EP4638455A1 - Agonistes de glp-1 hétérocycliques - Google Patents

Agonistes de glp-1 hétérocycliques

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Publication number
EP4638455A1
EP4638455A1 EP23848231.9A EP23848231A EP4638455A1 EP 4638455 A1 EP4638455 A1 EP 4638455A1 EP 23848231 A EP23848231 A EP 23848231A EP 4638455 A1 EP4638455 A1 EP 4638455A1
Authority
EP
European Patent Office
Prior art keywords
compound
alkyl
cycloalkyl
methyl
optionally substituted
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.)
Pending
Application number
EP23848231.9A
Other languages
German (de)
English (en)
Inventor
Wei Huang
Hui Lei
Chunliang Lu
Zhongmiao XU
Ding Xue
Haizhen ZHANG
Qiong Zhang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gasherbrum Bio Inc
Original Assignee
Gasherbrum Bio Inc
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Filing date
Publication date
Application filed by Gasherbrum Bio Inc filed Critical Gasherbrum Bio Inc
Publication of EP4638455A1 publication Critical patent/EP4638455A1/fr
Pending legal-status Critical Current

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Classifications

    • 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
    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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

Definitions

  • This disclosure relates to GLP-1 agonists, pharmaceutical compositions, and methods of use thereof.
  • Incretin metabolic hormones including glucagon-like peptide- 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), arc important in the regulation of glucose homeostasis.
  • GLP-1 glucose-dependent insulinotropic polypeptide
  • T2DM type 2 diabetes mellitus
  • Typical onset occurs in obese or otherwise sedentary adults and begins with insulin resistance.
  • lifestyle changes can be useful in management of this disorder, patients with T2DM may be required to take antidiabetic medications, including dipeptidyl peptidase-4 inhibitors, SGLT2 inhibitors, and sulfonylureas, among others.
  • GIP glucose-dependent insulinotropic polypeptide
  • GLP-1 glucagon-like peptide 1
  • the present application describes heterocyclic GLP-1 agonists, as well as pharmaceutical compositions comprising the compounds disclosed herein. Also provided are methods for treating GLP- 1-associated diseases, disorders, and conditions.
  • ring A, ring C, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , Y 1 , Y 2 , R 1 , R 2 , R 3 , R 5 , R 10 , n, p, and q are each independently as defined herein.
  • compositions comprising one or more compounds of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, and a pharmaceutically acceptable excipient.
  • compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, and a pharmaceutically acceptable excipient.
  • Also provided herein are methods for treating diabetes mellitus in a patient comprising determining that the patient has type 2 diabetes mellitus; and administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutical composition thereof.
  • the step of determining that the patient has type 2 diabetes mellitus includes performing an assay to determine the level of an analyte in a sample from the patient, wherein the analyte is selected from the group consisting of hemoglobin Ale (HbAlc), fasting plasma glucose, non-fasting plasma glucose, or any combination thereof.
  • HbAlc hemoglobin Ale
  • the level of HbAlc is greater than or about 6.5%. In some embodiments, the level of fasting plasma glucose is greater than or about 126 mg/dL. In some embodiments, the level of non-fasting plasma glucose is greater than or about 200 mg/dL.
  • the methods further comprise obtaining a sample from the patient.
  • the sample is a body fluid sample.
  • the patient is about 40 to about 70 years old and is overweight or obese.
  • the patient has a body mass index (BMI) greater than or about 22 kg/m 2 .
  • the patient has a BMI greater than or about 30 kg/m 2 .
  • the methods for the treatment of type 2 diabetes mellitus comprise a reduction in fasting plasma glucose levels.
  • the fasting plasma glucose levels are reduced to about or below 100 mg/dL.
  • the methods for the treatment of type 2 diabetes mellitus comprise a reduction in HbAlc levels.
  • the HbAlc levels are reduced to about or below 5.7 %.
  • the methods for the treatment of type 2 diabetes mellitus comprise a reduction in glucagon levels.
  • the methods for the treatment of type 2 diabetes mellitus comprise an increase in insulin levels.
  • the methods for the treatment of type 2 diabetes mellitus comprise a decrease in BMI.
  • the BMI is decreased to about or below 25 kg/m 2 .
  • the compound of Formula I or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutical composition thereof, is administered orally.
  • the methods of treatment for type 2 diabetes mellitus further comprise administering an additional therapy or therapeutic agent to the patient.
  • the additional therapy or therapeutic agent is selected from the group consisting of an antidiabetic agent, an anti-obesity agent, a GLP-1 receptor agonist, an agent to treat non-alcoholic steatohepatitis (NASH), anti- emetic agent, gastric electrical stimulation, dietary monitoring, physical activity, or any combinations thereof.
  • NASH non-alcoholic steatohepatitis
  • the antidiabetic agent is selected from the group consisting of a biguanide, a sulfonylurea, a glitazar, a thiazolidinedione, a dipeptidyl peptidase 4 (DPP-4) inhibitor, a meglitinide, a sodium-glucose linked transporter 2 (SGLT2) inhibitor, a glitazone, a GRP40 agonist, a glucose-dependent insulinotropic peptide (G1P), an insulin or insulin analogue, an alpha glucosidase inhibitor, a sodium-glucose linked transporter 1 (SGLT1) inhibitor, or any combinations thereof.
  • DPP-4 dipeptidyl peptidase 4
  • SGLT2 sodium-glucose linked transporter 2
  • GRP40 agonist a glucose-dependent insulinotropic peptide
  • G1P glucose-dependent insulinotropic peptide
  • an insulin or insulin analogue an alpha glucosidas
  • the biguanide is metformin.
  • the anti-obesity agent is selected from the group consisting of neuropeptide Y receptor type 2 (NPYR2) agonist, a NPYR1 or NPYR5 antagonist, a human proislet peptide (HIP), a cannabinoid receptor type 1 (CB1R) antagonist, a lipase inhibitor, a melanocortin receptor 4 agonist, a farnesoid X receptor (FXR) agonist, phentermine, zonisamide, a norepinephrine/dopamine reuptake inhibitor, a GDF-15 analog, an opioid receptor antagonist, a cholecystokinin agonist, a serotonergic agent, a methionine aminopeptidase 2 (MetAP2) inhibitor, diethylpropion, phendimetrazine, benzphetamine, a fibroblast growth factor receptor (FGFR) modulator
  • NPYR2
  • the GLP-1 receptor agonist is selected from the group consisting of liraglutide, exenatide, dulaglutide, albiglutide, taspoglutide, lixisenatide, semaglutide, or any combinations thereof.
  • the agent to treat NASH is selected from the group consisting of an FXR agonist, PF- 05221304, a synthetic fatty acid-bile conjugate, an anti-lysyl oxidase homologue 2 (LOXL2) monoclonal antibody, a caspase inhibitor, a MAPK5 inhibitor, a galectin 3 inhibitor, a fibroblast growth factor 21 (FGF21) agonist, a niacin analogue, a leukotriene D4 (LTD4) receptor antagonist, an acetyl-CoA carboxylase (ACC) inhibitor, a ketohexokinase (KHK) inhibitor, an ileal bile acid transporter (IBAT) inhibitor, an apoptosis signal-regulating kinase 1 (ASK1) inhibitor, or any combinations thereof.
  • FXR agonist an anti-lysyl oxidase homologue 2 (LOXL2) monoclonal antibody
  • LOD2 anti-lysyl oxid
  • the compound of Formula I or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutical composition thereof, and the additional therapeutic agent are administered as separate dosages sequentially in any order.
  • the modulation results in an increase of insulin levels.
  • the modulation results in a decrease of glucose levels.
  • Also provided herein are methods for treating a GLP-1 associated disease, disorder, or condition the method comprising administering to a patient in need thereof an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutical composition thereof.
  • the disease, disorder, or condition is selected from the group consisting of type 1 diabetes mellitus, type 2 diabetes mellitus, early onset type 2 diabetes mellitus, idiopathic type 1 diabetes mellitus (Type lb), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), latent autoimmune diabetes in adults (LADA), obesity, weight gain from use of other agents, gout, excessive sugar craving, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral adipose deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attacks, atherosclerotic cardiovascular disease, traumatic brain injury, peripheral vascular disease, endothelial dysfunction, impaired vascular compliance,
  • the disease, disorder, or condition is selected from the group consisting of type 2 diabetes mellitus, early onset type 2 diabetes mellitus, obesity, weight gain from use of other agents, gout, excessive sugar craving, hypertriglyceridemia, dyslipidemia, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral adipose deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attacks, atherosclerotic cardiovascular disease, hyperglycemia, post-prandial lipemia, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neurode
  • the disease, disorder, or condition includes, but is not limited to type 2 diabetes mellitus, early onset type 2 diabetes mellitus, obesity, weight gain from use of other agents, gout, excessive sugar craving, hypertriglyceridemia, dyslipidemia, gestational diabetes, adipocyte dysfunction, visceral adipose deposition, myocardial infarction, peripheral arterial disease, stroke, transient ischemic attacks, hyperglycemia, post-prandial lipemia, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, chronic renal failure, syndrome X, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, skin and connective tissue disorders, foot ulcerations, or any combination thereof.
  • heterocyclic GLP-1 agonists for use in the management of T2DM and other conditions where activation of GLP-1 activity is useful.
  • a dash that is not between two letters or symbols is used to indicate a point of attachment for a substituent.
  • -C(O)NH2 is attached through the carbon atom.
  • a dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning.
  • a wavy line or a dashed line drawn through a line in a structure indicates a specified point of attachment of a group. Unless chemically or structurally required, no directionality or stereochemistry is indicated or implied by the order in which a chemical group is written or named.
  • C u.v indicates that the following group has from u to v carbon atoms.
  • Ci-6 alkyl indicates that the alkyl group has from 1 to 6 carbon atoms.
  • Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se.
  • the term “about” includes the indicated amount ⁇ 10%.
  • the term “about” includes the indicated amount ⁇ 5%.
  • the term “about” includes the indicated amount ⁇ 1%.
  • to the term “about X” includes description of “X”.
  • the singular forms “a” and “the” include plural references unless the context clearly dictates otherwise.
  • reference to “the compound” includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art.
  • alkyl refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C1-20 alkyl), 1 to 12 carbon atoms (i.e., C1-12 alkyl), 1 to 8 carbon atoms (i.e., C1-8 alkyl), 1 to 6 carbon atoms (i.e., Ci-6 alkyl), or 1 to 4 carbon atoms (i.e., CM alkyl).
  • alkyl groups include, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec -butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.
  • butyl includes n-butyl (i.e., -(CHzhCEh), sec-butyl (i.e., -CHiCHsjCEbCEh), isobutyl (i.e., -CFTCHtCH ji), and tert-butyl (i.e., -QCFhh), and “propyl” includes n-propyl (i.e., -(ClfehCHs), and isopropyl (i.e., -CFKCFhh)-
  • alkenyl refers to an alkyl group containing at least one (e.g., 1-3, or 1) carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., alkenyl), 2 to 12 carbon atoms (i.e., alkenyl), 2 to 8 carbon atoms (i.e., C2-8 alkenyl), 2 to 6 carbon atoms (i.e., C2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C2-4 alkenyl).
  • alkenyl groups include, e.g., ethenyl, propenyl, butadienyl (including
  • Alkynyl refers to an alkyl group containing at least one (e.g., 1-3, or 1) carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., alkynyl), 2 to 12 carbon atoms (i.e., alkynyl), 2 to 8 carbon atoms (i.e., C2-8 alkynyl), 2 to 6 carbon atoms (i.e., C2-6 alkynyl), or 2 to 4 carbon atoms alkynyl).
  • alkynyl also includes those groups having one triple bond and one double bond.
  • a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc.
  • a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc.
  • a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc.
  • Alkoxy refers to the group “alkyl-O-”. Examples of alkoxy groups include, e.g., methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and
  • Haloalkyl refers to an unbranched or branched alkyl group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a halogen.
  • a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached.
  • Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be, but are not necessarily, the same halogen.
  • haloalkyl examples include, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.
  • Haloalkoxy refers to an alkoxy group as defined above, wherein one or more (e.g., 1 to 6, or 1 to 3) hydrogen atoms are replaced by a halogen.
  • Hydroxyalkyl refers to an alkyl group as defined above, wherein one or more (e.g., 1 to 6, or 1 to 3) hydrogen atoms are replaced by a hydroxy group.
  • Cyanoalkyl refers to an alkyl group as defined above, wherein one, or one or more (e.g., 1 to 6, or 1 to 3) hydrogen atoms are replaced by a hydroxy group.
  • Alkylthio refers to the group “alkyl-S-”.
  • acyl refers to a group -C(O)R, wherein R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • examples of acyl include formyl, acetyl, cylcohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.
  • “Amido” refers to both a “C-amido” group which refers to the group -C(O)NR y R z and an “N- amido” group which refers to the group -NR y C(O)R z , wherein R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein, or R y and R z are taken together to form a cycloalkyl or heterocyclyl; each of which may be optionally substituted, as defined herein.
  • Amino refers to the group -NR y R z wherein R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • Amino refers to -C(NR y )(NR z 2 ), wherein R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • Aryl refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) including fused systems.
  • aryl has 6 to 20 ring carbon atoms (i.e., C 6-20 aryl), 6 to 12 carbon ring atoms (i.e., C 6-12 aryl), or 6 to 10 carbon ring atoms (i.e., C 6-10 aryl).
  • Examples of aryl groups include, e.g., phenyl, naphthyl, fluorenyl, and anthryl.
  • Aryl does not encompass or overlap in any way with heteroaryl defined below.
  • the resulting ring system is heteroaryl regardless of point of attachment. If one or more aryl groups are fused with a heterocyclyl, the resulting ring system is heterocyclyl regardless of point of attachment. If one or more aryl groups are fused with a cycloalkyl, the resulting ring system is cycloalkyl regardless of point of attachment.
  • Carbamoyl refers to both an “O-carbamoyl” group which refers to the group -O-C(O)NR y R z and an “N-carbamoyl” group which refers to the group -NR y C(O)OR z , wherein R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • Carboxyl ester or “ester” refer to both -OC(O)R X and -C(O)OR X , wherein R x is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • Cycloalkyl refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings including fused, bridged, and spiro ring systems.
  • the term “cycloalkyl” includes cycloalkenyl groups (i.e., the cyclic group having at least one double bond) and carbocyclic fused ring systems having at least one sp 3 carbon atom (i.e., at least one non-aromatic ring).
  • cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C3-20 cycloalkyl), 3 to 14 ring carbon atoms (i.e., C3-12 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3.8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C36 cycloalkyl).
  • Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic groups include, for example, bicyclo [2.2. l]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.
  • cycloalkyl is intended to encompass any non-aromatic ring which may be fused to an aryl ring, regardless of the attachment to the remainder of the molecule.
  • cycloalkyl also includes “spirocycloalkyl” when there are two positions for substitution on the same carbon atom, for example spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl.
  • Imino refers to a group -C(NR y )R z , wherein R y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • Halogen refers to atoms occupying group VIIA of the periodic table, such as fluoro, chloro, bromo, or iodo.
  • Heteroalkyl refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic group.
  • the term “heteroalkyl” includes unbranched or branched saturated chain having carbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms may be independently replaced with the same or different heteroatomic group.
  • Heteroatomic groups include, but are not limited to, -NR-, -O-, -S-, -S(O)-, -S(O)2-, and the like, where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl or heterocyclyl, each of which may be optionally substituted.
  • heteroalkyl groups include -OCH 3 , -CH 2 OCH 3 , -SCH 3 , -CH 2 SCH 3 , -NRCH 3 , and -CH 2 NRCH 3 , where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionally substituted.
  • heteroalkyl include 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.
  • Heteroalkylene refers to a divalent heteroalkyl group. “Heteroalkylene” groups must have at least one carbon and at least one heteroatomic group within the chain. The term “heteroalkylene” includes unbranched or branched saturated chain having carbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms may be independently replaced with the same or different heteroatomic group.
  • Heteroatomic groups include, but are not limited to, -NR y -, -O-, -S-, -S(O)-, -S(O) 2 -, and the like, wherein R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.
