Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • 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

Definitions

• This invention relates to compounds, preferably thyroid hormone receptor beta (TOR beta) agonist compounds, compositions thereof, and methods of their preparation, and methods of agonizing THR beta and methods for treating disorders mediated by TOR beta.
• TOR beta thyroid hormone receptor beta
• THR beta diseases or disorders associated with THR beta include non-alcoholic steatohepatitis (NASH), non-alcoholic fatty' liver disease (NAFLD), metabolic syndrome, dyshpidemia, hypertriglyceridemia, and hypercholesterolemia.
• NASH non-alcoholic steatohepatitis
• NAFLD non-alcoholic fatty' liver disease
• metabolic syndrome dyshpidemia
• hypertriglyceridemia hypertriglyceridemia
• hypercholesterolemia hypercholesterolemia
• thyroid hormone analogs such as those that are THR beta agonists, and preferably those that avoid the undesirable effects of hyperthyroidism and hypothyroidism, and maintain the beneficial effects of thyroid hormones, e.g., for the treatment for patients with non-alcoholic steatohepatitis (NASH) in particular, there is a need to develop new thyroid hormone analogs that are selective agonists for THR beta, and preferably those that avoid the undesirable effects associated with agonism of THR alpha, and maintain the beneficial effects of thyroid hormones, e.g., for the treatment for patients with non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), metabolic syndrome, dyslipidemia, hypertriglyceridemia, or hypercholesterolemia.
• NASH non-alcoholic steatohepatitis
• ring A together with the carbonyl (keto) group within the ring fonn a 5 membered heterocycle containing 1-3 ring heteroatoms selected from the group consisting ofN, O, and S, wherein the heterocycle is optionally substituted with 1-2 Ci-C-3 alkyl or C3-C4 cycloalkyl groups, and wherein the carbonyl (keto) group is not adjacent to the atom attached to X;
• R 1 is C1-C4 alkyl optionally substituted with 1-5 halo or hydroxyl groups, C 3 -C5 cycloalkyl, CON (R 10 )2, or NR 10 CQR 10 ;
• R 2 is H or Ci-C 3 alkyl
• L is O, CT-fc, S, SO, SO2, CO, CHF, CF 2 , O R )C ⁇ .
• R 3 and R 4 are independently Cl, Br, methyl, or ethyl
• R 5 together with R 4 and the intervening atoms form a 5-7 membered cycloalkyl or a 5-7 membered heterocycle containing 1-2 ring heteroatoms;
• X is absent, O, NR i2 , C(0)NR 12 , NR i2 C(G), CR 12 R 12 , 0( R ’ R CR i2 R I2 Q, NR 12 CR 12 R 12 , CR i2 R !2 NR 12 , SO2NR 12 , or ⁇ R - ' SO ⁇ :
• each R 10 is independently C1-C 3 alkyl or H;
• each R 11 is independently C1-C2 alkyl optionally substituted with 1-5 halo, or two R 11 groups together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl ring;
• each R 12 is independently H or methyl.
• the compound is of formula (IIA) or (PB):
• R 1 , R 2 , R 3 , R 4 , R 3 , X, and L are as defined for the compound of formula (I).
• the compound is of formula (VD):
• R 1 , R 2 , R 3 , R 4 , and R 5 are as defined in claim 1.
• R 1 is C1-C4 alkyl optionally substituted with 1-2 halo or hydroxyl groups, or C3-C5 cycloalkyl. In some embodiments, R 1 is isopropyl, t-butyl,
• R 2 is H or -CH3.
• R 3 is chloro or -CH3.
• R 4 is chloro or -CIT; or R 5 together with R 4 and the intervening atoms form a 5-6 membered cycloalkyl.
• R 3 together with R 4 and the intervening atoms form cyclopentyl.
• R 5 is H or fluoro.
• X is a bond. In some embodiments, X is NR !2 C(0), OCR 12 R 12 , or NR 12 CR 12 R 12 ; and each R 12 is independently H or methyl. In some embodiments, X is
• L is O, CH2, SO2, CO, CHR 11 , or C(R n )R n ; and each R 1 1 is independently methyl or ethyl. In some embodiments, L is O, CHb, SO2, or CO.
• provided herein is a compound selected from the compounds in Table 1, or a pharmaceutically acceptable salt thereof.
• a pharmaceutical composition comprising a compound provided herein and at least one pharmaceutically acceptable excipient.
• THR beta agonizing thyroid hormone receptor beta
• a method of treating a disorder which is mediated by THR beta in a patient comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a therapeutically effective amount of a composition provided herein.
• the disorder is non-alcoholic steatohepatitis (NASH).
• compositions and methods include the recited elements, but not excluding others “Consisting essentially of’ when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination.
• a composition consisting essentially of the elements as defined herein would not exclude other elements that do not materially affect the basic and novel characteristic(s) of the claimed invention.
• Consisting of’ shall mean excluding more than trace amount of, e.g., other ingredients and substantial method steps recited. Embodiments defined by each of these transition terms are within the scope of this invention.
• Effective amount or dose of a compound or a composition refers to that amount of the compound or the composition that results in an intended result as desired based on the disclosure herein. Effective amounts can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., and without limitation, by determining the LDso (the dose lethal to 50 % of the population) and the EDso (the dose therapeutically effective in 50 % of the population).
• excipient means an inert or inactive substance that may be used in the production of a drug or pharmaceutical, such as a tablet containing a compound of the invention as an active ingredient.
• a drug or pharmaceutical such as a tablet containing a compound of the invention as an active ingredient.
• Various substances may be embraced by the tenn excipient, including without limitation any substance used as a binder, disintegrant, coating, compression/encapsulation aid, cream or lotion, lubricant, solutions for parenteral
• Binders include, e.g., carbomers, povidone, xanthan gum, etc.;
• disintegrants include, e.g., croscarmellose sodium, gellan gum, sodium starch glycolate, etc.
• creams or lotions include, e.g., maltodextrin, carrageenans, etc.
• lubricants include, e.g., magnesium stearate, stearic acid, sodium stearyl furnarate, etc.
• materials for chewable tablets include, e.g., dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.
• suspending/gelling agents include, e.g., carrageenan, sodium starch glycolate, xanthan gum, etc.
• sweeteners include, e.g., aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc
• Patient refers to mammals and includes humans and non-human mammals.
• patient examples include, but are not limited to mice, rats, hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cows, and humans. In some embodiments, patient refers to a human.
• “Pharmaceutically acceptable” refers to safe and non-toxic, preferably for in vivo, more preferably, for human administration.
• “Pharmaceutically acceptable salt” refers to a salt that is pharmaceutically acceptable. A compound described herein may be administered as a pharmaceutically acceptable salt.
• Prodrug refers to a compound that, after administration, is metabolized or otherwise converted to a biologically active or more active compound (or drug) with respect to at least one property.
• a prodrug, relative to the drug is modified chemically in a manner that renders it, relative to the drug, less active or inactive, but the chemical modification is such that the corresponding drug is generated by metabolic or other biological processes after the prodrug is administered.
• a prodrug may have, relative to the active drug, altered metabolic stability or transport characteristics, fewer side effects or lower toxicity, or improved flavor (for example, see the reference Nogrady, 1985, Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392, incorporated herein by reference).
• prodrug may be synthesized using reactants oilier than employing the corresponding drug.
• prodrags include, carboxy esters, linear and cyclic phosphate esters and phosphoramide and phosphoramidates, carbamates, preferably phenolic carbamates (i.e., carbamates where the hydroxy group is part of an aryl or heteroaryl moiety, where the aryl and heteroaryl may be optionally substituted), and the likes.
• Salt refers to an ionic compound formed between an acid and a base.
• salts include, without limitation, alkali metal, alkaline earth metal, and ammonium salts.
• ammonium salts include, salts containing protonated nitrogen bases and alkylated nitrogen bases.
• Exemplary and non-limiting cations useful in pharmaceutically acceptable salts include Na, K, Rb, Cs, NHg Ca, Ba, imidazolium, and ammonium cations based on naturally occurring amino acids.
• such salts include, without limitation, salts of organic acids, such as carboxylic acids and sulfonic acids, and mineral acids, such as hydrogen halides, sulfuric acid, phosphoric acid, and the likes.
• Exemplary and non-limiting anions useful in pharmaceutically acceptable salts include oxalate, maleate, acetate, propionate, succinate, tartrate, chloride, sulfate, bisulfate, mono-, di-, and tribasic phosphate, mesylate, tosylate, and the likes.
• “Therapeutically effective amount” or dose of a compound or a composition refers to that amount of the compound or the composition that results in reduction or inhibition of symptoms or a prolongation of survival in a patient. The results may require multiple doses of the compound or the composition.
• Treating” or“treatment” of a disease in a patient refers to 1) preventing die disease from occurring in a patient that is predisposed or does not yet display symptoms of the disease; 2) inhibiting the disease or arresting its development; or 3) ameliorating or causing regression of the disease.
• “treatment” or“treating” is an approach for obtaining beneficial or desired results including clinical results.
