Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
  • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D495/04—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
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • 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
  • A61P3/06—Antihyperlipidemics
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
  • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
  • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D309/10—Oxygen atoms
  • C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
  • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
  • C12P41/001—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by metabolizing one of the enantiomers
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12Y—ENZYMES
  • C12Y301/00—Hydrolases acting on ester bonds (3.1)
  • C12Y301/01—Carboxylic ester hydrolases (3.1.1)
  • C12Y301/01003—Triacylglycerol lipase (3.1.1.3)
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/07—Optical isomers
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

• Obesity is a health crisis of epic proportions.
• the health burden of obesity measured by quality-adjusted life-years lost per adult, has surpassed that of smoking to become the most serious, preventable cause of death.
• about 34% of adults have obesity, up from 31% in 1999 and about 15% in the years 1960 through 1980.
• Obesity increases the rate of mortality from all causes for both men and women at all ages and in all racial and ethnic groups. Obesity also leads to social stigmatization and discrimination, which decreases quality of life
• T2DM type-2 diabetes
• stroke and coronary heart disease a type-2 diabetes (T2DM)
• J2DM stroke and coronary heart disease
• Another ongoing problem is the lack of antifungal drugs with activity against a broad range of fungal pathogens. Often, a given antifungal drug will have activity against one fungal species but lack activity against other, even closely related, species, such as Candida albicans, Candida krusei, and Candida parapsilosis.
• the present disclosure relates to various crystalline forms of Compound 1, processes for making Compound 1 and its various forms, and methods of using such forms.
• Compound 1 also provides forms further described herein as “Compound 1 Form I,” “Compound 1 Form II,” “Compound 1 Form III,” “Compound 1 Form IV,” “Compound 1 Form V,” “Compound 1 Form VI,” “Compound 1 Form VII,” “Compound 1 Form VIII,” and “amorphous Compound 1.”
• crystalline forms of Compound 1 may include a salt, a co- crystal, a solvate, or a hydrate of Compound 1.
• crystalline forms of Compound 1 may include a salt of Compound 1.
• Compound 1 provide forms further described herein as “Compound 1 Sodium Form I,” “Compound 1 Sodium Form II,” “Compound 1 Calcium Form I,” “Compound 1 Magnesium Form I,” “Compound 1 Diethanolamine Form I,” and “Compound 1 Piperazine Form I.”
• Some embodiments provide for a process of preparing Compound 1, or a salt or co- crystal thereof, comprising:
• Some embodiments provide for a process of preparing Compound 1, or salt or co- crystal thereof, comprising:
• Figure 1A depicts a X-Ray powder diffraction (XRPD) pattern of Form I of
• Figure IB depicts another X-Ray powder diffraction (XRPD) pattern of Form I of Compound 1.
• Figure 2 depicts the ellipsoid diagram of Form I of Compound 1.
• Figure 3 A depicts a differential scanning calorimeter (DSC) curve of Form I of
• Figure 3B depicts another differential scanning calorimeter (DSC) curve of Form I of Compound 1.
• FIG. 4A depicts a thermogravimetric analysis (TGA) of Form I of Compound 1.
• FIG. 4B depicts another thermogravimetric analysis (TGA) of Form I of
• Figure 5 depicts the X-Ray powder diffraction pattern of Form II of Compound 1.
• Figure 6 depicts the X-Ray powder diffraction pattern of Form III of Compound 1.
• Figure 7 A depicts a X-Ray powder diffraction pattern of Form IV of Compound 1.
• Figure 7B depicts another X-Ray powder diffraction pattern of Form IV of
• Figure 8 depicts the differential scanning calorimeter (DSC) curve of Form IV of Compound 1.
• FIG. 9 depicts the thermogravimetric analysis (TGA) of Form IV of Compound 1.
• Figure 10 depicts the X-Ray powder diffraction pattern of Form V of Compound 1.
• Figure 11 A depicts a X-Ray powder diffraction pattern of Form VI of Compound 1.
• Figure 1 IB depicts another X-Ray powder diffraction pattern of Form VI of
• Figure 12 depicts the differential scanning calorimeter (DSC) curve of Form VI of Compound 1.
• FIG. 13 depicts the thermogravimetric analysis (TGA) of Form VI of Compound 1.
• Figure 14 depicts the X-Ray powder diffraction pattern of Form VII of Compound 1.
• Figure 15A depicts a X-Ray powder diffraction pattern of Form VIII of Compound 1.
• Figure 15B depicts another X-Ray powder diffraction pattern of Form VIII of Compound 1.
• Figure 16 depicts the differential scanning calorimeter (DSC) curve of Form VIII of Compound 1.
• FIG. 17 depicts the thermogravimetric analysis (TGA) of Form VIII of Compound 1.
• Figure 18 depicts the X-Ray powder diffraction pattern of amorphous Compound 1.
• Figure 19 depicts the X-Ray powder diffraction pattern of Compound 1 Sodium Form I.
• Figure 20 depicts the differential scanning calorimeter (DSC) curve of Compound 1 Sodium Form I.
• FIG. 21 depicts the thermogravimetric analysis (TGA) of Compound 1 Sodium Form I.
• Figure 22 depicts the X-Ray powder diffraction pattern of Compound 1 Sodium Form II.
• Figure 23 depicts the differential scanning calorimeter (DSC) curve of Compound 1 Sodium Form II.
• Figure 24 depicts the thermogravimetric analysis (TGA) of Compound 1 Sodium Form II.
• Figure 25 depicts the X-Ray powder diffraction pattern of Compound 1 Calcium Form I.
• Figure 26 depicts the differential scanning calorimeter (DSC) curve of Compound 1 Calcium Form I.
• FIG. 27 depicts the thermogravimetric analysis (TGA) of Compound 1 Calcium Form I.
• Figure 28 depicts the X-Ray powder diffraction pattern of Compound 1 Magnesium Form I.
• Figure 29 depicts the differential scanning calorimeter (DSC) curve of Compound 1 Magnesium Form I.
• Figure 30 depicts the therm ogravimetric analysis (TGA) of Compound 1 Magnesium Form I.
• Figure 31 depicts the X-Ray powder diffraction pattern of Compound 1
• Figure 32 depicts the differential scanning calorimeter (DSC) curve of Compound 1 Diethanolamine Form I.
• FIG. 33 depicts the therm ogravimetric analysis (TGA) of Compound 1
• Figure 34 depicts the X-Ray powder diffraction pattern of Compound 1 Piperazine Form I.
• Figure 35 depicts the differential scanning calorimeter (DSC) curve of Compound 1 Piperazine Form I.
• FIG. 36 depicts the thermogravimetric analysis (TGA) of Compound 1 Piperazine Form I.
• Figure 37 depicts the differential scanning calorimeter (DSC) curve of Form II of Compound 1.
• Figure 38 depicts the differential scanning calorimeter (DSC) curve of Form III of Compound 1.
• Figure 39 depicts the differential scanning calorimeter (DSC) curve of Form V of Compound 1.
• Figure 40 depicts the differential scanning calorimeter (DSC) curve of Form VII of Compound 1.
• thienopyrimidinedione compounds that bind to and inhibit Acetyl CoA Carboxylases 1 and 2.
• Such compounds include Compound 1 :
• Compound 1 ((R)-2-(l-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4- yl)oxy)ethyl)-5-methyl-6-(oxazol-2-yl)-2,4-dioxo-l,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)- 2-methylpropanoic acid), is designated as compound number 1-181, and the synthesis of Compound 1 is described in detail at Example 76 of U.S. Patent Publication 2013/0123231.
• Compound 1 is active in a variety of assays and therapeutic models, including those demonstrating inhibition of ACC1 and/or ACC2, inhibition of fatty acid synthesis, and stimulation of fatty acid oxidation. It would be desirable to provide solid forms of Compound 1 that impart characteristics such as improved aqueous solubility, stability, and ease of formulation.
• the present invention provides a solid form of Compound 1, or a salt, co-crystal, solvate, or hydrate thereof.
• the solid form of Compound 1 is a salt or co-crystal.
• the salt or co-crystal is a
• the present invention provides a solid form of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a solid form of Compound 1, or a pharmaceutically acceptable co-crystal thereof. In some embodiments, the present invention provides a solid form of Compound 1, or a pharmaceutically acceptable salt thereof, that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound contains no significant amount of extraneous matter. Such extraneous matter may include residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, Compound 1. In certain embodiments, at least about 95% by weight of Compound 1 is present.
• At least about 99% by weight of Compound 1 is present. In certain embodiments, at least about 95% by weight of Compound 1, as a salt or co-crystal thereof, is present. In still other embodiments of the invention, at least about 99% by weight of Compound 1, as a salt or co-crystal thereof is present.
• Compound 1 is present in an amount of at least about 97.0, 97.5, 98.0, 98.5, 99.0, 99.5, or 99.8 weight percent where the percentages are based on the total weight of the composition.
• Compound 1 contains no more that about 3.0 area percent HPLC of total organic impurities and, in certain embodiments, no more that about 1.5 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram.
• Compound 1 contains no more than about 1.0% area percent HPLC of any single impurity, and, in certain embodiments, no more than about 0.5 area percent HPLC of any single impurity, relative to the total area of the HPLC chromatogram.
• Compound 1 is present in an enantiomeric excess (e.e.) of about 90.0 to 99.95 percent. In some embodiments, Compound 1 is present in an enantiomeric excess (e.e.) of at least about 90.0, 91.0, 92.0, 93.0, 94.0, 95.0, 96.0, 97.0, 97.5, 98.0, 98.5, 99.0, 99.5, 99.7, 99.8, 99.9, or 99.95 percent. In some embodiments, Compound 1 is optically pure, and substantially free of its (S)-enantiomer.
• Compound 1 is present as a free acid. In some embodiments, Compound 1 is present as a salt. In some embodiments, Compound 1 is present as a
• Compound 1 is present as a co-crystal.
• Compound 1 is an amorphous form of a salt or a co-crystal of Compound 1.
• Compound 1 is a crystalline form of a salt or a co-crystal of Compound 1.
• the crystalline form of a salt or co-crystal of Compound I is: Compound 1 Sodium Form I, Compound 1 Sodium Form II, Compound 1 Calcium Form I, Compound 1 Magnesium Form I, Compound 1 Diethanolamine Form I, or Compound 1
• Compound 1 is also meant to include all tautomeric forms of Compound 1. Additionally structures depicted here are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention. [0071] It has been found that Compound 1 can exist in a variety of solid forms. Such forms include polymorphs, solvates, hydrates, and amorphous. All such forms are contemplated by the present invention. In certain embodiments, the present invention provides Compound 1 as a mixture of one or more solid forms selected from polymorphs, solvates, hydrates, and amorphous Compound 1.
• Compound 1 is an amorphous solid.
• Figure 18 depicts the X- Ray powder diffraction pattern of amorphous Compound 1.
• the present invention provides Compound 1 as an amorphous solid substantially free of crystalline
• the term "substantially free of crystalline Compound 1" means that the compound contains no significant amount of crystalline Compound 1. In certain embodiments, at least about 95% by weight of amorphous Compound 1 is present. In still other embodiments, of the invention, at least about 99% by weight of amorphous Compound 1 is present.
• polymorph refers to any of the different crystal structures in which a compound can crystallize.
• solvate refers to a crystal form with either a stoichiometric or non-stoichiometric amount of solvent incorporated into the crystal structure.
• hydrate refers specifically to a crystal form with either a stoichiometric or non-stoichiometric amount of water incorporated into the crystal structure.
• Compound 1 is a crystalline solid. In some embodiments, Compound 1 is a crystalline solid substantially free of amorphous Compound 1. As used herein, the term "substantially free of amorphous Compound 1" means that the compound contains no significant amount of amorphous Compound 1. In certain embodiments, at least about 95% by weight of crystalline Compound 1 is present. In still other embodiments, of the invention, at least about 99% by weight of crystalline Compound 1 is present.
• Compound 1 is substantially free of any water or other solvent. In some embodiments, Compound 1 is a neat crystal form, and thus does not have any water or other solvent incorporated into its crystal structure. It has now been found that
• Compound 1 can exist in at least one distinct neat (i.e. anhydrous, non-solvate) crystal form.
• neat crystal forms of Compound 1 include Form I, Form VII, and Form VIII, each of which is described in detail herein.
• the present invention provides a solvated crystalline form of Compound 1.
• solvated crystalline forms of Compound 1 include Form II (DMF solvate), Form III (DMSO solvate), Form IV (methanol solvate), Form V (NMP solvate), and Form VI (toluene solvate).
• the present invention provides a crystalline form of
• Compound 1 selected from any of those referred to as Form I, Form II, Form III, Form IV, Form V, Form VI, Form VII, or Form VIII. Methods for preparing each of Forms I through VIII of Compound 1 are described herein.
• the present invention provides a polymorphic form of Compound 1 referred to as Form I.
• the present invention provides Form I of Compound 1, having a powder X-ray diffraction pattern substantially similar to that depicted in Figure 1 A.
• the term "about,” when used in reference to a degree 2 ⁇ value refers to the stated value ⁇ 0.1 degree 2 ⁇ , obtained under the sample preparation and data collection conditions described in the exemplification. In some embodiments, the term “about,” when used in reference to a degree 2 ⁇ value refers to the stated value ⁇ 0.2 degree 2 ⁇ .
• the term “about,” when used in reference to a degree 2 ⁇ value refers to the stated value ⁇ 0.2 degree 2 ⁇ .
• Form I of Compound 1 is characterized in that it has one or more peaks in its powder X-ray diffraction pattern selected from those in Table 1 below.
• Form I of Compound 1 is characterized in that it has two or more peaks in its powder X-ray diffraction pattern selected from those in Table 1. In some embodiments, Form I of Compound 1 is characterized in that it has three or more peaks in its powder X-ray diffraction pattern selected from those in Table 1. In some embodiments, Form I of Compound 1 is characterized in that it has four or more peaks in its powder X-ray diffraction pattern selected from those in Table 1. In some embodiments, Form I of Compound 1 is characterized in that it has five or more peaks in its powder X-ray diffraction pattern selected from those in Table 1.
• Form I of Compound 1 is characterized in that it has ten of the peaks in Table 1 in its X-ray diffraction pattern. In some embodiments, Form I of Compound 1 is characterized in that it has fifteen of the peaks in Table 1 in its X-ray diffraction pattern. In some embodiments, Form I of Compound 1 is characterized in that it has twenty of the peaks in Table 1 in its X-ray diffraction pattern. In some embodiments, Form I of
• Compound 1 is characterized in that it has all of the peaks in Table 1 in its X-ray diffraction pattern.
• Form I of Compound 1 is characterized in that it has one or more peaks in its powder X-ray diffraction pattern selected from those at about 12.51, about 14.89, about 17.19, about 19.11, about 19.91, about 28.58, and about 38.91 degrees 2 ⁇ . In some embodiments, Form I of Compound 1 is characterized in that it has two or more peaks in its powder X-ray diffraction pattern selected from those at about 12.51, about 14.89, about 17.19, about 19.11, about 19.91, about 28.58, and about 38.91 degrees 2 ⁇ .
• Form I of Compound 1 is characterized in that it has three or more peaks in its powder X-ray diffraction pattern selected from those at about 12.51, about 14.89, about 17.19, about 19.11, about 19.91, about 28.58, and about 38.91 degrees 2 ⁇ . In some embodiments, Form I of Compound 1 is characterized in that it has four or more peaks in its powder X-ray diffraction pattern selected from those at about 12.51, about 14.89, about 17.19, about 19.11, about 19.91, about 28.58, and about 38.91 degrees 2 ⁇ .
• Form I of Compound 1 is characterized in that it has five or more peaks in its powder X-ray diffraction pattern selected from those at about 12.51, about 14.89, about 17.19, about 19.11, about 19.91, about 28.58, and about 38.91 degrees 2 ⁇ . In some embodiments, Form I of Compound 1 is characterized in that it has six or more peaks in its powder X-ray diffraction pattern selected from those at about 12.51, about 14.89, about 17.19, about 19.11, about 19.91, about 28.58, and about 38.91 degrees 2 ⁇ .
• Form I of Compound 1 is characterized in that it has all seven peaks in its powder X-ray diffraction pattern selected from those at about 12.51, about 14.89, about 17.19, about 19.11, about 19.91, about 28.58, and about 38.91 degrees 2 ⁇ .
• Form I of Compound 1 is characterized in that it has one or more peaks in its powder X-ray diffraction pattern selected from those at about 9.2, about 15.8, about 19.6, about 24.0, about 25.6, about 28.6, and about 8.7 degrees 2 ⁇ . In some embodiments, Form I of Compound 1 is characterized in that it has two or more peaks in its powder X-ray diffraction pattern selected from those at about 9.2, about 15.8, about 19.6, about 24.0, about 25.6, about 28.6, and about 8.7 degrees 2 ⁇ .
• Form I of Compound 1 is characterized in that it has three or more peaks in its powder X-ray diffraction pattern selected from those at about 9.2, about 15.8, about 19.6, about 24.0, about 25.6, about 28.6, and about 8.7 degrees 2 ⁇ . In some embodiments, Form I of Compound 1 is characterized in that it has four or more peaks in its powder X-ray diffraction pattern selected from those at about 9.2, about 15.8, about 19.6, about 24.0, about 25.6, about 28.6, and about 8.7 degrees 2 ⁇ .
• Form I of Compound 1 is characterized in that it has five or more peaks in its powder X-ray diffraction pattern selected from those at about 9.2, about 15.8, about 19.6, about 24.0, about 25.6, about 28.6, and about 8.7 degrees 2 ⁇ . In some embodiments, Form I of Compound 1 is characterized in that it has six or more peaks in its powder X-ray diffraction pattern selected from those at about 9.2, about 15.8, about 19.6, about 24.0, about 25.6, about 28.6, and about 8.7 degrees 2 ⁇ . In some embodiments, Form I of Compound 1 is characterized by an X-ray diffraction pattern comprising the following peaks: about 9.2, about 15.8, about 19.6, about 24.0, about 25.6, about 28.6, and about 8.7 degrees 2 ⁇ .
• Form I is characterized by an X-ray powder diffractogram comprising the following peaks: 9.3, 15.0, and 19.8 °2 ⁇ ⁇ 0.2 °2 ⁇ , as determined on a
• the diffractogram comprises additional peaks at 16.0, 24.0, 25.8, and 27.3 °2 ⁇ ⁇ 0.2 °2 ⁇ .
• Compound 1 Form I is also characterized by its X-ray diffraction pattern as substantially shown in Figure 1 A.
• Compound 1 Form I is also characterized by its X-ray diffraction pattern as substantially shown in Figure IB.
• Form I of Compound 1 has been characterized via single crystal analysis and the data are summarized in Table 2 and the ellipsoid diagram is shown in Figure 2.
• Form I of Compound 1 is characterized by a differential scanning calorimetry (DSC) curve that comprises an endotherm between about 189 °C to about 193 °C.
• DSC differential scanning calorimetry
• Form I of Compound 1 is also characterized by its DSC curve as substantially shown in Figure 3 A.
• Form I of Compound 1 is also characterized by its DSC curve as substantially shown in Figure 3B.
• Form I of Compound 1 is characterized by a
• thermogravimetric analysis (TGA) curve as substantially shown in Figure 4A.