  • heteroalkylene groups include, e.g., -CH 2 OCH 2 -, -CH(CH 3 )OCH 2 -, -CH 2 CH 2 OCH 2 -, -OCH 2 -, -CH(CH 3 )O-, -CH 2 CH 2 O-, -CH 2 CH 2 OCH 2 CH 2 OCH 2 -, -CH 2 CH 2 OCH 2 CH 2 O-, -CH 2 SCH 2 -, -CH(CH 3 )SCH 2 -, -CH 2 CH 2 SCH 2 -, -CH 2 CH 2 SCH 2 CH 2 SCH 2 -, -SCH2-, -CH(CH 3 )S-, -CH 2 CH 2 S-, -CH 2 CH 2 SCH 2 CH 2 S-, -CH 2 S(O) 2 CH 2 -, -CH(CH 3 )S(O) 2 CH 2 -, -CH 2 CH 2 S(O) 2 CH 2 -, -CH 2 CH 2 S
  • heteroalkylene includes 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.
  • heteroalkylene does not include groups such as amides or other functional groups having an oxo present on one or more carbon atoms.
  • Heteroaryl refers to an aromatic group having a single ring or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • heteroaryl includes 1 to 20 ring carbon atoms (i.e., C1-20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C 3 -i 2 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C 3 .g heteroaryl), and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur.
  • heteroaryl includes 5-10 membered ring systems, 5-7 membered ring systems, or 5-6 membered ring systems, each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur.
  • heteroaryl groups include, e.g., acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, henzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl, benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothienyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindo lyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1- oxidopyridinyl, 1 -oxidopyrimidinyl, 1-oxidopyra
  • fused-heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo [b] thienyl, indazolyl, benzo [d]imidazolyl, pyrazolo[l,5-a]pyridinyl, and imidazo[l,5-a]pyridinyl, where the heteroaryl can be bound via either ring of the fused system. Any aromatic ring, having a single or multiple fused rings, containing at least one heteroatom, is considered a heteroaryl regardless of the attachment to the remainder of the molecule (i.e., through any one of the fused rings). Heteroaryl does not encompass or overlap with aryl as defined above.
  • Heterocyclyl refers to a saturated or partially unsaturated cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • the term “heterocyclyl” includes heterocycloalkenyl groups (i.e., the heterocyclyl group having at least one double bond), bridged-heterocyclyl groups, fused-heterocyclyl groups, and spiro-heterocyclyl groups.
  • Any non-aromatic ring or fused ring system containing at least one heteroatom and one non-aromatic ring is considered a heterocyclyl, regardless of the attachment to the remainder of the molecule.
  • fused ring systems such as decahydroquinazolinyl, 1,2,3,4-tetrahydroquinazolinyl, and 5, 6,7,8- tetrahydroquinazolinyl are heterocyclyl, regardless of the attachment (i.e., can be bound through a carbon atom or a heteroatom).
  • heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring may be fused to a cycloalkyl, an aryl, or heteroaryl ring, regardless of the attachment to the remainder of the molecule.
  • heterocyclyl has 2 to 20 ring carbon atoms (i.e., C2-20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C2-12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C2-10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C2-8 heterocyclyl), 3 to 12 ring carbon atoms (i.e., C3-12 heterocyclyl), 3 to 8 ring carbon atoms (i.e., C3.8 heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C36 heterocyclyl); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur, or oxygen.
  • ring carbon atoms i.e., C2-20 heterocyclyl
  • 2 to 12 ring carbon atoms i.e
  • heterocyclyl groups include, e.g., azetidinyl, azepinyl, benzodioxolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-
  • heterocyclyl also includes “spiroheterocyclyl” when there are two positions for substitution on the same carbon atom.
  • spiro-heterocyclyl rings include, e.g., bicyclic and tricyclic ring systems, such as oxabicyclo [2.2.2]octanyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-l- azaspiro[3.3]heptanyL
  • fused-heterocyclyl rings include, but are not limited to, 1, 2,3,4- tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, where the heterocyclyl can be bound via either ring of the fused system.
  • “Sulfonyl” refers to the group -S(O)2R y , where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.
  • Alkylsulfonyl refers to the group -SCOjiR, where R is alkyl.
  • Alkylsulfinyl refers to the group -S(O)R, where R is alkyl.
  • the term “compound,” is meant to include any or all stereoisomers, geometric isomers, tautomers, and isotopically enriched analogs (e.g., deuterated analogs) of the structures depicted.
  • Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.
  • Tautomers are in equilibrium with one another.
  • amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown, and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, the amide containing compounds are understood to include their imidic acid tautomers. Likewise, the imidic acid containing compounds are understood to include their amide tautomers.
  • any compound or structure given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. These forms of compounds may also be referred to as “isotopically enriched analogs.” Isotopically labeled compounds have structures depicted herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 H, n C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 0, 31 P, 32 P, 35 S, 18 F, 36 C1, 123 I, and 125 I, respectively.
  • isotopically labeled compounds of the present disclosure for example those into which radioactive isotopes such as 3 H and 14 C arc incorporated.
  • Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single- photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single- photon emission computed tomography
  • isotopically enriched analogs includes “deuterated analogs” of compounds described herein in which one or more hydrogens is/are replaced by deuterium, such as a hydrogen on a carbon atom. Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound when administered to a mammal, particularly a human. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 5(12):524- 527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.
  • Deuterium labelled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements, and/or an improvement in therapeutic index.
  • An 18 F, 3 H, U C labeled compound may be useful for PET or SPECT or other imaging studies.
  • Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in a compound described herein.
  • the concentration of such a heavier isotope, specifically deuterium may be defined by an isotopic enrichment factor.
  • any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom.
  • a position is designated specifically as “H” or “hydrogen,” the position is understood to have hydrogen at its natural abundance isotopic composition.
  • any atom specifically designated as a deuterium (D) is meant to represent deuterium.
  • the compounds of this disclosure are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.
  • the term “pharmaceutically acceptable salt” of a given compound refers to salts that retain the biological effectiveness and properties of the given compound and which are not biologically or otherwise undesirable.
  • “Pharmaceutically acceptable salts” or “physiologically acceptable salts” include, for example, salts with inorganic acids and salts with an organic acid.
  • the free base can be obtained by basifying a solution of the acid salt.
  • an addition salt, particularly a pharmaceutically acceptable addition salt may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
  • Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like.
  • Salts derived from organic acids include, e.g., acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.
  • pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases.
  • Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of NIL, or primary, secondary, tertiary amines, such as salts derived from a N-containing heterocycle, a N- containing heteroaryl, or derived from an amine of formula N(R N )s (e.g., HN + (R N )s or (alkyl)N + (R N )3) where each R N is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each is optionally substituted, such as by one or more (e.g., 1-5 or 1-3) substituents (e.g., halo, cyano, hydroxy, amino, alkyl, alkenyl, alky
  • Suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, cthanolaminc, 2-dimcthylaminocthanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.
  • substituted means that any one or more hydrogen atoms on the designated atom or group is replaced with one or more substituents other than hydrogen, provided that the designated atom’s normal valence is not exceeded.
  • the one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof.
  • the one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanidino, halo, haloalkyl, hydroxyalkyl, haloalkoxy, haloalkoxyalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, imido, oxo, nitro, sulfinyl, sulfonic acid, sulfonyl, thiocyanate, thiol, thione, or combinations thereof.
  • impermissible substitution patterns e.g., methyl substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen ring atoms.
  • impermissible substitution patterns are well known to the skilled artisan.
  • substituted may describe other chemical groups defined herein. Unless specified otherwise, where a group is described as optionally substituted, any substituents of the group are themselves unsubstituted.
  • substituted alkyl refers to an alkyl group having one or more substituents including hydroxyl, halo, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • the one or more substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted.
  • the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.
  • “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
  • a “solvate” is formed by the interaction of a solvent and a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.
  • a ring when a ring is described as being “aromatic,” it means the ring has a continuous, delocalized ⁇ -electron system. Typically, the number of out of plane 7t-electrons corresponds to the Hiickel rule (4n+2). Examples of such rings include: benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thiazole, isoxazole, isothiazole, and the like.
  • a ring system comprising at least two rings is described as “aromatic,” it means the ring system comprises one or more aromatic ring(s). Accordingly, when a ring system comprising at least two rings is described as “non- aromatic,” none of the constituent rings of the ring system is aromatic.
  • a ring when a ring is described as being “partially unsaturated,” it means the ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributed to the ring itself; e.g., one or more double bonds between constituent ring atoms), provided that the ring is not aromatic.
  • additional degrees of unsaturation in addition to the degree of unsaturation attributed to the ring itself; e.g., one or more double bonds between constituent ring atoms
  • examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.
  • a ring system comprising at least two rings it means the ring system comprises one or more partially unsaturated ring(s), provided that none of the constituent rings of the ring system is aromatic.
  • the term “compound,” is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.
  • tautomer refers to compounds whose structures differ markedly in arrangement of atoms, but which exist in easy and rapid equilibrium, and it is to be understood that compounds provided herein may be depicted as different tautomers, and when compounds have tautomeric forms, all tautomeric forms are intended to be within the scope of the disclosure, and the naming of the compounds does not exclude any tautomer.
  • GLP-1R or “GLP-1 receptor” as used herein is meant to include, without limitation, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide strands, complementary sequences, peptides, polypeptides, proteins, homologous, and/or orthologous GLP-1R molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, different species, and active fragments thereof.
  • GLP-1 associated disease as used herein is meant to include, without limitation, all those diseases, disorders, or conditions in which modulating glucagon-like peptide- 1 (GLP-1) receptor signaling can alter the pathology and/or symptoms and/or progression of the disease, disorder, or condition.
  • GLP-1 agonist or “GLP-1 RA” as used herein refers to an agonist of the glucagon- like peptide- 1 (GLP-1) receptor.
  • GLP-1 RAs enhance glucose-dependent insulin secretion; suppress inappropriately elevated glucagon levels, both in fasting and postprandial states; and slow gastric emptying.
  • Karla et al. Glucagon-like peptide-1 receptor agonists in the treatment of type 2 diabetes: Past, present, and future, Indian J Endocrinol Metab. 2016 Mar-Apr; 20(2): 254-267.
  • GLP-1 RAs have been shown to treat type 2 diabetes.
  • GLP-1 RAs examples include, but are not limited to, albiglutide (Tanzeum®), dulaglutide (LY2189265, Trulicity®), efpeglenatide, exenatide (Byetta®, Bydureon®, Exendin-4), liraglutide (Victoza®, NN2211), lixisenatide (Lyxumia®), semaglutide (Ozempic®), tirzepatide, ZP2929, NNC0113-0987, BPI-3016, and TT401.
  • the term “pharmaceutically acceptable” as used herein indicates that the compound, or salt or composition thereof is compatible chemically and/or toxicologically with the other ingredients comprising a formulation and/or the subject being treated therewith.
  • administration or “administering” refers to a method of giving a dosage of a compound or pharmaceutical composition to a vertebrate or invertebrate, including a mammal, a bird, a fish, or an amphibian. The method of administration can vary depending on various factors, e.g., the components of the pharmaceutical composition, the site of the disease, and the severity of the disease.
  • an “effective amount” or “effective dosage” or “pharmaceutically effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of a chemical entity (e.g., a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof) being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated, and can include curing the disease. “Curing” means that the symptoms of active disease are eliminated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms.
  • a “therapeutically effective amount” of a compound as provided herein refers to an amount of the compound that is effective as a monotherapy or combination therapy.
  • excipient or “pharmaceutically acceptable excipient” means a pharmaceutically - acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material.
  • each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable bene lit/risk ratio.
  • composition refers to a mixture of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof as provided herein with other chemical components (referred to collectively herein as “excipients”), such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and/or thickening agents.
  • excipients such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and/or thickening agents.
  • excipients such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and/or thickening agents.
  • excipients such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and/or thickening agents.
  • the pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to, rectal, oral, intravenous, aerosol, parenteral, ophthalmic, pulmonary,
  • treat in the context of treating a disease, disorder, or condition, are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or to slowing the progression, spread or worsening of a disease, disorder or condition or of one or more symptoms thereof.
  • preventing is the prevention of the onset, recurrence or spread, in whole or in part, of the disease or condition as described herein, or a symptom thereof.
  • subject refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans.
  • the term refers to a subject, particularly a mammalian subject, for whom diagnosis, prognosis, or therapy is desired or needed.
  • the subject is a human.
  • the subject has experienced and/or exhibited at least one symptom of the disease, disorder, or condition to be treated and/or prevented.
  • treatment regimen and “dosing regimen” are used interchangeably to refer to the dose and timing of administration of each therapeutic agent in a combination.
  • pharmaceutical combination refers to a pharmaceutical treatment resulting from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • combination therapy refers to a dosing regimen of two different therapeutically active agents (i.e., the components or combination partners of the combination), wherein the therapeutically active agents are administered together or separately in a manner prescribed by a medical care taker or according to a regulatory agency as defined herein.
  • modulate refers to a regulation or an adjustment (e.g., increase or decrease) and can include, for example agonism, partial agonism or antagonism.
  • n is 0, 1, or 2
  • p is 0, 1, 2, 3, 4, or 5
  • q is 0, 1, or 2;
  • Y 1 is O, S, N, or CR 6 ; and Y 2 is N, or C; provided ring C is aromatic;
  • X 1 is O or C(R 7 ) 2 ;
  • X 2 is a bond, O, or C(R 7 ) 2 , provided that both X 1 and X 2 are not simultaneously O;
  • X 3 , X 4 , X 5 , and X 6 are each independently N or CR 4 ; provided that one of X 5 and X 6 is C bonded to X 2 , and no more than two of X 3 , X 4 , X 5 , and X 6 are N; or
  • X 3 is a bond and X 4 , X 5 , and X 6 are each independently O, S, N, NR 4 , or CR 4 ; provided that one of X 5 and X 6 is C bonded to X 2 , and the ring formed thereby is aromatic; ring A is aryl or heteroaryl;
  • R 1 is hydrogen, halo, cyano, hydroxy, Ci-6 alkyl, C 2 .6 alkenyl, C 2 .6 alkynyl, Ci-6 haloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, C3.6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; wherein each is independently optionally substituted with one to five substituents independently selected from halo, cyano, hydroxy, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, or C3-6 cycloalkyl;
  • R 2 is hydrogen or C1-6 alkyl optionally substituted with C1-6 alkoxy, Ci-6 thioalkoxy, Ci-6 haloalkoxy, S(O) 2 (Ci-6 alkyl), C3-6 cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, or 5- to 6- mcmbcrcd hctcroaryl; wherein each of the C3.6 cycloalkyl, 3- to 6-mcmbcrcd heterocyclyl, phenyl, or 5- to 6-membered heteroaryl is optionally substituted with one to four R 12 ; each R 3 is independently halo, cyano, nitro, oxo, -OR 8 , -SR 8 , -NR 8 R 9 , -C(O)R 8 , -C(O)OR 8 , -OC(O)R 8 , -OC(O)OR 8 , -C(O)NR 8 R 9 , -NR 8 C
  • a compound of Formula IA IA or a pharmaceuti ereoisomer, mixture of stereoisomers, or prodrug thereof; wherein ring A, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , R 1 , R 2 , R 3 , R 5 , n, and p are each independently as defined herein, and Y 1 is N or CR 6 .
  • Y 1 is N.
  • Y 1 is CR 6 .
  • Y 1 is CH.
  • Y 1 is N or CH.
  • each R 7 is independently hydrogen or C1-6 alkyl.
  • R 1 is hydrogen, halo, or C 1-6 alkoxy. In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is halo or C 1-6 alkoxy.
  • a compound of Formula IB IB or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof; wherein ring A, X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 4 , R 5 , n, p, and q are each independently as defined herein.
  • n is 1 or 2.
  • R 2 is C1-6 alkyl substituted with C3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; wherein each is optionally substituted with one to four, or one to three, or one or two, or one, R 12 .
  • R 2 is C 1-6 alkyl substituted with C 3-6 cycloalkyl, 3-6 membered heterocyclyl or 5-6 membered heteroaryl; wherein each is optionally substituted with one to four, or one to three, or one or two, or one, R 12 .
