subject a therapeutically effective amount of a compound selected from Compound Nos.143- 187 in Table 1, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the method of treating a desease or condition in a subject in need thereof comprises administering to the subject a therapeutically effective amount of a compound selected from Compound Nos.1-187 in Table 1, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt of any of the foregoing.
  • 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., osteoarth), steastea, stea,
  • 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 stereoisomer, tautomer, or a pharmaceutically acceptable salt of any of the foregoing.
  • a method of treating diabetes in a subject comprising administering to the subject a therapeutically effective amount of a compound described herein, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt of any of the foregoing.
  • 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.
  • a method of treating a liver disorder in a subject comprising administering to the subject a therapeutically effective amount of a compound described herein, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt of any of the foregoing.
  • Exemplary 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.
  • a compound described herein, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt of any of the foregoing 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 stereoisomer, tautomer, or a pharmaceutically acceptable salt of any of the foregoing.
  • 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. [0165] In some embodiments, the compounds and/or compositions may be administered directly into the bloodstream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • 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. [0167]
  • 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 stereoisomer, tautomer, or a pharmaceutically acceptable salt of any of the foregoing, 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 stereoisomer, tautomer, or a pharmaceutically acceptable salt of any of the foregoing, 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,
  • 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 a/d agonist (e.g., elafibranor), a synthetic fatty acid-bile acid conjugate (e.g., aramchol), a caspase inhibitor (e.g., emricasan), an anti-lysyl oxidase homologue 2 (LOXL2) monoclonal antibody (e.g., 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-9860
  • FXR agonist e
  • the present disclosure further provides articles of manufacture comprising a compound, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt of any of the foregoing 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 stereoisomer, tautomer, or a pharmaceutically acceptable salt of any of the foregoing 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).
  • the kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component(s) of the methods of the present disclosure.
  • the instructions included with the kit generally include information as to the components and their administration to an individual. Enumerated Embodiments 1.
  • Ring A is 5- to 12- membered heterocyclyl, which is optionally substituted by halo, CN, C 3 -C 6 cycloalkyl, or C 1 - C6 alkyl optionally substituted by halo or OH.
  • Ring A is 5- to 12- membered heterocyclyl, which is optionally substituted by halo, CN, C 3 -C 6 cycloalkyl, or C 1 - C6 alkyl optionally substituted by halo or OH.
  • Ring B is C3-C10 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, –COCH 3 , –CONH 2 , –S(O) 2 CH 3 and phenyl. 31.
  • 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, –COCH 3 , –CONH 2 , –S(O) 2 CH 3 and phenyl. 33.
  • Ring B is , each of which is independently optionally substituted by one to three substituents each independently selected from the group consisting of halo, CN, oxo, C1-C6 alkyl, –COCH3, –CONH2, – S(O)2CH3 and phenyl. 34.
  • 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, C1-C6 alkyl, –COCH3, – CONH2, –S(O)2CH3 and phenyl. 35.
  • the compound of embodiment 34 or a stereoisomer, tautomer, or a pharmaceutically 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, –COCH 3 , – CONH 2 , –S(O) 2 CH 3 and phenyl. 36.
  • 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, –COCH 3 , – CONH 2 , –S(O) 2 CH 3 and phenyl. 37.
  • a pharmaceutical composition comprising the compound of any one of embodiments 1-38, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutical acceptable excipient.
  • GLP- 1R glucagon-like peptide-1 receptor
  • 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 cirrhosis
  • PSC primary scle
  • Compounds of formula (S1) can be prepared from the 2-bromopyridine (1l) upon treatment with Alkyl or aryl alcohols, Alkyl or aryl amine and aryl boronic acids or boronate esters under palladium catalyst conditions such as, but not limited to, XantPhos Pd G4 and an inorganic base such as, but not limited to, cesium carbonate in an organic solvent such as, but not limited to, toluene at an elevated temperature.