• beneficial or desired results include, but are not limited to, one or more of the following: decreasing one more symptoms resulting from the disease or disorder, diminishing the extent of the disease or disorder, stabilizing the disease or disorder (e.g., preventing or delaying the worsening of the disease or disorder), delaying the occurrence or recurrence of the disease or disorder, delay or slowing the progression of the disease or disorder, ameliorating the disease or disorder state, providing a remission (whether partial or total) of the disease or disorder, decreasing the dose of one or more other medications required to treat the disease or disorder, enhancing the effect of another medication used to treat the disease or disorder, delaying the progression of the disease or disorder, increasing the quality of life, and/or prolonging survival of a patient.
• ‘'treatment” is a reduction of pathological consequence of the disease or disorder.
• the methods of the invention contemplate any one or more of these aspects of treatment.
• An“isotopomer” of a compound is a compound m winch one or more atoms of the compound have been replaced with isotopes of those same atoms.
• H has been replaced by D or T
• !2 C has been replaced by ! 1 C
• i4 N has been replaced by !5 N.
• replacement of with D can in some instances lead to reduced rates of metabolism and therefore longer half-lives.
• Replacement of H with T can provide radioligands potentially useful in binding studies.
• Replacement of i2 C with the short-lived isotope n C can provide ligands useful in Positron Emission Tomography (PET) scanning.
• PET Positron Emission Tomography
• Replacement of i4 N with i5 N provides compounds that can be detected/monitored by 15 N NMR spectroscopy.
• an isotopomer of a compound containing -CH2CH3 is that compound but containing -CD2CD3 instead of the -CH2CH3.
• the disclosure includes all isotopologues of the compounds disclosed herein, such as, for example, deuterated derivatives of the compounds (where H can be 2 H, i.e., D).
• Isotopologues can have isotopic replacements at any or at all locations in a structure, or can have atoms present in natural abundance at any or all locations in a structure.
• Stereoisomer or“stereoisomers” refer to compounds that differ in the stereogenicity of the constituent atoms such as, without limitation, in the chirality of one or more stereocenters or related to the cis or trans configuration of a carbon-carbon or carbon-nitrogen double bond.
• Stereoisomers include enantiomers and diastereomers.
• Alkyl refers to monovalent saturated aliphatic hydrocarbyi groups having from 1 to 12 carbon atoms, preferably from 1 to 10 carbon atoms, and more preferably from 1 to 6 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyi groups such as methyl ( ⁇ 3 ⁇ 4-), ethyl (CH3CH2-), «-propyl (CH3CH2CH2-), isopropyl ((CH ⁇ CH-), «-butyl (CH3CH2CH2CH2-), isobutyl ((CH ⁇ CHCHz-), sec-butyl ((CHsXCH ft CH-), i-butyl ((( ‘ 1 Md.
• Cx alkyl refers to an alkyl group having x number of carbon atoms.
• Cx alkenyl refers to an alkenyl group having x number of carbon atoms.
• Substituted alkyl refers to an alkyl group having from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, aeyioxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonyl amino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryioxy, arylthio, substituted arylthio, arylamino, substituted arydamino, heteroarylammo, substituted heteroarylamino, eycloalkyiamino, substituted cycloalkylamino,
• Substituted alkenyl refers to alkenyl groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyioxy, ammo, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminotliiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, arylamino, substituted aiylamino, heteroarylamino, substituted heteroarylamino, cycioaikylamino, substituted cycloaikylammo,
• Substituted alkynyl refers to alkynyl groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyioxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminotliiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy 7 , substituted aryloxy, arylthio, substituted arylthio, arylamino, substituted arylamino, heteroarylamino, substituted heteroarylamino, cycioaikylamino, substituted cycioaikylamino, substituted cycioaikylamino, substitute
• Alkoxy refers to the group -O-alkyl wherein alkyl is defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, «-propoxy, isopropoxy, «-butoxy, f-butoxy, xeobutoxy, and o-pentoxy.
• Substituted alkoxy refers to the group -0-(substituted alkyl) wherein substituted alkyl is defined herein.
• Preferred substituted alkyl groups in -0-(substituted alkyl) include halogenated alkyl groups and particularly halogenated methyl groups such as trifluoromethyl, difluromethyl, fluoromethyl and the like.
• Acyl refers to the groups 1 !-( (())-. alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl -C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocyclic-C(O)-, and substituted heterocyclic-C(O)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, wherein al
• R 30 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or substituted cycloalkyl; and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, and, substituted aryl, heteroaiyd, substituted
• Acyloxy refers to the groups alkyl-C(0)0-, substituted alkyl ⁇ C(Q)Q-,
• R 31 and R 32 are optionally joined, together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, provided that R 31 and R 32 are both not hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein .
• R 31 is hydrogen and R 32 is alkyl
• the substituted amino group is sometimes referred to herein as alkylamino.
• R 32 are alkyl, the substituted amino group is sometimes referred to herein as dialkylamino.
• a monosubstituted amino it is meant that either R 3i or R 32 is hydrogen but not both.
• R 31 nor R 32 are hydrogen
• Aminocarbonyl refers to the group -C(0)NR 33 R 34 where R 33 and R 34 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 33 and R 34 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic
• Aminothiocarbonyl refers to the group -C(S)NR 33 R 34 where R 33 and R 34 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 33 and R 34 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, aikynyi, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted and, heteroaryl, substituted heteroaryl, substituted heteroary
• Aminocarbonylamino refers to the group -NR 30 C(O)NR 33 R 34 where R 30 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalky], or substituted cycloalky], and R 33 and R 34 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 33 and R 34 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substitute
• Aminothiocarbonylamino refers to the group -NR 30 C(S)NR 33 R 34 where R 30 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or substituted cycloalkyl, and R 33 and R 34 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 33 and R 34 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alk
• Aminocarbonyloxy refers to the group -0-C(0)NR 33 R 34 where R 33 and R 34 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 33 and R 34 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heteroaryl, heteroary
• Aminosulfonyloxy refers to the group -0-S02NR 33 R 34 where R 33 and R 34 are independently selected from the group consisting of hydrogen , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, a ryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 33 and R 34 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted aikynyi, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryi,
• Aminosulfonylamino refers to the group -NR 30 -SO2NR 33 R 34 where R 30 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryi, substituted heteroaryi, cycloalkyi, or substituted cycloalkyi, and R 33 and R J4 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, aikynyi, substituted alkynyl, aryl, substituted aryl, cycloalkyi, substituted cycloalkyi, heteroaryi, substituted heteroaryi, heterocyclic, and substituted heterocyclic and w'here R 33 and R 34 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl
• Aryl refers to a monovalent aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g, phenyl (Ph)) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-l,4-benzoxazin-3(4H)-one-7-yl, and the like) provided that the point of attachment is at an aromatic carbon atom.
• Preferred aryl groups include phenyl and naphthyl.
• Substituted aryl refers to aryl groups which are substituted with 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylammo, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryioxy, arylthio, substituted arylthio, arylaniino, substituted aryiamino, heteroarylamino, substituted heteroarylamino, cycloalkyla
• heterocycloalkylamino substituted heterocyclylamino carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidmo, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroaryithio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocycly!oxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO H, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, alkylthi
• Aryloxy refers to the group -O-aryl, where aryl is as defined herein, that includes, by way of example, phenoxy and naphthoxy.
• Substituted aryloxy refers to the group -0-(substituted aryl) where substituted aryl is as defined herein.
• Arylthio refers to the group -S-aryl, where aryl is as defined herein.
• Substituted arylthio refers to the group -S-(substituted aryl), where substituted aryl is as defined herein.
• Arylamino refers to the group -NR 3 '(aryl), where aryl is as defined herein and R 37 is hydrogen, alkyl, or substituted alkyl.
• Substituted arylamino refers to the group -NR 37 (substituted aryl), where R 37 is hydrogen, alkyl, or substituted alkyl where substituted aryl is as defined herein.
• Carboxy or“carboxyl” refers to -COOH or salts thereof.
• Carboxyl ester or“carboxy ester” refers to the groups -C(0)0-alkyl
• -C(0)0-substituted alkyl -C(0)0-alkenyl, -C(0)0-substituted alkenyl, -C(0)0-alkynyl, -C(0)0-substituted alkynyl, -C(0)0-aryl, -C(0)0-substituted aryl, -C(0)0-cycloalkyl, -C(0)0-substituted cycloalkyl, -C(0)0-heteroaryl, -C(0)0-substituted heteroaryl,
• alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
• (Carboxyl ester)amino refers to the group -NR 30 -C(O)O-alkyl
• R J0 is alkyl or hy drogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
• (Carboxyl ester)oxy refers to the group -0-C(0)0-alkyl, -0-C(0)0-substituted alkyl, -0-C(0)0 ⁇ alkenyl, -0-C(0)0-substituted alkenyl, -0-C(0)0 ⁇ alkyny!,
• alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
• Cyano refers to the group -CoN.
• Cycloalkyl refers to saturated or unsaturated but nonaromatic cyclic alkyl groups of from 3 to 10 carbon atoms, preferably from 3 to 8 carbon atoms, and more preferably from 3 to 6 carbon atoms, having single or multiple cyclic rings including fused, bridged, and spiro ring systems.