  • each R 2 is independently cyano or C1-6 alkyl.
  • R 2 is C 1-6 alkyl substituted with C 3-6 cycloalkyl, 3-6 membered heterocyclyl or 5-6 membered heteroaryl; wherein each is optionally substituted with cyano or C1-6 alkyl.
  • R 2 is .
  • each R 3 is independently halo, cyano, C 1-6 haloalkyl, C 1-6 alkoxy, or C 3-10 cycloalkyl.
  • a compound of Formula IC IC or a pharmaceutic ally acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof; wherein ring A, ring B, X 1 , X 2 , R 1 , R 3 , R 4 , R 5 , and p are each independently as defined herein.
  • R 5 is hydrogen or C1-6 alkyl optionally substituted with hydroxy.
  • R 5 is C1-6 alkyl.
  • R 5 is hydrogen.
  • R 5 is other than a hydrogen.
  • R 5 is .S'-rnethy I.
  • a compound of Formula IC-a or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof; wherein ring A, ring B, X 1 , X 2 , R 1 , R 3 , R 4 , R 5 , and p are each independently as defined herein.
  • a compound of Formula IC-b or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof; wherein ring A, ring B, X 1 , X 2 , R 1 , R 3 , R 4 , R ⁇ and p are each independently as defined herein.
  • ring B is C3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; wherein each is optionally substituted with one to four R 12 .
  • X 1 is C(R 7 )2- In some embodiments, X 1 is CHR 7 . In some embodiments, X 1 is O. In some embodiments, X 1 is O or CHR 7 .
  • X 1 is O or CHR 7 ; and X 2 is a bond, O, or CH2. In some embodiments, X 1 is C(R 7 )2; and X 2 is a bond. In some embodiments, X 1 is CHR 7 ; and X 2 is a bond.
  • ring A, ring B, X 2 , R 1 , R 3 , R 4 , R 5 , R 7 and p are each independently as defined herein.
  • X 2 is O. In some embodiments, X 2 is a bond. In some embodiments, X 2 is C(R 7 ) 2 . In some embodiments, X 2 is CH 2 . In some embodiments, X 2 is a bond, O, or CH 2 .
  • a compound of Formula IE or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof; wherein ring A, ring B, R 1 , R 3 , R ⁇ R 7 , and p are each independently as defined herein.
  • a compound of Formula IF or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof; wherein ring A, ring B, R 1 , R 3 , R 5 , R 7 , and p are each independently as defined herein.
  • each R 7 is independently hydrogen or Ci-s alkyl. In some embodiments, each R 7 is independently hydrogen, methyl, or ethyl. [0124] In some embodiments, p is 1 or 2. In some embodiments, p is 1. In some embodiments, p is 2.
  • each R 3 is independently halo, cyano, Cns haloalkyl, Cns alkoxy, or
  • R 5 is hydrogen or C1-6 alkyl optionally substituted with hydroxy.
  • R 1 is halo or C1-6 alkoxy. In some embodiments, R 1 is halo or methoxy. In some embodiments, R 1 is fluoro or methoxy.
  • ring A is aryl. In some embodiments, ring A is phenyl.
  • ring A is heteroaryl. In some embodiments, ring A is a 5-9 membered heteroaryl.
  • ring A is phenyl or a 5-9 membered heteroaryl.
  • ring A is phenyl, thienyl, thiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or benzofuranyl.
  • ring A is phenyl.
  • ring B is thienyl.
  • ring B is benzofuranyl.
  • Y 1 is N or CR 6 ;
  • X 1 is O or C(R 7 ) 2 ;
  • X 2 is a bond, O or C(R 7 ) 2 , provided that both X 1 and X 2 are not simultaneously O;
  • X 3 , X 4 , X 3 , and X 6 are each independently N or CR 4 ; provided that one of X 5 and X 6 is C bonded to X 2 , and no more than two of X 3 , X 4 , X 5 , and X 6 are N; or
  • X 3 is a bond and X 4 , X 3 , and X 6 are each independently O, S, N, NR 4 , or CR 4 ; provided that one of X 5 and X 6 is C bonded to X 2 , and the ring formed thereby is aromatic;
  • ring A is aryl or heteroaryl;
  • R 1 is hydrogen, halo, cyano, hydroxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; wherein each is independently optionally substituted with one to five substituents independently selected from halo, cyano, hydroxy, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, or C3-6
  • a compound of Formula IG IG or a pharmaceuti ereoisomer, mixture of stereoisomers, or prodrug thereof; wherein ring A, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , R 1 , R 2 , R 3 , R 5 , n, and p, are each independently as defined herein.
  • a compound of Formula IG is 1 or 2; p is 1 or 2; X 1 is O or C(R 7 ) 2 ; X 2 is a bond, O or C(R 7 )2, provided that both X 1 and X 2 are not simultaneously O; X 3 , X 4 , X 5 , and X 6 are each independently N or CR 4 ; provided that one of X 5 and X 6 is C bonded to X 2 , and no more than two of X 3 , X 4 , X 5 , and X 6 are N; ring A is aryl or heteroaryl; R 1 is hydrogen, halo, cyano, hydroxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C1-6 haloalkoxy, C3-6 cycloalkyl, 3-6 membered hetero
  • a compound selected from Table 2 or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof:
  • the compounds of Formula I include pharmaceutically acceptable salts thereof.
  • the compounds of Formula I also include other salts of such compounds which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and/or purifying compounds of Formula I and/or for separating enantiomers of compounds of Formula I.
  • Non- limiting examples of pharmaceutically acceptable salts of compounds of Formula I include trifluoroacetic acid salts.
  • the compounds of Formula I or their salts may be isolated in the form of solvates, and accordingly that any such solvate is included within the scope of the present disclosure.
  • compounds of Formula I and salts thereof can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • compounds as described herein can be administered in the form of a pharmaceutical compositions.
  • a pharmaceutical compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated.
  • Administration can be topical (including transdermal, epidermal, ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral or parenteral.
  • Oral administration can include a dosage form formulated for once-daily or twice-daily (BID) administration.
  • Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration.
  • Parenteral administration can be in the form of a single bolus dose, or can be, for example, by a continuous perfusion pump.
  • Pharmaceutical compositions and formulations for topical administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders.
  • Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
  • compositions which contain, as the active ingredient, a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, in combination with one or more pharmaceutically acceptable excipients (carriers).
  • a pharmaceutical composition prepared using a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.
  • the composition is suitable for topical administration.
  • the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container.
  • an excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • the composition is formulated for oral administration.
  • the composition is a solid oral formulation.
  • the composition is formulated as a tablet or capsule.
  • compositions containing a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof with a pharmaceutically acceptable excipient can be prepared by intimately mixing the compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier can take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral).
  • the composition is a solid oral composition.
  • Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers can be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.
  • the compound or pharmaceutical composition can be administered in combination with one or more conventional pharmaceutical excipients.
  • Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self- emulsifying drug delivery systems (SEDDS) such as d- a- tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based
  • Cyclodextrins such as a-, 0, and y- cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3- hydroxypropyl-P-cyclodextrins, or other solubilized derivatives can also be used to enhance delivery of compounds described herein.
  • Dosage forms or compositions containing a chemical entity as described herein in the range of 0.005% to 100% with the balance made up from non-toxic excipient may be prepared.
  • the contemplated compositions may contain 0.001%-100% of a chemical entity provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%.
  • the compounds and pharmaceutical compositions described herein or a pharmaceutical composition thereof can be administered to patient in need thereof by any accepted route of administration.
  • Acceptable routes of administration include, but are not limited to, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intrabronchial, intrabursal, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal (e.g., intranasal), nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (
  • a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof as described herein or pharmaceutical compositions thereof can be formulated for parenteral administration, e.g., formulated for injection via the intraarterial, intrasternal, intracranial, intravenous, intramuscular, sub- cutaneous, or intraperitoneal routes.
  • parenteral administration e.g., formulated for injection via the intraarterial, intrasternal, intracranial, intravenous, intramuscular, sub- cutaneous, or intraperitoneal routes.
  • such compositions can be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for use to prepare solutions or suspensions upon the addition of a liquid prior to injection can also be prepared; and the preparations can also be emulsified.
  • devices are used for parenteral administration.
  • such devices may include needle injectors, microneedle injectors, needle-free injectors, and infusion techniques.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that it may be easily injected.
  • the form should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.
  • the carrier also can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars or sodium chloride are included.
  • prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • sterile injectable solutions are prepared by incorporating a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • sterile powders are used for the preparation of sterile injectable solutions.
  • the methods of preparation are vacuum-drying and freeze-drying techniques, which yield a powder of the active ingredient, plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • pharmacologically acceptable excipients usable in a rectal composition as a gel, cream, enema, or rectal suppository include, without limitation, any one or more of cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (like PEG ointments), glycerine, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol, Vaseline, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-oxybenzoate, sodium propyl p-oxybenzoate, diethylamine, carbomers, carbopol, methyloxybenzoate, macrogol cetoste
  • suppositories can be prepared by mixing a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or pharmaceutical compositions as described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum and release the active compound.
  • compositions for rectal administration are in the form of an enema.
  • a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, as described herein or a pharmaceutical composition thereof is formulated for local delivery to the digestive or GI tract by way of oral administration (e.g., solid or liquid dosage forms.).
  • oral administration e.g., solid or liquid dosage forms.
  • solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, poly vinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example,
  • the dosage form may also comprise buffering agents.
  • solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the pharmaceutical compositions will take the form of a unit dosage form such as a pill or tablet and thus the composition may contain, along with a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof as provided herein, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like.
  • a compound of Formula I or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof as provided herein, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder
  • another solid dosage form a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils, PEG’s, poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin or cellulose base capsule).
  • a capsule gelatin or cellulose base capsule.
  • unit dosage forms in which one or more compounds and pharmaceutical compositions as provided herein or additional active agents are physically separated are also contemplated; e.g., capsules with granules (or tablets in a capsule) of each drug; two-layer tablets; two- compartment gel caps, etc.
  • enteric coated or delayed release oral dosage forms are also contemplated.
  • other physiologically acceptable compounds may include wetting agents, emulsifying agents, dispersing agents or preservatives that are particularly useful for preventing the growth or action of microorganisms.
  • preservatives include, for example, phenol and ascorbic acid.
  • the excipients are sterile and generally free of undesirable matter.
  • these compositions can be sterilized by conventional, well-known sterilization techniques.
  • sterility is not required for various oral dosage form excipients such as tablets and capsules.
  • USP/NF United States Pharmacopeia/National Formulary
  • a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof as described herein or a pharmaceutical composition thereof is formulated for ocular administration.
  • ocular compositions can include, without limitation, one or more of any of the following: viscogens (e.g., carboxymethylcellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol); stabilizers (e.g., Pluronic (triblock copolymers), cyclodextrins); preservatives (e.g., benzalkonium chloride, EDTA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.)).
  • viscogens e.g., carboxymethylcellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol
  • stabilizers e.g., Pluronic (triblock copolymers), cyclodextrins
  • preservatives e.g., benzalkonium chloride, EDTA,
  • a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof as described herein or a pharmaceutical composition thereof is formulated for topical administration to the skin or mucosa (e.g., dermally or transdermally).
  • topical compositions can include ointments and creams.
  • ointments are semisolid preparations that are typically based on petrolatum or other petroleum derivatives.
  • creams containing the selected active agent are typically viscous liquid or semisolid emulsions, often either oil-in-water or water-in-oil.
  • cream bases are typically water-washable, and contain an oil phase, an emulsifier and an aqueous phase.
  • the oil phase also sometimes called the “internal” phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant.
  • the emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant.
  • an ointment base should be inert, stable, nonirritating and non- sensitizing.
  • compositions as described herein can include one or more one or more of the following: lipids, interbilayer crosslinked multilamellar vesicles, biodegradeable poly(D,L-lactic-co-glycolic acid) (PLGA)-based or poly anhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.
  • lipids interbilayer crosslinked multilamellar vesicles
  • PLGA biodegradeable poly(D,L-lactic-co-glycolic acid)
  • the amount of the compound in a pharmaceutical composition or formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compound of this disclosure based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. In one embodiment, the compound is present at a level of about 1-80 wt %. Representative pharmaceutical formulations are described below. Formulation Example 1 - Tablet formulation
  • a suppository of total weight 2.5 g is prepared by mixing the compound of this disclosure with Witepsol® H-15 (triglycerides of saturated vegetable fatty acid; Riches-Nelson, Inc., New York), and has the following composition:
  • the dosage for a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof is determined based on a multiple factors including, but not limited to, type, age, weight, sex, medical condition of the patient, severity of the medical condition of the patient, route of administration, and activity of the compound or pharmaceutically acceptable salt or solvate thereof.
  • proper dosage for a particular situation can be determined by one skilled in the medical arts.
  • the total daily dosage may be divided and administered in portions throughout the day or by means providing continuous delivery.
  • a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof is administered at a dose from about 0.01 to about 1000 mg.
  • a dose from about 0.01 to about 1000 mg.
  • the dose is a therapeutically effective amount.
  • a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof as described herein is administered at a dosage of from about 0.0002 mg/Kg to about 100 mg/Kg (e.g., from about 0.0002 mg/Kg to about 50 mg/Kg; from about 0.0002 mg/Kg to about 25 mg/Kg; from about 0.0002 mg/Kg to about 10 mg/Kg; from about 0.0002 mg/Kg to about 5 mg/Kg; from about 0.0002 mg/Kg to about 1 mg/Kg; from about 0.0002 mg/Kg to about 0.5 mg/Kg; from about 0.0002 mg/Kg to about 0.1 mg/Kg; from about 0.001 mg/Kg to about 50 mg/Kg; from about 0.001 mg/Kg to about 25 mg/Kg; from about 0.001 mg/Kg to about 10 mg/Kg; from
  • the foregoing dosages of a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof can be administered on a daily basis (e.g., as a single dose or as two or more divided doses) or non-daily basis (e.g., every other day, every two days, every three days, once weekly, twice weeks, once every two weeks, once a month).
  • a daily basis e.g., as a single dose or as two or more divided doses
  • non-daily basis e.g., every other day, every two days, every three days, once weekly, twice weeks, once every two weeks, once a month.
  • the period of administration of a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof as described herein is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.
  • a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.
  • a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof is administered to a patient for a period of time followed by a separate period of time where administration of the compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof is stopped.
  • a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof is administered for a first period and a second period following the first period, with administration stopped during the second period, followed by a third period where administration of the compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof is started and then a fourth period following the third period where administration is stopped.
  • a period of administration of a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof followed by a period where administration is stopped is repeated for a determined or undetermined period of time.
  • a period of administration is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.
  • a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.
  • a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof is orally administered to the patient one or more times per day (e.g., one time per day, two times per day, three times per day, four times per day per day or a single daily dose).
  • a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof is administered by parenteral administration to the patient one or more times per day (e.g., 1 to 4 times, one time per day, two times per day, three times per day, four times per day or a single daily dose).
  • a compound of Formula I or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, is administered by parenteral administration to the patient weekly.
  • this disclosure features methods for treating a patient (e.g., a human) having a disease, disorder, or condition in which modulation of GLP-1R (e.g., repressed or impaired and/or elevated or unwanted GLP-1R) is beneficial for the treatment of the underlying pathology and/or symptoms and/or progression of the disease, disorder, or condition.
  • the methods described herein can include or further include treating one or more conditions associated, co-morbid or sequela with any one or more of the conditions described herein.
  • a method for treating a GLP-1 associated disease, disorder, or condition comprising administering to a patient in need thereof an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutical composition as disclosed herein.