  • Treatment of the N-Boc (S1) with acid such as, but not limited to, trifluoroacetic acid and organic solvents such as, but not limited to, dichloromethane yields formula (S2).
  • Compounds of formula (S3) can be prepared from the benzyl chloride (1k) upon treatment with amine (S2) under base such as, but not limited to, potassium carbonate.
  • Treatment of the ester (S3) with hydroxide sources such as, but not limited to, lithium hydroxide in the presence of water and organic solvents such as, but not limited to, methanol and/or tetrahydrofuran yields carboxylic acid of formula (S4).
  • Scheme 2 [0178]
  • Compounds of formula (S4) may be prepared by general synthetic methods as shown in Scheme 2.
  • Treatment of the N-Boc (1l) with acid such as, but not limited to, trifluoroacetic acid and organic solvents such as, but not limited to, dichloromethane yields formula (2a).
  • Compounds of formula (2b) can be prepared from the benzyl chloride (1k) upon treatment with amine (2a) under base such as, but not limited to, potassium carbonate.
  • Compounds of formula (S3) can be prepared from the 2-bromopyridine (2b) upon treatment with Alkyl or aryl alcohols, Alkyl or aryl amine and aryl boronic acids or boronate esters under palladium catalyst conditions such as, but not limited to, XantPhos Pd G4 and an inorganic base such as, but not limited to, cesium carbonate in an organic solvent such as, but not limited to, toluene at an elevated temperature.
  • Compounds of formula (S8) can be prepared from the bromobenzene (S7) upon treatment with zinc cyanide under palladium catalyst conditions such as, but not limited to, Pd(PPh3)4 and an organic solvent such as, but not limited to, toluene at an elevated temperature.
  • treatment of the ester (S8) with hydroxide sources such as, but not limited to, lithium hydroxide in the presence of water and organic solvents such as, but not limited to, methanol and/or tetrahydrofuran yields carboxylic acid of formula (S9).
  • Scheme 4 [0180] Compounds of formula (S17& S18) may be prepared by general synthetic methods as shown in Scheme 4.
  • cyclamine (S10) with fluorobenzene (6a) in a suitable solvent such as ethanol with a base such as, but not limited to, triethylamine at a temperature from about room temperature to 35 °C and for a time varying from about 3 hours to about 16 hours can readily produce nitroaniline (S11).
  • the phenylenediamine (S12) can be formed by reduction of nitroaniline (S11) using a reductant such as, but not limited to, iron in a solvent such as, but not limited to acetic acid at a temperature from about room temperature to 40 °C and for a time varying from about 1 hour.
  • cyclization of phenylenediamine (S12) to compounds of formula (S13) can be carried out using a reagent such as, but not limited to, inodine and sodium bicarbonate in a suitable solvent such as ethanol, at a temperature from about room temperature and for a time varying from about 3 hours to about 16 hours.
  • Bromine compound (S14) can be prepared from compounds of formula (S13) upon treatment with NBS under initiator conditions such as, but not limited to, AIBN in an organic solvent such as, but not limited to, carbon tetrachloride at a reflux temperature and for a time varying from about 3 hours to about 8 hours.
  • Bromine compound (S14) with secondary amine (6f) in a suitable solvent such as acetontrile with a base such as, but not limited to, potassium carbonate in the presence of activator such as, but not limited to, potassium iodide at a refluxed temperature and for a time varying from about 3 hours to about 8 hours, can readily produce ester (S15).
  • a base such as, but not limited to, potassium carbonate
  • activator such as, but not limited to, potassium iodide at a refluxed temperature and for a time varying from about 3 hours to about 8 hours
  • ester (S15) Treatment of the ester (S15) with hydroxide sources such as, but not limited to, lithium hydroxide in the presence of water and organic solvents such as, but not limited to, methanol and/or tetrahydrofuran yields carboxylic acid of formula (S16).
  • Carboxylic acid (S16) and Carboxylic acid (S16) was separated by SFC.