• Form I of Compound 1 is characterized by a thermogravimetric analysis (TGA) curve as substantially shown in Figure 4B.
• At least about 95% by weight of Form I of Compound 1 is present. In some embodiments, at least about 99% by weight of Form I of Compound 1 is present.
• the crystalline form is at least about 85% of Form I. In some embodiments, the crystalline form is at least about 90% of Form I. In some embodiments, the crystalline form is at least about 95% of Form I. In some embodiments, the crystalline form is at least about 99% of Form I. In some embodiments, the crystalline form is at least about 99.5% of Form I. In some embodiments, the crystalline form is at least about 99.9% of Form I. In some embodiments, the crystalline form is at least about 99.99% of Form I.
• composition comprising
• the pharmaceutical composition comprises
• the pharmaceutical composition comprises Compound 1 wherein at least about 85% of Compound 1 is in Form I.
• the pharmaceutical composition comprises Compound 1 wherein at least about 90% of Compound 1 is in Form I.
• the pharmaceutical composition comprises Compound 1 wherein at least about 95% of Compound 1 is in Form I.
• the pharmaceutical composition comprises Compound 1 wherein at least about 99% of Compound 1 is in Form I.
• the pharmaceutical composition comprises Compound 1 wherein at least about 99.5% of Compound 1 is in Form I.
• the pharmaceutical composition comprises Compound 1 wherein at least about 99.9% of Compound 1 is in Form I.
• the pharmaceutical composition comprises Compound 1 wherein at least about 99.99% of Compound 1 is in Form I.
• the present invention provides a solvated crystalline form of Compound 1 referred to as Form II.
• the present invention provides Form II of Compound 1, having a powder X-ray diffraction pattern substantially similar to that depicted in Figure 5.
• Form II of Compound 1 is characterized in that it has one or more peaks in its powder X-ray diffraction pattern selected from those in Table 3 below.
• Form II of Compound 1 is characterized in that it has two or more peaks in its powder X-ray diffraction pattern selected from those in Table 3. In some embodiments, Form II of Compound 1 is characterized in that it has three or more peaks in its powder X-ray diffraction pattern selected from those in Table 3. In some embodiments, Form II of Compound 1 is characterized in that it has four or more peaks in its powder X-ray diffraction pattern selected from those in Table 3. In some embodiments, Form II of Compound 1 is characterized in that it has five or more peaks in its powder X-ray diffraction pattern selected from those in Table 3. In some embodiments, Form II of Compound 1 is characterized in that it has all of the peaks in Table 3 in its X-ray diffraction pattern.
• Form II of Compound 1 is characterized in that it has one or more peaks in its powder X-ray diffraction pattern selected from those at about 7.56, about 8.09, about 11.34, about 11.74, about 14.37, about 15.38, about 17.56, and about 23.00 degrees 2 ⁇ . In some embodiments, Form II of Compound 1 is characterized in that it has two or more peaks in its powder X-ray diffraction pattern selected from those at about 7.56, about 8.09, about 11.34, about 11.74, about 14.37, about 15.38, about 17.56, and about 23.00 degrees 2 ⁇ .
• Form II of Compound 1 is characterized in that it has three or more peaks in its powder X-ray diffraction pattern selected from those at about 7.56, about 8.09, about 11.34, about 11.74, about 14.37, about 15.38, about 17.56, and about 23.00 degrees 2 ⁇ . In some embodiments, Form II of Compound 1 is characterized in that it has four or more peaks in its powder X-ray diffraction pattern selected from those at about 7.56, about 8.09, about 11.34, about 11.74, about 14.37, about 15.38, about 17.56, and about 23.00 degrees 2 ⁇ .
• Form II of Compound 1 is characterized in that it has five or more peaks in its powder X-ray diffraction pattern selected from those at about 7.56, about 8.09, about 11.34, about 11.74, about 14.37, about 15.38, about 17.56, and about 23.00 degrees 2 ⁇ . In some embodiments, Form II of Compound 1 is characterized in that it has six or more peaks in its powder X-ray diffraction pattern selected from those at about 7.56, about 8.09, about 11.34, about 11.74, about 14.37, about 15.38, about 17.56, and about 23.00 degrees 2 ⁇ .
• Form II of Compound 1 is characterized in that it has seven or more peaks in its powder X-ray diffraction pattern selected from those at about 7.56, about 8.09, about 11.34, about 11.74, about 14.37, about 15.38, about 17.56, and about 23.00 degrees 2 ⁇ . In some embodiments, Form II of Compound 1 is characterized in that it has all eight peaks in its powder X-ray diffraction pattern selected from those at about 7.56, about 8.09, about 11.34, about 11.74, about 14.37, about 15.38, about 17.56, and about 23.00 degrees 2 ⁇ .
• Form II of Compound 1 is characterized in that it has one or more peaks in its powder X-ray diffraction pattern selected from those at about 12.2, about 12.8, about 17.0, about 19.6, about 21.0, and about 22.8 degrees 2 ⁇ .
• the present invention provides a solvated crystalline form of Compound 1 referred to as Form III.
• the present invention provides Form III of Compound 1, having a powder X-ray diffraction pattern substantially similar to that depicted in Figure 6.
• Form III of Compound 1 is characterized in that it has one or more peaks in its powder X-ray diffraction pattern selected from those in Table 4 below.
• Form III of Compound 1 is characterized in that it has two or more peaks in its powder X-ray diffraction pattern selected from those in Table 4. In some embodiments, Form III of Compound 1 is characterized in that it has three or more peaks in its powder X-ray diffraction pattern selected from those in Table 4. In some embodiments, Form III of Compound 1 is characterized in that it has four or more peaks in its powder X-ray diffraction pattern selected from those in Table 4. In some embodiments, Form III of
• Compound 1 is characterized in that it has five or more peaks in its powder X-ray diffraction pattern selected from those in Table 4. In some embodiments, Form III of Compound 1 is characterized in that it has all of the peaks in in Table 4 in its X-ray diffraction pattern.
• Form III of Compound 1 is characterized in that it has one or more peaks in its powder X-ray diffraction pattern selected from those at about 6.27, about 18.02, about 21.61, and about 24.14 degrees 2 ⁇ . In some embodiments, Form III of Compound 1 is characterized in that it has two or more peaks in its powder X-ray diffraction pattern selected from those at about 6.27, about 18.02, about 21.61, and about 24.14 degrees 2 ⁇ . In some embodiments, Form III of Compound 1 is characterized in that it has three or more peaks in its powder X-ray diffraction pattern selected from those at about 6.27, about 18.02, about 21.61, and about 24.14 degrees 2 ⁇ . In some embodiments, Form III of Compound 1 is characterized in that it has all four peaks in its powder X-ray diffraction pattern selected from those at about 6.27, about 18.02, about 21.61, and about 24.14 degrees 2 ⁇ .
• Form III of Compound 1 is characterized in that it has one or more peaks in its powder X-ray diffraction pattern selected from those at about 6.3, about 8.5, about 12.2, about 15.9, and about 21.6 degrees 2 ⁇ .
• the present invention provides a solvated crystalline form of Compound 1 referred to as Form IV.
• the present invention provides Form IV of Compound 1, having a powder X-ray diffraction pattern substantially similar to that depicted in Figure 7A.
• the present invention provides Form IV of Compound 1, having a powder X-ray diffraction pattern substantially similar to that depicted in Figure 7B.
• Form IV of Compound 1 is characterized in that it has one or more peaks in its powder X-ray diffraction pattern selected from those listed in Table 5 below. Table 5.
• Form IV of Compound 1 is characterized in that it has two or more peaks in its powder X-ray diffraction pattern selected from those in Table 5. In some embodiments, Form IV of Compound 1 is characterized in that it has three or more peaks in its powder X-ray diffraction pattern selected from those in Table 5. In some embodiments, Form IV of Compound 1 is characterized in that it has four or more peaks in its powder X-ray diffraction pattern selected from those in Table 5. In some embodiments, Form IV of
• Compound 1 is characterized in that it has five or more peaks in its powder X-ray diffraction pattern selected from those in Table 5.
• Form IV of Compound 1 is characterized in that it has all of the peaks in Table 5 in its X-ray diffraction pattern.
• Form IV of Compound 1 is characterized in that it has one or more peaks in its powder X-ray diffraction pattern selected from those at about 9.73, about 9.88, about 10.56, about 10.70, about 11.86, about 11.97, about 14.54, about 16.62, about 21.30, about 21.94, and about 26.72 degrees 2 ⁇ .
• Form IV of Compound 1 is characterized in that it has two or more peaks in its powder X-ray diffraction pattern selected from those at about 9.73, about 9.88, about 10.56, about 10.70, about 11.86, about 11.97, about 14.54, about 16.62, about 21.30, about 21.94, and about 26.72 degrees 2 ⁇ .
• Form IV of Compound 1 is characterized in that it has one or more peaks in its powder X-ray diffraction pattern selected from those at about 9.73, about 9.88, about 10.56, about 10.70, about 11.86, about 11.97, about 14.54, about 16.62, about 21.30, about 21.94, and about 26.
• Form IV of Compound 1 is characterized in that it has three or more peaks in its powder X-ray diffraction pattern selected from those at about 9.73, about 9.88, about 10.56, about 10.70, about 11.86, about 11.97, about 14.54, about 16.62, about 21.30, about 21.94, and about 26.72 degrees 2 ⁇ .
• Form IV of Compound 1 is characterized in that it has four or more peaks in its powder X-ray diffraction pattern selected from those at about 9.73, about 9.88, about 10.56, about 10.70, about 11.86, about 11.97, about 14.54, about 16.62, about 21.30, about 21.94, and about 26.72 degrees 2 ⁇ .
• Form IV of Compound 1 is characterized in that it has five or more peaks in its powder X-ray diffraction pattern selected from those at about 9.73, about 9.88, about 10.56, about 10.70, about 11.86, about 11.97, about 14.54, about 16.62, about 21.30, about 21.94, and about 26.72 degrees 2 ⁇ . In some embodiments, Form IV of Compound 1 is characterized in that it has six or more peaks in its powder X-ray diffraction pattern selected from those at about 9.73, about 9.88, about 10.56, about 10.70, about 11.86, about 11.97, about 14.54, about 16.62, about 21.30, about 21.94, and about 26.72 degrees 2 ⁇ .
• Form IV of Compound 1 is characterized in that it has seven or more peaks in its powder X-ray diffraction pattern selected from those at about 9.73, about 9.88, about 10.56, about 10.70, about 11.86, about 11.97, about 14.54, about 16.62, about 21.30, about 21.94, and about 26.72 degrees 2 ⁇ . In some embodiments, Form IV of Compound 1 is characterized in that it has nine or more peaks in its powder X-ray diffraction pattern selected from those at about 9.73, about 9.88, about 10.56, about 10.70, about 11.86, about 11.97, about 14.54, about 16.62, about 21.30, about 21.94, and about 26.72 degrees 2 ⁇ .
• Form IV of Compound 1 is characterized in that it has ten or more peaks in its powder X-ray diffraction pattern selected from those at about 9.73, about 9.88, about 10.56, about 10.70, about 11.86, about 11.97, about 14.54, about 16.62, about 21.30, about 21.94, and about 26.72 degrees 2 ⁇ . In some embodiments, Form IV of Compound 1 is characterized in that it has all eleven peaks in its powder X-ray diffraction pattern selected from those at about 9.73, about 9.88, about 10.56, about 10.70, about 11.86, about 11.97, about 14.54, about 16.62, about 21.30, about 21.94, and about 26.72 degrees 2 ⁇ .
• Form IV of Compound 1 is characterized in that it has one or more peaks in its powder X-ray diffraction pattern selected from those at about 9.9, about 10.6, about 11.9, about 14.5, about 16.6, about 21.9, and about 26.7 degrees 2 ⁇ .
• Form IV of Compound 1 is characterized by an X-ray powder diffractogram comprising the following peaks: 9.9, 10.7, 19.5, 22.0, and 26.8 °2 ⁇ ⁇ 0.2 °2 ⁇ , as determined on a diffractometer using Cu- ⁇ radiation at a wavelength of 1.54 A. The diffractogram comprises additional peaks at 8.7, 12.0, and 14.7 °2 ⁇ ⁇ 0.2 °2 ⁇ .
• Compound 1 Form IV is also characterized by its X-ray diffraction pattern as substantially shown in Figure 7A.
• Compound 1 Form IV is also characterized by its X-ray diffraction pattern as substantially shown in Figure 7B.
• Form IV of Compound 1 is characterized by a differential scanning calorimetry (DSC) curve that comprises an endotherms at 85 and 190 and 202 °C and exotherm at 146 °C.
• DSC differential scanning calorimetry
• Form IV of Compound 1 is also characterized by its DSC curve as substantially shown in Figure 8.
• Form IV of Compound 1 is characterized by a
• thermogravimetric analysis (TGA) curve as substantially shown in Figure 9.
• the present invention provides a solvated crystalline form of Compound 1 referred to as Form V.
• the present invention provides Form V of Compound 1, having a powder X-ray diffraction pattern substantially similar to that depicted in Figure 10.
• Form V of Compound 1 is characterized in that it has one or more peaks in its powder X-ray diffraction pattern selected from those in Table 6 below.
• Form V of Compound 1 is characterized in that it has two or more peaks in its powder X-ray diffraction pattern selected from those in Table 6. In some embodiments, Form V of Compound 1 is characterized in that it has three or more peaks in its powder X-ray diffraction pattern selected from those in Table 6. In some embodiments, Form V of Compound 1 is characterized in that it has four or more peaks in its powder X-ray diffraction pattern selected from those in Table 6. In some embodiments, Form V of Compound 1 is characterized in that it has five or more peaks in its powder X-ray diffraction pattern selected from those in Table 6. In some embodiments, Form V of Compound 1 is characterized in that it has all of the peaks in Table 6 in its X-ray diffraction pattern.
• Form V of Compound 1 is characterized in that it has one or more peaks in its powder X-ray diffraction pattern selected from those at about 5.85, about 8.23, about 11.02, about 11.15, about 12.69, about 13.34, about 16.23, about 16.28, about 17.32, about 18.93, about 23.47, about 24.56, and about 25.40 degrees 2 ⁇ .
• Form V of Compound 1 is characterized in that it has two or more peaks in its powder X-ray diffraction pattern selected from those at about 5.85, about 8.23, about 11.02, about 11.15, about 12.69, about 13.34, about 16.23, about 16.28, about 17.32, about 18.93, about 23.47, about 24.56, and about 25.40 degrees 2 ⁇ .
• Form V of Compound 1 is characterized in that it has three or more peaks in its powder X-ray diffraction pattern selected from those at about 5.85, about 8.23, about 11.02, about 11.15, about 12.69, about 13.34, about 16.23, about 16.28, about 17.32, about 18.93, about 23.47, about 24.56, and about 25.40 degrees 2 ⁇ .
• Form V of Compound 1 is characterized in that it has four or more peaks in its powder X-ray diffraction pattern selected from those at about 5.85, about 8.23, about 11.02, about 11.15, about 12.69, about 13.34, about 16.23, about 16.28, about 17.32, about 18.93, about 23.47, about 24.56, and about 25.40 degrees 2 ⁇ .
• Form V of Compound 1 is characterized in that it has five or more peaks in its powder X-ray diffraction pattern selected from those at about 5.85, about 8.23, about 11.02, about 11.15, about 12.69, about 13.34, about 16.23, about 16.28, about 17.32, about 18.93, about 23.47, about 24.56, and about 25.40 degrees 2 ⁇ .
• Form V of Compound 1 is characterized in that it has six or more peaks in its powder X-ray diffraction pattern selected from those at about 5.85, about 8.23, about 11.02, about 11.15, about 12.69, about 13.34, about 16.23, about 16.28, about 17.32, about 18.93, about 23.47, about 24.56, and about 25.40 degrees 2 ⁇ .
• Form V of Compound 1 is characterized in that it has seven or more peaks in its powder X-ray diffraction pattern selected from those at about 5.85, about 8.23, about 11.02, about 11.15, about 12.69, about 13.34, about 16.23, about 16.28, about 17.32, about 18.93, about 23.47, about 24.56, and about 25.40 degrees 2 ⁇ .
• Form V of Compound 1 is characterized in that it has eight or more peaks in its powder X-ray diffraction pattern selected from those at about 5.85, about 8.23, about 11.02, about 11.15, about 12.69, about 13.34, about 16.23, about 16.28, about 17.32, about 18.93, about 23.47, about 24.56, and about 25.40 degrees 2 ⁇ .
• Form V of Compound 1 is characterized in that it has nine or more peaks in its powder X-ray diffraction pattern selected from those at about 5.85, about 8.23, about 11.02, about 11.15, about 12.69, about 13.34, about 16.23, about 16.28, about 17.32, about 18.93, about 23.47, about 24.56, and about 25.40 degrees 2 ⁇ .
• Form V of Compound 1 is characterized in that it has ten or more peaks in its powder X-ray diffraction pattern selected from those at about 5.85, about 8.23, about 11.02, about 11.15, about 12.69, about 13.34, about 16.23, about 16.28, about 17.32, about 18.93, about 23.47, about 24.56, and about 25.40 degrees 2 ⁇ .
• Form V of Compound 1 is characterized in that it has eleven or more peaks in its powder X-ray diffraction pattern selected from those at about 5.85, about 8.23, about 11.02, about 11.15, about 12.69, about 13.34, about 16.23, about 16.28, about 17.32, about 18.93, about 23.47, about 24.56, and about 25.40 degrees 2 ⁇ .
• Form V of Compound 1 is characterized in that it has twelve or more peaks in its powder X-ray diffraction pattern selected from those at about 5.85, about 8.23, about 11.02, about 11.15, about 12.69, about 13.34, about 16.23, about 16.28, about 17.32, about 18.93, about 23.47, about 24.56, and about 25.40 degrees 2 ⁇ .
• Form V of Compound 1 is characterized in that it has all thirteen peaks in its powder X-ray diffraction pattern selected from those at about 5.85, about 8.23, about 11.02, about 11.15, about 12.69, about 13.34, about 16.23, about 16.28, about 17.32, about 18.93, about 23.47, about 24.56, and about 25.40 degrees 2 ⁇ .
• Form V of Compound 1 is characterized in that it has one or more peaks in its powder X-ray diffraction pattern selected from those at about 8.0, about 11.0, about 12.7, about 13.3, about 16.3, about 17.9, about 20.3, about 22.6, about 23.5, and about 24.6 degrees 2 ⁇ .
• the present invention provides a solvated crystalline form of Compound 1 referred to as Form VI.
• the present invention provides Form VI of Compound 1, having a powder X-ray diffraction pattern substantially similar to that depicted in Figure 11 A.
• the present invention provides Form VI of Compound 1, having a powder X-ray diffraction pattern substantially similar to that depicted in Figure 1 IB.
• Form VI of Compound 1 is characterized in that it has a peaks in its powder X-ray diffraction pattern selected from those in Table 7 below.
• Form VI of Compound 1 is characterized in that it has a peak at about 10.19 degrees 2 ⁇ in its powder X-ray diffraction pattern.
• Form VI is characterized by an X-ray powder diffractogram comprising the following peaks: 18.0, 23.4, and 25.3 °2 ⁇ ⁇ 0.2 °2 ⁇ , as determined on a diffractometer using Cu- ⁇ radiation at a wavelength of 1.54 A. The diffractogram comprises additional peaks at 10.5, 14.2, 15.1, and 18.8 °2 ⁇ ⁇ 0.2 °2 ⁇ .