  • the disease, disorder, or condition includes, but is not limited to type 1 diabetes mellitus, type 2 diabetes mellitus, early onset type 2 diabetes mellitus, idiopathic type 1 diabetes mellitus (Type lb), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), latent autoimmune diabetes in adults (LADA), obesity, weight gain from use of other agents, gout, excessive sugar craving, hypertriglyceridemia, dyslipidemia, malnutrition-related diabetes, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral adipose deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attacks, atherosclerotic cardiovascular disease, traumatic brain injury, peripheral vascular disease, endothelial dysfunction, impaired vascular
  • the disease, disorder, or condition includes, but is not limited to type 2 diabetes mellitus, early onset type 2 diabetes mellitus, obesity, weight gain from use of other agents, gout, excessive sugar craving, hypertriglyceridemia, dyslipidemia, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, visceral adipose deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attacks, atherosclerotic cardiovascular disease, hyperglycemia, post-prandial lipemia, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, angina pectoris, diabetic nephropathy, impaired glucose tolerance,
  • the disease, disorder, or condition includes, but is not limited to type 2 diabetes mellitus, early onset type 2 diabetes mellitus, obesity, weight gain from use of other agents, gout, excessive sugar craving, hypertriglyceridemia, dyslipidemia, gestational diabetes, adipocyte dysfunction, visceral adipose deposition, myocardial infarction, peripheral arterial disease, stroke, transient ischemic attacks, hyperglycemia, post-prandial lipemia, metabolic acidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, chronic renal failure, syndrome X, angina pectoris, diabetic nephropathy, impaired glucose tolerance, diabetic neuropathy, diabetic retinopathy, skin and connective tissue disorders, foot ulcerations, or any combination thereof.
  • the compounds and pharmaceutical compositions and methods for treating a patient described herein induce one or more of blood glucose reduction (e.g., reduce blood glucose levels), reduce blood hemoglobin Ale (HbAlc) levels, promote insulin synthesis, stimulate insulin secretion, increase the mass of 0-cells, modulate gastric acid secretion, modulate gastric emptying, decrease the body mass index (BMI), and/or decrease glucagon production (e.g., level).
  • the compounds and pharmaceutical compositions and methods for treating a patient described herein stabilize serum glucose and serum insulin levels (e.g., serum glucose and serum insulin concentrations).
  • a method for reducing the risk (e.g., by about at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80%) of major adverse cardiovascular events (MACE) in a patient in need thereof comprising administering to the patient an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutical composition as disclosed herein.
  • the patient is an adult that has been diagnosed with type 2 diabetes (T2D).
  • T2D type 2 diabetes
  • the patient is an adult that has been diagnosed with a heart disease.
  • the patient is an adult that has been diagnosed with type 2 diabetes (T2D) and a heart disease. In certain embodiments, the patient is an adult that has type 2 diabetes (T2D). In certain embodiments, the patient is an adult that has a heart disease. In certain embodiments, the patient has type 2 diabetes (T2D) and a heart disease.
  • T2D type 2 diabetes
  • the condition, disease or disorder is obesity and conditions, diseases or disorders that are associated with or related to obesity.
  • obesity and obesity related conditions include symptomatic obesity, simple obesity, childhood obesity, morbid obesity, and abdominal obesity (central obesity characterized by abdominal adiposity).
  • Non-limiting examples of symptomatic obesity include endocrine obesity (e.g., Cushing syndrome, hypothyroidism, insulinoma, obese type II diabetes, pseudohypoparathyroidism, hypogonadism), hypothalamic obesity, hereditary obesity (e.g., Prader-Willi syndrome, Laurence-Moon-Biedl syndrome), and drug-induced obesity (e.g., steroid, phenothiazine, insulin, sulfonylurea agent, or [3-blocker-induced obesity).
  • endocrine obesity e.g., Cushing syndrome, hypothyroidism, insulinoma, obese type II diabetes, pseudohypoparathyroidism, hypogonadism
  • hypothalamic obesity e.g., hereditary obesity (e.g., Prader-Willi syndrome, Laurence-Moon-Biedl syndrome)
  • drug-induced obesity e.g., steroid, phenothiazine, insulin,
  • the condition, disease or disorder is associated with obesity.
  • diseases or disorders include, without limitation, glucose tolerance disorders, diabetes (e.g., type 2 diabetes, obese diabetes), lipid metabolism abnormality, hyperlipidemia, hypertension, cardiac failure, hyperuricemia, gout, fatty liver (including non-alcoholic steatohepatitis (NASH)), coronary heart disease (e.g., myocardial infarction, angina pectoris), cerebral infarction (e.g., brain thrombosis, transient cerebral ischemic attack), bone or articular disease (e.g., knee osteoarthritis, hip osteoarthritis, spondylitis deformans, lumbago), sleep apnea syndrome, obesity hypoventilation syndrome (Pickwickian syndrome), menstrual disorder (e.g., abnormal menstrual cycle, abnormality of menstrual flow and cycle, amenorrhea, abnormal catamenial symptom), visceral obesity syndrome, and
  • diabetes e.g., type 2
  • the condition, disease or disorder is diabetes.
  • diabetes include type 1 diabetes mellitus, type 2 diabetes mellitus (e.g., diet-treated type 2-diabetes, sulfonylurea-treated type 2-diabetes, a far-advanced stage type 2-diabetes, long-term insulin-treated type 2-diabetes), diabetes mellitus (e.g., non-insulin-dependent diabetes mellitus, insulin-dependent diabetes mellitus), gestational diabetes, obese diabetes, autoimmune diabetes, and borderline type diabetes.
  • type 1 diabetes mellitus e.g., type 2 diabetes mellitus (e.g., diet-treated type 2-diabetes, sulfonylurea-treated type 2-diabetes, a far-advanced stage type 2-diabetes, long-term insulin-treated type 2-diabetes), diabetes mellitus (e.g., non-insulin-dependent diabetes
  • the condition, disease or disorder is type 2 diabetes mellitus (e.g., diet-treated type 2- diabetes, sulfonylurea-treated type 2-diabetes, a far-advanced stage type 2-diabetes, long-term insulin- treated type 2-diabetes).
  • type 2 diabetes mellitus e.g., diet-treated type 2- diabetes, sulfonylurea-treated type 2-diabetes, a far-advanced stage type 2-diabetes, long-term insulin- treated type 2-diabetes.
  • a method of treating a diabetes mellitus in a patient comprising (a) determining that the patient has type 2 diabetes mellitus, and (b) administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutical composition as disclosed herein.
  • a method for treating type 2 diabetes mellitus in a patient comprising administering to a patient identified or diagnosed as having type 2 diabetes mellitus a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutical composition as disclosed herein.
  • Also provided herein is a method of treating type 2 diabetes mellitus in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutical composition as disclosed herein.
  • the compounds and pharmaceutical compositions and methods for treating a patient with a condition, disease, or disorder (e.g., type 2 diabetes mellitus) described herein reduce fasting plasma glucose levels. In some embodiments, the compounds and pharmaceutical compositions and methods for treating a patient with a condition, disease, or disorder (e.g., type 2 diabetes mellitus) described herein reduce non-fasting plasma glucose levels. In some embodiments, the compounds and pharmaceutical compositions and methods for treating a patient with a condition, disease, or disorder (e.g., type 2 diabetes mellitus) described herein reduce HbAlc levels.
  • the compounds and pharmaceutical compositions and methods for treating a patient with a condition, disease, or disorder (e.g., type 2 diabetes mellitus) described herein reduce glucagon levels. In some embodiments, the compounds and pharmaceutical compositions and methods for treating a patient with a condition, disease, or disorder (e.g., type 2 diabetes mellitus) described herein increase insulin levels. In some embodiments, the compounds and pharmaceutical compositions and methods for treating a patient with a condition, disease, or disorder (e.g., type 2 diabetes mellitus) described herein reduce BMI.
  • a reduction in fasting plasma glucose levels of about 5% to about 95% indicates treatment of type 2 diabetes mellitus. In some embodiments, a reduction in fasting plasma glucose levels of about 15% to about 80% indicates treatment of type 2 diabetes mellitus. In some embodiments, a reduction in fasting plasma glucose levels of about 25% to about 60% indicates treatment of type 2 diabetes mellitus. In some embodiments, a reduction in fasting plasma glucose levels to about or below 126 mg/dL, about or below 110 mg/dL, or about or below 90 mg/dL indicates treatment of the type 2 diabetes mellitus.
  • a reduction in non-fasting plasma glucose levels of about 5% to about 95% indicates treatment of type 2 diabetes mellitus. In some embodiments, a reduction in non-fasting plasma glucose levels of about 15% to about 80% indicates treatment of type 2 diabetes mellitus. In some embodiments, a reduction in non-fasting plasma glucose levels of about 25% to about 60% indicates treatment of type 2 diabetes mellitus. In some embodiments, a reduction in non-fasting plasma glucose levels to about or below 200 mg/dL, about or below 150 mg/dL, or about or below 130 mg/dL indicates treatment of type 2 diabetes mellitus.
  • a reduction in HbAlc levels of about 5% to about 95% indicates treatment of type 2 diabetes mellitus. In some embodiments, a reduction in HbAlc levels of about 15% to about 80% indicates treatment of type 2 diabetes mellitus. In some embodiments, a reduction in HbAlc levels of about 25% to about 60% indicates treatment of type 2 diabetes mellitus. In some embodiments, reduction in HbAlc levels to about or below 6.5%, about or below 6.0%, or about or below 5.0% indicates treatment of type 2 diabetes mellitus.
  • a reduction in glucagon levels of about 5% to about 95% indicates treatment of type 2 diabetes mellitus. In some embodiments, a reduction in glucagon levels of about 15% to about 80% indicates treatment of type 2 diabetes mellitus. In some embodiments, a reduction in glucagon levels of about 25% to about 60% indicates treatment of type 2 diabetes mellitus. In some embodiments, an increase in insulin levels of about 5% to about 95% indicates treatment of type 2 diabetes mellitus. In some embodiments, an increase in insulin levels of about 15% to about 80% indicates treatment of type 2 diabetes mellitus. In some embodiments, an increase in insulin levels of about 25% to about 60% indicates treatment of type 2 diabetes mellitus.
  • a reduction in BMI of about 5% to about 95% indicates treatment of type 2 diabetes mellitus. In some embodiments, a reduction in BMI of about 15% to about 80% indicates treatment of the type 2 diabetes mellitus. In some embodiments, a reduction in BMI of about 25% to about 60% indicates treatment of type 2 diabetes mellitus. In some embodiments, a reduction in BMI of about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% indicates treatment of type 2 diabetes mellitus. In some embodiments, a reduction in BMI to about or below 40, about or below 30, or about or below 20 indicates treatment of type 2 diabetes mellitus.
  • the condition, disease or disorder is associated with diabetes (e.g., a complication of diabetes).
  • disorders associated with diabetes include obesity, obesity-related disorders, metabolic syndrome, neuropathy, nephropathy (e.g., diabetic nephropathy), retinopathy, diabetic cardiomyopathy, cataract, macroangiopathy, osteopenia, hyperosmolar diabetic coma, infectious disease (e.g., respiratory infection, urinary tract infection, gastrointestinal infection, dermal soft tissue infections, inferior limb infection), diabetic gangrene, xerostomia, hypacusis, cerebrovascular disorder, diabetic cachexia, delayed wound healing, diabetic dyslipidemia peripheral blood circulation disorder, cardiovascular risk factors, (e.g., coronary artery disease, peripheral artery disease, cerebrovascular disease, hypertension, and risk factors related to unmanaged cholesterol and/or lipid levels, and/or inflammation), NASH, bone fracture, and cognitive dysfunction
  • nephropathy e.g., diabetic nephropathy
  • disorders related to diabetes include pre -diabetes, hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, high LDL-cholesterolemia, low HDL-cholesterolemia, postprandial hyperlipemia), metabolic syndrome (e.g., metabolic disorder where activation of GLP-1R is beneficial, metabolic syndrome X), hypertension, impaired glucose tolerance (IGT), insulin resistance, and sarcopenia.
  • the condition, disease or disorder is diabetes and obesity (diabesity).
  • the compounds described herein are also useful in improving the therapeutic effectiveness of metformin.
  • the condition, disease or disorder is a disorder of a metabolically important tissue.
  • metabolically important tissues include liver, fat, pancreas, kidney, and gut.
  • the condition, disease or disorder is a fatty liver disease.
  • Fatty liver diseases include, but are not limited to, non-alcoholic fatty acid liver disease (NAFLD), steatohepatitis, non-alcoholic steatohepatitis (NASH), fatty liver disease resulting from hepatitis, fatty liver disease resulting from obesity, fatty liver disease resulting from diabetes, fatty liver disease resulting from insulin resistance, fatty liver disease resulting from hypertriglyceridemia, Abetalipoproteinemia, glycogen storage diseases, Weber-Christian disease, Wolman’s disease, acute fatty liver of pregnancy, and lipodystrophy.
  • NAFLD non-alcoholic fatty acid liver disease
  • NASH non-alcoholic steatohepatitis
  • fatty liver disease resulting from obesity fatty liver disease resulting from diabetes
  • fatty liver disease resulting from insulin resistance fatty liver disease resulting from hypertriglyceridemia
  • Abetalipoproteinemia glycogen storage diseases
  • Weber-Christian disease
  • Non-alcoholic fatty liver disease represents a spectrum of disease occurring in the absence of alcohol abuse and is typically characterized by the presence of steatosis (fat in the liver).
  • NAFLD is believed to be linked to a variety of conditions, e.g., metabolic syndrome (including obesity, diabetes and hypertriglyceridemia) and insulin resistance. It can cause liver disease in adults and children and may ultimately lead to cirrhosis (Skelly et al., J Hepatol 2001; 35: 195-9; Chitturi et al., Hepatology 2002; 35(2):373-9).
  • NAFLD nonalcoholic fatty liver or NAFL
  • NAFL nonalcoholic fatty liver
  • NASH non-alcoholic steatohepatitis
  • the patient is a pediatric patient.
  • pediatric patient refers to a patient under the age of 21 years at the time of diagnosis or treatment.
  • the term “pediatric” can be further be divided into various subpopulations including: neonates (from birth through the first month of life); infants (1 month up to two years of age); children (two years of age up to 12 years of age); and adolescents (12 years of age through 21 years of age (up to, but not including, the twenty-second birthday)).
  • Berhman RE Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: W.B. Saunders Company, 1996; Rudolph AM, et al. Rudolph’s Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994.
  • a pediatric patient is from birth through the first 28 days of life, from 29 days of age to less than two years of age, from two years of age to less than 12 years of age, or 12 years of age through 21 years of age (up to, but not including, the twenty-second birthday).
  • a pediatric patient is from birth through the first 28 days of life, from 29 days of age to less than 1 year of age, from one month of age to less than four months of age, from three months of age to less than seven months of age, from six months of age to less than 1 year of age, from 1 year of age to less than 2 years of age, from 2 years of age to less than 3 years of age, from 2 years of age to less than seven years of age, from 3 years of age to less than 5 years of age, from 5 years of age to less than 10 years of age, from 6 years of age to less than 13 years of age, from 10 years of age to less than 15 years of age, or from 15 years of age to less than 22 years of age.
  • the patient is an adult patient.
  • disorders in metabolically important tissues include joint disorders (e.g., osteoarthritis, secondary osteoarthritis), steatosis (e.g. in the liver); gall stones; gallbladder disorders; gastroesophageal reflux; sleep apnea; hepatitis; fatty liver; bone disorder characterized by altered bone metabolism, such as osteoporosis, including post-menopausal osteoporosis, poor bone strength, osteopenia, Paget's disease, osteolytic metastasis in cancer patients, osteodistrophy in liver disease and the altered bone metabolism caused by renal failure or hemodialysis, bone fracture, bone surgery, aging, pregnancy, protection against bone fractures, and malnutrition polycystic ovary syndrome; renal disease (e.g., chronic renal failure, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal disease); muscular dystrophy, angina pector
  • the condition, disease or disorder is a cardiovascular disease.
  • cardiovascular disease include congestive heart failure, atherosclerosis, arteriosclerosis, coronary heart disease, coronary artery disease, congestive heart failure, coronary heart disease, hypertension, cardiac failure, cerebrovascular disorder (e.g., cerebral infarction), vascular dysfunction, myocardial infarction, elevated blood pressure (e.g., 130/85 mm Hg or higher), and prothrombotic state (exemplified by high fibrinogen or plasminogen activator inhibitor in the blood).
  • cerebrovascular disorder e.g., cerebral infarction
  • vascular dysfunction vascular dysfunction
  • myocardial infarction myocardial infarction
  • elevated blood pressure e.g., 130/85 mm Hg or higher
  • prothrombotic state exemplified by high fibrinogen or plasminogen activator inhibitor in the blood.