• C x cycloalkyl refers to a cycloalkyl group having x number of ring carbon atoms. Examples of suitable cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl.
• One or more the rings can be aryl, heteroaryl, or heterocyclic pro vided that the point of atachment is through the non-aromatic, non-heterocyclic ring saturated carbocyclic ring.
• “Substituted eycloalkyi” refers to a cycloalkyl group having from 1 to 5 or preferably 1 to 3 substituents selected from the group consisting of oxo, thione, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylammo, acy!oxy, am o, substituted amino, aminocarbonyl, aminotliioearbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl
• Cycloalkyloxy refers to -O-cycloalkyl.
• Substituted cycloalkyloxy refers to -0-(substituted cycloalkyl).
• Cycloalkylamino refers to the group -NR 37 (cycloalkyl) where R 37 is hydrogen, alkyl, or substituted alkyl.
• Substituted cycloalkylamino refers to the group -NR 37 (substituted cycloalkyl) where R 37 is hydrogen, alkyl, or substituted alkyl and substituted cycloalkyl is as defined herein.
• Cycloalkylthio refers to -S-cycloalkyl.
• Substituted cycloalkylthio refers to -S-(substituted cycloalkyl).
• each R 36 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and two R 36 groups attached to a common guanidino nitrogen atom are optionally joined toge ther with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, provided that at least one R 36 is not hydrogen, and wherein said substituents are as defined herein.
• "Halo" or “halogen” refers to fluoro, chloro, bromo and iodo and preferably is fluoro or chloro.
• Heteroalkylene refers to an alkylene group wherein one or more carbons is replaced with -0-, -S-, SO ⁇ . -N R 0 -.
• substituted heteroalkylene refers to heteroalkynylene groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the substituents disclosed for substituted alkylene.
• Heteroaryl refers to an aromatic group of from 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur within the ring.
• Such heteroaryl groups can have a single ring (e.g., pyridinyl or furyl) or multiple condensed rings (e.g. , indolizinyl or benzothienyl) wherein the condensed rings may or may not be aromatic and/or contain a heteroatom provided that the point of attachment is through an atom of the aromatic heteroaryl group.
• the nitrogen and/or the sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N 0), sulfinyl, or sulfonyl moieties.
• Preferred heteroaryls include 5 or 6 membered heteroaryls such as pyridinyl, pyrrolyl, thiophenyl, and furanyl.
• Other preferred heteroaryls include 9 or 10 membered heteroaryls, such as indolyl, qu ohnyl, quinolonyl, isoquinolinyl, and isoquinolonyl.
• Substituted heteroaryl refers to heteroaryl groups that are substituted with from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of the same group of substituents defined for substituted aryl.
• Heteroaryloxy refers to -O-heteroaryl.
• Substituted heteroaryloxy refers to the group -O -(substituted heteroaryl).
• Heteroarylthio refers to the group -S-heteroaryl .
• Substituted heteroarylthio refers to the group -S-(substituted heteroaryl).
• Heteroarylamino refers to the group -NR 37 (heteroaryl) where R 3 7 is hydrogen, alkyl, or substituted alkyl .
• “Substituted heteroarylamino” refers to the group -NR 37 (substituted heteroaryl), where R 37 is hydrogen, alkyl, or substituted alkyl and substituted heteroaryl is defined as herein.
• “Heterocycle” or “heterocyclic” or“heterocycloalkyl” or“heterocyclyl” refers to a saturated or partially saturated, but not aromatic, group having from 1 to 10 ring carbon atoms, preferably from 1 to 8 carbon atoms, and more preferably from 1 to 6 carbon atoms, and from 1 to 4 ring heteroatoms, preferably from 1 to 3 heteroatoms, and more preferably from 1 to 2 heteroatoms selected from the group consisting of nitrogen, sulfur, or oxygen Cx
• heterocycloalkyl refers to a heterocycloalkyl group having x number of ring atoms including the ring heteroatoms.
• Heterocycle encompasses single ring or multiple condensed rings, including fused bridged and spiro ring systems.
• fused ring systems one or more the rings can be cycloalkyl, aryl or heteroaryl provided that the point of attachment is through the non-aromatic ring.
• the nitrogen and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N -oxide, sulfmyi, sulfonyl moieties.
• Heterocyciylene refers to a divalent saturated or partially saturated, but not aromatic, group having from 1 to 10 ring carbon atoms and from 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur, or oxygen.
• Substituted heterocyciylene refers to heterocyciylene groups that are substituted with from 1 to 5 or preferably 1 to 3 of the same substituents as defined for substituted cycloalkyl
• Substituted heterocyclic or“substituted heterocycloalkyl” or“substituted heterocyclyl” refers to heterocyclyl groups that are substituted with from 1 to 5 or preferably 1 to 3 of the same substituents as defined for substituted cycloalkyl.
• Heterocyclyloxy refers to the group -O-heterocycyl.
• Substituted heterocyclyloxy refers to the group -0-(substituted heterocycyl).
• Heterocyclylthio refers to the group -S-heterocyey!.
• Substituted heterocyclylthio refers to the group -S-(substituted heterocycyl).
• Heterocyclylamino refers to the group -NR3 7 (heterocyclyl) where R 37 is hydrogen, alkyl, or substituted alkyl.
• Substituted heterocyclylamino refers to the group -NR 37 (substituted heterocyclyl), where R 37 is hydrogen, alkyl, or substituted alkyl and substituted heterocyclyl is defined as herein.
• heterocyclyl and heteroaryl include, but are not limited to, azetidinyl, pyrrolyl, imidazo!yl, pyrazoly!, pyridyl, pyrazyl, pyrimidyl, pyridazyl, indolizyl, isoindolyl, indolyl, dihydroindolyl, indazolyl, purinyl, quinolizinyl, isoquinolinyl, quinolinyl, phthaiazinyi, naphthylpyridmyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, carboimyl, phenanthridinyl, acridinyl, phenanthrolinyi, isothiazoiyl, phenazinyl, isoxazolyl, phenoxa
• thiamorpholinyl 1,1-dioxothiomorpholinyl, piperidinyl, pyrcolidinyl, and tetrahydrofuranyl.
• Niro refers to the group -NO2.
• “Spiro ring systems” refers to bicyclic ring systems that have a single ring carbon atom common to both rings.
• Substituted sulfonyl refers to the group -SCh-alkyl, -SC -substituted
• alkyl -SO2-QH, -S02-alkenyl, -S02-substituted alkenyl, -SG2-cycloalkyl, -S02-substituted cylcoalky], -SQr-aryl, -SCh-substituted aryl, -SC -heteroaxyl, -S02-substituted
• heteroaryl -SC -heterocyclic, -SOz-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
• Substituted sulfonyl includes groups such as methyl-SC -, phenyl-SC -, and -rnethylphenyl-SO .
• Preferred substituted alkyl groups on the substituted alkyl-SCh- include halogenated alkyl groups and particularly halogenated methyl groups such as trifluoromethyi, difluromethyl, fluoromethyl and the like.
• Substituted sulfinyi refers to the group -SO-alkyl, -SO-substituted
• alkyl -SO-alkenyl, -SO-substituted alkenyl, -SQ-cycloalkyi, -SO-substituted
• heteroaryl -SO-heterocyclic, -SO-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
• Substituted sulfinyi includes groups such as methyl-SO-, phenyl-SO-, and 4-methylphenyl-SO-.
• Preferred substituted alkyl groups on the substituted alkyl-SO- include halogenated alkyl groups and particularly halogenated methyl groups such as trifluoromethyi, difluromethyl, fluoromethyl and the like.
• alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted and, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
• “Sulfonylamino” refers to the group -NR 37 ( substituted sulfonyl) where R 57 is hydrogen, alkyl, or substituted alkyl and substituted sulfonyl is as defined here.
• Thioacyl refers to the groups H-C(S)-, alkyl-C(S)-, substituted alkyl-C(S)-, alkenyl-C(S)-, substituted alkenyl-C(S)-, alkynyl-C(S)-, substituted alkynyl-C(S)-,
• cycloalkyl C(S)- substituted cycloalkyl-C(S)-, aryl-C(S)-, substituted aryl-C(S)-,
• heteroaryl-C(S)- substituted heteroaryl-C(S)-, heterocyclic-C(S)-, and substituted
• heterocyclic-C(S)- wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
• Forml refers to the group -C(0)H.
• Alky!thio refers to the group -S-a!kyl wherein alkyl is as defined herein.
• Substituted alkylthio refers to the group -S-(substituted alkyl) wherein substituted alkyl is as defined herein.
• Preferred substituted alkyl groups on -S-(substituted alkyl) include halogenated alkyl groups and particularly halogenated methyl groups such as trifluoromethyl, difluromethyl, fluoromethyi and the like.
• the tenn“optionally substituted” refers to a substituted or unsubstituted group.
• the substituted group may be substituted with one or more substituents, such as e.g., 1 , 2, 3, 4 or 5 substituents.
• the substituents are selected from the functional groups provided herein.