  • Scheme 5 Compounds of formula (S27& S28) may be prepared by general synthetic methods as shown in Scheme 5.
  • the compounds of formula (S21) can be formed by reduction of nitroaniline (S20) using a reductant such as, but not limited to, iron in a solvent such as, but not limited to acetic acid at a temperature from about room temperature to 40 °C and for a time varying from about 1 hour.
  • a reductant such as, but not limited to, iron
  • a solvent such as, but not limited to acetic acid
  • the cyclization of phenylenediamine (S22) to compounds of formula (S21) can be carried out using a reagent such as, but not limited to, inodine and sodium bicarbonate in a suitable solvent such as ethanol, at a temperature from about room temperature and for a time varying from about 3 hours to about 16 hours.
  • Bromine compound (S23) can be prepared from phenylenediamine (S22) upon treatment with NBS under initiator conditions such as, but not limited to, AIBN in an organic solvent such as, but not limited to, carbon tetrachloride at a reflux temperature and for a time varying from about 3 hours to about 8 hours.
  • initiator conditions such as, but not limited to, AIBN in an organic solvent such as, but not limited to, carbon tetrachloride at a reflux temperature and for a time varying from about 3 hours to about 8 hours.
  • Treatment of Bromine compound (S23) with secondary amine (S24) in a suitable solvent such as acetontrile with a base such as, but not limited to, potassium carbonate in the presence of activator such as, but not limited to, potassium iodide at a refluxed temperature and for a time varying from about 3 hours to about 8 hours, can readily produce ester (S25).
  • Scheme 6 [0182] Scheme 6 can be used for the synthesis of Compound 9. Detailed procedures are described in Example 9.
  • Scheme 7 [0183] Scheme 7 can be used for the synthesis of Compound 10. Detailed procedures are described in Example 10.
  • Scheme 8 [0184] Scheme 8 can be used for the synthesis of Compound 11. Detailed procedures are described in Example 11.
  • Scheme 9 [0185] Compounds of formula (S33) may be prepared by general synthetic methods as shown in Scheme 9.
  • Compounds of formula (12b) can be prepared from the 2,6- dibromopyridine (12a) upon treatment with boronate esters (6j) under palladium catalyst conditions such as, but not limited to, Pd(dppf)Cl2.CH2Cl2 in the presence of water and an inorganic base such as, but not limited to, potassium carbonate in an organic solvent such as, but not limited to, DMSO at an elevated temperature for a time varying from about 16 hours under N2 atmosphere.
  • palladium catalyst conditions such as, but not limited to, Pd(dppf)Cl2.CH2Cl2 in the presence of water and an inorganic base such as, but not limited to, potassium carbonate in an organic solvent such as, but not limited to, DMSO at an elevated temperature for a time varying from about 16 hours under N2 atmosphere.
  • Compounds of formula (S29) can be prepared from the bromopyridine (12b) upon treatment with boronate esters or amines under palladium catalyst conditions such as, but not limited to, Pd2(dba)3 in the presence of BINAP and an inorganic base such as, but not limited to, caesium carbonate in an organic solvent such as, but not limited to, toluene at an elevated temperature.
  • boronate esters or amines under palladium catalyst conditions such as, but not limited to, Pd2(dba)3 in the presence of BINAP and an inorganic base such as, but not limited to, caesium carbonate in an organic solvent such as, but not limited to, toluene at an elevated temperature.
  • tert-butyl carbamate (S30) can be formed by reduction of compound of formula (S29) in a solvent such as, but not limited to methanol at room temperature and for a time varying from about 2 hours.
  • amine of formula (S31) Treatment of the tert-butyl carbamate (S30) with acid such as, but not limited to, THF in the presence of organic solvents such as, but not limited to, DCM yields amine of formula (S31).
  • Compounds of formula (S32) can be prepared from the benzyl chloride (1k) upon treatment with amine (S31) under base such as, but not limited to, potassium carbonate.