  • the condition, disease or disorder is related to a vascular disease.
  • vascular diseases include peripheral vascular disease, macrovascular complications (e.g., stroke), vascular dysfunction, peripheral artery disease, abdominal aortic aneurysm, carotid artery disease, cerebrovascular disorder (e.g., cerebral infarction), pulmonary embolism, chronic venous insufficiency, critical limb ischemia, retinopathy, nephropathy, and neuropathy.
  • the condition, disease or disorder is a neurological disorder (e.g., neurodegenerative disorder) or a psychiatric disorder.
  • neurological disorders include brain insulin resistance, mild cognitive impairment (MCI), Alzheimer’s disease (AD), Parkinson’s disease (PD), anxiety, dementia (e.g., senile dementia), traumatic brain injury, Huntington’s chores, tardive dyskinesia, hyperkinesia, mania, Morbus Parkinson, steel-Richard syndrome, Down’s syndrome, myasthenia gravis, nerve trauma, brain trauma, vascular amyloidosis, cerebral hemorrhage I with amyloidosis, brain inflammation, Friedrich’s ataxia, acute confusion disorder, amyotrophic lateral sclerosis (ALS), glaucoma, and apoptosis-mediated degenerative diseases of the central nervous system (e.g., Creutzfeld-Jakob Disease, bovine spongiform encephalopathy (mad cow disease), and
  • Non-limiting examples of psychiatric disorders include drug dependence/addiction (narcotics and amphetamines and attention deficit/hyperactivity disorder (ADHD).
  • the compounds and pharmaceutical compositions described herein can be useful in improving behavioral response to addictive drugs, decreasing drug dependence, prevention drug abuse relapse, and relieving anxiety caused by the absence of a given addictive substance. See, e.g., US2012/0021979A1.
  • the compounds and pharmaceutical compositions described herein are useful in improving learning and memory by enhancing neuronal plasticity and facilitation of cellular differentiation, and also in preserving dopamine neurons and motor function in Morbus Parkinson.
  • the condition, disease or disorder is impaired fasting glucose (IFG), impaired fasting glycemia (IFG), hyperglycemia, insulin resistance (impaired glucose homeostasis), hyperinsulinemia, elevated blood levels of fatty acids or glycerol, a hypoglycemic condition, insulin resistant syndrome, paresthesia caused by hyperinsulinemia, hyperlipidemia, hypercholesteremia, impaired wound healing, leptin resistance, glucose intolerance, increased fasting glucose, dyslipidemia (e.g., hyperlipidemia, atherogenic dyslipidemia characterized by high triglycerides and low HDL cholesterol), glucagonoma, hyperprolactinemia, hypoglycemia (e.g., nighttime hypoglycemia), and concomitant comatose endpoint associated with insulin.
  • IGF impaired fasting glucose
  • IGF impaired fasting glycemia
  • hyperglycemia insulin resistance
  • hyperinsulinemia elevated blood levels of fatty acids or glycerol
  • the compounds and pharmaceutical compositions described herein can reduce or slow down the progression of borderline type, impaired fasting glucose or impaired fasting glycemia into diabetes.
  • the condition, disease or disorder is an autoimmune disorder.
  • autoimmune disorders include multiple sclerosis, experimental autoimmune encephalomyelitis, autoimmune disorder is associated with immune rejection, graft versus host disease, uveitis, optic neuropathies, optic neuritis, transverse myelitis, inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, myasthenia gravis, and Graves’ disease. See, e.g., US20120148586A1.
  • the condition, disease or disorder is a stomach or intestine related disorder.
  • these disorders include ulcers of any etiology (e.g. peptic ulcers, Zollinger-Ellison syndrome, drug-induced ulcers, ulcers related to infections or other pathogens), digestion disorders, malabsorption, short bowel syndrome, cul-de-sac syndrome, inflammatory bowel diseases (Crohn’s disease and ulcerative colitis), celiac sprue, hypogammaglobulinemic sprue, chemotherapy and/or radiation therapy-induced mucositis and diarrhea, gastrointestinal inflammation, short bowel syndrome, colitis ulcerosa, gastric mucosal injury (e.g., gastric mucosal injury caused by aspirin), small intestinal mucosal injury, and cachexia (e.g., cancerous cachexia, tuberculous cachexia, cachexia associated with blood disease, cachexia associated with endocrine disease, cachexia associated with infectious disease, and
  • the compounds and pharmaceutical compositions described herein can be used to reduce body weight (e.g., excess body weight), prevent body weight gain, induce weight loss, decrease body fat, or reduce food intake in a patient (e.g., a patient in need thereof).
  • the weight increase in a patient may be attributed to excessive ingestion of food or unbalanced diets, or may be weight increase derived from a concomitant drug (e.g., insulin sensitizers having a PPARy agonist-like action, such as troglitazone, rosiglitazone, englitazone, ciglitazone, pioglitazone and the like).
  • the weight increase may be weight increase before reaching obesity, or may be weight increase in an obese patient.
  • the weight increase may also be medication-induced weight gain or weight gain subsequent to cessation of smoking.
  • the condition, disease or disorder is an eating disorder, such as hyperphagia, binge eating, bulimia, or compulsive eating.
  • the condition, disease or disorder is an inflammatory disorder.
  • inflammatory disorders include chronic rheumatoid arthritis, spondylitis deformans, arthritis deformans, lumbago, gout, post-operational or post-traumatic inflammation, bloating, neuralgia, laryngopharyngitis, cystitis, pneumonia, pancreatitis, enteritis, inflammatory bowel disease (including inflammatory large bowel disease), inflammation in metabolically important tissues including liver, fat, pancreas, kidney and gut, and a proinflammatory state (e.g., elevated levels of proinflammatory cytokines or markers of inflammation-like C-reactive protein in the blood).
  • a proinflammatory state e.g., elevated levels of proinflammatory cytokines or markers of inflammation-like C-reactive protein in the blood.
  • the condition, disease or disorder is cancer.
  • suitable examples of cancer include breast cancer (e.g., invasive ductal breast cancer, noninvasive ductal breast cancer, inflammatory breast cancer), prostate cancer (e.g., hormone-dependent prostate cancer, hormone-independent prostate cancer), pancreatic cancer (e.g., ductal pancreatic cancer), gastric cancer (e.g., papillary adenocarcinoma, mucous adenocarcinoma, adenosquamous carcinoma), lung cancer (e.g., non-small cell lung cancer, small-cell lung cancer, malignant mesothelioma), colon cancer (e.g., gastrointestinal stromal tumor), rectal cancer (e.g., gastrointestinal stromal tumor), colorectal cancer (e.g., familial colorectal cancer, hereditary non-polyposis colorectal cancer, gastrointestinal stromal tumor), small intestinal cancer (e.g., non-Hodgkin’
  • breast cancer e.
  • the condition, disease or disorder is related to the hypothalamic-pituitary- gonadal axis.
  • the condition, disease or disorder is related to the hypothalamus-pituitary- ovary axis.
  • the condition, disease or disorder is related to the hypothalamus- pituitary-testis axis.
  • Hypothalamic-pituitary -gonadal axis diseases include, but are not limited to, hypogonadism, polycystic ovary syndrome, hypothyroidism, hypopituitarism, sexual dysfunction, and Cushing’s disease.
  • the condition, disease or disorder associated with diabetes is related to the hypothalamic -pituitary-gonadal axis .
  • the condition, disease or disorder is related to a pulmonary disease.
  • Pulmonary diseases include, but are not limited to, asthma, idiopathic pulmonary fibrosis, pulmonary hypertension, obstructive sleep apnoea-hypopnoea syndrome, and chronic obstructive pulmonary disease (COPD) (e.g., emphysema, chronic bronchitis, and refractory (non-reversible) asthma).
  • COPD chronic obstructive pulmonary disease
  • the condition, disease or disorder associated with diabetes is a pulmonary disease.
  • this disclosure contemplates both monotherapy regimens as well as combination therapy regimens.
  • the methods described herein can further include administering one or more additional therapies (e.g., one or more additional therapeutic agents and/or one or more therapeutic regimens) in combination with administration of the compounds described herein.
  • the methods described herein include administering a compound described herein in combination with one or more of a diet therapy (e.g., dietary monitoring, diet therapy for diabetes), an exercise therapy (e.g., physical activity), blood sugar monitoring, gastric electrical stimulation (e.g., TANTALUS®), and diet modifications.
  • a diet therapy e.g., dietary monitoring, diet therapy for diabetes
  • an exercise therapy e.g., physical activity
  • blood sugar monitoring e.g., blood sugar monitoring
  • gastric electrical stimulation e.g., TANTALUS®
  • the compounds of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof as described herein can be administered in combination with one or more additional therapeutic agents.
  • Representative additional therapeutic agents include, but are not limited to, anti-obesity agents, therapeutic agents for diabetes, therapeutic agents for diabetic complications, therapeutic agents for hyperlipidemia, antihypertensive agents, diuretics, chemotherapeutics, immunotherapeutics, anti- inflammatory drugs, antithrombotic agents, anti-oxidants, therapeutic agents for osteoporosis, vitamins, antidementia drugs, erectile dysfunction drugs, therapeutic drugs for urinary frequency or urinary incontinence, therapeutic agents for NAFLD, therapeutic agents for NASH, therapeutic agents for dysuria and anti -emetic agents.
  • anti-obesity agents include, but are not limited to, anti-obesity agents, therapeutic agents for diabetes, therapeutic agents for diabetic complications, therapeutic agents for hyperlipidemia, antihypertensive agents, diuretics, chemotherapeutics, immunotherapeutics, anti- inflammatory drugs, antithrombotic agents, anti-oxidants, therapeutic agents for osteoporosis, vitamins, antidementia drugs, erectile
  • the one or more additional therapeutic agents include those useful, for example, as anti-obesity agents.
  • Non-limiting examples include monoamine uptake inhibitors (e.g., tramadol, phentermine, sibutramine, mazindol, fluoxetine, tesofensine), serotonin 2C receptor agonists (e.g., lorcaserin), serotonin 6 receptor antagonists, histamine H3 receptor modulator, GABA modulator (e.g., topiramate), including GABA receptor agonists (e.g., gabapentin, pregabalin), neuropeptide Y antagonists (e.g., velneperit), cannabinoid receptor antagonists (e.g., rimonabant, taranabant), ghrelin antagonists, ghrelin receptor antagonists, ghrelin acylation enzyme inhibitors, opioid receptor antagonists (e.g., GSK-1521498), orexin receptor
  • FGF21 preparations e.g., animal FGF21 preparations extracted from the pancreas of bovine or swine; human FGF21 preparations genetically synthesized using Escherichia coli or yeast; fragments or derivatives of FGF21), anorexigenic agents (e.g., P-57), human proislet peptide (HIP), farnesoid X receptor (FXR) agonist, phentermine, zonisamide, norepinephrine/dopamine reuptake inhibitor, GDF-15 analog, methionine aminopeptidase 2 (MetAP2) inhibitor, diethylpropion, phendimetrazine, benzphetamine, fibroblast growth factor receptor (FGFR) modulator, and AMP-activated protein kinase (AMPK) activator.
  • FGF21 preparations e.g., animal FGF21 preparations extracted from the pancreas of bovine or swine; human FGF21 preparations genetically
  • the one or more additional therapeutic agents include those useful, for example, as anti-diabetic agents.
  • Non-limiting examples include insulin and insulin preparations (e.g., animal insulin preparations extracted from the pancreas of bovine or swine; human insulin preparations genetically synthesized using Escherichia coli or yeast; zinc insulin; protamine zinc insulin; fragment or derivative of insulin (e.g., INS- 1), oral insulin preparation, synthetic human insulin), insulin sensitizers (e.g., pioglitazone or a salt thereof), biguanides (e.g., metformin, buformin or a salt thereof (e.g., hydrochloride, fumarate, succinate)), glucagon analogs (e.g., any of glucagon analogs described, e.g., in WO 2010/011439), agents which antagonize the actions of or reduce secretion of glucagon, sulfonylurea agents (e
  • a-glucosidase inhibitors e.g., voglibose, acarbose, miglitol, emiglitate
  • insulin secretagogues such as prandial glucose regulators (sometimes called “short-acting secretagogues”), e.g., meglitinides (e.g.
  • cholinesterase inhibitors e.g., donepezil, galantamine, rivastigmine, tacrine
  • NMDA receptor antagonists dual GLP-l/GIP receptor agonists (e.g., LBT-2000, ZPD1-70), GLP-1R agonists (e.g., exenatide, liraglutide, albiglutide, dulaglutide, abiglutide, taspoglutide, lixisenatide, semaglutide, AVE-0010, S4P and Boc5), and dipeptidyl peptidase IV (DPP-4) inhibitors (e.g., vildagliptin, dutogliptin, gemigliptin, alogliptin, saxagliptin, sitagliptin, linagliptin, berberine, adogliptin, BI1356, GRC8200, MP-5
  • DPP-4 dipeptidyl peptida
  • the one or more additional therapeutic agents include those useful, for example, for treating NAFL and NASH.
  • Non-limiting examples include FXR agonists, PF-05221304, a synthetic fatty acid-bile conjugate, an anti-lysyl oxidase homologue 2 (LOXL2) monoclonal antibody, a caspase inhibitor, a MAPK5 inhibitor, a galectin 3 inhibitor, a fibroblast growth factor 21 (FGF21 ), a niacin analogue, a leukotriene D4 (LTD4) receptor antagonist, an acetyl-CoA carboxylase (ACC) inhibitor, a ketohexokinase (KHK) inhibitor, an apoptosis signal-regulating kinase 1 (ASK1) inhibitor, an ileal bile acid transporter (IBAT) inhibitor, glycyrrhizin, Schisandra extract, ascorbic acid, glutathione, silymarin, lip
  • the one or more additional therapeutic agents include those useful, for example, for treating diabetic complications.
  • Non-limiting examples include aldose reductase inhibitors (e.g., tolrestat, epalrestat, zopolrestat, fidarestat, CT-112, ranirestat, lidorestat), neurotrophic factor and increasing agents thereof (e.g., NGF, NT-3, BDNF, neurotrophic production/secretion promoting agents described in WOOl/14372 (e.g., 4-(4-chlorophenyl)-2-(2-methyl-l-imidazolyl)-5-[3-(2- methylphenoxyl)propyl]oxazole), compounds described in W02004/039365), PKC inhibitors (e.g., ruboxistaurin mesylate), AGE inhibitors (e.g., AET946, N-phenacylthiazolium bromide (AET766), EXO-226, pyridorin
  • the one or more additional therapeutic agents include those useful, for example, for treating hyperlipidemia.
  • HMG-COA reductase inhibitors e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin or a salt thereof (e.g., sodium salt, calcium salt)
  • squalene synthase inhibitors e.g., compounds described in WO97/10224, e.g., N-[[(3R,5S)- l-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2- oxo- l,2,3,5-tetrahydro-4, l-benzoxazepin-3-yl]acetyl]piperidin-4-acetic acid), fibrate compounds (e.g., bezafib
  • the one or more additional therapeutic agents include those useful, for example, as anti-hypertensive agents.
  • Non-limiting examples include angiotensin converting enzyme inhibitors (e.g., captopril, enalapril, delapril), angiotensin II antagonists (e.g., candesartan cilexetil, candesartan, losartan, losartan potassium, eprosartan, valsartan, telmisartan, irbesartan, tasosartan, olmesartan, olmesartan medoxomil, azilsartan, azilsartan medoxomil), calcium antagonists (e.g., manidipine, nifedipine, amlodipine, efonidipine, nicardipine, cilnidipine) and P-blockers (e.g., metoprolol, atenolo
  • the one or more additional therapeutic agents include those useful, for example, as diuretics.
  • Non-limiting examples include xanthine derivatives (e.g., theobromine sodium salicylate, theobromine calcium salicylate), thiazide preparations (e.g., ethiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penfluthiazide, polythiazide, methyclothiazide), antialdosterone preparations (e.g., spironolactone, triamterene), carbonic anhydrase inhibitors (e.g., acetazolamide) and chlorobenzenesulfonamide agents (e.g., chlortalidone, mefruside, indapamide).