• Compound 1 Form VI is also characterized by its X-ray diffraction pattern as substantially shown in Figure 11 A.
• Compound 1 Form VI is also characterized by its X-ray diffraction pattern as substantially shown in Figure 11B.
• Form VI of Compound 1 is characterized by a differential scanning calorimetry (DSC) curve that comprises an endotherms at 131 °C, 193 °C, and 205 °C.
• DSC differential scanning calorimetry
• Form VI of Compound 1 is also characterized by its DSC curve as substantially shown in Figure 12.
• Form VI of Compound 1 is characterized by a
• thermogravimetric analysis (TGA) curve as substantially shown in Figure 13.
• the present invention provides a polymorphic form of Compound 1 referred to as Form VII.
• the present invention provides Form VII of Compound 1, having a powder X-ray diffraction pattern substantially similar to that depicted in Figure 14.
• Form VII of Compound 1 is characterized in that it has one or more peaks in its powder X-ray diffraction pattern selected from those in Table 8 below.
• Form VII of Compound 1 is characterized in that it has two or more peaks in its powder X-ray diffraction pattern selected from those in Table 8. In some embodiments, Form VII of Compound 1 is characterized in that it has three or more peaks in its powder X-ray diffraction pattern selected from those in Table 8. In some embodiments, Form VII of Compound 1 is characterized in that it has four or more peaks in its powder X-ray diffraction pattern selected from those in Table 8. In some embodiments, Form VII of
• Compound 1 is characterized in that it has five or more peaks in its powder X-ray diffraction pattern selected from those in Table 8. In some embodiments, Form VII of Compound 1 is characterized in that it has all of the peaks in Table 8 in its X-ray diffraction pattern.
• Form VII of Compound 1 is characterized in that it has one or more peaks in its powder X-ray diffraction pattern selected from those at about 8.94, about 17.90, and about 27.76 degrees 2 ⁇ ; in addition to having one or more peaks selected from about 9.16, about 13.73, about 14.74, about 17.05, about 18.22, about 18.38, about 19.47, about 19.51, about 22.37, about 23.85, about 23.94, about 25.53, about 25.96, and about 27.17 degrees 2 ⁇ .
• Form VII of Compound 1 is characterized in that it has two or more peaks in its powder X-ray diffraction pattern selected from those at about 8.94, about 17.90, and about 27.76 degrees 2 ⁇ ; in addition to having one or more peaks selected from about 9.16, about 13.73, about 14.74, about 17.05, about 18.22, about 18.38, about 19.47, about 19.51, about 22.37, about 23.85, about 23.94, about 25.53, about 25.96, and about 27.17 degrees 2 ⁇ .
• Form VII of Compound 1 is characterized in that it has one or more peaks in its powder X-ray diffraction pattern selected from those at about 8.94, about 17.90, and about 27.76 degrees 2 ⁇ ; in addition to having a peak at about 25.96 degrees 2 ⁇ . In some embodiments, Form VII of Compound 1 is characterized in that it has one or more peaks in its powder X-ray diffraction pattern selected from those at about 8.94, and about 27.76 degrees 2 ⁇ ; in addition to having a peak at about 25.96 degrees 2 ⁇ . In some embodiments, Form VII of Compound 1 is characterized in that it has all three peaks in its powder X-ray diffraction pattern selected from those at about 8.94, about 27.76, and about 25.96 degrees 2 ⁇ .
• Form VII of Compound 1 is characterized in that it has one or more peaks in its powder X-ray diffraction pattern selected from those at about 9.2, about 13.7, about 14.7, about 17.1, about 18.4, about 19.5, about 22.4, about 23.9, about 25.5, and about 26.0 degrees 2 ⁇ .
• the present invention provides a polymorphic form of Compound 1 referred to as Form VIII.
• the present invention provides Form VIII of Compound 1, having a powder X-ray diffraction pattern substantially similar to that depicted in Figure 15 A.
• the present invention provides Form VIII of Compound 1, having a powder X-ray diffraction pattern substantially similar to that depicted in Figure 15B.
• Form VIII of Compound 1 is characterized in that it has one or more peaks in its powder X-ray diffraction pattern selected from those in Table 9 below. Table 9.
• Form VIII of Compound 1 is characterized in that it has two or more peaks in its powder X-ray diffraction pattern selected from those in Table 9. In some embodiments, Form VIII of Compound 1 is characterized in that it has three or more peaks in its powder X-ray diffraction pattern selected from those in Table 9. In some embodiments, Form VIII of Compound 1 is characterized in that it has four or more peaks in its powder X-ray diffraction pattern selected from those in Table 9. In some embodiments, Form VIII of
• Compound 1 is characterized in that it has five or more peaks in its powder X-ray diffraction pattern selected from those in Table 9. In some embodiments, Form VIII of Compound 1 is characterized in that it has all of the peaks in Table 9 in its X-ray diffraction pattern.
• Form VIII of Compound 1 is characterized in that it has one or more peaks in its powder X-ray diffraction pattern selected from those at about 5.50, about 10.31, about 18.77, about 22.23, and about 25.83 degrees 2 ⁇ . In some embodiments, Form VIII of Compound 1 is characterized in that it has two or more peaks in its powder X-ray diffraction pattern selected from those at about 5.50, about 10.31, about 18.77, about 22.23, and about 25.83 degrees 2 ⁇ .
• Form VIII of Compound 1 is characterized in that it has three or more peaks in its powder X-ray diffraction pattern selected from those at about 5.50, about 10.31, about 18.77, about 22.23, and about 25.83 degrees 2 ⁇ . In some embodiments, Form VIII of Compound 1 is characterized in that it has four or more peaks in its powder X-ray diffraction pattern selected from those at about 5.50, about 10.31, about 18.77, about 22.23, and about 25.83 degrees 2 ⁇ .
• Form VIII of Compound 1 is characterized in that it has all five peaks in its powder X-ray diffraction pattern selected from those at about 5.50, about 10.31, about 18.77, about 22.23, and about 25.83 degrees 2 ⁇ .
• Form VIII of Compound 1 is characterized in that it has one or more peaks in its powder X-ray diffraction pattern selected from those at about 5.5, about 10.3, about 15.8, about 18.8, about 20.4, about 22.7, and about 25.8 degrees 2 ⁇ .
• Form VIII is characterized by an X-ray powder diffractogram comprising the following peaks: 16.0, 20.5, and 22.8 °2 ⁇ ⁇ 0.2 °2 ⁇ , as determined on a diffractometer using Cu- ⁇ radiation at a wavelength of 1.54 A. The diffractogram comprises additional peaks at 9.1, 10.5, 18.8, and 25.8 °2 ⁇ ⁇ 0.2 °2 ⁇ .
• Compound 1 Form VIII is also characterized by its X-ray diffraction pattern as substantially shown in Figure 15 A.
• Compound 1 Form VIII is also characterized by its X-ray diffraction pattern as substantially shown in Figure 15B.
• Form VIII of Compound 1 is characterized by a differential scanning calorimetry (DSC) curve that comprises an endotherm at 205 °C.
• DSC differential scanning calorimetry
• Form VIII of Compound 1 is also characterized by its DSC curve as substantially shown in Figure 16.
• Form VIII of Compound 1 is characterized by a
• thermogravimetric analysis (TGA) curve as substantially shown in Figure 17.
• Some embodiments herein provide for a crystalline form of a sodium salt or co- crystal of Compound 1, which is referred to as Compound 1 Sodium Form I.
• Compound 1 Sodium Form I a crystalline form of a sodium salt or co- crystal of Compound 1, which is referred to as Compound 1 Sodium Form I.
• Compound 1 Sodium Form I is characterized by an X-ray powder diffractogram comprising the following peaks: 7.5, 8.2, 20.4, and 20.9 °2 ⁇ ⁇ 0.2 °2 ⁇ , as determined on a diffractometer using Cu- ⁇ radiation at a wavelength of 1.54 A. The diffractogram comprises additional peaks at 14.8, 17.5, 24.0, and 27.7 °2 ⁇ ⁇ 0.2 °2 ⁇ .
• Compound 1 Sodium Form I is also characterized by its full X-ray diffraction pattern as substantially shown in Figure 19.
• Compound 1 Sodium Form I is characterized by a differential scanning calorimetry (DSC) curve that comprises an endotherm at about 37 °C and an endotherm at about 283 °C. Compound 1 Sodium Form I also is characterized by its DSC curve as substantially shown in Figure 20. [0129] In some embodiments, Compound 1 Sodium Form I is characterized by a thermogravimetric analysis (TGA) curve as substantially shown in Figure 21.
• DSC differential scanning calorimetry
• TGA thermogravimetric analysis
• Compound 1 Sodium Form II provides for a crystalline form of a sodium salt or co- crystal of Compound 1, which is referred to as Compound 1 Sodium Form II.
• Compound 1 Sodium Form II is characterized by an X-ray powder diffractogram comprising the following peaks: 4.8, 6.7, 15.6, and 24.2 °2 ⁇ ⁇ 0.2 °2 ⁇ , as determined on a diffractometer using Cu- ⁇ radiation at a wavelength of 1.54 A. The diffractogram comprises additional peaks at 17.9, 29.2, 32.5, and 38.0 °2 ⁇ ⁇ 0.2 °2 ⁇ .
• Compound 1 Sodium Form II is also characterized by its full X-ray diffraction pattern as substantially shown in Figure 22.
• Compound 1 Sodium Form II is characterized by a differential scanning calorimetry (DSC) curve that comprises an endotherm at about 19 °C, an endotherm at about 78 °C, and an endotherm at about 136 °C.
• DSC differential scanning calorimetry
• Compound 1 Sodium Form II also is characterized by its DSC curve as substantially shown in Figure 23.
• Compound 1 Sodium Form II is characterized by a thermogravimetric analysis (TGA) curve as substantially shown in Figure 24.
• TGA thermogravimetric analysis
• Compound 1 Calcium Form I a crystalline form of a calcium salt or co- crystal of Compound 1, which is referred to as Compound 1 Calcium Form I.
• Compound 1 Calcium Form I is characterized by an X-ray powder diffractogram comprising the following peaks: 10.1, 14.3, and 20.4 °2 ⁇ ⁇ 0.2 °2 ⁇ , as determined on a diffractometer using Cu- ⁇ radiation at a wavelength of 1.54 A. The diffractogram comprises additional peaks at 3.6, 7.8, 21.6, 27.3, 28.9 °2 ⁇ ⁇ 0.2 °2 ⁇ .
• Compound 1 Calcium Form I is also characterized by its full X-ray diffraction pattern as substantially shown in Figure 25.
• Compound 1 Calcium Form I is characterized by a differential scanning calorimetry (DSC) curve that comprises an endotherm at about 17 °C, an endotherm at about 72 °C, an endotherm at about 180 °C, and an endotherm at about 202 °C.
• DSC differential scanning calorimetry
• Compound 1 Calcium Form I also is characterized by its DSC curve as substantially shown in Figure 26.
• Compound 1 Calcium Form I is characterized by a
• thermogravimetric analysis (TGA) curve as substantially shown in Figure 27.
• Compound 1 Magnesium Form I a crystalline form of a magnesium salt or co- crystal of Compound 1, which is referred to as Compound 1 Magnesium Form I.
• Compound 1 Magnesium Form I is characterized by an X-ray powder
• diffractogram comprising the following peaks: 8.2, 16.9, 19.1, and 21.2 °2 ⁇ ⁇ 0.2 °2 ⁇ , as determined on a diffractometer using Cu- ⁇ radiation at a wavelength of 1.54 A.
• the diffractogram comprises additional peaks at 15.8, 24.1, 26.1, and 27.1 °2 ⁇ ⁇ 0.2 °2 ⁇ .
• Compound 1 Magnesium Form I is also characterized by its full X-ray diffraction pattern as substantially shown in Figure 28.
• Compound 1 Magnesium Form I is characterized by a differential scanning calorimetry (DSC) curve that comprises an endotherm at about 53 °C.
• Compound 1 Magnesium Form I also is characterized by its DSC curve as substantially shown in Figure 29.
• Compound 1 Magnesium Form I is characterized by a thermogravimetric analysis (TGA) curve as substantially shown in Figure 30.
• TGA thermogravimetric analysis
• Compound 1 Diethanolamine Form I a crystalline form of a diethanolamine salt or co-crystal of Compound 1, which is referred to as Compound 1 Diethanolamine Form I.
• Compound 1 Diethanolamine Form I is characterized by an X-ray powder diffractogram comprising the following peaks: 5.1, 8.0, 17.0, 25.1 °2 ⁇ ⁇ 0.2 °2 ⁇ , as determined on a diffractometer using Cu- ⁇ radiation at a wavelength of 1.54 A. The diffractogram comprises additional peaks at 13.4, 16.4, 20.4, and 22.6 °2 ⁇ ⁇ 0.2 °2 ⁇ .
• Diethanolamine Form I is also characterized by its full X-ray diffraction pattern as substantially shown in Figure 31.
• Compound 1 Diethanolamine Form I is characterized by a differential scanning calorimetry (DSC) curve that comprises an endotherm at about 118 °C.
• Compound 1 Diethanolamine Form I also is characterized by its DSC curve as substantially shown in Figure 32.
• Compound 1 Diethanolamine Form I is characterized by a thermogravimetric analysis (TGA) curve as substantially shown in Figure 33.
• TGA thermogravimetric analysis
• Compound 1 Piperazine Form I a crystalline form of a piperazine salt or co- crystal of Compound 1, which is referred to as Compound 1 Piperazine Form I.
• Compound 1 Piperazine Form I is characterized by an X-ray powder
• Compound 1 Piperazine Form I is also characterized by its full X-ray diffraction pattern as substantially shown in Figure 34.
• Compound 1 Piperazine Form I is characterized by a differential scanning calorimetry (DSC) curve that comprises an endotherm at about 27 °C and an endotherm at about 139 °C. Compound 1 Piperazine Form I also is characterized by its DSC curve as substantially shown in Figure 35. [0144] In some embodiments, Compound 1 Piperazine Form I is characterized by a thermogravimetric analysis (TGA) curve as substantially shown in Figure 36.
• DSC differential scanning calorimetry
• TGA thermogravimetric analysis
• aliphatic or "aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle,” “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule.
• aliphatic groups contain 1-6 aliphatic carbon atoms.
• aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms.
• cycloaliphatic (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as
• lower alkyl refers to a Ci-4 straight or branched alkyl group.
• exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.
• lower haloalkyl refers to a Ci-4 straight or branched alkyl group that is substituted with one or more halogen atoms.
• heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), H (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)).
• Ci-8 (or Ci- 6 ) saturated or unsaturated, straight or branched, hydrocarbon chain
• bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.
• alkylene refers to a bivalent alkyl group.
• An "alkylene chain” is a polymethylene group, i.e., -(03 ⁇ 4) ⁇ -, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
• a substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
• alkenylene refers to a bivalent alkenyl group.
• a substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
• Alkoxy refers to the group “alkyl-O-”. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n- hexoxy, and 1,2-dimethylbutoxy.
• halogen means F, CI, Br, or I.
• ring means a cycloalkyl group or heterocyclic ring as defined herein.
• aryl used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
• aryl may be used interchangeably with the term “aryl ring.”
• aryl used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic and bicyclic ring systems having a total of five to 10 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members.
• aryl may be used interchangeably with the term “aryl ring”.
• aryl refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.
• aryl is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
• aralkyl refers to aryl-alkylene, wherein aryl and alkylene are as defined herein.
• aralkoxy refers to aryl-alkoxy, wherein aryl and alkoxy are as defined herein.
• aryloxyalkyl refers to aiyl-O-alkylene, wherein aryl and alkylene are as defined herein.
• heteroaryl and “heteroar-,” used alone or as part of a larger moiety e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 ⁇ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
• Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
• heteroaryl and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring.
• Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin-3(4H)-one.
• heteroaryl group may be mono- or bicyclic.
• heteroaryl may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted.
• heteroarylkyl refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.
• heterocycle As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7 to 10-membered bicyclic heterocyclic moiety that is either saturated or partially
• nitrogen includes a substituted nitrogen.
• the nitrogen in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), H (as in pyrrolidinyl), or + R (as in N-substituted pyrrolidinyl).
• a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
• saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.
• heterocycle refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
• partially unsaturated refers to a ring moiety that includes at least one double or triple bond.
• partially unsaturated is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
• substituted moieties.
• substituted whether preceded by the term
• an "optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
• Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
• stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
• R° may be substituted as defined below and is independently hydrogen, Ci-6 aliphatic, -CHzPh, -0(CH 2 )o-iPh, -CH 2 -(5-6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.
• independent occurrences of R° together with their intervening atoms are independently halogen, -(CH 2 )o- 2 R*, -(haloR*), -(CH 2 )o- 2 OH, -(CH 2 )o- 2 OR*, -(CH 2 )o- 2 CH(OR*) 2 , -O(haloR'), -CN, -N 3 , -(CH 2 )o- 2 C(0)R*, -(CH 2 )o- 2 C(0)OH, -(CH 2 )o- 2 C(0)OR*, -(CH 2 )o- 2 SR*, -(CH 2 )o- 2 SH, -(CH 2 )o- 2 NH 2 , -(CH 2 )o- 2 NHR*, -(CH 2 )o- 2 NR* 2 , -NO2, -SiR* 3 , -OSiR* 3 , -C(0)SR* straight or branched al
• Suitable divalent substituents that are bound to vicinal substitutable carbons of an "optionally substituted” group include: -0(CR * 2 ) 2 - 3 0-, wherein each independent occurrence of R * is selected from hydrogen, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• Suitable substituents on the aliphatic group of R * include halogen,
• each R* is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently Ci-4 aliphatic, -CH 2 Ph, -0(CH 2 )o-iPh, or a 5-6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R ⁇ , - R ⁇ 2 , -C(0)R ⁇ , -C(0)OR ⁇ , -C(0)C(0)R ⁇ , -C(0)CH 2 C(0)R ⁇ ,
• each R ⁇ is independently hydrogen, Ci-6 aliphatic which may be substituted as defined below,
• unsubstituted -OPh or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R ⁇ , taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• Suitable substituents on the aliphatic group of R ⁇ are independently halogen, -R*, -(haloR*), -OH, -OR*, -O(haloR'), -CN, -C(0)OH, -C(0)OR*, -NH 2 , -NHR*, -NR* 2 , or -N0 2 , wherein each R* is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently Ci-4 aliphatic, -CHzPh, -0(CH 2 )o-iPh, or a 5-6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• co-crystal refers to a molecular complex of an ionized or non-ionized Compound 1 (or any other compound disclosed herein) and one or more non-ionized co-crystal formers (such as a pharmaceutically acceptable salt) connected through non-covalent interactions.
• the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
• Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, as does the Handbook of Pharmaceutical Salts: Properties, Selection, and Use, 2 nd Revised Edition, P. Heinrich Stahl and Camille G. Wermuth, Eds. Wiley, April, 2011, each of which is incorporated herein by reference.
• Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
• suitable inorganic and organic acids and bases include those derived from suitable inorganic and organic acids and bases.
• pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
• salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate
• Salts derived from appropriate bases include metal ions (including aluminum, zinc, alkali metals, alkaline earth metals), ammonium and N + (Ci-4alkyl)4 salts.
• Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
• Further pharmaceutically acceptable salts include, when appropriate, those derived from nontoxic ammonium, quaternary ammonium, and primary, secondary or tertiary amine cations, including but not limited to those derived from natural or non-naturally-occurring amino acids.
• Representative amine or ammonium-based salts include but are not limited to those derived from arginine, betaine, hydrabamine, choline, diethylamine, lysine, benzathine, 2-(diethylamino)- ethanol, ethanolamine, l-(2-hydroxyethyl)-pyrrolidine, diethanolamine, ammonia, deanol, N- methyl-glucamine, tromethamine, triethanolamine, 4-(2-hydroxyethyl)-morpholine, lH-imidazole, ethylenediamine, piperazine, procaine, and benethamine.
• structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
• structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
• compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
• Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.
• reaction conditions is intended to refer to the physical and/or
• reaction conditions include, but are not limited to, one or more of following: reaction temperature, solvent, pH, pressure, reaction time, mole ratio of reactants, the presence of a base or acid, or catalyst, radiation, concentration, etc.
• reaction conditions may be named after the particular chemical reaction in which the conditions are employed, such as, coupling conditions, hydrogenation conditions, acylation conditions, reduction conditions, etc. Reaction conditions for most reactions are generally known to those skilled in the art or can be readily obtained from the literature. Exemplary reaction conditions sufficient for performing the chemical
• reaction conditions can include reagents in addition to those listed in the specific reaction.
• G-l, G-l-a, G-2, G-2-a, G-2-b, G-3, G-3-b, G-4, G-4-a, G-4-b, G-5, G-5-a, G-6, G-6- a, G-7, G-7-a, G-8, G-8-a, G-8-b, G-9, G-9-a, G-10, G-ll, G-12, G-13, G-13-a, etc ) may be accomplished as described in the following examples. If available, reagents may be purchased commercially, e.g. from Sigma Aldrich or other chemical suppliers.
• the necessary starting materials generally may be determined by inspection. Starting materials are typically obtained from commercial sources or synthesized using published methods. For synthesizing compounds which are embodiments of the present disclosure, inspection of the structure of the compound to be synthesized will provide the identity of each substituent group. The identity of the final product will generally render apparent the identity of the necessary starting materials by a simple process of inspection, given the examples herein.
• 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 typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process and purification conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
• 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, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA).
• Others may be prepared by procedures or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon
• solvent refers to a solvent inert under the conditions of the reaction being described in conjunction therewith (including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (“TUF”), 2-methyltetrahydrofuran (“MeTHF”), dimethylformamide (“DMF”), chloroform, methylene chloride (or
• the solvents used in the reactions of the present disclosure are inert organic solvents, and the reactions are carried out under an inert gas, preferably nitrogen.
• each of the exemplary schemes it may be advantageous to separate reaction products from one another and/or from starting materials.
• the desired products of each step or series of steps is separated and/or purified (hereinafter separated) to the desired degree of homogeneity by the techniques common in the art.
• separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography.
• Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; high, medium, and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed (SMB) and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography.
• SMB simulated moving bed
• Another class of separation methods involves treatment of a mixture with a reagent selected to bind to or render otherwise separable a desired product, unreacted starting material, reaction by product, or the like.
• reagents include adsorbents or absorbents such as activated carbon, molecular sieves, ion exchange media, or the like.
• the reagents can be acids in the case of a basic material, bases in the case of an acidic material, binding reagents such as antibodies, binding proteins, selective chelators such as crown ethers, liquid/liquid ion extraction reagents (LIX), or the like.
• a single stereoisomer, e.g., an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Stereochemistry of Carbon Compounds, (1962) by E. L. Eliel, McGraw Hill; Lochmuller, C. H., (1975) J. Chromatogr 113, 3) 283- 302).
• Racemic mixtures of chiral compounds of the disclosure can be separated and isolated by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions.
• diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, a-methyl- -phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid.
• the diastereomeric salts may be induced to separate by fractional crystallization or ionic chromatography.
• the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a diastereomeric pair
• Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the free, enantiomerically enriched substrate.
• a method of determining optical purity involves making chiral esters, such as a menthyl ester, e.g., (-) menthyl
• a racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase (Chiral Liquid Chromatography (1989) W. J. Lough, Ed. Chapman and Hall, New York; Okamoto, (1990) J. of Chromatogr . 513 :375-378).
• Enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism.
• compounds of the present invention of formula I can be generally prepared according to the method described in 2013/0123231 Al, the entirety of which is incorporated herein by reference.
• the present invention provides synthetic methods and synthetic intermediates for the production of compounds of formula I:
• R a is an optionally substituted group selected from a 3-7 membered ring having 0-2 heteroatoms selected from nitrogen, oxygen, and sulfur, and a Ci-6 aliphatic;
• R 2 is hydrogen, or optionally substituted Ci-6 aliphatic
• R 5 is hydrogen or halogen.
• R a is an optionally substituted group selected from 3-7 membered ring and a Ci-6 aliphatic. In some embodiments, R a is an optionally substituted 3-7 membered ring. In some embodiments, R a is an optionally substituted 6-membered monocyclic ring. In some embodiments, R a is an optionally substituted 6-membered monocyclic
• R a is tetrahydropyranyl. In some embodiments, R a is tetrahydropyran-4-yl. In some embodiments, R a is an optionally substituted Ci-6 aliphatic group. In some embodiments, R a is an optionally substituted Ci-6 alkyl group.
• R 2 is hydrogen, or optionally substituted Ci-6 aliphatic. In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is optionally substituted Ci-6 aliphatic. In some embodiments, R 2 is optionally substituted Ci-6 alkyl. In some embodiments, R 2 is Ci-6 alkyl. In some embodiments, R 2 is methyl.
• R 5 is hydrogen or halogen. In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is halogen. In some embodiments, R 5 is fluoro.
• compounds of formula I are prepared according the method depicted in Scheme 1, wherein each of R a , R e , R 2 , R 5 are as defined in classes and subclasses herein, both singly and in combination.
• R is a leaving group.
• R is a halogen or sulfonate.
• R H is a halogen.
• R H is chloro.
• R H is bromo.
• R H is iodo.
• R H is a sulfonate.
• R is a mesylate, a triflate, a benzenesulfonate, a tosylate, a brosylate, or a nosylate.
• R e is a carboxyl protecting group.
• R e is -Si(R p ) 3 or optionally substituted Ci-6 aliphatic; wherein each R p is independently Ci-6 aliphatic or phenyl.
• R e is -Si(R p ) 3 .
• R e is optionally substituted Ci-6 aliphatic.
• R e is optionally substituted Ci-6 alkyl.
• R e is t-butyl.
• R e is benzyl.
• R e is benzhydryl.
• R e is trityl.
• step S-l comprises the alkylation of intermediate G-2 by intermediate G-l, thereby forming intermediate G-3.
• the alkylation is mediated by a base.
• the base is an alkoxide base.
• the base is an alkali metal alkoxide.
• the base is potassium t-butoxide.
• the base is sodium t-butoxide.
• the base is potassium t-amyloxide.
• the base is a carbonate base.
• the carbonate base is an alkali metal carbonate.
• the alkali metal carbonate is potassium carbonate or cesium carbonate.
• the alkali metal carbonate is potassium carbonate, potassium bicarbonate, cesium carbonate, or cesium bicarbonate.
• the alkali metal carbonate is potassium carbonate.
• the alkali metal carbonate is potassium carbonate or potassium bicarbonate.
• the alkali metal carbonate is cesium carbonate.
• the alkali metal carbonate is cesium carbonate or cesium bicarbonate.
• step S-l proceeds in a polar solvent.
• the polar solvent is a polar aprotic solvent.
• the polar aprotic solvent is N-methylpyrrolidone (NMP). In some embodiments, the polar aprotic solvent is dimethylformamide (DMF). In some embodiments, the polar aprotic solvent is dimethylacetamide (DMA). In some embodiments, crystalline intermediate G-3 is purified by crystallization.
• step S-2 comprises the coupling of intermediate G-3 with an oxazole synthon (oxazole), thereby forming intermediate G-4.
• the coupling is a metal-catalyzed coupling.
• the metal-catalyzed coupling is a Negishi coupling.
• a Negishi coupling is a transition metal-catalyzed cross-coupling of an organic halide or sulfonate compound with an organozinc compound.
• the oxazole synthon is an oxazole zincate.
• the oxazole zincate is formed by metal exchange between 2-lithio-oxazole and a zinc salt.
• the zinc salt is ZnCh.
• the 2-lithio- oxazole is formed by treating oxazole with n-butyllithium.
• the 2-lithio- oxazole is formed at a temperature below -40 °C.
• the 2-lithio-oxazole is formed at a temperature below about -40 °C.
• the 2-lithio-oxazole is formed at a temperature below -60 °C.
• the 2-lithio-oxazole is formed at a temperature below about -60 °C.
• the metal catalyst is a palladium catalyst.
• the palladium catalyst is Pd(PPh 3 ) 4 .
• crystalline intermediate G-4 is purified by crystallization.
• the oxazole is treated with a metalating agent selected from isopropyl magnesium chloride, isopropyl magnesium bromide, TMPZnCl-LiCl, TMPMgCl- LiCl, and isopropyl magnesium chloride/lithium chloride (wherein TMP refers to 2,2,6,6,- tetramethylpiperidine).
• the metalating agent is isopropyl magnesium chloride.
• the oxazole is treated with isopropyl magnesium chloride (2 M in THF).
• the oxazole is treated with a metalating agent at about -20 °C to about -10 °C.
• the oxazole is treated with a metalating agent at about -15 °C.
• the solvent is tetrahydrofuran, 2-methyltetrahydrofuran, or a mixture thereof. In some embodiments, the solvent is tetrahydrofuran and 2-methyltetrahydrofuran.
• the reaction further comprises adding ZnCh to form an oxazole zincate. In some embodiments, the reaction further comprises adding ZnCh as a solution in 2- methyltetrahydrofuran.
• the catalyst used in the Negishi coupling is a palladium catalyst selected from Pd(PPh 3 )4, tBuXPhos Pd precatalyst, XPhos Pd precatalyst, RuPhos Pd precatalyst, and Pd-PEPPSI-IPent (dichloro[l,3-bis(2,6-di-3-pentylphenyl)imidazol- 2-ylidene](3-chloropyridyl)palladium(II)).
• Such precatalysts are described in, for example, Bruneau et al., ACS Catal., 2015, 5(2), pp. 1386-1396.
• the catalyst is Pd(PPh 3 ) 4 .
• the reaction mixture is heated to greater than about 50 °C after addition of ZnCh. In some embodiments, the reaction mixture is heated to about 65 °C.
• step S-3 comprises the deprotection of ester intermediate G-4 to provide a compound of formula I.
• the deprotection is a catalytic hydrogenation using a hydrogen source.
• the catalyst is a palladium catalyst.
• the palladium catalyst is palladium on carbon.
• the hydrogen source is H 2 .
• residual hydrogen catalyst is removed by means of a palladium scavenger.
• the palladium scavenger is a thiol.
• the thiol is SiliaMetS thiol.
• the deprotection is a hydrolysis reaction.
• the hydrolysis is an acidic hydrolysis.
• the acid is a strong, protic acid.
• the acid is sulfuric acid.
• the acid is sulfuric acid, tetrafluoroboric acid, methanesulfonic acid, nitric acid, or hydrochloric acid.
• the reaction occurs in a co-solvent, wherein the co-solvent is an alcohol.
• the co-solvent is 2-propanol, t-butanol, t-amyl alcohol, or ethanol.
• the co-solvent is 2-propanol, t-butanol, t-amyl alcohol, ethanol, or acetonitrile.
• the temperature of the hydrolysis reaction is maintained between 5 and 10 °C. In some embodiments, the temperature of the hydrolysis reaction is between about 0 and about 20 °C. In some embodiments, the temperature of the hydrolysis reaction is between about 2 and about 8 °C. In some embodiments, the temperature of the hydrolysis reaction is maintained between about 2 and about 10 °C.
• the product is purified by crystallization. In some embodiments, the product is crystallized from an alcohol solution. In some embodiments, the alcohol solution is a mixture of ethanol and water. In some embodiments, the product is crystallized from a mixture of acetonitrile and water.
• intermediates of formula G-l are prepared according to the method depicted in Scheme 2, wherein each of R a , R H , R 2 , R 5 are as defined in classes and subclasses herein, both singly and in combination.
• step S-4 comprises the conversion of the hydroxyl group of intermediate G-5 to a leaving group, R H .
• intermediate G-5 is an alcohol or an oxygen anion thereof.
• R H is a sulfonate group
• G-5 is treated with a sulfonylating reagent.
• the sulfonate group is a mesylate, a triflate, a benzenesulfonate, a tosylate, a brosylate, or a nosylate.
• the sulfonate group is a mesylate, a triflate, a benzenesulfonate, a tosylate, a brosylate, or a nosylate.
• sulfonylating reagent is a sulfonyl halide. In some embodiments the sulfonylating reagent is a sulfonyl chloride. In some embodiments the sulfonyl chloride is methanesulfonyl chloride.
• R H is a halogen
• the hydroxyl group is converted directly to a halogen by means of a halogenating reagent.
• the halogenating reagent is a brominating reagent.
• the hydroxyl group is first converted to a first leaving group, and then that first leaving group is further converted to the halogen.
• the first leaving group is a sulfonate.
• the sulfonate is a mesylate, a triflate, a benzenesulfonate, a tosylate, a brosylate, or a nosylate. In some embodiments, the sulfonate is a methanesulfonate. In some embodiments, the
• methanesulfonylate is formed by treatment of G-5 with methanesulfonyl chloride.
• the sulfonate is formed in the presence of a base.
• the base is an amine base.
• the amine base is triethylamine, diisopropylethylamine (Hunig's base), l,8-diazabicyclo[5.4.0]undec-7-ene, pyridine, or dimethylaminopyridine (DMAP).
• the amine base is trimethylamine.
• the amine base is triethylamine.
• the solvent is 2-methyltetrahydrofuran, tetrahydrofuran, or dichloromethane. In some embodiments, the solvent is 2- methyltetrahydrofuran.
• the reaction further comprises a promoter. In some embodiments, the promoter is Nal or tetrabutylammonium iodide. In some embodiments, the reaction takes place at about 20 °C to about 30 °C. In some embodiments, the reaction takes place at about 22 °C.
• the first leaving group is further converted to a halogen by displacement with halide.
• the halide is bromide.
• the source of halide is a metal halide.
• the source of bromide is a metal bromide.
• the metal bromide is an alkali metal bromide.
• the alkali metal bromide is LiBr.
• the alkali metal bromide is NaBr.
• the alkali metal bromide is KBr.
• this displacement further comprises a promoter.
• the promoter is a phase transfer catalyst.
• the promoter can include, but is not limited to tetramethylammonium bromide or tetrabutylammonium bromide.
• the displacement takes place in a polar solvent.
• the polar solvent is a polar aprotic solvent.
• the polar aprotic solvent is N-methylpyrrolidone ( MP). In some embodiments, the polar aprotic solvent is dimethylformamide (DMF). In some embodiments, the polar aprotic solvent is dimethylacetamide (DMAc). In some embodiments, the polar aprotic solvent is ethyl acetate (EtOAc). In some embodiments, the reaction takes place at about 50 °C to about 60 °C. In some embodiments, the reaction takes place at about 55 °C. In some embodiments, leaving group formation step S-4 and alkylation step S-l are performed together without the isolation of intermediate G-l. [0209] In some embodiments, intermediates of formula G-5 are prepared according to the method depicted in Scheme 3, wherein each of R a , R 2 , R 5 are as defined in classes and subclasses herein, both singly and in combination.
• step S-5 comprises the epoxidation of aldehyde G-6, thereby forming the epoxide of formula rac-G-7.
• the epoxidation is a Corey- Chaykovsky epoxidation.
• a Corey-Chaykovsky epoxidation is the use of a sulfur ylide to convert a carbonyl compound to its corresponding epoxide.
• the sulfur ylide is formed from a trimethylsulfonium or trimethylsulfoxonium salt.
• the sulfur ylide is formed from
• the sulfur ylide is formed from
• step S-6 comprises epoxide opening of intermediate rac-G-7 by an alcohol of formula R a -OH, wherein R a is as defined in classes and subclasses herein, thereby forming intermediate rac-G-5.
• the epoxide opening is acid catalyzed.
• the acid is a Lewis acid.
• the Lewis acid is a metal halide or metal sulfonate.
• the Lewis acid is an iron salt.
• the Lewis acid is FeCb.
• step S-6 is conducted without additional solvent.
• the Lewis acid is BF3-Et 2 0.
• step S-6 is toluene.
• the acid is HBF4-OEt 2 , HBF4-water, or camphorsulfonic acid.
• the solvent of step S-6 is di chl oromethane .
• step S-7 comprises the selective acylation of the (R)-isomer of intermediate G-5, with an [acyl] donor, thereby producing intermediate (R)-G-8 and residual (S)-G-5.
• the [acyl] donor is of the formula R x C(0)OR y , wherein R x is optionally substituted Ci-4 aliphatic; and R y is optionally substituted Ci-4 aliphatic or optionally substituted Ci-4 acyl.
• the [acyl] donor provides a C4-acyl group.
• the [acyl] donor is an optionally substituted 4-7 membered lactone or an optionally substituted 4-7 membered cyclic anhydride.
• the [acyl] donor is an optionally substituted 4-7 membered cyclic anhydride.
• the [acyl] donor is vinyl acetate, and [acyl] is acetyl.
• the [acyl] donor is vinyl butyrate, and [acyl] is butyryl.
• the [acyl] donor is succinic anhydride, and [acyl] is succinyl.
• the acylation is a kinetic resolution. In some embodiments the kinetic resolution is accomplished by a lipase enzyme. In some embodiments, the lipase enzyme is Candida antarctica lipase B (CAL-B). In some embodiments, the lipase enzyme is Novozyme 435. In some embodiments, the acylation reaction is conducted in THF solvent. In some embodiments, the acylation reaction is conducted in toluene solvent. In some
• the acylation reaction is conducted in a mixture of THF and toluene.
• [acyl] is succinyl
• unreacted intermediate G-5 is separated from (R)-G-8 by forming the succinate anion under aqueous basic conditions and extracting the unreacted neutral alcohol species into an organic solvent.
• step S-8 comprises the hydrolysis of enantiomerically enriched intermediate (R)-G-8, thereby forming (R)-G-5.
• the hydrolysis is an aqueous hydrolysis.
• the aqueous hydrolysis is an alkaline hydrolysis.
• the aqueous hydrolysis is mediated by hydroxide.
• the aqueous hydrolysis is mediated by sodium hydroxide.
• steps S-7 and S-8 are performed without the isolation of intermediate (R)-G-8.
• the (R)-G-8 produced has an enantiomeric excess of greater than 70%, 80%, 90%, 95%, 97%, 98%, 99%, or 99.5%.
• compounds of formula G-4 are prepared according to the method depicted in Scheme 4, wherein each of R a , R e , R H , R 2 , R 5 are as defined in classes and subclasses herein, both singly and in combination.