• the substituents are selected from oxo, halo, -CN, NCh, -CO2R 100 , -OR 100 , -SR 100 , -SOR 100 , -SQ2R 100 , -NR i01 R 102 , ⁇ CONR 10i R 102 ,
• the substituents are selected from the group consisting of chloro, fluoro, -OCH3, methyl, ethyl, isopropyl, cyclopropyl, -OCF3, -CF3 and -OCHF2.
• R 101 and R 102 independently are hydrogen; C;-Cs alkyl, optionally substituted with
• each R I independently is hydrogen or CI-CK alkyl; C3-Ci2 cycioalkyl; C4-Cio heterocyclyl; Ce-Cwaryl; or C2-C ] 2 heteroaryl;
• each cycioalkyl, heterocyclyl, ar ⁇ , or heteroaryl is optionally substituted with 1-3 alkyl groups or 1-3 halo groups, or R !ul and R 102 together with the nitrogen atom they are attached to form a 5-7 membered heterocycle.
• alkoxycarbonylalkyl refers to the group (alkoxy )-C(0)-(alkyl)-.
• impermissible substitution patterns e.g., methyl substituted with 4 fluoro groups.
• impermissible substitution patterns are well known to the skilled artisan.
• ring A together with the carbonyl (keto) group within the ring form a 5 membered heterocycle containing 1-3 ring heteroatoms selected from the group consisting of N, O, and S, wdierein the heterocyle is optionally substituted with 1-2 substituents selected from the group consisting of C1-C3 alkyl and C3-C4 cycloalkyl, and wherein the carbonyl (keto) group is not adjacent to the atom attached to X;
• R 1 is C1-C4 alkyl; C1-C4 alkyl optionally substituted with 1-5 halo, preferably fluoro, or hydroxyl groups; C3-C5 cycloalkyl, CON(R l0 )2, or NR ]ll COR t0 , wherein each R !0 is
• R 2 is H or C1-C 3 alkyl
• L is O, P 1 -. S, SO, SO2, CO, CHF, CF 2 , C(R n )CN such as C(Me)CN, CHR 11 , or ( (R )R .
• R n is C1-C2 alkyl optionally substituted with 1-5 halo, preferably fluoro, or the 2 R 11 groups together with the carbon atom they are attached to form a cyclopropyl or cyclobutyl ring;
• each of R 3 and R 4 is independently Cl, Br, Me, or ethyl;
• R 3 is H, halo, C1-C4 alkyl preferably Ctb, or C3-C4 cycloalkyl, or R 5 together with R 4 and the intervening atoms form a 5-7 membered cycloalkyl or a 5-7 membered heterocycle containing 1- 2 ring heteroatoms; and
• X is absent (i.e., X is a bond), or is O, NR 12 , C(Q)NR !2 , NR i2 C(Q), CR i2 R 12 , OCR i2 R 12 ,
• the compound of fonnula (I) is a pharmaceutically acceptable salt thereof.
• the compound of formula (1) is a compound of formula (IIA):
• the compound of formula (1) is a compound of formula (IIB):
• the compound of formula (1) is a compound of formula (IPA).
• the compound of formula (1) is a compound of formula (MB):
• the compound of formula (I) is a compound of formula (IIIC):
• the compound of formula (I) is a compound of formula (HID):
• the compound of formula (I) is a compound of formula (IV A):
• the compound of formula (I) is a compound of fonnula (IVB):
• the compound of formula (I) is a compound of fonnula (IV C):
• the compound of formula (I) is a compound of formula (IVD):
• the compound of formula (I) is a compound of formula (VA):
• the compound of formula (I) is a compound of formula (VB):
• the compound of formula (I) is a compound of formula (VC):
• the compound of formula (I) is a compound of formula (VD):
• the compound of formula (I) is a compound of formula (VIA):
• the compound of formula (I) is a compound of formula (VIB):
• the compound of formula (I) is a compound of formula (VIC):
• the compound of formula (I) is a compound of formula (VID):
• the compound of formula (I) is a compound of formula (VIIA).
• R 2 is H or methyl, and the variables are defined as in formula (1).
• the compound of formula (I) is a compound of formula (VHB):
• R 2 is H or methyl, and the variables are defined as in formula (I).
• the compound of formula (I) is a compound of formula (VIIC):
• R 2 is H or methyl, and the variables are defined as in formula (I).
• the compound of formula (I) is a compound of formula (VIID):
• R 2 is H or methyl, and the variables are defined as in formula (I).
• the compound of fonnula (I) is a compound of formula (VIIIA):
• R 2 is H or methyl, and the variables are defined as in formula (I).
• the compound of formula (I) is a compound of formula (VIIIB):
• the compound of formula (I) is a compound of formula (VH!C):
• the compound of fonnula (I) is a compound of formula (VIIID):
• the compound of formula (I) is a compound of fonnula (IXA), (IXB), (IXC), (IXD), (IXE), or (IXF): wherein the variables are defined as in formula (I)
• the compound is of formula (IXA).
• the compound is of formula (IXB).
• the compound is of formula (1XC).
• the compound is of formula (IXD).
• the compound is of formula (IXE).
• the compound is of fonnula (IXF).
• ring A together with the carbonyl (keto) group within the ring form a 5 membered heterocycle containing 1-3 ring heteroatoms selected from the group consisting of N, O, and S, and wherein the keto group is not adjacent to the atom attached to X.
• ring A together with the carbonyl (keto) group within the ring form a 5 membered heterocycle containing 1-3 ring heteroatoms selected from the group consisting of N, O, and S, wherein the heterocyle is substituted with 1-2 C1-C 3 alkyl or C 3 -C4 cycloalkyl, and wherein the keto group is not adjacent to the atom attached to X
• the 5 membered heterocycle contains 1 -3 ring heteroatoms selected from the group consisting of N and O.
• ring A together with the carbonyl (keto) group within the ring is
• ring A together with the carbonyl (keto) group within the ring
• R 1 is C1-C4 alkyl. In some embodiments, R 1 is methyl, ethyl, n- propyl, isopropyl, «-butyl, or t-butyl. In some embodiments, R 1 is C3-C4 alkyl. In one embodiment, R ! is isopropyl. In some embodiments, R ! is t-butyl. In one embodiment, R 1 is C1-C4 alkyl optionally substituted with 1-5 halo, preferably fluoro. In some embodiments, R ! is C1-C4 alkyl optionally substituted with 1-2 halo, such as fluoro or chloro. In one embodiment, R ! is Ci - alkyl optionally substituted with 1-5 halo or hydroxyl groups. In some embodiments, R 1 is methyl, ethyl, n- propyl, isopropyl, «-butyl, or t-butyl. In some embodiments, R 1 is
• R ! is C2-C4 alkyl optionally substituted with 1-5 halo or hydroxyl groups.
• R 1 is C 1 -C 4 alkyl optionally substituted with 1 -2 halo or hydroxyl groups.
• R 1 is C1-C4 alkyl optionally substituted with 1 -5 hydroxyl groups. In some embodiments, R ! is Ci-C 4 alkyl optionally substituted with 1-2 hydroxyl groups. In some embodiments, R 1 is C1-C4 alkyl substituted with 1 hydroxyl group. In some embodiments, R 1 is C1-C4 alkyl optionally substituted with 1-2 halo or hydroxyl groups. In some embodiments, R! is HO-CH(CH3)-. In some embodiments, R 1 is HO-CH(CH2CH3)-. In some embodiments, R 1 is H0-C(CH3 ⁇ 2 . In some embodiments, R ! is HO-CH2CH(CH3)-.
• R 1 is C3- Cs cycloalkyl.
• R ! is a monocyclic C3-C5 cycloalkyl.
• R ’! is cyclopropyl, cyclobutyl, or cyclopentyl.
• R ] is cyclopropyl.
• R ! is a fused bicyclic C3-C5 cycloalkyl.
• R 1 is a bridged bicyclic C3-C5 cycloalkyl. some embodiments.
• R 1 is
• R 1 is CON(R 10 )2. In one embodiment, R 1 is NR 10 CQR 10 .
• each R 10 is independently C1-C3 alkyl. In some embodiments, each R 10 is independently methyl, ethyl, «-propyl, or isopropyl. In some embodiments, each R 10 is methyl. In one embodiment, each R !0 is H. In some embodiments, one R 10 is H and the other R i0 is C1-C3 alkyl. In some embodiments, one R 10 is H and the other R 10 is methyl. [0155] In one embodiment, R 2 is H. In one embodiment, R 2 is C1-C3 alkyl. In some embodiments, R 2 is methyl, ethyl, «-propyl, or isopropyl. In some embodiments, R 2 is methyl. In some embodiments, R 2 is H or -CH 3 .
• L is O. In one embodiment, L is CH2. In one embodiment, L is S. In one embodiment, L is SO. In one embodiment, L is SO2. In one embodiment, L is CO. In one embodiment, L is CHF. In one embodiment, L is CF 2 . In one embodiment, L is C(R n )CN. In one embodiment, L is C(Me)CN.