  • hydroxide sources such as, but not limited to, lithium hydroxide in the presence of water and organic solvents such as, but not limited to, methanol and/or tetrahydrofuran yields carboxylic acid of formula (S33).
  • Compounds of formula (S35) may be prepared by general synthetic methods as shown in Scheme 10.
  • Compounds of formula (14a) can be prepared from the bromopyridine (10a) upon treatment with boronate esters (9a) under palladium catalyst conditions such as, but not limited to, Pd(PPh3)2Cl2 in the presence of water and an inorganic base such as, but not limited to, sodium carbonate in an organic solvent such as, but not limited to, dioxane at an elevated temperature for a time varying from about 16 hours under N2 atmosphere.
  • amine (14b) can be formed by reduction of phenylmethanol (14a) in a solvent such as, but not limited to methanol at room temperature and for a time varying from about 6 hours.
  • Compounds of formula (14c) can be prepared from the benzyl chloride (1k) upon treatment with amine (14b) under base such as, but not limited to, potassium carbonate.
  • Compounds of formula (15b) can be prepared from the fluorobenzene (1h) upon treatment with amine (15a) in the presence of water and an organic solvent such as, but not limited to, tetrahydrofuran under an inorganic base such as, but not limited to, triethylamine at an elevated temperature.
  • amine (15c) can be formed by reduction of nitrobenzene (15b) in a solvent such as, but not limited to methanol at room temperature and for a time varying from about 2 hours.
  • Scheme 12 [0188] Scheme 12 can be used for the synthesis of Compound 16. Detailed procedures are described in Example 16. Scheme 13 [0189] Scheme 13 can be used for the synthesis of Compound 17. Detailed procedures are described in Example 17. Scheme 14 [0190] Scheme 14 can be used for the synthesis of Compound 18. Detailed procedures are described in Example 18.
  • Scheme 15 can be used for the synthesis of Compound 19. Detailed procedures are described in Example 19.
  • Scheme 16 can be used for the synthesis of Compound 20. Detailed procedures are described in Example 20.
  • Scheme 17 [0193] Compounds of formula (S47) may be prepared by general synthetic methods as shown in Scheme 17. Treatment of pyrazol (S40) with di-tert-butyl dicarbonate in a suitable solvent such as, but not limited to, dichloromethane with a base such as, but not limited to, triethylamine at room temperature, can readily produce Compounds of formula (S41).
  • a suitable solvent such as, but not limited to, dichloromethane
  • a base such as, but not limited to, triethylamine at room temperature
  • the Compounds of formula (S42) can be prepared from the hydroxyl pyrazole (S41) upon treatment with benzyl bromide in a suitable solvent such as, but not limited to, dimethyl formamide with a base such as, but not limited to, potassium carbonate, in the presence of salt such as, but not limited to, sodium iodide at an elevated temperature.
  • a suitable solvent such as, but not limited to, dimethyl formamide
  • a base such as, but not limited to, potassium carbonate
  • salt such as, but not limited to, sodium iodide at an elevated temperature.
  • the N-Boc (S42) with acid such as, but not limited to, trifluoroacetic acid and organic solvents such as, but not limited to, dichloromethane yields formula (S43).
  • the Compounds of formula (S44_2) can be prepared from compounds of formula (S44_1) upon treatment with paladium catalyst or DAST in a suitable solvent such as, but not limited to, dioxane at an elevated temperature.
  • a suitable solvent such as, but not limited to, dioxane at an elevated temperature.
  • the N-Boc (S44_2) with acid such as, but not limited to, trifluoroacetic acid and organic solvents such as, but not limited to, dichloromethane yields formula (S45).
  • Compounds of formula (S46) can be prepared from the benzyl chloride (1k) upon treatment with amine (S45) under base such as, but not limited to, potassium carbonate.
  • Scheme 18 can be used for the synthesis of Compound 23. Detailed procedures are described in Example 23.