• Scheme 4 Alternate S nthesis of Intermediates of Formula G-4
• step S-9 comprises the alkylation of intermediate G-9 by alkyl halide G-1, thereby forming intermediate G-4.
• the alkylation is mediated by a base.
• the base is an alkoxide base.
• the base is an alkali metal alkoxide.
• the base is potassium t-butoxide.
• the base is sodium t-butoxide.
• the base is potassium t- amyloxide.
• the base is a carbonate base.
• the carbonate base is an alkali metal carbonate.
• the alkali metal carbonate is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, cesium bicarbonate, potassium phosphate tribasic, or potassium phosphate dibasic.
• the alkali metal carbonate is potassium carbonate or cesium carbonate.
• the alkali metal carbonate is potassium carbonate.
• the alkali metal carbonate is potassium bicarbonate.
• the alkali metal carbonate is cesium bicarbonate.
• step S-9 proceeds in a polar solvent.
• the polar solvent is a polar aprotic solvent.
• the polar aprotic solvent is N-methylpyrrolidone (NMP).
• the polar aprotic solvent is dimethylformamide (DMF).
• the polar aprotic solvent is
• the reaction takes place at a temperature of about 90 °C to about 100 °C. In some embodiments, the reaction takes place at a temperature of about 100 °C to about 140 °C. In some embodiments, the reaction takes place at a temperature of about 115 °C.
• step S-10 comprises a urea formation between intermediates G-10 (or a salt thereof), and G-ll (or a salt thereof), thereby forming the intermediate of formula G-12.
• the urea formation proceed using a carbonyl source.
• the carbonyl source is carbonyldiimidazole (CDI).
• the carbonyl source is triphosgene.
• the intermediate of formula G-ll is used as its hydrochloride salt.
• an additional base is used.
• the base is an amine base.
• the amine base is triethylamine.
• step S-ll comprises the bromination of an intermediate of formula G-12, thereby forming an intermediate of formula G-13.
• the brominating reagent is N-bromosuccinimide.
• the bromination is conducted in a polar aprotic solvent.
• the polar aprotic solvent is dimethylformamide (DMF).
• step S-12 comprises the intramolecular cyclization of an intermediate of formula G-13, thereby forming an intermediate of formula G-2.
• the intramolecular cyclization is effected by a strong base.
• the strong base is an alkali metal alkoxide.
• the alkali metal alkoxide is potassium t-butoxide.
• the intramolecular cyclization is conducted in an ether solvent.
• the ether solvent is 1,4-dioxane.
• step S-13 comprises the coupling of intermediate G-2 with an oxazole synthon (oxazole or oxazole metallate), thereby forming intermediate G-9.
• the coupling is a metal-catalyzed coupling.
• the metal- catalyzed coupling is a Negishi coupling.
• a Negishi coupling is a transition metal-catalyzed cross-coupling of an organic halide or sulfonate compound with an organozinc compound.
• the oxazole synthon is an oxazole zincate.
• the oxazole zincate is formed by metal exchange between 2-lithio-oxazole and a zinc salt.
• the zinc salt is ZnCh.
• the 2-lithio-oxazole is formed by treating oxazole with n-butyllithium.
• the 2-lithio-oxazole is formed at a temperature below -40 °C.
• the 2-lithio-oxazole is formed at a temperature below -60 °C.
• the transition metal catalyst is a palladium catalyst.
• the palladium catalyst is Pd(PPh 3 ) 4 .
• crystalline intermediate G-4 is purified by crystallization.
• the oxazole is treated with a metalating agent selected from isopropyl magnesium chloride, isopropyl magnesium bromide, TMPZnCl-LiCl, TMPMgCl- LiCl, and isopropyl magnesium chloride/lithium chloride (wherein TMP refers to 2,2,6,6,- tetramethylpiperidine).
• the metalating agent is isopropyl magnesium chloride.
• the oxazole is treated with isopropyl magnesium chloride (2 M in THF).
• the oxazole is treated with a metalating agent at about -20 °C to about -10 °C.
• the oxazole is treated with a metalating agent at about -15 °C.
• the solvent is tetrahydrofuran, 2-methyltetrahydrofuran, or a mixture thereof. In some embodiments, the solvent is tetrahydrofuran and 2- methyltetrahydrofuran.
• the reaction further comprises adding ZnCh to form an oxazole zincate. In some embodiments, the reaction further comprises adding ZnCh as a solution in 2-methyltetrahydrofuran.
• the catalyst used in the Negishi coupling is a palladium catalyst selected from Pd(PPh 3 ) 4 , tBuXPhos Pd precatalyst, XPhos Pd precatalyst, RuPhos Pd precatalyst, and Pd-PEPPSI-IPent (dichloro[l,3-bis(2,6-di-3- pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)).
• Pd-PEPPSI-IPent platinum-PEPPSI-IPent
• the catalyst is Pd(PPh 3 ) 4 .
• the reaction mixture is heated to greater than about 50 °C after addition of ZnCh. In some embodiments, the reaction mixture is heated to about 65 °C.
• step S-ll comprises the chlorination of an intermediate of formula G-12, thereby forming an intermediate of formula G-13-a.
• the chlorinating reagent is N-chlorosuccinimide.
• G-13-a can be used in step S-12 in place of G-13 as described above to form the chloro analog of G-2, which can be used in step S-13 in place of G-2.
• Some embodiments provide for a rocess for preparing compound G-4-a:
• R H is halogen
• R H is bromo
• Some embodiments provide for a process for preparing an enantiomerically enriched compound of formula (R)-G-5:
• R a is an optionally substituted group selected from a 3-7 membered ring having 0-2 heteroatoms selected from nitrogen, oxygen, and sulfur, and Ci-6 aliphatic;
• R 2 is hydrogen, or optionally substituted Ci-6 aliphatic
• R 5 is hydrogen or halogen
• [acyl] is a C1-C7 acyl group; and b) removing the [acyl] group;
• the compound of formula (R)-G-5 is:
• the [acyl] donor is an optionally substituted 4-7 membered lactone or 4-7 membered optionally substituted cyclic anhydride; or a compound of the formula
• R x C(0)OR y wherein R x is optionally substituted Ci-4 aliphatic; and R y is optionally substituted
• Ci-4 aliphatic or optionally substituted Ci-4 acyl are optionally substituted Ci-4 acyl.
• the [acyl] is a C 4 acyl group.
• the lipase enzyme is Candida antarctica lipase B.
• Some embodiments provide for a process of preparing a compound G-9-a:
• the reaction conditions comprise a solvent, wherein the solvent is tetrahydrofuran, 2-methyltetrahydrofuran, or a mixture thereof.
• the solvent is tetrahydrofuran and 2-methyltetrahydrofuran.
• the reaction conditions comprise a metalating agent.
• the metalating agent selected from isopropyl magnesium chloride, isopropyl magnesium bromide, TMPZnCl-LiCl, TMPMgCl-LiCl, and isopropyl magnesium
• the metalating agent is isopropyl magnesium chloride.
• the reaction conditions comprise contacting the oxazole and metalating agent at about -20 °C to -10 °C or about -15 °C.
• the reaction conditions comprise adding ZnCh.
• the catalyst is a palladium catalyst selected from Pd(PPh 3 ) 4 , tBuXPhos Pd precatalyst, XPhos Pd precatalyst, RuPhos Pd precatalyst, and Pd-PEPP SI-IP ent (dichloro[l,3- bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)).
• the catalyst is Pd(PPh 3 ) 4 .
• the reaction mixture is heated to greater than about 50 °C after addition of ZnCh. In some embodiments, the reaction mixture is heated to about 60 °C to about 70 °C after addition of ZnCh.
• Some embodiments provide for a process of preparing a compound (R)-G-l-a:
• the sulfonylating reagent is methanesulfonyl chloride.
• the reaction conditions of step (a) comprise a base.
• the base is triethylamine, diisopropylethylamine (Hunig's base), 1,8- diazabicyclo[5.4.0]undec-7-ene, pyridine, or dimethylaminopyridine (DMAP).
• the base is triethylamine.
• the reaction conditions of step (a) comprise a solvent selected from 2-methyltetrahydrofuran, tetrahydrofuran, and
• the reaction conditions of step (a) comprise a promoter.
• the promoter is Nal or tetrabutylammonium iodide.
• the reaction conditions of step (a) comprise a temperature of about 20 °C to about 30 °C. In some embodiments, the reaction conditions of step (a) comprise a temperature of about 22 °C.
• the bromide salt is LiBr, NaBr, or KBr.
• the bromide salt is LiBr. In some embodiments, the bromide salt is an ammonium salt. In some embodiments, the bromide salt is tetrabutylammonium bromide.
• reaction conditions of step (b) comprise a solvent selected from N-methylpyrrolidone ( MP), dimethylformamide (DMF), and dimethylacetamide
• the solvent is NMP.
• the reaction conditions of step (b) comprise a temperature of about 50 °C to about 60 °C. In some embodiments, In some embodiments, the reaction conditions of step (b) comprise a temperature of about 55 °C.
• the reaction conditions of step (a) comprise a solvent, wherein the solvent is tetrahydrofuran, 2-methyltetrahydrofuran, or a mixture thereof.
• the solvent is tetrahydrofuran and 2-methyltetrahydrofuran.
• the reaction conditions of step (a) comprise a metalating agent.
• the metalating agent selected from isopropyl magnesium chloride, isopropyl magnesium bromide, TMPZnCl-LiCl, TMPMgCl-LiCl, and isopropyl magnesium chloride/lithium chloride (wherein TMP refers to 2,2,6,6,-tetramethylpiperidine).
• the metalating agent is isopropyl magnesium chloride.
• the reaction conditions of step (a) comprise contacting the oxazole and metalating agent at about -20 °C to -10 °C or about -15 °C.
• the reaction conditions of step (a) comprise adding ZnCh.
• the catalyst is a palladium catalyst selected from Pd(PPh 3 ) 4 , tBuXPhos Pd precatalyst, XPhos Pd precatalyst, RuPhos Pd precatalyst, and Pd-PEPPSI-IPent.
• the catalyst is Pd(PPh 3 ) 4 .
• the reaction mixture is heated to greater than about 50 °C after addition of ZnCh. In some embodiments, the reaction mixture is heated to about 60 °C to about 70 °C after addition of ZnCh.
• the reaction conditions of step (b) comprise a base.
• the base is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, cesium bicarbonate, potassium phosphate tribasic, or potassium phosphate dibasic.
• the base is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, or cesium bicarbonate.
• the base is potassium carbonate.
• the base is potassium carbonate or potassium bicarbonate.
• the reaction conditions of step (b) comprise a solvent selected from N-methylpyrrolidone (NMP), dimethylformamide (DMF), and dimethylacetamide (DMA).
• NMP N-methylpyrrolidone
• DMF dimethylformamide
• DMA dimethylacetamide
• the solvent is NMP.
• reaction conditions of step (b) comprise a temperature of about 100 °C to about 140 °C. In some embodiments, the reaction conditions of step (b) comprise a temperature of about 115 °C.
• the reaction conditions of step (c) comprise an acid.
• the acid is sulfuric acid, tetrafluoroboric acid, methanesulfonic acid, nitric acid, or hydrochloric acid.
• the acid is sulfuric acid.
• the acid is hydrochloric acid.
• the reaction conditions of step (c) comprise a co-solvent.
• the co-solvent is an alcohol.
• the co-solvent is 2- propanol, t-butanol, t-amyl alcohol, ethanol, or acetonitrile.
• the reaction conditions of step (c) comprise a temperature of about 5 and 10 °C. In some embodiments, the reaction conditions of step (c) comprise a temperature between about 0 and about 20 °C. In some embodiments, the reaction conditions of step (c) comprise between about 2 and about 8 °C.
• the bromide salt is LiBr, NaBr, or KBr.
• the bromide salt is LiBr. In some embodiments, the bromide salt is an ammonium salt. In some embodiments, the bromide salt is tetrabutyl ammonium bromide.
• reaction conditions of step (a) comprise a solvent selected from N-methylpyrrolidone ( MP), dimethylformamide (DMF), and dimethylacetamide
• the solvent is NMP. In some embodiments, In some
• the reaction conditions of step (a) comprise a temperature of about 50 °C to about 60 °C. In some embodiments, In some embodiments, the reaction conditions of step (a) comprise a temperature of about 55 °C.
• the bromide salt is LiBr, NaBr, or KBr.
• the bromide salt is LiBr. In some embodiments, the bromide salt is an ammonium salt. In some embodiments, the bromide salt is tetrabutyl ammonium bromide.
• the reaction conditions of step (b) comprise a solvent, wherein the solvent is tetrahydrofuran, 2-methyltetrahydrofuran, or a mixture thereof.
• the solvent is tetrahydrofuran and 2-methyltetrahydrofuran.
• the reaction conditions of step (b) comprise a metalating agent.
• the metalating agent selected from isopropyl magnesium chloride, isopropyl magnesium bromide, TMPZnCl-LiCl, TMPMgCl-LiCl, and isopropyl magnesium chloride/lithium chloride (wherein TMP refers to 2,2,6,6,-tetramethylpiperidine).
• the metalating agent is isopropyl magnesium chloride.
• the reaction conditions of step (b) comprise contacting the oxazole and metalating agent at about -20 °C to -10 °C or about -15 °C.
• the reaction conditions of step (b) comprise adding ZnCh.
• the catalyst is a palladium catalyst selected from Pd(PPh 3 ) 4 , tBuXPhos Pd precatalyst, XPhos Pd precatalyst, RuPhos Pd precatalyst, and Pd-PEPPSI-IPent.
• the catalyst is Pd(PPh 3 ) 4 .
• the reaction mixture is heated to greater than about 50 °C after addition of ZnCh. In some embodiments, the reaction mixture is heated to about 60 °C to about 70 °C after addition of ZnCh.
• the reaction conditions of step (c) comprise a base.
• the base is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, cesium bicarbonate, potassium phosphate tribasic, or potassium phosphate dibasic.
• the base is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, cesium bicarbonate, potassium phosphate tribasic, or potassium phosphate dibasic.
• the base is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, or cesium bicarbonate.
• the base is potassium carbonate.
• the base is potassium carbonate or potassium bicarbonate.
• reaction conditions of step (c) comprise a solvent selected from N-methylpyrrolidone ( MP), dimethylformamide (DMF), and dimethylacetamide (DMA).
• the solvent is NMP.
• the reaction conditions of step (c) comprise a temperature of about 90 °C to about 100 °C. In some embodiments, the reaction conditions of step (c) comprise a temperature of about 100 °C to about 140 °C. In some embodiments, the reaction conditions of step (c) comprise a temperature of about 115 °C.
• the reaction conditions of step (d) comprise an acid.
• the acid is sulfuric acid, tetrafluoroboric acid, methanesulfonic acid, nitric acid, or hydrochloric acid.
• the acid is sulfuric acid.
• the acid is hydrochloric acid.
• the reaction conditions of step (d) comprise a co-solvent.
• the co-solvent is an alcohol.
• the co-solvent is 2- propanol, t-butanol, t-amyl alcohol, ethanol, or acetonitrile.
• the reaction conditions of step (d) comprise a temperature of about 5 and 10 °C. In some embodiments, the reaction conditions of step (d) comprise a temperature between about 0 and about 20 °C. In some embodiments, the reaction conditions of step (e) comprise between about 2 and about 8 °C.
• the sulfonylating reagent is methanesulfonyl chloride.
• the reaction conditions of step (a) comprise a base.
• the base is triethylamine, diisopropylethylamine (Hunig's base), 1,8- diazabicyclo[5.4.0]undec-7-ene, pyridine, or dimethylaminopyridine (DMAP).
• the base is triethylamine.
• the reaction conditions of step (a) comprise a solvent selected from 2-methyltetrahydrofuran, tetrahydrofuran, and
• the reaction conditions of step (a) comprise a promoter.
• the promoter is Nal or tetrabutylammonium iodide.
• the reaction conditions of step (a) comprise a temperature of about 20 °C to about 30 °C. In some embodiments, the reaction conditions of step (a) comprise a temperature of about 22 °C.
• the bromide salt is LiBr, NaBr, or KBr.
• the bromide salt is LiBr. In some embodiments, the bromide salt is an ammonium salt. In some embodiments, the bromide salt is tetrabutylammonium bromide.
• reaction conditions of step (b) comprise a solvent selected from N-methylpyrrolidone ( MP), dimethylformamide (DMF), and dimethylacetamide
• the solvent is NMP.
• the reaction conditions of step (b) comprise a temperature of about 50 °C to about 60 °C. In some embodiments, In some embodiments, the reaction conditions of step (b) comprise a temperature of about 55 °C.
• the reaction conditions of step (c) comprise a solvent, wherein the solvent is tetrahydrofuran, 2-methyltetrahydrofuran, or a mixture thereof.
• the solvent is tetrahydrofuran and 2-methyltetrahydrofuran.
• the reaction conditions of step (c) comprise a metalating agent.
• the metalating agent selected from isopropyl magnesium chloride, isopropyl magnesium bromide, TMPZnCl-LiCl, TMPMgCl-LiCl, and isopropyl magnesium chloride/lithium chloride (wherein TMP refers to 2,2,6,6,-tetramethylpiperidine).
• the metalating agent is isopropyl magnesium chloride.
• the reaction conditions of step (c) comprise contacting the oxazole and metalating agent at about -20 °C to -10 °C or about -15 °C.
• the reaction conditions of step (c) comprise adding ZnCh.
• the catalyst is a palladium catalyst selected from Pd(PPh 3 ) 4 , tBuXPhos Pd precatalyst, XPhos Pd precatalyst, RuPhos Pd precatalyst, and Pd-PEPPSI-IPent.
• the catalyst is Pd(PPh 3 ) 4 .
• the reaction mixture is heated to greater than about 50 °C after addition of ZnCh. In some embodiments, the reaction mixture is heated to about 60 °C to about 70 °C after addition of ZnCh.
• the reaction conditions of step (d) comprise a base.
• the base is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, cesium bicarbonate, potassium phosphate tribasic, or potassium phosphate dibasic.
• the base is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, cesium bicarbonate, potassium phosphate tribasic, or potassium phosphate dibasic.
• the base is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, or cesium bicarbonate.
• the base is potassium carbonate.
• the base is potassium carbonate or potassium bicarbonate.
• reaction conditions of step (d) comprise a solvent selected from N-methylpyrrolidone ( MP), dimethylformamide (DMF), and dimethylacetamide (DMA).
• the solvent is NMP.
• the reaction conditions of step (d) comprise a temperature of about 90 °C to about 100 °C. In some embodiments, the reaction conditions of step (d) comprise a temperature of about 100 °C to about 140 °C. In some embodiments, the reaction conditions of step (d) comprise a temperature of about 115 °C.
• the reaction conditions of step (e) comprise an acid.
• the acid is sulfuric acid, tetrafluoroboric acid, methanesulfonic acid, nitric acid, or hydrochloric acid.
• the acid is sulfuric acid.
• the acid is hydrochloric acid.
• the reaction conditions of step (e) comprise a co-solvent.
• the co-solvent is an alcohol.
• the co-solvent is 2- propanol, t-butanol, t-amyl alcohol, ethanol, or acetonitrile.
• the reaction conditions of step (e) comprise a temperature of about 5 and 10 °C.