• L is CHR !1 or C(R u )R n , wherein each R 11 is independently C1-C2 alkyl optionally substituted with 1-5 halo, preferably fluoro, or the 2 R 11 groups together with the carbon atom they are attached to fonn a cyclopropyl or cyclobutyl ring.
• L is CHR !1 .
• L is C(R I ! )R n .
• each R 11 independently is C1-C2 alkyl, i.e., is methyl or ethyl.
• each R u independently is C1-C2 alkyl substituted with 1 -5 halo, preferably fluoro.
• the 2 R u groups together with the carbon atom they are attached to form a cyclopropyl or cyclobutyl ring.
• L is O, CH2, SO2, CO, CHR !! , or C(R U )R !1
• each R !1 is independently methyl or ethyl.
• L is O, CH2, SO2, or CO.
• R 3 is Cl. In one embodiment, R 3 is Br. In one embodiment, R 3 is Me. In one embodiment, R 3 is ethyl. In some embodiments, R 3 is Cl or -CH 3 . In one embodiment, R 4 is Cl. In one embodiment, R 4 is Br. In one embodiment, R 4 is Me. In one embodiment, R 4 is ethyl. In one embodiment, R 3 and R 4 are each Cl. In some embodiments, R 3 and R 4 are each methyl. In some embodiments, R 3 is Cl and R 4 is methyl. In some embodiments, R 3 is Cl and R 4 is methyl. In some embodiments, R 3 is Cl and R 4 is methyl. In some embodiments, R 3 is Br. In one embodiment, R 3 is Me. In one embodiment, R 3 is ethyl. In some embodiment, R 3 and R 4 are each Cl. In some embodiments, R 3 and R 4 are each methyl. In some embodiments, R 3 is Cl and R 4 is methyl. In some
• R 3 is methyl and R 4 is Cl.
• R 3 is H. In one embodiment, R 3 is halo. In some embodiments,
• R 5 is fluoro, ch!oro, or bromo. In some embodiments, R 5 is fluoro. In one embodiment, R 5 is C1-C4 alkyl. In some embodiments, R 5 is C1-C3 alkyl. In some embodiments, R 5 is methyl, ethyl, «-propyl, or isopropyl. In one embodiment, R 5 is CH 3 . In some embodiments, R 3 is H or -CH 3 . In one embodiment, R 5 is C.3-C4 cycloalkyl. In some embodiments, R 3 is cyclopropyl. In some embodiments, R 3 is cyclobutyl.
• R 4 together with R 5 and the intervening atoms form a 5-7 membered cycloalkyl. In some embodiments, R 4 together with R 3 and the intervening atoms form cyclopentyl or cyclohexyl. In some embodiments, R 4 together with R 5 and the intervening atoms form cyclopentyl. In one embodiment, R 4 together with R 5 and the intervening atoms form a 5-7 membered heterocycle containing 1-2 ring heteroatoms. Preferred heteroatoms include one or more of N, O, and S.
• X is absent (i.e., X is a bond). In one embodiment, X is O. In one embodiment, X is NR 12 . In one embodiment, X is C(0)NR ] 2 . In one embodiment, X is NR i2 C(0). In one embodiment, X is NR i2 S02. In one embodiment, X is SO2NR 12 . In one embodiment, X is NR 12 C(0). In one embodiment, X is CR i2 R !2 . In one embodiment, X is QCR i2 R 12 . In one embodiment, X is CR 12 R i2 Q. In one embodiment, X is CR !2 R i2 NH.
• X is NR 12 CR 12 R !2 . In some embodiments, X is NR !2 C(0), QCR! 2 R 12 , or NR !2 CR i2 R 12 , and each R 12 is independently H or methyl. In some embodiments, X is N(CH3)CH2. In one embodiment, X is CR 12 R i2 NR ]2 In one embodiment, X is NH. In one embodiment, X is CH2. In one embodiment, X is OCtb. In one embodiment, X is CH2O. In one embodiment, X is NHCH2. In one embodiment, X is CH2NH. In one embodiment, X is NHC(O). In one embodiment, X is C(0)NH.
• X is SO2NH. In one embodiment, X is NHSO2. In some embodiments, X is OCH2, NHCH2, NHC(O), N(CH3)CH2, or N ⁇ 1 1)0 !((. ' ! 1 ⁇ ⁇ . In one embodiment, R !2 is H. In one embodiment, R !2 is methyl. In some embodiments, all R 12 groups in a given moiety, such as OCR i2 R !2 , are H. In some
• all R 12 groups in a given moiety are methyl.
• the R 12 groups in a given moiety, such as QCR 12 R i2 are a combination of H and methyl.
• R 2 is H or C1-C3 alkyl
• R J is Cl or methyl
• R 4 is Cl or methyl
• R 5 is H, halo, or Ci-Cr alkyl
• (IX) L is O, CH 2 , SC , or CO.
• (I) applies. In one variation, (II) applies. In one variation, (III) applies. In one variation, (IV) applies. In one variation, (V) applies. In one variation, (VI) applies. In one variation, (VII) applies. In one variation, (VIII) applies. In one variation, (IX) applies. In one aspect of this variation, (I), (II), (III), (IV), (V), (VI), (VIII), and (IX) apply. In another aspect of this variation, (I), (II), (III), (IV), (VII), (VIII), and (IX) apply. In one variation, (i), (iii), and (vi) apply.
• (ii), (iii), and (v) apply. In one variation, (i), (in), and (vi) apply. In one variation, (i), (iv), and (vi) apply. In one variation, (1), (iii), (VII), and (vi) apply.
• the compound of formula (I) is an agonist of THR beta. In some embodiments, the compound of formula (I) is an agonist of TOR beta and is selective over TOR alpha. In some embodiments, the compound of formula (I) has at least 2-fold selectivity for TOR beta over THR alpha. In some embodiments, the compound of formula (I) has at least 5 -fold selectivity for THR beta over THR alpha. In some embodiments, the compound of formula (I) has at least 10-fold selectivity for TOR beta over TOR alpha. In some embodiments, the compound of formula (I) has at least 20-fold selectivity for THR beta over TOR alpha.
• the compound of formula (I) has at least 50-fold selectivity for THR beta over TOR alpha. In some embodiments, the compound of formula (I) has at least 75 -fold selectivity for THR beta over TOR alpha. In some embodiments, the compound of formula (I) has at least 100-fold selectivity for TOR beta over THR alpha.
• the compound of formula (I) has at least 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 25-, 30-, 35-, 40-, 45-, 50-, 55-, 60-, 65-, 70-, 75-, 80-, 85-, 90-, 95-, or 100-fold selectivity for TOR beta over THR alpha.
• selectivity is assessed via a biochemical assay, such as the TR-FRET assay described in Example B 1.
• a compound selected from the compounds in Table 1, or pharmaceutically acceptable salt thereof is provided.
• certain compounds described in the present disclosure, including in Table 1, are presented as specific stereoisomers and/or in a non stereochemical form, it is understood that any or all stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms of any of the compounds of the present disclosure, including in Table 1, are herein described.
• provided herein is a compound selected from those listed in Table 1 or a pharmaceutically acceptable salt thereof.
• the invention also includes all salts, such as pharmaceutically acceptable salts, of compounds referred to herein.
• the invention also includes any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms, such as N-oxides, solvates, prodrags, or isotopomers, of the compounds described. Unless stereochemistry' is explicitly indicated in a chemical structure or name, the structure or name is intended to embrace all possible stereoisomers of a compound depicted. In addition, where a specific stereochemical form is depicted, it is understood that other stereochemical forms are also embraced by the invention. All forms of the compounds are also embraced by the invention, such as crystalline or non-crystalline forms of the compounds.
• compositions comprising a compound of the invention are also intended, such as a composition of substantially pure compound, including a specific stereochemical form thereof.
• Compositions comprising a mixture of compounds of the invention in any ratio are also embraced by the invention, including mixtures of two or more stereochemical forms of a compound of the invention in any ratio, such that racernic, non-racemic, enantioenriehed and scalemic mixtures of a compound are embraced.
• T Br, CN, NH
• R 1 , R 3 , R 4 , and R 5 are as defined for the compound of formula (I); T is Br, CN, or NHL ⁇ ; and PG and G are suitable protecting groups.
• the biaryl-ether core of the compounds disclosed herein can be prepared as outlined in Scheme 1. Reaction of 3,6-dichloropyridazine and compounds of general formula R'-CCbH with ammonium persulfate provides R ⁇ substituted dichloropyridazine compounds, which can then be reacted with phenol derivatives, hydrolyzed, and optionally N-protected to provide the desired intermediate compounds.
• R 1 is as defined for the compound of formula (I).
• Scheme G provides an alternative synthesis of the pyridazines used for the preparation of compounds of fonnula (I) disclosed herein. Reaction of 3,6-dichloro-l,2,4,5-tetrazine with R ! -substituted acetylenes affords R ! -substituted dichloropyridazine compounds.
• R 1 , R 3 , R 4 , and R 5 are as defined for the compound of formula (I); and G is a suitable protecting group.
• Scheme la outlines a synthesis wherein G is an alkyl group and T is Nhb.
• Compounds having the biaryl-ether core with an amine moiety can undergo phthalimide protection, N- alkylation, and subsequent deprotection to provide the desired intermediate compounds.