  • xanthine derivatives e.g., theobromine sodium salicy
  • the one or more additional therapeutic agents include those useful, for example, as immunotherapeutic agents.
  • immunotherapeutic agents include microbial or bacterial compounds (e.g., muramyl dipeptide derivative, picibanil), polysaccharides having immunoenhancing activity (e.g., lentinan, sizofiran, krestin), cytokines obtained by genetic engineering approaches (e.g., interferon, interleukin (IL) such as IL-1, IL-2, IL-12), and colony-stimulating factors (e.g., granulocyte colony-stimulating factor, erythropoietin).
  • IL interleukin
  • colony-stimulating factors e.g., granulocyte colony-stimulating factor, erythropoietin.
  • the one or more additional therapeutic agents include those useful, for example, as anti-thrombotic agents.
  • Non-limiting examples include heparins (e.g., heparin sodium, heparin calcium, enoxaparin sodium, dalteparin sodium) warfarin (e.g., warfarin potassium); anti- thrombin drugs (e.g., aragatroban, dabigatran) FXa inhibitors (e.g., rivaroxaban, apixaban, edoxaban, betrixaban, YM150, compounds described in W002/06234, W02004/048363, W02005/030740, W02005/058823, and W02005/113504) thrombolytic agents (e.g., urokinase, tisokinase,reteplase, nateplase, monteplase, pamiteplase), and platelet aggregation inhibitors
  • the one or more additional therapeutic agents include those useful, for example, for treating osteoporosis.
  • Non-limiting examples include alfacalcidol, calcitriol, elcatonin, calcitonin salmon, estriol, ipriflavone, pamidronate disodium, alendronate sodium hydrate, incadronate disodium, and risedronate disodium.
  • vitamins include vitamin Bl and vitamin B12.
  • erectile dysfunction drugs include apomorphine and sildenafil citrate.
  • Suitable examples of therapeutic agents for urinary frequency or urinary incontinence include flavorxate hydrochloride, oxybutynin hydrochloride and propiverine hydrochloride.
  • Suitable examples of therapeutic agents for dysuria include acetylcholine esterase inhibitors (e.g., distigmine).
  • Suitable examples of anti-inflammatory agents include nonsteroidal anti-inflammatory drugs such as aspirin, acetaminophen, indomethacin.
  • Other exemplary additional therapeutic agents include agents that modulate hepatic glucose balance (e.g., fructose 1,6-bisphosphatase inhibitors, glycogen phosphorylase inhibitors, glycogen synthase kinase inhibitors, glucokinase activators), agents designed to treat the complications of prolonged hyperglycemia, such as aldose reductase inhibitors (e.g. epalrestat and ranirestat), agents used to treat complications related to micro -angiopathies, anti-dyslipidemia agents, such as HMG-CoA reductase inhibitors (statins, e.g.
  • agents that modulate hepatic glucose balance e.g., fructose 1,6-bisphosphatase inhibitors, glycogen phosphorylase inhibitors, glycogen synthase kinase inhibitors, glucokinase activators
  • agents designed to treat the complications of prolonged hyperglycemia such as aldose reductase inhibitors (e.g
  • rosuvastatin cholesterol-lowering agents
  • bile acid sequestrants e.g., cholestyramine
  • cholesterol absorption inhibitors e.g. plant sterols such as phytosterols
  • CETP cholesteryl ester transfer protein
  • IBAT inhibitors inhibitors of the ileal bile acid transport system
  • bile acid binding resins nicotinic acid (niacin) and analogues thereof
  • anti-oxidants e.g., probucol
  • omega-3 fatty acids e.g., antihypertensive agents, including adrenergic receptor antagonists, such as beta blockers (e.g. atenolol), alpha blockers (e.g.
  • alpha/beta blockers e.g. labetalol
  • adrenergic receptor agonists including alpha-2 agonists (e.g. clonidine), angiotensin converting enzyme (ACE) inhibitors (e.g. lisinopril), calcium channel blockers, such as dihydropridines (e.g. nifedipine), phenylalkylamines (e.g. verapamil), and benzothiazepines (e.g. diltiazem), angiotensin II receptor antagonists (e.g. candesartan), aldosterone receptor antagonists (e.g.
  • alpha-2 agonists e.g. clonidine
  • angiotensin converting enzyme (ACE) inhibitors e.g. lisinopril
  • calcium channel blockers such as dihydropridines (e.g. nifedipine), phenylalkylamines (e.g
  • centrally acting adrenergic drugs such as central alpha agonists (e.g. clonidine), diuretic agents (e.g. furosemide), haemostasis modulators, including antithrombotics (e.g., activators of fibrinolysis), thrombin antagonists, factor Vila inhibitors, anticoagulants (e.g., vitamin K antagonists such as warfarin), heparin and low molecular weight analogues thereof, factor Xa inhibitors, and direct thrombin inhibitors (e.g. argatroban), antiplatelet agents (e.g., cyclooxygenase inhibitors (e.g.
  • adenosine diphosphate (ADP) receptor inhibitors e.g. clopidogrel
  • phosphodiesterase inhibitors e.g. cilostazol
  • glycoprotein IIB/IIA inhibitors e.g. tirofiban
  • adenosine reuptake inhibitors e.g. dipyridamole
  • noradrenergic agents e.g. phentermine
  • serotonergic agents e.g.
  • DGAT diacyl glycerolacyltransferase
  • PDK pyruvate dehydrogenase kinase
  • serotonin receptor modulators monoamine transmission-modulating agents, such as selective serotonin reuptake inhibitors (SSRI) (e.g. fluoxetine), noradrenaline reuptake inhibitors (NARI), noradrenaline-serotonin reuptake inhibitors (SNRI), and monoamine oxidase inhibitors (MAOI) (e.g.
  • SSRI selective serotonin reuptake inhibitors
  • NARI noradrenaline reuptake inhibitors
  • SNRI noradrenaline-serotonin reuptake inhibitors
  • MAOI monoamine oxidase inhibitors
  • GPR40 agonists e.g., fasiglifam or a hydrate thereof, compounds described in W02004/041266, W02004/106276, W02005/063729, W02005/063725, W02005/087710, W02005/095338, W02007/013689 and W02008/001931), SGLT1 inhibitors, adiponectin or agonist thereof, IKK inhibitors (e.g., AS-2868), somatostatin receptor agonists, ACC2 inhibitors, cachexia-ameliorating agents, such as a cyclooxygenase inhibitors (e.g., indomethacin), progesterone derivatives (e.g., megestrol acetate), glucocorticoids (e.g., dex
  • the one or more additional therapeutic agents include those useful, for example, as anti-emetic agents.
  • an “anti-emetic” agent refers to any agent that counteracts (e.g., reduces or removes) nausea or emesis (vomiting). It is to be understood that when referring to a therapeutically effective amount of an anti-emetic agent, the amount administered is an amount needed to counteract (e.g., reduce or remove) nausea or emesis (vomiting).
  • administering one or more anti-emetic agents in combination with the formula (I) compounds described herein may allow higher dosages of the formula (I) compounds to be administered, e.g., because the patient may be able to have a normal food intake and thereby respond faster to the treatment.
  • Non-limiting examples of anti-emetic agents include 5HT3-receptor antagonists (serotonin receptor antagonists), neuroleptics/anti-psychotics, antihistamines, anticholinergic agents, steroids (e.g., corticosteroids), NK1 -receptor antagonists (e.g., Neurokinin 1 substance P receptor antagonists), antidopaminergic agents/dopamine receptor antagonists, benzodiazepines, cannabinoids.
  • the antiemetic agent can be selected from the group consisting of; neuroleptics, antihistamines, anti-cholinergic agents, steroids, 5HT-3-receptor antagonists, NK1 -receptor antagonists, anti- dopaminergic agents/dopamine receptor antagonists, benzodiazepines and non- psychoactive cannabinoids.
  • the anti-emetic agent is a 5HT3-receptor antagonist (serotonin receptor antagonist).
  • 5HT3-receptor antagonists include: granisetron (Kytril), dolasetron, ondansetron (Zofran), tropisetron, ramosetron, palonosetron, alosetron, azasetron, bemesetron, zatisetron, batanopirde, MDL-73147EF; metoclopramide, N-3389 (endo-3,9-dimethyl-3,9-diazabicyclo[3,3,l]non-7-yl-l H- indazole-3-carboxamide dihydrochloride), Y- 25130 hydrochloride, MDL 72222, Tropanyl-3,5-dimethylbenzoate, 3-(4-Allylpiperazin-l-yl)-2- quinoxalinecarbonitrile
  • 5HT3-receptor antagonists include: cilansetron, clozapine, cyproheptadine, dazopride, hydroxyzine, lerisetron, metoclopramide, mianserin, olanzapine, palonosetron (and netupitant), quetiapine, qamosetron, ramosteron, ricasetron, risperidone, ziprasidone, and zatosetron.
  • the 5HT-3-receptor antagonist is granisetron, dolasetron, ondansetron hydrochloride, tropisetron, ramosetron, palonosetron, alosetron, bemesetron, zatisetron, batanopirde, MDL-73147EF, metoclopramide, N-3389, Y- 25130 hydrochloride, MDL 72222, tropanyl-3,5- dimethylbenzoate 3-(4-AIIyI- piperazin- l-yl)-2-quinoxalinecarbonitrile maleate, zacopride hydrochloride and mirtazepine.
  • the 5HT-3-receptor antagonist is granisetron, dolasetron, ondansetron hydrochloride, tropisetron, ramosetron, palonosetron, alosetron, bemesetron, and zatisetron.
  • the 5 HT- 3 -receptor antagonist is granisetron, dolasetron and ondansetron.
  • the 5HT-3-receptor antagonist is granisetron.
  • the 5HT-3-receptor antagonist is ondansetron.
  • the anti-emetic agent is an antihistamine.
  • antihistamines include: piperazine derivatives (e.g., cyclizine, meclizine, and cinnarizine); promethazine; dimenhydrinate (Dramamine, Gravol); diphenhydramine; hydroxyzine; buclizine; and meclizine hydrochloride (Bonine, Antivert), doxylamine, and mirtazapine.
  • the anti-emetic agent is an anticholinergic agent (Inhibitors of the acetylcholine receptors).
  • anticholinergic agents include: atropine, scopolamine, glycopyrron, hyoscine, artane (Trihexy-5 trihexyphenidyl hydrochloride), cogentin (benztropine mesylate), akineton (biperiden hydrochloride), disipal (Norflex orphenadrine citrate), diphenhydramine, hydroxyzine, hyoscyamine, and kemadrin (procyclidine hydrochloride).
  • the anti-emetic agent is a steroid (e.g., a corticosteroid).
  • steroids include: betamethasone, dexamethasone, methylprednisolone, Prednisone®, and trimethobenzamide (Tigan).
  • the anti-emetic agent is an NK1 -receptor antagonists (e.g., Neurokinin 1 substance P receptor antagonists).
  • NK1 -receptor antagonists include: aprepitant, casopitant, ezlopitant, fosaprepitant, maropitant, netupitant, rolapitant, and vestipitant.
  • NK1 -receptor antagonists include: MPC-4505, GW597599, MPC-4505, GR205171, L-759274, SR 140333, CP-96,345, BIIF 1149, NKP 608C, NKP 608A, CGP 60829, SR 140333 (Nolpitantium besilate/chloride), LY 303870 (Lanepitant), MDL-105172A, MDL- 103896, MEN-11149, MEN-11467, DNK 333A, YM- 49244, YM-44778, ZM-274773, MEN-10930, S- 19752, Neuronorm, YM-35375, DA-5018, MK-869, L-754030, CJ-11974, L-758298, DNK- 33A, 6b-l, CJ-11974 j.
  • TAK-637 [(aR,9R)-7-[3,5-bis(trifhioromethyl)benzyl]- 8,9,10,1 l-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[l ,4]diazocino[2,l-g] [1 ,7]naphthyridine-6,13- dione], PD 154075, ([(2-benzofuran)-CH 2 OCO]-(R)-alpha-MeTrp-(S)- NHCH(CH 3 ) Ph), FK888, and (D- Pro4, D- Trp7,9,10, Phell)SP4-ll.
  • the anti-emetic agent is an anti- dopaminergic agents/dopamine receptor antagonist (e.g., dopamine receptor antagonist, e.g., D2 or D3 antagonists).
  • dopamine receptor antagonist e.g., D2 or D3 antagonists.
  • Non-limiting examples include phenothiazines (e.g., promethazine, chlorpromazine, prochlorperazine, perphenazine, hydroxyzine, thiethylperazine, metopimazine,); benzamides (e.g., metoclopramide, domperidone), butyrophenones (e.g., haloperidol, droperidol); alizapride, bromopride, clebopride, domperidone, itopride, metoclopramide, trimethobenzamide, and amisulpride.
  • phenothiazines e.g., promethazine, chlorpro
  • the anti-emetic agent is a non-psychoactive cannabinoids (e.g., Cannabidiol (CBD), Cannabidiol dimethylheptyl (CBD-DMH), Tetra-hydro-cannabinol (THC), Cannabinoid agonists such as WIN 55-212 (a CB1 and CB2 receptor agonist), Dronabinol (Marinol®), and Nabilone (Cesamet)).
  • CBD Cannabidiol
  • CBD-DMH Cannabidiol dimethylheptyl
  • THC Tetra-hydro-cannabinol
  • Cannabinoid agonists such as WIN 55-212 (a CB1 and CB2 receptor agonist), Dronabinol (Marinol®), and Nabilone (Cesamet)
  • anti-emetic agents include: c-9280 (Merck); benzodiazepines (diazepam, midazolam, lorazepam); neuroleptics/anti-psychotics (e.g., dixyrazine, haloperidol, and Prochlorperazine (Compazine®)); cerium oxalate; propofol; sodium citrate; dextrose; fructose(Nauzene); orthophosphoric acid; fructose; glucose (Emetrol); bismuth subsalicylate (Pepto Bismol); ephedrine; vitamin B6; peppermint, lavender, and lemon essential oils; and ginger.
  • c-9280 Merck
  • benzodiazepines diazepam, midazolam, lorazepam
  • neuroleptics/anti-psychotics e.g., dixyrazine, haloperidol, and Prochlorperazine (Compazine®)
  • Still other exemplary anti-emetic agents include those disclosed in US 20120101089A1; US 10,071,088 B2; US 6,673,792 Bl; US 6,197,329 Bl; US 10,828,297 B2; US 10,322,106 B2; US 10,525,033 B2; WO 2009080351 Al; WO 2019203753 A2; WO 2002020001 A2; US 8,119,697 B2; US 5,039,528; US20090305964A1; and WO 2006/111169, each of which is incorporated by reference in its entirety.
  • the additional therapeutic agent or regimen is administered to the patient prior to contacting with or administering the compounds and pharmaceutical compositions (e.g., about one hour prior, or about 6 hours prior, or about 12 hours prior, or about 24 hours prior, or about 48 hours prior, or about 1 week prior, or about 1 month prior).
  • the additional therapeutic agent or regimen is administered to the patient at about the same time as contacting with or administering the compounds and pharmaceutical compositions.
  • the additional therapeutic agent or regimen and the compounds and pharmaceutical compositions are provided to the patient simultaneously in the same dosage form.
  • the additional therapeutic agent or regimen and the compounds and pharmaceutical compositions are provided to the patient concurrently in separate dosage forms.
  • the methods described herein further include the step of identifying a patient (e.g., a subject) in need of such treatment (e.g., by way of blood assay, body mass index, or other conventional method known in the art).
  • the methods described herein further include the step of identifying a patient (e.g., patient) that has a disease, disorder, or condition as provided here (e.g., a GLP-1 associated disease, disorder, or condition).
  • a patient e.g., patient
  • a disease, disorder, or condition e.g., a GLP-1 associated disease, disorder, or condition.
  • the methods described herein further include the step of identifying a patient (e.g., patient) that has type 2 diabetes mellitus.
  • determining if the patient has type 2 diabetes mellitus includes performing an assay to determine the level of hemoglobin Ale (HbAlc), fasting plasma glucose, non-fasting plasma glucose, or any combination thereof.
  • HbAlc hemoglobin Ale
  • the level of HbAlc is about 6.5% to about 24.0%.