• the reaction conditions of step (e) comprise a temperature between about 0 and about 20 °C.
• the reaction conditions of step (e) comprise between about 2 and about 8 °C.
• [acyl] is R x C(0)-, wherein R x is optionally substituted Ci-4 aliphatic;
• R a is an optionally substituted group selected from a 3-7 membered ring having 0-2 heteroatoms selected from nitrogen, oxygen, and sulfur, and a Ci-6 aliphatic;
• R 2 is hydrogen, or optionally substituted Ci-6 aliphatic; and R 5 is hydrogen or halogen.
• R x is optionally substituted C3-4 aliphatic.
• R x is optionally substituted Ci-4 aliphatic.
• R x is optionally substituted Ci-4 aliphatic.
• R H is a leaving group
• R a is an optionally substituted group selected from a 3-7 membered ring heteroatoms selected from nitrogen, oxygen, and sulfur, and a Ci-6 aliphatic;
• R 2 is hydrogen, or optionally substituted Ci-6 aliphatic;
• R 5 is hydrogen or halogen.
• R is a leaving group
• R is a leaving group
• R H is halogen or sulfonate. In some embodiments, R H is bromo. In some embodiments, R H is mesylate. In some embodiments, [acyl] is succinyl. In some embodiments, the [acyl] donor is succinic anhydride.
• the invention provides a composition comprising a compound of this invention or a pharmaceutically acceptable salt, ester, or salt of ester thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
• a composition comprising a compound as described herein, or a pharmaceutically acceptable salt or co-crystal thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
• compositions comprising a crystalline form of Compound 1 as described herein.
• the amount of compound in compositions of this invention is such that is effective to measurably inhibit ACC, in a biological sample or in a patient.
• the amount of compound in compositions of this invention is such that is effective to measurably inhibit ACC, in a biological sample or in a patient.
• a composition of this invention is formulated for administration to a patient in need of such composition. In some embodiments, a composition of this invention is formulated for oral administration to a patient.
• a compound as used herein, means an ACC inhibitor of Formula I (including but not limited to Compound 1), or a salt or solid form thereof.
• a compound is Compound 1 or a pharmaceutically acceptable salt thereof.
• a compound is the free acid of Compound 1.
• a compound is a solid form of
• a compound is a crystalline form of Compound 1.
• a compound is Form I, Form II, Form III, Form IV, Form V, Form VI, Form VII, or Form VIII of Compound 1.
• a compound is a polymorph of the free acid of Compound 1.
• a compound is Form I, Form VII, or Form VIII of Compound 1.
• a compound is a pseudopolymorph of the free acid of Compound 1.
• a compound is Form I of Compound 1.
• a compound is Form II of Compound 1.
• a compound is Form III of Compound 1.
• a compound is Form IV of Compound 1.
• a compound is Form V of Compound 1. In some embodiments, a compound is Form VI of Compound 1. In some embodiments, a compound is Form VII of Compound 1. In some embodiments, a compound is Form VIII of Compound 1. In some embodiments, a compound is a solvate of Compound 1. In some embodiments, a compound is amorphous Compound 1. In some embodiments, a compound is a salt or co-crystal of
• a compound is Compound 1 Sodium Form I. In some embodiments, a compound is Compound 1 Sodium Form II. In some embodiments, a compound is Compound 1 Calcium Form I. In some embodiments, a compound is Compound 1 Magnesium Form I. In some embodiments, a compound is Compound 1 Diethanolamine Form I. In some embodiments, a compound is Compound 1 Piperazine Form I. [0296]
• patient means an animal, preferably a mammal, and most preferably a human.
• compositions of this invention refers to a nontoxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
• pharmaceutically acceptable carriers, adjuvants or diluents that may be used in the compositions of this invention include, but are not limited to, antiadherents, binders, coatings, colorants, disintegrants, flavors, glidants, lubricants, preservatives, sorbents, and vehicles.
• carriers, adjuvants, and diluents include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, 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 substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
• ion exchangers alumina, aluminum stearate, lecithin
• serum proteins such as human serum albumin
• buffer substances such as phosphates, glycine,
• a "pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof.
• inhibitorily active metabolite or residue thereof means that a metabolite or residue thereof is also an inhibitor of ACC.
• the inhibitorily active metabolite or residue thereof is selected from the followin :
• the present invention provides a metabolite of Compound 1, wherein the metabolite is the M+glucuronide conjugate.
• the M+glucuronide conjugate has an IC50 at ACC1 of 5 nM.
• the present invention provides a metabolite of Compound 1, wherein the metabolite is a M-CH3 demethylated metabolite.
• the M-CH3 metabolite of Compound 1 has an IC50 at ACC1 of 22 nM.
• a provided metabolite of Compound 1 is isolated.
• compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
• parenteral as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
• the compositions are administered orally, intraperitoneally or intravenously.
• Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
• the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
• a nontoxic parenterally acceptable diluent or solvent for example as a solution in 1,3-butanediol.
• acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil may be employed including synthetic mono- or di-glycerides.
• Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
• These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
• Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
• compositions of this invention may be orally
• a pharmaceutically acceptable composition comprising a form of Compound 1 as described herein is administered as a capsule.
• a pharmaceutically acceptable composition comprising a form of Compound 1 as described herein is administered as a tablet.
• compositions of this invention may be administered in the form of suppositories for rectal administration.
• suppositories for rectal administration.
• suppositories can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
• suitable non-irritating excipient include cocoa butter, beeswax and polyethylene glycols.
• compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
• Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
• compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
• Carriers for topical administration of compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
• provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more
• Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
• compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzyl alkonium chloride.
• the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.
• compositions of this invention may also be administered by nasal aerosol or inhalation.
• Such compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
• compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food.
• compositions of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration.
• provided compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.
• a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
• the amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.
• a crystalline form of Compound 1 is administered at a dose of about 2 milligrams to about 500 milligrams per day, about 2 milligrams to about 400 milligrams per day, about 2 milligrams to about 300 milligrams per day, about 2 milligrams to about 200 milligrams per day, or about 2 milligrams to about 100 milligrams per day.
• a crystalline form of Compound 1 is administered at a dose of about 5 milligrams per day, about 6 milligrams per day, about 7 milligrams per day, about 8 milligrams per day, about 9 milligrams per day, about 10 milligrams per day, about 11 milligrams per day, about 12 milligrams per day, about 13 milligrams per day, about 14 milligrams per day, about 15 milligrams per day, 16 milligrams per day, 17 milligrams per day, 18 milligrams per day, 19 milligrams per day, 20 milligrams per day, 21 milligrams per day, 22 milligrams per day, 23 milligrams per day, 24 milligrams per day, or 25 milligrams per day.
• a crystalline form of Compound 1 is administered at a dose of greater than about 5 milligrams per day, greater than about 10 milligrams per day, greater than about 15 milligrams per day, greater than about 20 milligrams per day, greater than about 25 milligrams per day, greater than about 30 milligrams per day, greater than about 35 milligrams per day, greater than about 40 milligrams per day, greater than about 45 milligrams per day, or greater than about 50 milligrams per day.
• Compound 1 is administered at a dose of less than about 300 milligrams per day, less than about 275 milligrams per day, less than about 250 milligrams per day, less than about 225 milligrams per day, less than about 200 milligrams per day, less than about 175 milligrams per day, less than about 150 milligrams per day, less than about 125 milligrams per day, less than about 100 milligrams per day.
• a crystalline form of Compound 1 is administered at a dose of about 5 milligrams once daily, about 20 milligrams once daily, about 30 milligrams once daily, about 50 milligrams once daily, about 80 milligrams once daily, about 100 milligrams once daily, about 150 milligrams once daily, about 200 milligrams once daily, about 500 milligrams once daily, about 800 milligrams once daily, or about 1000 milligrams once daily.
• a crystalline form of Compound 1 is administered at a dose of about 10 milligrams twice daily, about 25 milligrams twice daily, about 50 milligrams twice daily, or about 100 milligrams twice daily.
• treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein.
• treatment may be administered after one or more symptoms have developed.
• treatment may be administered in the absence of symptoms.
• treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
• terapéuticaally effective amount refers to an amount of the compound as described herein that is sufficient to effect treatment as defined above, when administered to a patient (particularly a human) in need of such treatment in one or more doses.
• therapeutically effective amount will vary, depending upon the patient, the disease being treated, the weight and/or age of the patient, the severity of the disease, or the manner of administration as determined by a qualified prescriber or care giver.
• Acetyl-CoA carboxylase catalyzes the ATP-dependent carboxylation of acetyl-CoA to form malonyl-CoA.
• This reaction which proceeds in two half-reactions, a biotin carboxylase (BC) reaction and a carboxyltransferase (CT) reaction, is the first committed step in fatty acid (FA) biosynthesis and is the rate-limiting reaction for the pathway.
• BC biotin carboxylase
• CT carboxyltransferase
• malonyl-CoA In addition to its role as a substrate in FA biosynthesis, malonyl-CoA, the product of the ACC-catalyzed reaction, also plays an important regulatory role in controlling mitochondrial FA uptake through allosteric inhibition of carnitine palmitoyltransferase I (CPT-I), the enzyme catalyzing the first committed step in mitochondrial FA oxidation.
• CPT-I carnitine palmitoyltransferase I
• Malonyl-CoA therefore, is a key metabolic signal for the control of FA production and utilization in response to dietary changes and altered nutritional requirements in animals, for example during exercise, and therefore plays a key role in controlling the switch between carbohydrate and fat utilization in liver and skeletal muscle (Harwood, 2005).
• ACC exists as two tissue-specific isozymes, ACC1 which is present in lipogenic tissues (liver, adipose) and ACC2, which is present in oxidative tissues (liver, heart, skeletal muscle).
• ACC1 and ACC2 are encoded by separate genes, display distinct cellular distributions, and share 75% overall amino acid sequence identity, except for an extension at the N-terminus of ACC2 that direct ACC2 to the mitochondrial membrane.
• ACC1 which lacks this targeting sequence, is localized to the cytoplasm.
• the malonyl-CoA formed by ACC2 functions to regulate FA oxidation.
• the malonyl-CoA formed in the cytoplasm through the actions of ACC1 is utilized for FA synthesis and elongation leading to triglyceride formation and VLDL production, whereas the malonyl-CoA formed at the mitochondrial surface by ACC2 acts to regulate FA oxidation (Tong and Harwood, J. Cellular Biochem. 99: 1476, 2006).
• This compartmentalization of malonyl-CoA results from a combination of synthesis proximity (Abu- Elheiga et al, PNAS (USA) 102: 12011, 2005) and the rapid action of malonyl-CoA
• ACC2 knock-out mice exhibit reduced skeletal and cardiac muscle malonyl- CoA, increased muscle FA oxidation, reduced hepatic fat, reduced total body fat, elevated skeletal muscle uncoupling protein-3 (UCP3) which is indicative of increased energy expenditure, reduced body weight, reduced plasma free FAs, reduced plasma glucose, and reduced tissue glycogen, and are protected from diet-induced diabetes and obesity.
• UCP3 skeletal muscle uncoupling protein-3
• CP-640186 also stimulated FA oxidation in C2C12 cells and in rat muscle slices and increased CPT-I activity in Hep-G2 cells. In experimental animals, CP- 640186 acutely reduced malonyl-CoA concentration in both lipogenic and oxidative tissues in both the fed and fasted state, reduced liver and adipose tissue FA synthesis, and increased whole body FA oxidation.
• CP-640186 time- and dose-dependently reduced liver, muscle and adipose triglycerides, reduced body weight due to selective fat reduction without reducing lean body mass, reduced leptin levels, reduced the hyperinsulinemia produced by the high sucrose diet without changing plasma glucose levels, and improved insulin sensitivity.
• ACC is the rate-limiting enzyme in fatty acid synthesis and its product, malonyl CoA, serves as an important regulator of fatty acid oxidation.
• ACC inhibitors both reduce de novo lipid synthesis and promote the oxidation of existing fat. This dual effect on lipid metabolism raises the possibility that ACC inhibitors will be substantially more effective in reducing excess fat than other mechanisms.
• ACC inhibitors will impact insulin sensitivity, plasma and tissue triglycerides, and fasting plasma glucose as a consequence of whole-body and tissue-specific fat mass reduction without the need for poly-pharmacy.
• ACC inhibitors need only access the liver and muscle in the peripheral compartment.
• ACC inhibitors are also expected to have superior safety profiles to existing metabolic disease agents. For example, it is unlikely that an ACC inhibitor will precipitate life-threatening hypoglycemia as is often seen with insulin mimetics, insulin secretagogues, and insulin degradation inhibitors. Also, since ACC inhibitors will reduce whole-body fat mass, they will be superior to the glitazones that increase whole-body fat mass as part of their mechanism of action.
• a peripherally acting agent that causes significant weight loss and improves other metabolic endpoints fits well within the U.S. FDA's requirements for approval of a new obesity agent.
• ACC inhibitors could be approved for familial combined hyperlipidemia and non-alcoholic steatohepatitis (NASH).
• NASH non-alcoholic steatohepatitis
• an isozyme- nonselective ACC inhibitor would represent first-in-class therapy for treating obesity and metabolic syndrome, in addition to other disorders mediated by ACC enzymes.
• the activity of a provided compound as an inhibitor of ACC or treatment for obesity or metabolic syndrome may be assayed in vitro or in vivo.
• An in vivo assessment of the efficacy of the compounds of the invention may be made using an animal model of obesity or metabolic syndrome, e.g., a rodent or primate model.
• Cell-based assays may be performed using, e.g., a cell line isolated from a tissue that expresses ACC.
• biochemical or mechanism-based assays e.g., transcription assays using a purified protein, Northern blot, RT- PCR, etc., may be performed.
• In vitro assays include assays that determine cell morphology, protein expression, and/or the cytotoxicity, enzyme inhibitory activity, and/or the subsequent functional consequences of treatment of cells with compounds of the invention. Alternate in vitro assays quantitate the ability of the inhibitor to bind to protein or nucleic acid molecules within the cell. Inhibitor binding may be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor/target molecule complex and determining the amount of radiolabel bound. Alternatively, inhibitor binding may be determined by running a competition experiment where new inhibitors are incubated with purified proteins or nucleic acids bound to known radioligands. Detailed conditions for assaying a compound utilized in this invention as an inhibitor of ACC are set forth in the Examples below. The aforementioned assays are exemplary and not intended to limit the scope of the invention. The skilled practitioner can appreciate that modifications can be made to conventional assays to develop equivalent assays that obtain the same result.
• a provided compound or composition thereof may be administered using any amount and any route of administration effective for treating or lessening the severity of a metabolic disorder or condition, cancer, a bacterial infection, a fungal infection, a parasitic infection (e.g. malaria), an autoimmune disorder, a neurodegenerative or neurological disorder, schizophrenia, a bone-related disorder, liver disease, or a cardiac disorder.
• a provided compound or composition thereof may be administered using any amount and any route of administration effective for treating or lessening the severity of a disease associated with ACC (Tong et al. "Acetyl-coenzyme A carboxylase: crucial metabolic enzyme and attractive target for drug discovery” Cell and Molecular Life Sciences (2005) 62, 1784-1803).
• a provided compound or composition thereof may be administered using any amount and any route of administration effective for treating or lessening the severity of a metabolic disorder, disease, or condition.
• the metabolic disorder is obesity, metabolic syndrome, diabetes or diabetes-related disorders including Type 1 diabetes (insulin-dependent diabetes mellitus, IDDM) and Type 2 diabetes (non-insulin-dependent diabetes mellitus, NIDDM), impaired glucose tolerance, insulin resistance, hyperglycemia, diabetic complications, including, but not limited to atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, nephropathy, hypertension, neuropathy and nephropathy; obesity comorbidities including but not limited to metabolic syndrome, dyslipidemia, hypertension, insulin resistance, diabetes (including Type 1 and Type 2 diabetes), coronary artery disease, and heart failure.
• the metabolic disorder, disease or condition is non-alcoholic fatty liver disease or hepatic insulin resistance.
• the metabolic disorder is non-alcoholic steatohepati
• the present invention provides a method of treating a metabolic disorder, disease, or condition described herein, comprising administering a compound of the invention in conjunction with one or more pharmaceutical agents.
• Suitable pharmaceutical agents that may be used in combination with the compounds of the present invention include anti-obesity agents (including appetite suppressants), anti-diabetic agents, anti- hyperglycemic agents, lipid lowering agents, and anti-hypertensive agents.
• Suitable lipid lowering agents that can be used in conjunction with a provided compound or composition thereof include but are not limited to, bile acid sequestrants, HMG- CoA reductase inhibitors, HMG-CoA synthase inhibitors, cholesterol absorption inhibitors, acyl coenzyme A-cholesterol acyl transferase (ACAT) inhibitors, CETP inhibitors, squalene synthetase inhibitors, PPAR-alpha agonists, FXR receptor modulators, LXR receptor modulators, lipoprotein synthesis inhibitors, renin-angiotensin system inhibitors, PPAR-delta partial agonists, bile acid reabsorption inhibitors, PPAR-gamma agonists, triglyceride synthesis inhibitors, microsomal triglyceride transport inhibitors, transcription modulators, squalene epoxidase inhibitors, low density lipoprotein receptor inducers, platelet aggregation inhibitor
• Suitable anti-hypertensive agents that can be used in conjunction with a provided compound or composition thereof include but are not limited to diuretics, beta-adrenergic blockers, calcium channel blockers, angiotensin converting enzyme (ACE) inhibitors, neutral endopeptidase inhibitors, endothelin antagonists, vasodilators, angiotensin II receptor antagonists, alpha/beta adrenergic blockers, alpha 1 blockers, alpha 2 agonists, aldosterone inhibitors, mineralocorticoid receptor inhibitors, renin inhibitors, and angiopoietin 2 binding agents.
• ACE angiotensin converting enzyme
• Suitable anti-diabetic agents that can be used in conjunction with a provided compound or composition thereof include but are not limited to other acetyl-CoA carboxylase (ACC) inhibitors, DGAT-1 inhibitors, AZD7687, LCQ908, DGAT-2 inhibitors,
• ACC acetyl-CoA carboxylase
• monoacylglycerol O-acyltransferase inhibitors PDE-10 inhibitors, AMPK activators, sulfonylureas (e.g. acetohexamide, chlorpropamide, diabinese, glibenclamide, glipizide, glyburide, blimipiride, gliclazide, glipentide, gliquidone, glisolamide, tolazamide, tolbutamide), meglitinides, alpha-amylase inhibitors (e.g. tendamistat, treastatin, AL-3688), alpha-glucoside hydrolase inhibitors (e.g.
• alpha-glucosidase inhibitors e.g. adiposine, camiglibose, emiglitate, miglitol, voglibose, pradimicin-Q, sarbostatin
• PPAR-gamma agonists e.g.
• balaglitazone e.g. CLX-0940, GW-1536, GW-1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767, SB-219994), biguanides (e.g.