• R 1 , R 3 , R 4 , R 3 , and R 1 -' are as defined for the compound of formula (I); and PG, G, and Gi are suitable protecting groups
• Scheme 2 outlines the synthesis of certain compounds of formula (I) disclosed herein.
• Compounds having the biaryl-ether core with an amine moiety can undergo N-alkylation and second amine derivatization, followed by reaction with NH2OH, treatment with a carbonyl transfer reagent, and optional deprotection to afford the desired compounds.
• R 1 , R 3 , R 4 , R 5 , and R 12 are as defined for the compound of formula (I); and PG and Gi are suitable protecting groups.
• Scheme 2a outlines an alternative synthesis of certain compounds of formula (1) disclosed herein.
• Compounds having the biaryl-ether core with an amine moiety can undergo N ⁇ alkylation, protection of the amine group, reaction with NH2OH, treatmen t with a carbonyl transfer reagent, and optional deprotection or hydrolysis to afford the desired compounds.
• R 1 , R 3 , R 4 , R 5 , and ring A are as defined for the compound of formula (I); and G and Gi are suitable protecting groups
• Scheme 3 show's the synthesis of certain compounds of formula (I). Reaction of biaryl- ether derivatives containing an amine moiety with carboxylic acid deri vatives of ring A provides amide bond formation to form the desired compounds.
• Scheme 4 shows the synthesis of certain compounds of formula (I). Reaction of biaryl- ether derivatives containing an amine moiety with carboxylic acid deri vatives of ring A provides amide bond formation to form the desired compounds.
• R 1 , R 3 , R 4 , R'. and R 12 are as defined for the compound of formula (I); and G and PG are suitable protecting groups.
• Scheme 4 shows the synthesis of certain compounds of formula (I). Palladium- mediated hydroxylation of biaryl -ether derivatives containing a bromo group, followed by O- alkylation, reaction with NthOH, treatment with a carbonyl transfer reagent, and optional deprotection or hydrolysis provides the desired compounds.
• Scheme 5 shows the synthesis of certain compounds of formula (I) Treatment of biaryl-ether derivatives containing a cyano group with NtbOH, followed by treatment with a carbonyl transfer reagent provides tire desired compounds.
• R 1 , R 3 , R 4 , and R D are as defined for the compound of formula (I).
• Scheme 6 shows the synthesis of certain compounds of formula (I).
• Treatment of biaryl-ether derivatives containing a cyano group with NH2OH, followed by treatment with a carbonyl transfer reagent and hydrolysis provides the desired compounds.
• R 1 , R 3 , R 4 , and R 3 are as defined for the compound of formula (I); and G is a suitable protecting group.
• Scheme 7 shows the synthesis of certain compounds of fonnula (I).
• enantiomer of a compound may be accomplished from a corresponding mixture of enantiomers using any suitable conventional procedure for separating or resolving enantiomers.
• diastereomeric derivatives may be produced by reaction of a mixture of enantiomers, e.g., a racemate, and an appropriate chiral compound. The diastereomers may then be separated by any convenient means, for example by crystallization, and the desired enantiomer recovered.
• a racemate may be separated using chiral High Perfonnance Liquid
• Chromatography, recrystallization and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify a product of a reaction.
• Solvates and/or polymorphs of a compound provided herein or a pharmaceutically acceptable salt thereof are also contemplated.
• Solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are often formed during the process of crystallization. Hydrates are formed when the solvent is water, or aicoholates are formed when the solvent is alcohol .
• Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and/or solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.
• compositions of any of the compounds detailed herein are embraced by this invention.
• the invention includes pharmaceutical compositions comprising a compound of the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
• the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid.
• phrases according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation.
• a compound as detailed herein may in one aspect be in a purified form and compositions comprising a compound in purified forms are detailed herein.
• Compositions comprising a compound as detailed herein or a salt thereof are provided, such as compositions of substantially pure compounds.
• a composition containing a compound as detailed herein or a salt thereof is in substantially pure form.
• substantially pure intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than the compound compri sing the majority of the composition or a salt thereof.
• a composition of a substantially pure compound selected from a compound of Table 1 intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than the compound or a salt thereof.
• a composition of substantially pure compound or a salt thereof is provided wherein the composition contains no more than 25% impurity.
• a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 20% impurity.
• a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 10% impurity.
• a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 5% impurity.
• a composition of substantially pure compound or a salt thereof wherein the composition contains or no more than 3% impurity .
• a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 1% impurity.
• a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 0.5% impurity in yet other variations, a composition of substantially pure compound means that the composition contains no more than 15% or preferably no more than 10% or more preferably no more than 5% or even more preferably no more than 3% and most preferably no more than 1 % impurity, which impurity may be the compound in a different stereochemical form.
• a composition of substantially pure (S) compound means that the composition contains no more than 13% or no more than 10% or no more than 5% or no more than 3% or no more than 1% of the (R) form of the compound.
• the compounds herein are synthetic compounds prepared for administration to an individual such as a human.
• compositions are provided containing a compound in substantially pure form.
• the invention embraces pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier or excipient.
• methods of administering a compound are provided .
• the purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein.
• the compound may be formulated for any available delivery route, including an oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular, subcutaneous or intravenous), topical or transdermal delivery form.
• oral e.g., nasal, sublingual, vaginal, buccal or rectal
• parenteral e.g., intramuscular, subcutaneous or intravenous
• topical or transdermal delivery form e.g., topical or transdermal delivery form.
• a compound may be formulated with suitable carriers to provide delivery forms that include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal spray or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water- in-oil liquid emulsions), solutions and elixirs.
• suitable carriers include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices),
• One or several compounds described herein can be used in the preparation of a formulation, such as a pharmaceutical formulation, by combining the compound or compounds as an active ingredient with a pharmaceutically acceptable carrier, such as those mentioned above.
• a pharmaceutically acceptable carrier such as those mentioned above.
• the carrier may be in various forms.
• pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants. Fonnulations comprising the compound may also contain other substances which have valuable therapeutic properties.
• Pharmaceutical formulations may be prepared by known pharmaceutical methods. Suitable formulations can be found, e.g, in Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21 st ed. (2005), winch is incorporated herein by reference.
• Compounds as described herein may be administered to individuals (e.g., a human) in a form of generally accepted oral compositions, such as tablets, coated tablets, and gel capsules in a hard or in soft shell, emulsions or suspensions.
• Examples of earners, which may be used for the preparation of such compositions are lactose, com starch or its derivatives, talc, stearate or its salts, etc.
• Acceptable carriers for gel capsules with soft shell are, for instance, plant oils, wax, fats, semisolid and liquid polyols, and so on.
• pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-weting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.
• any of the compounds described herein can be formulated in a tablet in any dosage form described.
• compositions comprising a compound provided herein are also described.
• the composition comprises a compound and a pharmaceutically acceptable carrier or excipient.
• a composition of substantially pure compound is provided.
• Compounds and compositions detailed herein such as a pharmaceutical composition containing a compound of any formula provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient, may be used in methods of administration and treatment as provided herein.
• the compounds and compositions may also be used in in vitro methods, such as in vitro methods of administering a compound or composition to cells for screening purposes and/or for conducting quality control assays.
• TOR beta agonizing thyroid hormone receptor beta
• a method of treating a disorder, which is mediated by TOR beta, in a patient comprising administering to the patient in need thereof a therapeutically effective amount of a compound pro vided herein, or a therapeutically effective amount of a composition provided herein.
• Me thods of treating a disorder mediated by TOR beta including without limitation non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and symptoms and
• a method of agonizing thyroid hormone receptor beta comprising contacting either an effective amount of a compound provided herein, or a salt thereof, such as a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition provided herein, with the TOR beta.
• a method of selectively agonizing TOR beta over TOR alpha comprising contacting either an effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition provided herein, with the TOR beta.
• the method selectively agonizes TOR beta over TOR alpha by at least 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 25-, 30-, 35-, 40-, 45-, 50-, 55-, 60-, 65-, 70-, 75-, 80-, 85-, 90-, 95-, or 100-fold.
• selectivity is assessed via a biochemical assay, such as the TR-FRET assay described in Example Bl.
• provided herein is a method of treating a disease or disorder that is mediated by THR beta in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a therapeutically effective amount of a composition provided herein.
• the disease or disorder is a liver disease or disorder.
• a method of treating a disease or disorder of the liver associated with sub-optimal TOR beta agonism in a patient in need thereof comprising administering to the patient a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound selectively agonizes TOR beta over THR alpha.
• provided herein is a method of treating non-alcoholic fatty liver disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a therapeutically effective amount of a composition provided herein.
• a method of treating non-alcoholic steatohepatitis (NASH) in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a therapeutically effective amount of a composition provided herein.
• NASH non-alcoholic steatohepatitis
• provided herein is a method of treating metabolic syndrome in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a therapeutically effective amount of a composition provided herein.
• a method of treating dyslipidemia in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a therapeutically effective amount of a composition provided herein.
• a method of treating hypertriglyceridemia in a patient need thereof comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a therapeutically effective amount of a composition provided herein.