  • the level of HbAlc is greater than or about 6.5%.
  • the level of HbAlc is greater than or about 8.0%.
  • the level of HbAlc is greater than or about 10.0%.
  • the level of HbAlc is greater than or about 12.0%. In some embodiments, the level of HbAlc is greater than or about 14.0%. In some embodiments, the level of HbAlc is greater than or about 16.0%. In some embodiments, the level of HbAlc is greater than or about 18.0%. In some embodiments, the level of HbAlc is greater than or about 20.0%. In some embodiments, the level of HbAlc is greater than or about 22.0%. In some embodiments, the level of HbAlc is greater than or about 24.0%.
  • the level of fasting plasma glucose is greater than or about 120 mg/dL to greater than or about 750 mg/dL. In some embodiments, the level of fasting plasma glucose is greater than or about 200 mg/dL to greater than or about 500 mg/dL. In some embodiments, the level of fasting plasma glucose is greater than or about 300 mg/dL to greater than or about 700 mg/dL.
  • the level of non-fasting plasma glucose is greater than or about 190 mg/dL to greater than or about 750 mg/dL. In some embodiments, the level of non-fasting plasma glucose is greater than or about 250 mg/dL to greater than or about 450 mg/dL. In some embodiments, the level of non-fasting plasma glucose is greater than or about 400 mg/dL to greater than or about 700 mg/dL.
  • determining if the patient has type 2 diabetes mellitus further includes determining the patient’s BMI.
  • the BMI of the patient is greater than or about 22 kg/m 2 to greater than or about 100 kg/m 2 . In some embodiments, the BMI of the patient is greater than or about 30 kg/m 2 to greater than or about 90 kg/m 2 . In some embodiments, the BMI of the patient is greater than or about 40 kg/m 2 to greater than or about 80 kg/m 2 . In some embodiments, the BMI of the patient is greater than or about 50 kg/m 2 to greater than or about 70 kg/m 2 . [0259] In some embodiments, additional factors (e.g.,
  • the patient’s age is greater than or about 10 years. In some embodiments, the patient’s age is greater than or about 15 years. In some embodiments, the patient’s age is greater than or about 20 years. In some embodiments, the patient’s age is greater than or about 25 years. In some embodiments, the patient’s age is greater than or about 30 years. In some embodiments, the patient’s age is greater than or about 35 years. In some embodiments, the patient’s age is greater than or about 40 years. In some embodiments, the patient’s age is greater than or about 42 years. In some embodiments, the patient’s age is greater than or about 44 years.
  • the patient’s age is greater than or about 46 years. In some embodiments, the patient’s age is greater than or about 48 years. In some embodiments, the patient’s age is greater than or about 50 years. In some embodiments, the patient’s age is greater than or about 52 years. In some embodiments, the patient’s age is greater than or about 54 years. In some embodiments, the patient’s age is greater than or about 56 years. In some embodiments, the patient’s age is greater than or about 58 years. In some embodiments, the patient’s age is greater than or about 60 years. In some embodiments, the patient’s age is greater than or about 62 years. In some embodiments, the patient’s age is greater than or about 64 years.
  • the patient’s age is greater than or about 66 years. In some embodiments, the patient’s age is greater than or about 68 years. In some embodiments, the patient’s age is greater than or about 70 years. In some embodiments, the patient’s age is greater than or about 72 years. In some embodiments, the patient’s age is greater than or about 74 years. In some embodiments, the patient’s age is greater than or about 76 years. In some embodiments, the patient’s age is greater than or about 78 years. In some embodiments, the patient’s age is greater than or about 80 years. In some embodiments, the patient’s age is greater than or about 85 years. In some embodiments, the patient’s age is greater than or about 90 years. In some embodiments, the patient’s age is greater than or about 95 years. In some embodiments, the ethnicity of the patient may be African American, American Indian or Alaska Native, Asian American, Hispanics or Latinos, or Native Hawaiian or Pacific Islander.
  • the compounds of this disclosure can be prepared from readily available starting materials using, for example, the following general methods, and procedures. It will be appreciated that where certain process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting certain functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, and references cited therein.
  • the compounds of this disclosure may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this disclosure, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like.
  • the starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof.
  • many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance CA USA), EMKA-Chemie Gmbh & Co. KG (Eching Germany), or Millipore Sigma (Burlington MA USA).
  • Scheme I illustrates a general method which can be employed for the synthesis of compounds described herein, where ring A, ring C, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , Y 1 , Y 2 , R 1 , R 2 , R 3 , R 5 , R 10 , n, p, and q are each independently as defined herein, LG is a leaving group, such as halo (e.g., Cl, Br, or I), and R is hydrogen a suitable carboxyl protecting group, such as alkyl or benzyl.
  • LG is a leaving group, such as halo (e.g., Cl, Br, or I)
  • R is hydrogen a suitable carboxyl protecting group, such as alkyl or benzyl.
  • Compounds of Formula I can be provided by coupling compound 1-1 with compound 1-2 under suitable coupling reaction conditions, such as SN2 reaction conditions.
  • suitable reaction conditions include, but are not limited to, a polar aprotic solvent (e.g., acetonitrile), optionally in the presence of a base (e.g., potassium carbonate).
  • a base e.g., potassium carbonate
  • Further derivatization can be performed of the resulting product via methods and chemical transformations which are known to those of skill in the art can provide alternative compounds of Formula I.
  • the leaving group is an electrophile, such as an aldehyde
  • the coupling reaction conditions may comprise reductive amination reaction conditions.
  • the conversion may comprise more than one reaction or set of reactants.
  • various compounds of Formula I can be prepared by contacting compounds where one or more R 4 is a leaving group (e.g., halo, such as Cl, Br, or I, or a pseudohalide, such as a triflate, sulfonate, or phosphate), with a compound of Formula (R 3 ) m -(Ring B)-M, wherein M is a suitable functional group such as, but not limited to, a boronic acid or a derivative thereof, such as a boronic ester, zinc or magnesium halide, an organotin compound, such as tributylstannane or trimethylstannane, fluorosulfonyl esters, tin, sodium, hydrogen, and the like.
  • a leaving group e.g., halo, such as Cl, Br, or I, or a pseudohalide, such as a triflate, sulfonate, or phosphate
  • Such reactions are commonly utilized for aromatic functionalization, and are typically conducted in the presence of suitable catalyst such as, but not limited to, a palladium catalyst including [l,l’-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, Pd(OAc)2, Pd(PPh3)4, PdCLfPPhsh or tris(dibenzylideneacetone)dipalladium(0), and the like, or a copper catalyst such as CuCl or Cui, and if required suitable mediator, co-catalyst and/or base known to one skilled in the art using suitable solvents/solvent mixtures.
  • a palladium catalyst including [l,l’-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, Pd(OAc)2, Pd(PPh3)4, PdCLfPPhsh or tris(dibenzylideneacetone)dipalladium(0), and the like
  • compounds of Formula I can be recovered by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration and the like.
  • proper control of reaction conditions and selection of substituents for the reagents can at least partially dictate or preserve the formation of the various stereoisomers.
  • the various substituents of Formula 1-1 or 1-2 are as defined herein.
  • derivatization thereof prior to reacting in any step, and/or further derivatization of the resulting reaction product provides various compounds of Formula 1.
  • Appropriate starting materials and reagents can be purchased or prepared by methods known to one of skill in the art.
  • each of the intermediate or final compounds can be recovered, and optionally purified, by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration, and the like. Other modifications to arrive at compounds of this disclosure are within the skill of the art.
  • a process for preparing a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof comprising contacting a compound of Formula 1-1 : with a compound of Formula 1-2: wherein the dashed bonds, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , Y 1 , Y 2 , R 1 , R 2 , R 3 , R 5 , R 10 , n, p, and q arc each independently as defined herein; LG is a leaving group; and R is hydrogen or Ci-6 alkyl optionally substituted with phenyl, under conditions sufficient to provide the compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.
  • the process further comprises a hydrolysis or transesterification step prior to or after the contacting.
  • the process comprises a base.
  • the process comprises elevated temperature.
  • Step A tert-butyl 4-(3-bromo-2-nitrophenyl)-3-oxopiperaz.ine-l -carboxylate
  • Step B tert-butyl 4-(2-amino-3-bromophenyl)-3-oxopiperazine-l-carboxylate
  • Step C tert-butyl 9-bromo-l,2,3,4-tetrahydrobenzo[4,5]imidazo[l,2-a]pyrazine-2-carboxylate
  • Step D tert-butyl 9-[(4-chloro-2-fluorophenyl)methyl]-l, 2,3,4- tetrahydrobenzo[ 4, 5 ]imidazo[ 1,2-a ]pyrazine-2-carboxylate
  • Step E 9-[(4-chloro-2-fluorophenyl)methyl]-l,2,3,4-tetrahydrobenzo[4,5]imidazo[l,2- ajpyrazine TFA salt
  • Step F methyl 2-( ⁇ 9-[(4-chloro-2-fluorophenyl)methyl]-l, 2,3,4- tetrahydrobenzo[ 4, 5 ]imidazo[ 1,2-a ]pyrazin-2-yl]methyl)-3- ⁇ [ ( 2S )-oxetan-2- yl]methyl ⁇ benzo[d]imidazole-5-carboxylate
  • Step G 2-( ⁇ 9-[(4-chloro-2-fluorophenyl)methyl]-l,2,3,4-tetrahydrobenzo[4,5]imidazo[l,2- a]pyrazin-2-yl ⁇ methyl)-3- ⁇ [(2S)-oxetan-2-yl]methyl ⁇ benzo[d]imidazole-5-carboxylic acid (Compound 101)
  • Example compounds 103, 107, 124, 125, 127, 128, 136, 120, 121, 122 and 138 were synthesized using a similar procedure described in the Example 1 above using the appropriate materials.
  • Example A2 2- ⁇ [(1S)-9-[(4-chloro-2-fluorophenyl)methyl]-1-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2- a]pyrazin-2-yl]methyl ⁇ -3- ⁇ [(2S)-oxetan-2-yl]methyl ⁇ benzo[d]imidazole-5-carboxylic acid (Compound 119) 80 [0289] Step A 3-methylpiperazin-2-one
  • Step B tert-butyl 2-methyl-3-oxopiperazine-l-carboxylate
  • Step C tert-butyl 4-(3-bromo-2-nitrophenyl)-2-methyl-3-oxopiperazine-l-carboxylate
  • Step E tert-butyl 9-bromo-l-methyl-l,2,3,4-tetrahydrobenzo [4,5] imidazo[l,2-a] pyrazine-2- carboxylate
  • Step F tert-butyl 9-[(4-chloro-2-fluoroplienyl) methyl]-l-methyl-l,2,3,4-tetrahydrobenzo [4,5] imidazo[l,2-a] pyrazine-2-carboxylate
  • Step G 9-[(4-chloro-2-fluorophenyl) methyl]-l,2,3,4-tetrahydrobenzo [4,5] imidazo[l,2-a] pyrazine TFA salt
  • Step H methyl 2-(((S)-9-(4-chloro-2-fluorobenzyl)-l-methyl-3,4-dihydrobenzo[4,5]imidazo[l,2- a]pyrazin-2(lH]-yl)methyl]-l-(((S]-oxetan-2-yV)methyl)-lH-benzo[d]imidazole-6-carboxylate
  • Example compounds 117, 131 and 133 were synthesized using a similar procedure described in the Example A2 above using the appropriate materials.
  • Example A3 2- ⁇ [(1S)-9-[(4-chloro-2-cyanophenyl)methyl]-1-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[3,2- a]pyrazin-2-yl]methyl ⁇ -3- ⁇ [(2S)-oxetan-2-yl]methyl ⁇ benzo[d]imidazole-5-carboxylic acid (Compound 132)
  • Step A tert-butyl 4-(3-methoxy-2-nitrophenyl)-2-methyl-3-oxopiperazine-l-carboxylate [0313] To a solution of tert-butyl 2-methyl-3-oxopiperazine-l-carboxylate (11.6 g, 54.14 mmol) in DMF (110 mL) was added 60% NaH (1.95 g, 48.75 mmol) under Ar. The reaction mixture was stirred at 25 °C for 1 h. Then l-fhioro-3-methoxy-2-nitrobenzene (9.26 g, 54.14 mmol) was added. The reaction was stirred at 60 °C for 16 h.
  • Step B tert-butyl 4-(2-amino-3-methoxyphenyl)-2-methyl-3-oxopiperazine-l-carboxylate
  • Step C tert-butyl 9-methoxy-l-methyl-3,4-dihydrobenzo[4,5]imidazo[l,2-a]pyrazine-2(lH)- carboxylate
  • Step E tert-butyl (S)-9-hydroxy-l-methyl-3,4-dihydrobenzo[4,5]imidazo[l,2-a]pyrazine-2(lH)- carboxylate
  • the residue was purified by flash silica gel chromatography (80 g SepaFlash® Silica Flash Column, Eluent of 0-50% EtOAc/PE gradient @ 100 mL/min) to afford tert- butyl 9-hydroxy-l-methyl-3,4-dihydrobenzo[4,5]imidazo[l,2-a]pyrazine-2(lH)-carboxylate (3.9 g, 65.4% yield).
  • the racemic mixture was further purified by SFC separation (Column: DAICELCHIRALPAK®IG 250*40 mm*10 Lin i.
  • Step F tert-butyl (lS)-9- ⁇ [(4-chloro-2-cyanophenyl)methyl]oxy ⁇ -l-methyl-l, 2,3,4- tetrahydrobenzo[4,5]imidazo[3,2-a]pyrazine-2-carboxylate
  • tert-butyl (lS)-9-hydroxy-l-methyl-l,2,3,4-tetrahydrobenzo[4,5]imidazo[3,2- a]pyrazine-2 -carboxylate 400 mg, 1.319 mmol
  • 2-(bromomethyl)-5- chlorobenzene-1 -carbonitrile (303.9 mg, 1.319 mmol) and potassium carbonate (546.7 mg, 3.956 mmol).
  • Step G 5-chloro-2-( ⁇ [(lS)-l-methyl-l, 2,3, 4-tetrahydrobenzo[4,5]imidazo[3,2-a]pyrazin-9- yl]oxy)methyl)benzene-l-carbonitrile TFA salt
  • Step H methyl 2-(((S)-9-((4-chloro-2-cyanobenzyl)oxy)-l-methyl-3,4- dihydrobenzo[4,5]imidazo[l ,2-a]pyrazin-2(l H)-yl)methyl)-4-fluoro-l-(((S)-oxetan-2-yl)methyl)-lH- benzo[d Jimidazole- 6-carboxylate
  • Example compounds 114, 130, 131, 134, 135, 140, 142, 144, 146, 147, 148, 149 and 150 were synthesized using a similar procedure described in the Example A4 above using the appropriate materials.