  • Scheme 19 [0195] Compounds of formula (S53) may be prepared by general synthetic methods as shown in Scheme 19. Treatment of pyrazol (S48) with tert-butyl 4- ((methylsulfonyl)oxy)piperidine-1-carboxylate in a suitable solvent such as , but not limited to, dimethyl formamide with a base such as, but not limited to, cesium carbonate at an elevated temperature, can readily produce Compounds of formula (S49).
  • a suitable solvent such as , but not limited to, dimethyl formamide
  • a base such as, but not limited to, cesium carbonate at an elevated temperature
  • the Compounds of formula (S50) can be prepared from the iodopyrazole (S49) upon treatment with an alcohol or amine under palladium catalyst conditions such as, but not limited to, XPhos Pd G3 in an inorganic base such as, but not limited to, sodium 2-methylpropan-2-olate in an organic solvent such as, but not limited to, toluene at an elevated temperature.
  • an alcohol or amine under palladium catalyst conditions
  • an alcohol or amine under palladium catalyst conditions such as, but not limited to, XPhos Pd G3 in an inorganic base such as, but not limited to, sodium 2-methylpropan-2-olate in an organic solvent such as, but not limited to, toluene at an elevated temperature.
  • Treatment of the N- Boc (S50) with acid such as, but not limited to, trifluoroacetic acid and organic solvents such as, but not limited to, dichloromethane yields formula (S51).
  • Compounds of formula (S52) can be prepared from the benzyl chloride (1k) upon treatment with amine (S51) under base such as, but not limited to, potassium carbonate. Treatment of the ester (S52) with hydroxide sources such as, but not limited to, lithium hydroxide in the presence of water and organic solvents such as, but not limited to, methanol and/or tetrahydrofuran yields carboxylic acid of formula (S53).
  • Scheme 20 [0196] Scheme 20 can be used for the synthesis of Compound 26. Detailed procedures are described in Example 26.
  • Scheme 21 [0197] Compounds of formula (S59) may be prepared by general synthetic methods as shown in Scheme 21.
  • the Compounds of formula (S56) can be prepared from the halide (S55) upon treatment with a piperazine under palladium catalyst conditions such as, but not limited to, Tris(dibenzylideneacetone)dipalladium(0) in the presence of ligand such as, but not limited to, 2-(Dicyclohexylphosphanyl)-2,4,6-tris(isopropyl)biphenyl and an inorganic base such as, but not limited to, sodium 2-methylpropan-2-olate in an organic solvent such as, but not limited to, toluene at an elevated temperature.
  • a piperazine under palladium catalyst conditions such as, but not limited to, Tris(dibenzylideneacetone)dipalladium(0) in the presence of ligand such as, but not limited to, 2-(Dicyclohexylphosphanyl)-2,4,6-tris(isopropyl)biphenyl and an inorganic base such as
  • Scheme 23 can be used for the synthesis of Compound 32. Detailed procedures are described in Example 32.
  • Scheme 24 [0200] Compounds of formula (S61) may be prepared by general synthetic methods as shown in Scheme 24. The preparation of intermediate 110e please consult the procedure of Example 110.
  • the Compounds of formula (S60) can be prepared from the pyridone (110e) upon treatment with benzyl bromide or chloride in a suitable solvent such as, but not limited to, toluene with a base such as, but not limited to, silver carbonate, at an elevated temperature.
  • the Compounds of formula (S64) can be prepared from the ortho-nitroaniline (S63) upon treatment with palladium catalyst and hydrogen in a suitable solvent such as, but not limited to, methanol at room temperature or elevated temperature.
  • the Compounds of benzimidazole (S65) can be prepared from compounds (S64) upon treatment with 2-chloro-1,1,1- trimethoxyethane in a suitable solvent such as, but not limited to, toluene at an elevated temperature.
  • Treatment of pyrazol (S65) with amine (S66) in a suitable solvent such as , but not limited to, acetonitrile with a base such as, but not limited to, potassium carbonate at an elevated temperature can readily produce Compounds of formula (S67).