• provided herein is a method of treating hypercholesterolemia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a therapeutically effective amount of a composition provided herein.
• a patient having a disease or disorder associated with THR beta agonism may include, but is not limited to, a patient with an underlying hypothyroid disorder.
• a method of delaying the onset and/or development of a disease or disorder that is mediated by THR beta in a patient (such as a human) who is at risk for developing the disease or disorder in a patient (such as a human) who is at risk for developing the disease or disorder. It is appreciated that delayed development may encompass prevention in the event the individual does not develop the disease or disorder.
• An individual at risk of developing a disease or disorder that is mediated by TOR beta in one aspect has one or more risk factors for developing the disease or disorder, such as age, increased waist circumference, high body to mass index or the presence of an associated comorbidity.
• provided herein is a method of delaying the onset and/or development of non-alcoholic fatty liver disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a therapeutically effective amount of a composition provided herein.
• a method of delaying the onset and/or development of non-alcoholic steatohepatitis (NASH) in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a therapeutically effective amount of a composition provided herein.
• NASH non-alcoholic steatohepatitis
• provided herein is a method of delaying the onset and/or development of metabolic syndrome in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a therapeutically effective amount of a composition provided herein.
• a method of delaying the onset and/or development of dyslipidemia in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a therapeutically effective amount of a composition provided herein.
• provided herein is a method of delaying the onset and/or development of hypertriglyceridemia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a therapeutically effective amount of a composition provided herein.
• a method of delaying the onset and/or development of hypercholesterolemia in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a therapeutically effective amount of a composition provided herein.
• a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof for use in therapy.
• a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof or pharmaceutical composition comprising such compound or a pharmaceutically acceptable salt thereof, for use in the treatment of non-alcoholic fatty liver disease.
• a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof or pharmaceutical composition comprising such compound or a pharmaceutically acceptable salt thereof, for use in the treatment of non alcoholic steatohepatitis (NASH).
• NASH non alcoholic steatohepatitis
• a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof for use in tire manufacture of a medicament for the treatment of non-alcoholic fatty- liver disease.
• a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the treatment of non alcoholic steatohepatitis (NASH).
• NASH non alcoholic steatohepatitis
• the medicament is for the treatment of dyslipidemia.
• the medicament is for the treatment of hypertriglyceridemia.
• the medicament is for the treatment of dyslipidemia.
• the medicament is for the treatment of hypercholesterolemia.
• the individual is a mammal. In some embodiments, the individual is a primate, dog, cat, rabbit, or rodent. In some embodiments, the individual is a primate. In some embodiments, the individual is a human. In some embodiments, the human is at least about or is about any of 18, 21, 30, 50, 60, 65, 70, 75, 80, or 85 years old. In some embodiments, the human is a child. In some embodiments, the human is less than about or about any of 21, 18, 15, 10, 5, 4, 3, 2, or 1 years old.
• the dose of a compound described herein, or a stereoisomer, tautomer, solvate, or salt thereof, administered to an individual may vary with the particular compound or salt thereof, the method of administration, and the particular disease or disorder, such as non alcoholic fatty liver disease, non-alcoholic steatohepatitis (NASH), metabolic syndrome, hypertriglyceridemia, dyslipidemia, or hypercholesterolemia, being treated.
• the amount of the compound, or a stereoisomer, tautomer, solvate, or salt thereof is a therapeutically effective amount.
• Hie compounds provided herein or a salt thereof may be administered to an individual via various routes, including, e.g., intravenous, intramuscular, subcutaneous, oral, and transdennal.
• the effective amount of the compound may in one aspect be a dose of between about 0.01 and about 100 mg/kg.
• Effective amounts or doses of the compounds of the present disclosure may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., the mode or route of administration or drug delivery , the pharmacokinetics of the agen t, the severity and course of the disease to be treated , the subject's health status, condition, and weight.
• An exemplary dose is in the range of about from about 0.7 mg to 7 g daily, or about 7 mg to 350 mg daily, or about 350 mg to 1.75 g daily, or about 1.75 to 7 g daily.
• Any of the methods provided herein may in one aspect comprise administering to an individual a pharmaceutical composition that contains an effective amount of a compound provided herein, or a stereoisomer, tautomer, solvate, or salt thereof, and a pharmaceutically acceptable excipient.
• a compound or composition provided herein may he administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer, which in some variations may be for the duration of the individual’s life.
• the compound is administered on a daily or intermittent schedule.
• the compound can be administered to an individual continuously (for example, at least once daily) over a period of time.
• the dosing frequency can also be less than once daily, e.g., about a once weekly dosing.
• the dosing frequency can be more than once daily, e.g. , twice or three times daily.
• the dosing frequency can also be intennittent, including a "drug holiday’ (e.g. , once daily dosing for 7 days followed by no doses for 7 days, repeated for any 14 day time period, such as about 2 months, about 4 months, about 6 months or more). Any of the dosing frequencies can employ any of the compounds described herein together with any of the dosages described herein.
• the present disclosure further provides articles of manufacture comprising a compound described herein or a salt thereof, a composition described herein, or one or more unit dosages described herein m suitable packaging.
• the article of manufacture is for use in any of the methods described herein.
• Suitable packaging is known in the art and includes, for example, vials, vessels, ampules, bottles, jars, flexible packaging and the like.
• An article of manufacture may further be sterilized and/or sealed.
• kits for carrying out the methods of the present disclosure which comprises one or more compounds described herein or a composition comprising a compound described herein.
• the kits may employ any of the compounds disclosed herein.
• the kit employs a compound described herein or pharmaceutically acceptable salt thereof
• the kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for the treatment of any disease or described herein, for example for the treatment of non-alcoholic steatohepatitis (NASH).
• NASH non-alcoholic steatohepatitis
• Kits generally comprise suitable packaging.
• the kits may comprise one or more containers comprising any compound described herein.
• Each component if there is more than one component
• kits may be in unit dosage forms, bulk packages (e.g. , multi-dose packages) or sub-unit doses.
• kits may be provided that contain sufficient dosages of a compound as disclosed herein and/or an additional pharmaceutically active compound useful for a disease detailed herein to provide effective treatment of an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more.
• Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).
• kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component(s) of the methods of the present disclosure.
• the instructions included with the kit generally include information as to the components and their administration to an individual.
• ring A together with the carbonyl (keto) group within the ring form a 5 membered heterocycle containing 1-3 ring heteroatoms selected from N, O, and S, wherein the heterocycle is optionally substituted with 1-2 C1-C3 alkyl or C3-C4 cycloalkyl, and wherein the carbonyl (keto) group is not adjacent to the atom attached to X;
• R 1 is C1-C4 alkyl; C1-C4 alkyl optionally substituted with 1-5 halo, preferably fluoro; C3-C5 cycloalkyl, CON(R ]0 )2, or NR t0 C()
• R 2 is H or C1-C3 alkyl
• L is O, CEE, S, SO, SO2, CO, CHF, CF 2 , C(R U )CN, CHR ! ! , or C(R i ! )R u , wherein each R n is C1-C2 alkyl optionally substituted with 1-5 halo, preferably fluoro, or the 2 R u groups together with the carbon atom they are attached to form a cyclopropyl or cyclobutyl ring; each of R 3 and R 4 is independently Cl, Br, Me, or ethyl;
• R 5 is H, halo, C1-C4 alkyl, or C3-C4 cycloalkyl, or R 5 together with R 4 and the intervening atoms form a 5-7 membered cycioalkyl or a 5-7 membered heterocycle containing 1-2 ring heteroatoms;
• X is absent (i.e., X is a bond), or is O, NR 12 , C(Q)NR i2 , N R ' ( (() ⁇ . C R ' R OCR ’R
• each R 12 independently is H or methyl.
• Embodiment 2 The compound of embodiment 1 of formula (IIA), (IIB), (TIIA), (IIIB), (IRC), (IV A), (IVB), (IVC), (IV A), (VB), (VC), (VIA), (VIB), or (VIC):
• Embodiment 3 The compound of embodiment 1 , of formula (VIIA), (VIIIA), (VIIIB), or (VIIIC):
• Embodiment 4 Tlie compound of embodiment 1, wherein R 1 is isopropyl.
• Embodiment 5 The compound of embodiment 1, wherein R 2 is H.
• Embodiment 6 The compound of embodiment 1 , wherein R 3 is chloro.
• Embodiment 7 The compound of embodiment 1, wherein R 4 is chloro.
• Embodiment 8 Idle compound of embodiment 1, wherein R 5 is hydrogen.
• Embodiment 9 The compound of embodiment 1, wherein X is a bond.
• Embodiment 10 The compound of embodiment 1, wherein X is CHR 11 , OCHR 11 ,
• Embodiment 11 The compound of embodiment 1 , wherein X is NH, CH2, OCH2,
• Embodiment 12 The compound of embodiment 1, wherein -X- is -NH-CH2-, - NHC(O)- or -O-CH2-.
• Embodiment 13 The compound of embodiment 1, wherein -L- is O.
• Embodiment 14 A compound selected from those tabulated in Table 1.