  • Example A5 2-(((S)-9-((4-chloro-2-cyanobenzyl)oxy)-1-methyl-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin- 2(1H)-yl)methyl)-4-methoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 143) [0331] 2-(((S)-9-((4-chl o[4,5]imidazo[1,2-a]pyrazin- 2(1H)-yl)methyl)-4-methoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d
  • Step A tert-butyl 4-(2-brom()-6-nitrophenyl)-3-oxopiperaz.ine-l-carboxylate
  • Step B tert-butyl 4-(2-amino-6-bromophenyl)-3-oxopiperazine-l-carboxylate
  • Step C tert-butyl 6-bromo-3,4-dihydrobenzo[4,5]imidazo[l,2-a]pyrazine-2(lH)'-carboxylate
  • Step D tert-butyl 6-(4-chloro-2-fluorobenzyl)-3,4-dihydrobenzo[4,5]imidazo[l,2-a]pyrazine- 2(1 H)-carboxylate
  • Step F methyl (S)-2-((6-(4-chloro-2-fluorobenzyl)-3,4-dihydrobenzo[4,5]imidazo[l,2- a]pyrazin-2(lH)-yl)methyl)-l-(()xetan-2-ylinethyl)-lH-benzo[d]imidaz.ole-6-carboxylate
  • Step B l-(l-bromoethyl)-4-chloro-2-fluorobenzene
  • Step C tert-butyl 9-(l-(4-chloro-2-fluorophenyl)ethyl)-3,4-dihydrobenzo[4,5]imidazo[l,2- a]pyrazine-2( lH)-carboxylate
  • Step D 9-(l-(4-chloro-2-fluorophenyl)ethyl)-l,2,3,4-tetrahydrobenzo[4,5]imidazo[l,2- ajpyrazine TFA salt
  • Step E methyl 2-((9-(l-(4-chloro-2-fluorophenyl)ethyl)-3,4-dihydrobenzo[4,5]imidazo[l,2- a]pyrazin-2(lH)-yl)methyl)-l-(((S)-oxetan-2-yl)methyl)-lH-benzo[d]imidazole-6-carboxylate
  • Step F methyl 2-( ⁇ 9-[(lR)-l-(4-chloro-2-fluorophenyl)ethyl]-l, 2,3,4- tetrahydrobenzo[ 4, 5 ]imidazo[ 1,2-a ]pyrazin-2-yl]methyl)-3- ⁇ [ ( 2S )-oxetan-2- yl]methyl ⁇ benzo[d]imidazole-5-carboxylate and methyl 2-( ⁇ 9-[(lS)-l-(4-chloro-2-fluorophenyl)ethyl]- l,2,3,4-tetrahydrobenzo[4,5]imidazo[l,2-a]pyrazin-2-yl ⁇ methyl)-3- ⁇ [(2S)-oxetan-2- yl]methyl ⁇ benzo[d]imidazole-5-carboxylate
  • Example compounds 104 and 129 were synthesized using a similar procedure described in the Example A7 above using the appropriate materials.
  • Example A8 2-( ⁇ 9-[(4-chloro-2-fluorophenyl)methyl]-7-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2- a]pyrazin-2-yl ⁇ methyl)-3- ⁇ [(2S)-oxetan-2-yl]methyl ⁇ benzo[d]imidazole-5-carboxylic acid (Compound 110) O O H
  • Step C tert-butyl 9-bromo-7-methyl-3,4-dihydrobenzo[4,5]imidazo[l,2-a]pyrazine-2(lH)- carboxylate
  • Step D tert-butyl 9-(4-chloro-2-fluorobenzyl)-7-methyl-3,4-dihydrobenzo[4,5]imidazo[l,2- a]pyrazine-2(lH)-carboxylate
  • Step E 2-( ⁇ 9-[(4-chloro-2-fluorophenyl)methyl]-7-methyl-1,2,3,4- tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-2-yl ⁇ methyl)-3- ⁇ [(2S)-oxetan-2- yl]methyl ⁇ benzo[d]imidazole-5-carboxylic acid (compound 110) ethyl]-7-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2- a]pyrazin-2-yl ⁇ methyl)-3- ⁇ [(2S)-oxetan-2-yl]methyl ⁇ benzo[d]imidazole-5-carboxylic acid (compound 110) was synthesized according to the procedures described for the preparation of Example A1 (step E, F and G) by using tert-butyl 9-(4-chlor
  • Step A [(4-chloro-2-fluorophenyl)ethynyl]trimethylsilane [0377] To a solution of 4-chloro-2-fluoro-l -iodobenzene (2 g, 7.80 mmol) in DMSO (10 mL) was added ethynyltrimethylsilane (1.15 g, 11.699 mmol), bis(triphenylphosphine)palladium(II) chloride (0.22 g, 0.31 mmol), Cui (0.03 g, 0.16 mmol) and TEA (1 mL, 7.19 mmol). The reaction mixture was stirred at 25 °C for 5 h under N2.
  • Step B 4-chloro-l-ethynyl-2-fluorobenzene
  • Step C tert-butyl 9-[(4-chloro-2-fluorophenyl)ethynyl]-l,2,3,4- tetrahydrobenzo[4,5]imidazo[3,2-a]pyrazine-2-carboxylate
  • Step D tert-butyl 9-[2-(4-chloro-2-fluorophenyl)ethyl]-1,2,3,4- tetrahydrobenzo[4,5]imidazo[3,2-a]pyrazine-2-carboxylate utyl 9-[(4-chloro-2-fluorophenyl)ethynyl]-1,2,3,4- tetrahydrobenzo[4,5]imidazo[3,2-a]pyrazine-2-carboxylate (153 mg, 0.359 mmol) in EtOAc (10 mL) was added 10% Pd/C (19.12 mg).
  • Step E 2-( ⁇ 9-[2-(4-chloro-2-fluorophenyl)ethyl]-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2- a]pyrazin-2-yl ⁇ methyl)-3- ⁇ [(2S)-oxetan-2-yl]methyl ⁇ benzo[d]imidazole-5-carboxylic acid (compound 113) [ ] - - - - -c o o- - uorophenyl)ethyl]-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-2- yl ⁇ methyl)-3- ⁇ [(2S)-oxetan-2-yl]methyl ⁇ benzo[d]imidazole-5-carboxylic acid (Compound 113) was synthesized according to the procedures described for the preparation of Example A1 (step E, F and G) by using tert-butyl 9-[[
  • reaction mixture was stirred at -78 °C for 1 h under N2, then 5-chlorothiophene-2- carbaldehyde (208.09 mg, 1.420 mmol) in THF (2 mL) was added.
  • the reaction mixture was continued to stir at 25 °C 16 h under N2.
  • the mixture was quenched with sat. aq. NH4Cl (20 mL), extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated.
  • Step B tert-butyl 9-[(5-chlorothiophen-2-yl)methyl]-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2- a]pyrazine-2-carboxylate
  • yl 9-[(5-chlorothiophen-2-yl)(hydroxy)methyl]-1,2,3,4- tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-2-carboxylate 120 mg, 0.286 mmol
  • DCM (10 mL) were added triethylsilane (166.15 mg, 1.429 mmol) at 0 °C under N2.
  • Step C 2-( ⁇ 9-[(5-chlorothiophen-2-yl)methyl]-1,2,3,4-tetrahydrobenzo[4,5]imidazo[3,2- a]pyrazin-2-yl ⁇ methyl)-3- ⁇ [(2S)-oxetan-2-yl]methyl ⁇ benzo[d]imidazole-5-carboxylic acid
  • Compound 139 p y yl]-1,2,3,4-tetrahydrobenzo[4,5]imidazo[3,2-a]pyrazin-2- yl ⁇ methyl)-3- ⁇ [(2S)-oxetan-2-yl]methyl ⁇ benzo[d]imidazole-5-carboxylic acid (Compound 139) was synthesized according to the procedures described for the preparation of Example A1 (step E, F and G) by using tert-butyl 9-[(5-chlorothiophen-2-yl)methyl]-1,2,3,4-tetrahydro
  • Step B tert-butyl 9- ⁇ [(4-chloro-2-fluorophenyl)oxy]methyl ⁇ -l, 2,3,4- tetrahydrobenzo[4,5]imidazo[3,2-a]pyrazine-2-carboxylate
  • Step C 2-[(9- ⁇ [(4-chloro-2-j'luorophenyl)oxy]methyl ⁇ -l,2,3,4-tetrahydrobenzo[4,5]imidazo[3,2- a]pyrazin-2-yl)methyl]-3- ⁇ [(2S)-oxetan-2-yl]methyl]benzo[d]imidazole-5-carboxylic acid (Compound 123)
  • Example compound 126 was synthesized using a similar procedure described in the Example All above using the appropriate materials.
  • Activation of GLP-1 receptor is known to stimulate cyclic AMP (cAMP) production in cells which indicates primary coupling to the G as subunit of the G protein heterotrimeric complex.
  • cAMP cyclic AMP
  • HEK293/CRE-Luc cell line developed by HDB stably expressing the GLP-1 Receptor was used. 200x concentration of compound working solutions were prepared (Agilent Technologies Bravo) with l/21og serial dilution in 384-well Echo LDV plate (Labcyte, Cat#LP-0200) .
  • cAMP assay signal was generated using cAMP dynamic 2 Kit (Cisbio) .
  • 5pL cAMP-d2 working solution was added to each well, followed with 5pL Anti-cAMP antibody - cryptate working solution added to each well using ThermoFisher Multidrop Combi. Incubate at room temperature for 1 hour protected from light. Read the fluorescence at 665 and 615 nm with Reader PerkinElmer EnVision.
  • %Activity 100% x (mean RLU of test sample -mean RLU of vehicle control) /
  • Table 3 shows the biological activity of compounds in GLP-1R agonist cAMP stimulation assay

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Abstract

La présente invention concerne de manière générale des agonistes de GLP-1 et des compositions pharmaceutiques les comprenant, ainsi que des procédés de traitement d'une maladie, d'un trouble ou d'un état associés à GLP-1.
EP23848231.9A 2022-12-22 2023-12-21 Agonistes de glp-1 hétérocycliques Pending EP4638455A1 (fr)

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TW202521533A (zh) 2023-09-14 2025-06-01 香港商歌禮製藥(中國)有限公司 Glp-1r 激動劑及其治療方法
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Family Cites Families (46)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5039528A (en) 1989-12-11 1991-08-13 Olney John W EAA antagonists as anti-emetic drugs
AU6944296A (en) 1995-09-13 1997-04-01 Takeda Chemical Industries Ltd. Benzoxazepine compounds, their production and use as lipid lowering agents
US6197329B1 (en) 1999-05-03 2001-03-06 Drugtech Corporation Anti-nausea compositions and methods
AR035016A1 (es) 1999-08-25 2004-04-14 Takeda Chemical Industries Ltd Composicion de azol promotor de produccion/secrecion de neurotrofina, compuesto prodroga del mismo, composicion farmaceutica que lo comprende y uso del mismo para preparar esta ultima.
WO2002006234A1 (fr) 2000-07-17 2002-01-24 Takeda Chemical Industries, Ltd. Derives de sulfonate, procede de production et utilisation de ces derives
EP1357916A2 (fr) 2000-09-05 2003-11-05 Odyssey Pharmaceuticals LLC Composition anti-emetique bi-composant
IL148244A0 (en) 2002-02-19 2002-09-12 Yissum Res Dev Co Anti-nausea and anti-vomiting activity of cannabidiol compounds
US6673792B1 (en) 2002-07-11 2004-01-06 Upchuck, Llc Broad-spectrum anti-emetic compositions and associated methods
NZ540381A (en) 2002-11-01 2007-11-30 Takeda Pharmaceutical 5-membered aromatic heterocycle derivatives as prophylactic and therapeutic agents for treating neuropathy
AU2003277576A1 (en) 2002-11-08 2004-06-07 Takeda Pharmaceutical Company Limited Receptor function controlling agent
AU2003284596A1 (en) 2002-11-22 2004-06-18 Takeda Pharmaceutical Company Limited Imidazole derivative, process for producing the same, and use
EP1630152A4 (fr) 2003-05-30 2009-09-23 Takeda Pharmaceutical Compose cyclique condense
US7534887B2 (en) 2003-09-30 2009-05-19 Takeda Pharmaceutical Company Limited Thiazoline derivative and use of the same
JP4769082B2 (ja) 2003-12-17 2011-09-07 武田薬品工業株式会社 ウレア誘導体、その製造法及び用途
AU2004309271A1 (en) 2003-12-25 2005-07-14 Takeda Pharmaceutical Company Limited 3-(4-benzyloxyphenyl)propanoic acid derivatives
EP1698624B1 (fr) 2003-12-26 2012-06-27 Takeda Pharmaceutical Company Limited Derives d'acide phenylpropanoique
US7786165B2 (en) 2004-03-15 2010-08-31 Takeda Pharmaceutical Company Limited Aminophenylpropanoic acid derivative
JP4859665B2 (ja) 2004-03-30 2012-01-25 武田薬品工業株式会社 アルコキシフェニルプロパン酸誘導体
TWI396686B (zh) 2004-05-21 2013-05-21 Takeda Pharmaceutical 環狀醯胺衍生物、以及其製品和用法
US20060275288A1 (en) 2005-01-20 2006-12-07 Grihalde Nelson D GLP-1 receptor agonist and allosteric modulator monoclonal antibodies and uses thereof
EP2308839B1 (fr) 2005-04-20 2017-03-01 Takeda Pharmaceutical Company Limited Composés hétérocycliques condensés
WO2006111169A1 (fr) 2005-04-21 2006-10-26 Gastrotech Pharma A/S Préparations pharmaceutiques d'une molécule de glp-1 et d'un médicament antiémétique
JPWO2007013694A1 (ja) 2005-07-29 2009-02-12 武田薬品工業株式会社 フェノキシアルカン酸化合物
JP5084503B2 (ja) 2005-07-29 2012-11-28 武田薬品工業株式会社 シクロプロパンカルボン酸化合物
KR20080033524A (ko) 2005-08-10 2008-04-16 다케다 야쿠힌 고교 가부시키가이샤 당뇨병 치료제
JP2007063225A (ja) 2005-09-01 2007-03-15 Takeda Chem Ind Ltd イミダゾピリジン化合物
BRPI0713378A8 (pt) 2006-06-27 2018-01-02 Takeda Pharmaceutical composto, pró-droga, modulador da função do receptor gpr40, agente farmacêutico uso do composto, e, método de produção de uma forma opticamente ativa de um composto
EP2077267A4 (fr) 2006-10-18 2010-04-07 Takeda Pharmaceutical Composé hétérocyclique fusionné
US7652133B2 (en) 2006-10-19 2010-01-26 Takeda Pharmaceutical Company Limited Indole compound
WO2008093639A1 (fr) 2007-01-29 2008-08-07 Takeda Pharmaceutical Company Limited Composé de pyrazole
EP2118066A1 (fr) 2007-02-09 2009-11-18 Takeda Pharmaceutical Company Limited Composés à cycles fusionnés utiles en tant qu'agonistes partiels de ppar-gamma
JPWO2008136428A1 (ja) 2007-04-27 2010-07-29 武田薬品工業株式会社 含窒素５員複素環化合物
EP2157859A4 (fr) 2007-06-19 2011-01-12 Takeda Pharmaceutical Composés d'indazole permettant d'activer la glucokinase
EP2072050A1 (fr) 2007-12-21 2009-06-24 Santhera Pharmaceuticals (Schweiz) AG Composés à effet anti-émétique
DK2300035T3 (en) 2008-06-17 2015-11-16 Univ Indiana Res & Tech Corp Mixed GIP-based agonists for the treatment of metabolic diseases and obesity
US20120148586A1 (en) 2009-08-27 2012-06-14 Joyce Ching Tsu Chou Glucagon-like protein-1 receptor (glp-1r) agonists for treating autoimmune disorders
EP2722045B1 (fr) 2009-11-18 2016-07-06 Helsinn Healthcare SA Compositions pour traiter les nausées et vomissements à médiation centrale
GB201004020D0 (en) 2010-03-11 2010-04-21 Acacia Pharma Ltd New therapeutic use
US20120021979A1 (en) 2010-06-24 2012-01-26 Vanderbilt University GLP-1 receptor modulation of addiction, neuropsychiatric disorders and erectile dysfunction
US20120101089A1 (en) 2010-10-26 2012-04-26 Ashwani Agarwal Anti-Emetic Substance
WO2014004126A1 (fr) 2012-06-26 2014-01-03 Fleming C Andrew Traitement de la nausée et des vomissements postopératoires
GB201506116D0 (en) 2015-04-10 2015-05-27 Acacia Pharma Ltd Kit and combination therapy for nausea and vomiting
WO2019203753A2 (fr) 2017-12-15 2019-10-24 Montero Gida Sanayi Ve Ticaret Anonim Sirketi Combinaison pharmaceutique comprenant de la dapoxétine, un inhibiteur de phosphodiestérase de type 5 et un agent antiémétique
CA3209593A1 (fr) * 2021-01-28 2022-08-04 Carmot Therapeutics, Inc. Agonistes du recepteur gpcr, compositions pharmaceutiques les comprenant, et leurs procedes d'utilisation
CN114907351A (zh) * 2021-02-07 2022-08-16 杭州中美华东制药有限公司 三环类glp-1受体激动剂及其用途
CN115703792B (zh) * 2021-08-06 2024-08-13 深圳信立泰药业股份有限公司 一种并三环类衍生物及其制备方法和医药用途

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