• metformin, buformin), GLP-1 modulators (exendin-3, exendin-4), liraglutide, albiglutide, exenatide (Byetta), taspoglutide, lixisenatide, dulaglutide, semaglutide, N,N-9924, TTP-054, PTP-1B inhibitors (trodusquemine, hyrtiosal extract), SIRT-1 inhibitors (e.g. resveratrol, GSK2245840,
• DPP-IV inhibitors e.g. sitagliptin, vildagliptin, alogliptin, dutogliptin, linagliptin, saxagliptin
• insulin secretagogues fatty acid oxidation inhibitors
• A2 antagonists J K inhibitors
• glucokinase activators e.g. TTP-399, TTP-355, TTP-547, AZD1656, ARRY403, MK-0599, TAK-329, AZD5658, GKM-001
• insulin insulin mimetics
• glycogen phosphorylase inhibitors e.g.
• GSK1362885 VPAC2 receptor agonists
• SGLT2 inhibitors diapagliflozin, canaghflozin, BI-10733, tofogliflozin, ASP-1941, THR1474, TS-071, ISIS388626, LX4211
• glucagon receptor modulators GPR119 modulators (e.g. MBX-2982, GSK1292263, APD597, PSN821), FGF21 derivatives, TGR5 (GPBAR1) receptor agonists (e.g. INT777), GPR40 agonists (e.g.
• TAK-875 GPR120 agonists, nicotinic acid receptor (HM74A) activators, SGLT1 inhibitors (e.g. GSK1614235), carnitine palmitoyl transferase enzyme inhibitors, fructose 1,6- diphosphatase inhibitors, aldose reductase inhibitors, mineralocorticoid receptor inhibitors, TORC2 inhibitors, CCR2 inhibitors, CCR5 inhibitors, PKC (e.g.
• PKC-alpha, PKC-beta, PKC- gamma) inhibitors fatty acid synthetase inhibitors, serine palmitoyl transferase inhibitors, GPR81 modulators, GPR39 modulators, GPR43 modulators, GPR41 modulators, GPR105 modulators, Kvl .3 inhibitors, retinol binding protein 4 inhibitors, glucocorticoid receptor modulators, somatostatin receptor (e.g. SSTR1, SSTR2, SSTR3, SSTR5) inhibitors, PDHK2 inhibitors, PDHK4 inhibitors, MAP4K4 inhibitors, ILl-beta modulators, and RXR-alpha modulators.
• SSTR1, SSTR2, SSTR3, SSTR5 somatostatin receptor
• Suitable anti-obesity agents include but are not limited to, 11-beta-hydroxy steroid dehydrogenase 1 inhibitors, stearoyl-CoA desaturase (SCD-1) inhibitors, MCR-4 agonists, CCK-A agonists, monoamine reuptake inhibitors (e.g. sibutramine), sympathomimetic agents, beta-3 -adrenergic receptor agonists, dopamine receptor agonists (e.g. bromocriptine), melanocyte-stimulating hormone and analogs thereof, 5-HT 2 c agonists (e.g.
• melanin concentrating hormone antagonists melanin concentrating hormone antagonists
• leptin leptin analogs
• leptin agonists galanin antagonists
• lipase inhibitors e.g. tetrahydrolipstatin / Orlistat
• anorectic agents e.g. bombesin agonists
• PY antagonists e.g. velneperit
• PYY3-36 and analogs thereof
• BRS3 modulators opioid receptor mixed antagonists, thyromimetic agents, dehydroepiandrosterone, glucocorticoid agonists or antagonists, orexin antagonists, GLP-1 agonists, ciliary neurotrophic factors (e.g.
• Axokine human agouti -related protein (AGRP) inhibitors, H3 antagonists or inverse agonists, neuromedin U agonists, MTP/ApoB inhibitors (e.g. gut-selective MTP inhibitors such as dirlotapide, JTT130, Usistapide, SLX4090), MetAp2 inhibitors (e.g. ZGN-433), agents with mixed modulatory activity at two or more of glucagon, GIP, and GLP1 receptors (e.g. MAR- 701, ZP2929), norepinephrine reuptake inhibitors, opioid antagonists (e.g.
• naltrexone CB 1 receptor antagonists or inverse agonists, ghrelin agonists or antagonists, oxyntomodulin and analogs thereof, monoamine uptake inhibitors (e.g. tesofensine), and combination agents (e.g. buproprion plus zonisamide (Empatic), pramlintide plus metreleptin, buproprion plus naltrexone (Contrave), phentermine plus topiramate (Qsymia).
• monoamine uptake inhibitors e.g. tesofensine
• combination agents e.g. buproprion plus zonisamide (Empatic), pramlintide plus metreleptin, buproprion plus naltrexone (Contrave), phentermine plus topiramate (Qsymia).
• the anti-obesity agents used in combination with a provided compound or composition thereof are selected from gut-selective MTP inhibitors (e.g.
• CCK-A agonists e.g. lorcaserin / Belviq
• MCR4 agonists e.g. Cetilistat
• lipase inhibitors e.g. Cetilistat
• PYY3-36 including analogs and PEGylated analogs thereof
• opioid antagonists e.g. nal
• a provided compound or composition, according to the method of the present invention may be administered using any amount and any route of administration effective for treating or lessening the severity of a LKB1 or Kras associated disease.
• the LKB1 or Kras associated disease is selected from
• the LKB1 or Kras associated disease is a Kras positive/LKB 1 deficient lung tumor.
• a provided compound or composition, according to the method of the present invention may be administered using any amount and any route of administration effective for treating or lessening the severity of a cancer, or inhibiting the growth of or inducing apoptosis in cancer cells (Wang et al. "Acetyl-CoA Carboxylase-alpha Inhibitor TOFA Induces Human Cancer Cell Apoptosis" Biochem Biophys Res Commun.
• a provided compound or composition, according to the method of the present invention may be administered using any amount and any route of administration effective for treating or lessening the severity of a melanoma.
• the melanoma is one bearing an activated MAPK pathway (Petti et al. "AMPK activators inhibit the proliferation of human melanomas bearing the activated MAPK pathway” Melanoma Research (2012) 22, 341-350).
• a provided compound finds special utility in triple negative breast cancer, as the tumor suppressor protein BRCA1 binds and stabilizes the inactive form of ACC, thus regulating de novo lipid synthesis. Deletion or mutation of this tumor suppressor protein results in the loss of the binding and stabilization of the inactive form of ACC, resulting in increased capacity for ACC-driven de novo lipogenesis, resulting in cancer cell proliferation. See Brunet et al.
• a provided compound or composition, according to the method of the present invention may be administered using any amount and any route of administration effective for treating or lessening the severity of a liposarcoma.
• Liposarcomas have been shown to depend on de novo long-chain fatty acid synthesis for growth, and inhibition of ACC by soraphen A inhibited lipogenesis as well as tumor cell growth (Olsen et al. "Fatty acid synthesis is a therapeutic target in human liposarcoma" International J. of Oncology (2010) 36, 1309-1314).
• a provided compound or composition, according to the method of the present invention may be administered using any amount and any route of administration effective for treating or lessening the severity of a liver disease.
• the liver disease is selected from alcoholic fatty liver disease (AFLD), familial combined hyperlipidemia, hepatitis (including hepatitis A, hepatitis B, and hepatitis C), hepatocellular carcinoma, non-alcoholic fatty liver disease (NAFLD), non-alcoholic fatty liver disease
• liver disease is non-alcoholic steatoheptatitis. In some embodiments, the liver disease is hepatocellular carcinoma.
• NASH non-alcoholic steatohepatitis
• Some embodiments provided herein provide for the use of a crystalline form of Compound 1 as described herein or a composition as described herein in the treatment of treating non-alcoholic steatohepatitis (NASH). [0350] Some embodiments provided herein provide for methods of treating non-alcoholic steatohepatitis (NASH) comprising administering a therapeutically effective amount of Form I of Compound 1 or a composition comprising Form I of Compound 1.
• NASH non-alcoholic steatohepatitis
• Some embodiments provided herein provide for the use of Form I of Compound 1 or a composition comprising Form I of Compound 1 in the treatment of treating non-alcoholic steatohepatitis (NASH).
• NASH non-alcoholic steatohepatitis
• Some embodiments provided herein provide for methods of treating hepatocellular carcinoma (HCC) comprising administering a therapeutically effective amount of a crystalline form of Compound 1 as described herein or a composition as described herein. Some embodiments provided herein provide for the use of a crystalline form of Compound 1 as described herein or a composition as described herein in the treatment of HCC. In some embodiments, a crystalline form of Compound 1 is administered as an adjuvant therapy. In some embodiments, the crystalline form of Compound 1 or composition described herein are administered after curative surgery, local ablation, or liver transplantation.
• HCC hepatocellular carcinoma
• Some embodiments provided herein provide for methods of treating hepatocellular carcinoma (HCC) comprising administering a therapeutically effective amount of Form I of Compound 1 or a composition comprising Form I of Compound 1.
• HCC hepatocellular carcinoma
• a method of treating hepatocellular carcinoma comprises administering a therapeutically effective amount of a crystalline form of Compound 1 as described herein or a composition as described herein in combination with surgical resection, liver transplantation, radiofrequency ablation, percutaneous ethanol injection, transarterial embolization, radiation, or chemotherapy.
• a method of treating hepatocellular carcinoma comprises administering a therapeutically effective amount of Form I of Compound 1 or a composition comprising Form I of Compound 1 in combination with surgical resection, liver transplation, radiofrequency ablation, percutaneous ethanol injection, transarterial embolization, radiation, or chemotherapy.
• a provided compound or composition, according the method of the present invention may be administered in combination with sorafenib for the treatment of hepatocellular carcinoma.
• a provided compound or composition, according to the method of the present invention may be administered using any amount and any route of administration effective for treating or lessening the severity of a bacterial infection or inhibiting the growth of bacteria.
• the bacterial infection is acne vulgaris.
• a provided compound or composition, according to the method of the present invention may be administered using any amount and any route of administration effective for treating or lessening the severity of a fungal infection or inhibiting the growth of fungal cells (Shen et al. "A Mechanism for the Potent Inhibition of Eukaryotic Acetyl-Coenzyme A Carboxylase by Soraphen A, a Macrocyclic Polyketide Natural Product” Molecular Cell (2004) 16, 881-891).
• a provided compound inhibits one or more species of fungi at an MIC of 2 ⁇ g/mL or less.
• a compound of the present invention inhibits at least one of C. albicans, C. krusei, and C. parapsilosis at a concentration of 2 ⁇ g/mL or less.
• a compound of the present invention inhibits at least one of C. albicans, C. krusei, and C. parapsilosis at a concentration of 1 ⁇ g/mL or less.
• a compound of the present invention inhibits at least two of C. albicans, C. krusei, and C.
• a compound of the present invention inhibits at least two of C. albicans, C. krusei, and C. parapsilosis at a concentration of 1 ⁇ g/mL or less. In some embodiments, a compound of the present invention inhibits each of C. albicans, C. krusei, and C. parapsilosis at a concentration of 2 ⁇ g/mL or less. In some embodiments, a compound of the present invention inhibits each of C. albicans, C. krusei, and C. parapsilosis at a concentration of 1 ⁇ g/mL
• a provided compound inhibits at least one of Botrtyis cinerea, Collectotrichum graminicola, Diplodia maydis, Fusarium moniliforme, Fusarium virguliforme, Phytophthora capsici, Rhizoctonia solani, and Septoria at a concentration of 2 ⁇ g/mL or less. In some embodiments, a provided compound inhibits at least one of Botrtyis cinerea,
• Collectotrichum graminicola, Diplodia maydis, Fusarium moniliforme, Fusarium virguliforme, Phytophthora capsici, Rhizoctonia solani, and Septoria at a concentration of 1 ⁇ g/mL or less.
• a compound of the present invention inhibits at least two of Botrtyis cinerea, Collectotrichum graminicola, Diplodia maydis, Fusarium moniliforme, Fusarium virguliforme, Phytophthora capsici, Rhizoctonia solani, and Septoria at a concentration of 2 ⁇ g/mL or less.
• a compound of the present invention inhibits at least two of Botrtyis cinerea, Collectotrichum graminicola, Diplodia maydis, Fusarium moniliforme, Fusarium virguliforme, Phytophthora capsici, Rhizoctonia solani, and Septoria at a
• a compound of the present invention inhibits at least three of Botrtyis cinerea, Collectotrichum graminicola, Diplodia maydis, Fusarium moniliforme, Fusarium virguliforme, Phytophthora capsici, Rhizoctonia solani, and Septoria at a concentration of 2 ⁇ g/mL or less.
• a compound of the present invention inhibits at least three of Botrtyis cinerea, Collectotrichum graminicola, Diplodia maydis, Fusarium moniliforme, Fusarium virguliforme, Phytophthora capsici,
• Rhizoctonia solani and Septoria at a concentration of 1 ⁇ / ⁇ . or less.
• a provided compound or composition, according to the method of the present invention may be administered using any amount and any route of administration effective for treating or lessening the severity of a bacterial infection (Tong, L. et al. J. Cell. Biochem. (2006) 99, 1476-1488).
• a provided compound or composition, according to the method of the present invention may be administered using any amount and any route of administration effective for treating or lessening the severity of a viral infection (Munger et al. Nat. Biotechnol. (2008) 26, 1179-1186).
• the viral infection is Hepatitis C.
• the viral infection is Hepatitis B.
• the viral infection is Hepatitis A.
• a provided compound or composition, according to the method of the present invention may be administered using any amount and any route of administration effective for treating or lessening the severity of a neurological disease
• a provided compound or composition, according to the method of the present invention may be administered using any amount and any route of administration effective for treating or lessening the severity of a parasitic infection or inhibiting the growth of parasites (e.g. malaria and toxoplasma: Gornicki et al. "Apicoplast fatty acid biosynthesis as a target for medical intervention in apicomplexan parasites" International Journal of Parasitology (2003) 33, 885-896; Zuther et al. "Growth of Toxoplasma gondii is inhibited by aryloxyphenoxy propionate herbicides targeting acetyl-CoA carboxylase” PNAS (1999) 96 (23) 13387-13392).
• parasites e.g. malaria and toxoplasma: Gornicki et al. "Apicoplast fatty acid biosynthesis as a target for medical intervention in apicomplexan parasites" International Journal of Parasitology (2003) 33, 885-896; Zuther
• a provided compound or composition, according to the method of the present invention may be administered using any amount and any route of administration effective for treating or lessening the severity of a cardiac disorder.
• the cardiac disorder is cardiac hypertrophy.
• the cardiac disorder is treated or its severity lessened by the cardioprotective mechanism resulting from increased fatty acid oxidation via ACC inhibition (Kolwicz et al. "Cardiac-specific deletion of acetyl CoA carboxylase 2 (ACC2) prevents metabolic remodeling during pressure-overload hypertrophy" Circ. Res. (2012); DOI: 10.1161/CIRCRESAHA.112.268128).
• a provided compound or composition may be used as herbicides.
• the present invention provides a method to inhibit the growth or viability of plants comprising treating plants with compounds of the present invention.
• a provided compound or composition can be used to inhibit the growth or viability of plants by inhibiting ACC.
• the method of the present invention comprises using a provided compound or composition to inhibit fatty acid production in or increase fatty acid oxidation in plants.
• a provided compound or composition of the invention is preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
• dosage unit form refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of a provided compound or composition of the present invention will be decided by the attending physician within the scope of sound medical judgment.
• the specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.
• a pharmaceutically acceptable composition of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated.
• a provided compound of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
• Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
• the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
• the oral compositions can also include adj
• Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
• the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
• the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S. P. and isotonic sodium chloride solution.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil can be employed including synthetic mono- or diglycerides.
• fatty acids such as oleic acid are used in the preparation of injectables.
• the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
• compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention 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 or vaginal cavity and release the active compound.
• Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
• the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier 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,
• 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 solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. 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 polethylene glycols and the like.
• a provided compound can also be in micro-encapsulated form with one or more excipients as noted above.
• the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
• the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
• Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
• the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
• buffering agents include polymeric substances and waxes.
• Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
• the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
• Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention.
• the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
• Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
• Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
• the invention relates to a method of inhibiting ACC in a biological sample comprising the step of contacting said biological sample with a provided compound, or a composition comprising said compound.
• the invention relates to a method of modulating fatty acid levels in a biological sample comprising the step of contacting said biological sample with a provided compound, or a composition comprising said compound.
• biological sample includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
• Inhibition of enzymes in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to biological assays, gene expression studies, and biological target identification.
• Another embodiment of the present invention relates to a method of inhibiting ACC in a patient comprising the step of administering to said patient a provided compound, or a composition comprising said compound.
• the invention relates to a method of inhibiting fatty acid production, stimulating fatty acid oxidation, or both, in a patient comprising the step of administering to said patient a provided compound, or a composition comprising said compound.
• the invention relates to a method of inhibiting fatty acid production, stimulating fatty acid oxidation, or both in a patient, leading to decreasing obesity or alleviating symptoms of metabolic syndrome, comprising the step of administering to said patient a provided compound, or a composition comprising said compound.
• the present invention provides a method for treating a disorder mediated by ACC, in a patient in need thereof, comprising the step of administering to said patient a provided compound or pharmaceutically acceptable composition thereof. Such disorders are described in detail herein.
• a provided compound or composition thereof may be used in a method of treating obesity or another metabolic disorder.
• a provided compound or composition thereof may be used to treat obesity or other metabolic disorder in a mammal.
• the mammal is a human patient.
• a provided compound or composition thereof may be used to treat obesity or other metabolic disorder in a human patient.
• the present invention provides a method of treating obesity or another metabolic disorder, comprising administering a provided compound or composition thereof to a patient with obesity or another metabolic disorder.
• the method of treating obesity or another metabolic disorder comprises administering a provided compound or composition thereof to a mammal.
• the mammal is a human.
• the metabolic disorder is dyslipidemia or hyperlipidemia.
• the obesity is a symptom of Prader-Willi syndrome, Bardet-Biedl syndrome, Cohen syndrome or MOMO syndrome.
• the obesity is a side effect of the administration of another medication, including but not limited to insulin, sulfonylureas, thiazolidinediones, antipsychotics, antidepressants, steroids, anticonvulsants (including phenytoin and valproate), pizotifen, or hormonal contraceptives.
• another medication including but not limited to insulin, sulfonylureas, thiazolidinediones, antipsychotics, antidepressants, steroids, anticonvulsants (including phenytoin and valproate), pizotifen, or hormonal contraceptives.
• the present invention provides a method of treating cancer or another proliferative disorder, comprising administering a provided compound or composition thereof to a patient with cancer or another proliferative disorder.
• the method of treating cancer or another proliferative disorder comprises administering a provided compound or composition thereof to a mammal.
• the mammal is a human.
• the terms “inhibition of cancer” and “inhibition of cancer cell proliferation” refer to the inhibition, or decrease in the rate, of the growth, division, maturation or viability of cancer cells, and/or causing the death of cancer cells, individually or in aggregate with other cancer cells, by cytotoxicity, nutrient depletion, or the induction of apoptosis.
• tissues containing cancerous cells whose proliferation is inhibited by the a provided compound or composition thereof described herein and against which the methods described herein are useful include but are not limited to breast, prostate, brain, blood, bone marrow, liver, pancreas, skin, kidney, colon, ovary, lung, testicle, penis, thyroid, parathyroid, pituitary, thymus, retina, uvea, conjunctiva, spleen, head, neck, trachea, gall bladder, rectum, salivary gland, adrenal gland, throat, esophagus, lymph nodes, sweat glands, sebaceous glands, muscle, heart, and stomach.