• Embodiment 15 A pharmaceutical composition comprising a compound of embodiment 1 and at least one pharmaceutically acceptable excipient.
• Embodiment 16 A method of agonizing thyroid hormone receptor beta (THR beta) comprising contacting either an effective amount of a compound of embodiment 1, or an effective amount of the composition of embodiment 15, with the THR beta.
• THR beta thyroid hormone receptor beta
• Embodiment 17 A method of treating a disorder, which is mediated by TOR beta, in a patient, comprising administering to the patient a therapeutically effective amount of a compound of embodiment 1, or a therapeutically effective amount of the composition of embodiment 15.
• the mixture was stirred at 120°C for 6 hours. LCMS showed the starting material was consumed completely and desired MS was detected.
• the reaction mixture was concentrated under reduced pressure to remove AcOH.
• the solid was dissolved in water and the pH was adjusted to 9 with saturate NaHCCb solution (10 mL). Then the mixture as partitioned with ethyl acetate (30 mL * 2) andHiO (30 mL). The combined organic phase was washed with brine (10 mL*3), dried with anhydrous NazSOr, filtered and concentrated in vacuum.
• the solid was diluted in ethyl acetate (10 mL), and then petroleum ether (50 mL) was added in the mixture by portions. The mixture was filtered to collect solid.
• Example 3 PI and P2: 3-(l-((3,5-dichloro-4-((5-isopropyl-l-methyl-6-oxo-l,6- dihydropyridazin-3-yl)oxy)phenyl)amino)ethyl)-l,2,4-oxadiazol-5(4H)-one
• 6-(4-bromo-2,6-dichSorophenoxy)-4-isopropylpyridazin-3(2H)-one (6h).
• a mixture of 6-(4-bromo-2,6-dichloro-phenoxy)-3-chloro-4-isopropyl-pyridazine (6a) (1 g, 2.52 mmol) and NaOAc (827.59 mg, 10.09 mmol) in AcOH (10 mL) was stirred at 120°C for 18 hours. LCMS showed the starting material was consumed completely and the desired MS was found. The mixture was concentrated in vacuum. The solid was dissolved in water and the pH was adjusted to 9 with saturated NaHCOi (2 mL).
• 6-(2,6-didi!oro-4-hydroxyphenoxy)-4-isopropyl-2-methySpyridazin ⁇ 3(2H) ⁇ one (6d).
• Example 7 S-(3,5-dichIero-4-((5-isoprGpyl-l-meihyl-6-oxo-l,6-dihydropyridazin-3- yl)oxy)phenyl)isoxazol-3(2H)-one
• N'-hydroxy-4-((5-isopropyl-l -methyl-6-oxo-l,6-dihydropyridazin-3yl)oxy)benzimidaniide (25 mg, 67.35 umol) in THF (3 mL) was added DSC (22.43 mg, 87.55 umol) and TEA (13.63 mg, 134.69 umol, 18 75 uL). The mixture was stirred at 60°C for 16 hours. LCMS showed the starting material was consumed completely and desired MS was detected. The mixture was concentrated in vacuum to give a residue.
• Example 12 3-(((3,5-dichloro-4-((5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazin-3- yl)oxy)-2-methylphenyl)amino)methyl)-l,2,4-oxadiazol-5(4H)-one
• Example 15 3-(((3,5-dichloro-4-((5-isopropyl-6-oxo-l ,6-dihydropyridazin-3- yl)methyl)phenyl)amino)methyl)-l,2,4-oxadiazoI-5(4H)-one
• Example 16 3-(((3,5-dkhloro-4-((5-isoprGpy!-l-meihyt-6-oxG-l,6-dihydropyridazm-3- yl)methyS)phenyi)am!no)methyi) ⁇ l ,2,4-oxadiazol-5(4H)-one
• Example 17 N-(3,5-dichloro-4-(5-isopropyl-l-methyl-6-oxo-l ,6-dihydropyridazine-3- carbonyl)phenyl)-5-oxo-4,5-dihydro-l,2,4-oxadiazole-3-carboxamide
• Example 18 3-(((3,5-dichloro-4-(5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazine-3 ⁇
• acetonitrile (18a) (53 mg, 139.75 umol) in THF (3 mL) was added DMAP (17.07 mg, 139.75 umol) and B0C2O (274 51 mg, 1.26 mmol, 288 95 uL). The mixture was stirred at 25°C for 5 minutes. The mixture was partitioned between ethyl acetate (10 mL*2) and H 2 0 (10 mL*2). The combined organic phase was washed with brine (10 mL*2), dried with anhydrous NaiSOr, filtered and concentrated in vacuum to give a residue.
• Hie residue was purified by prep-TLC (S1O2, petroleum ether : ethyl acetate ::: 1 : 1) to give 19k.
• Example 20 N-(3,5-dichloro-4-((5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazin-3- yl)suIfonyl)phenyl)-5-oxo-4,5-dihydro-l,2,4-oxadiazole-3-carboxamide
• Hie residue was purified by Prep-HPLC (aqueous acetonitrile w/ TFA) to give Example 20.
• reaction mixture was diluted with saturated NaHC03 (5 mL) and extracted with DCM (10 mL * 2). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give a residue.
• Example 22 was checked by HPLC and purified by prep-HPLC (column: Waters Abridge 150*25 5u; mobile phase: [water (lOmM NH4HC03)-ACN] ; B%: 5%-35%, 14 min) to give Example 22 as a white solid.
• Example 24 N-(6-chloro-7-((5-isopropyl-l-methyl-6-oxo-l,6-dihydropyridazm-3-yl)oxy)- 2,3-dihydro-lH-inden-4-yI)-5-oxo-4,5-dihydro-l ,2,4-oxadiazole-3-carboxamide
• Example 24 To a solution of 24d (10 mg, 29.96 umol, 1 eq) THF (5 mL) was added TEA (9.09 mg, 89.87 umol, 12.51 uL) and 5-oxo-4H-l,2,4-oxadiazole-3 -carbonyl chloride (4e) (6.67 mg, 44.94 umol). Tire mixture was stirred at 25°C for 0.5 hours. Tire reaction mixture was quenched by addition MeOH (1 mL) at 25 °C, and then concentrated under reduced pressure to give a residue.
• 6-(4-amino-2,6-dichloro-3-fluorophenoxy)-4-isopropyl-2-methylpyridazin-3(2H)- one (26a).
• 6-(4-amino-2,6-dichloro-phenoxy)-4-isopropyl-2-methyl- pyridazin-3-one (le) (20 g, 60.94 mmol) in CLLCN (200 rriL) and THF (60 mL) under a nitrogen atmosphere was added NaHCOi (15.36 g, 182.82 mmol).
• Select F 21.59 g, 60.94 mmol
• Hie mixture was diluted with 1M HC1 to modified pH 6-7 and extracted with EtOAc 300 mL (100 mL * 3). The combined organic layers were washed with brine 150 mL, dried over anhydrous NarSOi, filtered to give a light yellow liquid The light yellow liquid was concentrated under reduced pressure to remove solvent and until the solid was dissolved out. The mixture was stirred at 20°C for 1 hour and filtered to give Example 26.
• Hie mixture was stirred at 80°C for 1 hour.
• Hie reaction mixture was concentrated under reduced pressure to remove DMF.
• the residue was partitioned between ethyl acetate 10 mL and H2O 5 ml. twice.
• the combined organic phase was washed with brine (5 mL*3), dried with anhydrous NaiSOr, filtered and concentrated in vacuum.
• MS mass calculated for [M+l] + (C21H26CI2FN5O5) required m/z 518.4, LCMS found m/z 518.0.
• tert-butyl (3,5-dichloro-2-fluoro-4-((5-isopropyl-l-methyl-6-oxo-l,6- dihydropyridazin-3-yl)oxy)phenyl)((5-oxo-4,5-dihydro-l,2,4-oxadiazol-3- yl)methyl)carbamate (27d).
• Example 28 N-(4-((5-(tert-butyl)-6-oxo-l,6-dihydropyridazin-3-yl)oxy)-3,5- diehlorophenyl)-5-o o-4,S-dihydro-l,2,4-oxadiazole-3-carboxamide
• Example 29 N-(3,5-dichloro-4-((5-(l-hydroxyethyl)-6-oxo-l,6- dihydropyridazin-3-yl)oxy)phenyI)-5-oxo-4,5-dihydro-l ,2,4-oxadiazole-3-cartaoxamide
• Example 29 The N-(3,5-dichloro-4- ((5-(l-hydroxyethyl)-6-oxo-l,6-dihydropyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-l,2,4- oxadiazole-3-carboxamide (Example 29) was checked and purified by Chiral SFC (column: DAICEL CHIRALPAK AD (250mm*30mm, lOum); mobile phase: [0.1%NH3*H2O MeOH]; B%: 40%-40%, 10mm) to give Example 29-PI and Example 29-P2.
• Example 29-P2 MS mass calculated for [M+l]+( C15H11 C12N506) required m/z 428.0, LCMS found m/z 427 9; 1 1 N R (400 MHz, DMSO-de) d 12.26 (s, !H), 10 74 (br s,

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