  • Example 4 2-((4-(6-(6-cyano-8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)pyridin-2-yl)piperazin-1- yl)methyl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid [0225]
  • the title compound was prepared according to Scheme 2.
  • This General Procedure D exemplifies Scheme 2 and provides particular synthetic details as applied to the title compound.
  • the filter cake was purified by prep-HPLC (neutral condition; column: mobile phase: [water (10mM NH4HCO3)-ACN];B%: 25%-55%,10min) to give Compound 4 as a white solid.
  • Example 7 (General Procedure G) (R)-5-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)-1,2,4,5- tetrahydrobenzo[4,5]imidazo[1,2-d][1,4]oxazepine-9-carboxylic acid and (S)-5-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)-1,2,4,5- tetrahydrobenzo[4,5]imidazo[1,2-d][1,4]oxazepine-9-carboxylic acid [0247] The title compound was prepared according to Scheme 5. This General Procedure G exemplifies Scheme 5 and provides particular synthetic details as applied to the title compound.
  • HATU (579.36 mg, 1.52 mmol, 1.2 eq) and DIPEA (492.32 mg, 3.81 mmol, 663.50 uL, 3 eq) was added to the solution of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (15a, 386.16 mg, 1.59 mmol, 1.3 eq) in DCM (6 mL) at 20°C. Then the solution was stirred at 20°C for 0.5 hour. Then (S)-methyl 4-amino-3-((oxetan-2-ylmethyl)amino)benzoate (300 mg, 1.27 mmol, 1 eq) was added to the solution at 20°C.
  • the mixture was extracted with Ethyl acetate (20 mL * 3).
  • the combined Ethyl acetate was washed with brine (15 mL), dried over Na2SO4, filtered and concentrated.
  • Example 20 (General Procedure T) 2-(((R)-3-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3-methylpyrrolidin-1-yl)methyl)-1- ((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid and 2-(((S)-3-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3-methylpyrrolidin-1-yl)methyl)-1- ((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid [0352] The title compound was prepared according to Scheme 16. This General Procedure T exemplifies Scheme 16 and provides particular synthetic details as applied to the title compound.
  • Example 26 (General Procedure Z) (S)-1-(oxetan-2-ylmethyl)-2-((4-(3-(phenoxymethyl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)- 1H-benzo[d]imidazole-6-carboxylic acid and (S)-1-(oxetan-2-ylmethyl)-2-((4-(5-(phenoxymethyl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)- 1H-benzo[d]imidazole-6-carboxylic acid [0398] The title compound was prepared according to Scheme 20. This General Procedure Z exemplifies Scheme 20 and provides particular synthetic details as applied to the title compound.
  • Example 28 (General Procedure BB) (S)-2-((4-(3-benzyl-3H-imidazo[4,5-b]pyridin-5-yl)piperazin-1-yl)methyl)-1-(oxetan-2- ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid [0414] The title compound was prepared according to Scheme 21. This General Procedure BB exemplifies Scheme 21 and provides particular synthetic details as applied to the title compound. [0415] 3-benzyl-5-bromo-3H-imidazo[4,5-b]pyridine(28b).
  • Example 54 (S)-2-((4-(6-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)pyridin-2-yl)piperazin-1- yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid [0483]
  • the title compound was prepared and can be prepared similarly following the procedures described by General Procedure C.
  • Example 70 (S)-2-((4-(6-(naphthalen-2-ylmethoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2- ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid [0515]
  • the title compound was prepared and can be prepared similarly following the procedures described by General Procedure C.
  • Example 80 (S)-2-((4-(6-(9-cyano-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)pyridin-2-yl)piperazin-1- yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid [0535]
  • the title compound was prepared and can be prepared similarly following the procedures described by General Procedure B.
  • Example 84 2-((4-(6-((S)-6-cyano-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)pyridin-2-yl)piperazin-1- yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid [0543]
  • the title compound was prepared and can be prepared similarly following the procedures described by General Procedure B.

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