• the cancer treated by a provided compound or composition thereof is a melanoma, liposarcoma, lung cancer, breast cancer, prostate cancer, leukemia, kidney cancer, esophageal cancer, brain cancer, lymphoma or colon cancer.
• the cancer is a primary effusion lymphoma (PEL).
• the cancer to be treated by a provided compound or composition thereof is one bearing an activated MAPK pathway.
• the cancer bearing an activated MAPK pathway is a melanoma.
• the cancer treated by a provided compound or composition thereof is one associated with BRCA1 mutation.
• the cancer treated by a provided compound or composition thereof is a triple negative breast cancer.
• the diseases which can be treated by a provided compound or composition thereof are neurological disorders.
• the neurological disorder is Alzheimer's Disease, Parkinson's Disease, epilepsy, ischemia, Age Associated Memory Impairment, Mild Cognitive Impairment, Friedreich's Ataxia, GLUT 1 -deficient epilepsy, Leprechaunism, Rabson-Mendenhall Syndrome, Coronary Arterial Bypass Graft dementia, anaesthesia-induced memory loss, amyotrophic lateral sclerosis, glioma or
• the disease which can be treated by a provided compound or composition thereof is an infectious disease.
• the infectious disease is a viral infection.
• the viral infection is cytomegalovirus infection or influenza infection.
• the infectious disease is a fungal infection.
• the infectious disease is a bacterial infection.
• additional therapeutic agents which are normally administered to treat that condition, may be administered in combination with a provided compound or composition thereof. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated.”
• a provided compound or composition thereof is
• the one or more additional antifungal (antimycotic) agents are selected from polyene antifungals (including but not limited to amphotericin B (as amphotericin B deoxycholate, amphotericin B lipid complex, or liposomal amphotericin B), candicidin, filipin, hamycin, natamycin, nystatin, and rimocidin), azole antifungals (including but not limited to abafungin, albaconazole, bifonazole, butoconazole, clotrimazole, econazole, efinaconazole, epoxiconazole, fenticonazole, fluconazole,
• polyene antifungals including but not limited to amphotericin B (as amphotericin B deoxycholate, amphotericin B lipid complex, or liposomal amphotericin B), candicidin, filipin, hamycin, natamycin,
• allylamines including but not limited to amorolfin, butenafine, naftifine, and terbinafine
• a provided compound or composition thereof is
• a provided compound or composition thereof is administered in combination with one or more other therapeutic agents.
• therapeutic agents include, but are not limited to agents such as orlistat (Xenical), CNS stimulants, Qsymia, or Belviq.
• a provided compound or a composition thereof is administered in combination with another anti-cancer, cytotoxin, or chemotherapeutic agent, to a patient in need thereof.
• the anti-cancer or chemotherapeutic agents used in combination with a provided compound or composition thereof include, but are not limited to, metformin, phenformin, buformin, imatinib, nilotinib, gefitinib, sunitinib, carfilzomib, salinosporamide A, retinoic acid, cisplatin, carboplatin, oxaliplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide, azathioprine, mercaptopurine, doxifluridine, fluorouracil, gemcitabine, methotrexate, tioguanine, vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, etoposide, teniposide, tafluposide, paclitaxel, docetaxel, irinotecan
• Stimulating Factor Halotestin ®, Herceptin ®, Hexadrol, Hexalen ®, Hexamethylmelamine, HMM, Hycamtin ®, Hydrea ®, Hydrocort Acetate ®, Hydrocortisone, Hydrocortisone Sodium Phosphate, Hydrocortisone Sodium Succinate, Hydrocortone Phosphate, Hydroxyurea,
• Ibritumomab Ibritumomab, Tiuxetan, Idamycin ®, Idarubicin Ifex ®, IFN-alpha, Ifosfamide, IL-11, IL-2, Imatinib mesylate, Imidazole Carboxamide, Interferon alfa, Interferon Alfa-2b (PEG Conjugate), Interleukin-2, Interleukin-11, Intron A® (interferon alfa-2b), Iressa ®, Irinotecan, Isotretinoin, Ixabepilone, IxempraTM, Kidrolase ®, Lanacort ®, Lapatinib, L- asparaginase, LCR, Lenalidomide, Letrozole, Leucovorin, Leukeran, LeukineTM, Leuprolide, Leurocristine, LeustatinTM, Liposomal Ara-C, Liquid Pred ®, Lo
• a provided compound or composition may be administered together with a biguanide selected from metformin, phenformin, or buformin, to a patient in need thereof.
• the patient administered a combination of a provided compound and a biguanide is suffering from a cancer, obesity, a liver disease, diabetes or two or more of the above.
• a provided compound or composition may be administered together alone or with one or more additional therapeutic agents for the treatment of acne vulgaris.
• the one or more additional therapeutic agents for the treatment of acne vulgaris are selected from topical anti-acne agents (e.g.
• retinoids topical antibiotics, benzoyl peroxides), or systemic anti-acne agents (e.g. hormonal therapies, oral antibiotics, isotretinoin).
• hormonal therapy is an oral contraceptive or an androgen blocker.
• the oral antibiotic is doxycycline, minocycline, tetracycline, or erythromycin.
• a provided compound or composition may be administered together alone or with one or more additional therapeutic agents for the treatment of seborrhea. In some embodiments, a provided compound or composition may be administered together alone or with one or more additional therapeutic agents for the treatment of seborrheic dermatitis. In some embodiments, a provided compound or composition may be administered together alone or with one or more additional therapeutic agents for the treatment of seborrheic keratosis.
• a combination of two or more therapeutic agents may be administered together with a provided compound.
• a combination of 3 or more therapeutic agents may be administered with a provided compound.
• agents the compounds of this invention may also be combined with include, without limitation: vitamins and nutritional supplements, cancer vaccines, treatments for neutropenia (e.g. G-CSF, filgrastim, lenograstim), treatments for neutropenia (e.g. G-CSF, filgrastim, lenograstim), treatments for neutropenia (e.g. G-CSF, filgrastim, lenograstim), treatments for neutropenia (e.g. G-CSF, filgrastim, lenograstim), treatments for neutropenia (e.g. G-CSF, filgrastim, lenograstim), treatments for neutropenia (e.g. G-CSF, filgrastim, lenograstim), treatments for neutropenia (e.g. G-CSF, filgrastim, lenograstim), treatments for neutropenia (e.g. G-CSF, filgrastim, lenograstim), treatments for neutropeni
• thrombocytopenia e.g. blood transfusion, erythropoietin
• PI3K PI3 kinase
• MEK inhibitors e.g. MEK inhibitors
• AMPK activators e.g. PCSK9 inhibitors
• SREBP site 1 protease inhibitors e.g. HMG CoA- reductase inhibitors
• antiemetics e.g. antiemetics
• 5-HT3 receptor antagonists dopamine antagonists, K1 receptor antagonists, histamine receptor antagonists, cannabinoids, benzodiazepines, or anticholinergics
• Alzheimer's Disease such as Aricept ® and Excel on ®
• treatments for Parkinson's Disease such as L-DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine
• agents for treating Multiple Sclerosis (MS) such as beta interferon (e.g., Avonex ® and Rebif ® ), Copaxone ® , and mitoxantrone;
• agents for treating asthma such as albuterol and Singulair ® ; agents for treating schizophrenia such as zyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole, and anti-Parkinsonian agents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates,
• a provided compound, or a pharmaceutically acceptable composition thereof are administered in combination with antisense agents, a monoclonal or polyclonal antibody or a siRNA therapeutic.
• the present invention provides a method of treating, stabilizing or lessening the severity or progression of a non-alcoholic fatty liver disease
• NAFLD comprising administering to a patient in need thereof a provided compound, or a pharmaceutically acceptable composition thereof, in combination with one or more additional therapeutic agents.
• the one or more additional therapeutic agents are independently selected from the group consisting of angiotensin II receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, caspase inhibitors, cathepsin B inhibitors, CCR2 chemokine antagonists, CCR5 chemokine antagonists, chloride channel stimulators, cholesterol solubilizers, diacylglycerol O-acyltransf erase 1 (DGAT1) inhibitors, dipeptidyl peptidase IV (DPPIV) inhibitors, farnesoid X receptor (FXR) agonists, FXR/TGR5 dual agonists, galectin-3 inhibitors, glucagon-like peptide 1 (GLPl) agonists, glutathione precursors, hepatitis C virus NS3 protease inhibitors, HMG Co
• a provided compound, or a pharmaceutically acceptable composition thereof is administered in combination with one or more additional therapeutic agents, wherein at least one of the additional therapeutic agents is an angiotensin II receptor antagonist.
• a provided compound, or a pharmaceutically acceptable composition thereof is administered in combination with one or more additional therapeutic agents, wherein at least one of the additional therapeutic agents is an angiotensin converting enzyme (ACE) inhibitor.
• ACE angiotensin converting enzyme
• the ACE inhibitor is enalapril.
• a provided compound, or a pharmaceutically acceptable composition thereof is administered in combination with one or more additional therapeutic agents, wherein at least one of the additional therapeutic agents is a caspase inhibitor.
• the caspase inhibitor is emricasan.
• a provided compound, or a pharmaceutically acceptable composition thereof is administered in combination with one or more additional therapeutic agents, wherein at least one of the additional therapeutic agents is a cathepsin B inhibitor.
• the cathepsin B inhibitor is a mixed cathepsin B/hepatitis C virus NS3 protease inhibitor.
• the mixed cathepsin B/hepatitis C virus NS3 protease inhibitor is VBY-376.
• a provided compound, or a pharmaceutically acceptable composition thereof is administered in combination with one or more additional therapeutic agents, wherein at least one of the additional therapeutic agents is a CCR2 chemokine antagonist.
• the additional therapeutic agent is a mixed CCR2/CCR5 chemokine antagonist.
• the mixed CCR2/CCR5 chemokine antagonist is cenicriviroc.
• a provided compound, or a pharmaceutically acceptable composition thereof is administered in combination with one or more additional therapeutic agents, wherein at least one of the additional therapeutic agents is a CCR5 chemokine antagonist.
• a provided compound, or a pharmaceutically acceptable composition thereof is administered in combination with one or more additional therapeutic agents, wherein at least one of the additional therapeutic agents is a chloride channel stimulator.
• the chloride channel stimulator is cobiprostone.
• a provided compound, or a pharmaceutically acceptable composition thereof is administered in combination with one or more additional therapeutic agents, wherein at least one of the additional therapeutic agents is a cholesterol solubilizer.
• a provided compound, or a pharmaceutically acceptable composition thereof is administered in combination with one or more additional therapeutic agents, wherein at least one of the additional therapeutic agents is a diacylglycerol O- acyltransferase 1 (DGAT1) inhibitor.
• the DGAT1 inhibitor is LCQ908.
• a provided compound, or a pharmaceutically acceptable composition thereof is administered in combination with one or more additional therapeutic agents, wherein at least one of the additional therapeutic agents is a dipeptidyl peptidase IV (DPPIV) inhibitor.
• the DPPIV inhibitor is linagliptin.
• a provided compound, or a pharmaceutically acceptable composition thereof is administered in combination with one or more additional therapeutic agents, wherein at least one of the additional therapeutic agents is a farnesoid X receptor (FXR) agonist.
• the FXR agonist is INT-747 (obeticholic acid).
• the FXR agonist is PX- 102.
• a provided compound, or a pharmaceutically acceptable composition thereof is administered in combination with one or more additional therapeutic agents, wherein at least one of the additional therapeutic agents is an FXR/TGR5 dual agonist.
• the FXR/TGR5 dual agonist is INT-767.
• a provided compound, or a pharmaceutically acceptable composition thereof is administered in combination with one or more additional therapeutic agents, wherein at least one of the additional therapeutic agents is a galectin-3 inhibitor.
• the galectin-3 inhibitor is GR-MD-02.
• a provided compound, or a pharmaceutically acceptable composition thereof is administered in combination with one or more additional therapeutic agents, wherein at least one of the additional therapeutic agents is a glucagon-like peptide 1 (GLPl) agonist.
• the GLPl agonist is liraglutide.
• the GLPl agonist is exenatide.
• a provided compound, or a pharmaceutically acceptable composition thereof is administered in combination with one or more additional therapeutic agents, wherein at least one of the additional therapeutic agents is a glutathione precursor.
• a provided compound, or a pharmaceutically acceptable composition thereof is administered in combination with one or more additional therapeutic agents, wherein at least one of the additional therapeutic agents is a hepatitis C virus NS3 protease inhibitor.
• the heptatitis C virus NS3 protease inhibitor is a mixed cathepsin B/hepatitis C virus NS3 protease inhibitor.
• the mixed cathepsin B/hepatitis C virus NS3 protease inhibitor is VBY-376.
• a provided compound, or a pharmaceutically acceptable composition thereof is administered in combination with one or more additional therapeutic agents, wherein at least one of the additional therapeutic agents is an HMG CoA reductase inhibitor.
• the HMG-CoA reductase inhibitor is a statin.
• the HMG-CoA reductase inhibitor is atorvastatin.
• a provided compound, or a pharmaceutically acceptable composition thereof is administered in combination with one or more additional therapeutic agents, wherein at least one of the additional therapeutic agents is an 1 ⁇ -hydroxy steroid dehydrogenase (1 ⁇ -HSDl) inhibitor.
• the 1 ⁇ -HSDl inhibitor is RO5093151.
• a provided compound, or a pharmaceutically acceptable composition thereof is administered in combination with one or more additional therapeutic agents, wherein at least one of the additional therapeutic agents is an IL- ⁇ antagonist.
• a provided compound, or a pharmaceutically acceptable composition thereof is administered in combination with one or more additional therapeutic agents, wherein at least one of the additional therapeutic agents is an IL-6 antagonist.
• the IL-6 antagonist is a mixed IL-6/IL- ⁇ /TNFa ligand inhibitor.
• the mixed IL-6/IL- ⁇ /TNFa ligand inhibitor is BLX-1002.
• a provided compound, or a pharmaceutically acceptable composition thereof is administered in combination with one or more additional therapeutic agents, wherein at least one of the additional therapeutic agents is an IL-10 agonist.
• the IL-10 agonist is peg-ilodecakin.
• a provided compound, or a pharmaceutically acceptable composition thereof is administered in combination with one or more additional therapeutic agents, wherein at least one of the additional therapeutic agents is an IL-17 antagonist.
• the IL-17 antagonist is KD-025.
• a provided compound, or a pharmaceutically acceptable composition thereof is administered in combination with one or more additional therapeutic agents, wherein at least one of the additional therapeutic agents is an ileal sodium bile acid cotransporter inhibitor.
• the ileal sodium bile acid cotransporter inhibitor is SHP-626.
• a provided compound, or a pharmaceutically acceptable composition thereof is administered in combination with one or more additional therapeutic agents, wherein at least one of the additional therapeutic agents is a leptin analog.
• the leptin analog is metreleptin.
• a provided compound, or a pharmaceutically acceptable composition thereof is administered in combination with one or more additional therapeutic agents, wherein at least one of the additional therapeutic agents is a 5 -lipoxygenase inhibitor.
• the 5 -lipoxygenase inhibitor is a mixed 5-lipoxygenase/PDE3/PDE4/PLC inhibitor.
• the mixed 5-lipoxygenase/PDE3/PDE4/PLC inhibitor is tipelukast.
• a provided compound, or a pharmaceutically acceptable composition thereof is administered in combination with one or more additional therapeutic agents, wherein at least one of the additional therapeutic agents is a LPL gene stimulator.
• the LPL gene stimulator is alipogene tiparvovec.
• a provided compound, or a pharmaceutically acceptable composition thereof is administered in combination with one or more additional therapeutic agents, wherein at least one of the additional therapeutic agents is a lysyl oxidase homolog 2 (LOXL2) inhibitor.
• the LOXL2 inhibitor is an anti-LOXL2 antibody.
• the anti-LOXL2 antibody is GS-6624.
• a provided compound, or a pharmaceutically acceptable composition thereof is administered in combination with one or more additional therapeutic agents, wherein at least one of the additional therapeutic agents is a PDE3 inhibitor.
• the PDE3 inhibitor is a mixed 5-lipoxygenase/PDE3/PDE4/PLC inhibitor.
• the mixed 5-lipoxygenase/PDE3/PDE4/PLC inhibitor is tipelukast.
• a provided compound, or a pharmaceutically acceptable composition thereof is administered in combination with one or more additional therapeutic agents, wherein at least one of the additional therapeutic agents is a PDE4 inhibitor.
• the PDE4 inhibitor is ASP-9831.
• the PDE4 inhibitor is a mixed 5-lipoxygenase/PDE3/PDE4/PLC inhibitor.
• the mixed 5- lipoxygenase/PDE3/PDE4/PLC inhibitor is tipelukast.
• a provided compound, or a pharmaceutically acceptable composition thereof is administered in combination with one or more additional therapeutic agents, wherein at least one of the additional therapeutic agents is a phospholipase C (PLC) inhibitor.
• the PLC inhibitor is a mixed 5-lipoxygenase/PDE3/PDE4/PLC inhibitor.
• the mixed 5-lipoxygenase/PDE3/PDE4/PLC inhibitor is tipelukast.
• a provided compound, or a pharmaceutically acceptable composition thereof is administered in combination with one or more additional therapeutic agents, wherein at least one of the additional therapeutic agents is a PPARa agonist.
• the PPARa agonist is a mixed PPARa/ ⁇ agonist.
• the mixed PPARa/ ⁇ agonist is GFT505.
• a provided compound, or a pharmaceutically acceptable composition thereof is administered in combination with one or more additional therapeutic agents, wherein at least one of the additional therapeutic agents is a PPARy agonist.
• the PPARy agonist is pioglitazone.
• a provided compound, or a pharmaceutically acceptable composition thereof is administered in combination with one or more additional therapeutic agents, wherein at least one of the additional therapeutic agents is a PPAR5 agonist.
• a provided compound, or a pharmaceutically acceptable composition thereof is administered in combination with one or more additional therapeutic agents, wherein at least one of the additional therapeutic agents is a Rho associated protein kinase 2 (ROCK2) inhibitor.
• the ROCK2 inhibitor is KD-025.
• a provided compound, or a pharmaceutically acceptable composition thereof is administered in combination with one or more additional therapeutic agents, wherein at least one of the additional therapeutic agents is a sodium glucose transporter- 2 (SGLT2) inhibitor.
• the SGLT2 inhibitor is remogliflozin etabonate.
• a provided compound, or a pharmaceutically acceptable composition thereof is administered in combination with one or more additional therapeutic agents, wherein at least one of the additional therapeutic agents is a stearoyl CoA desaturase-1 inhibitor.
• the stearoyl CoA desaturase-1 inhibitor is aramchol.
• the stearoyl CoA desaturase-1 inhibitor is CVT-12805.
• a provided compound, or a pharmaceutically acceptable composition thereof is administered in combination with one or more additional therapeutic agents, wherein at least one of the additional therapeutic agents is a thyroid hormone receptor ⁇ agonist.
• the thyroid hormone receptor ⁇ agonist is MGL-3196.
• a provided compound, or a pharmaceutically acceptable composition thereof is administered in combination with one or more additional therapeutic agents, wherein at least one of the additional therapeutic agents is a tumor necrosis factor a (TNFa) ligand inhibitor.
• TNFa tumor necrosis factor a
• a provided compound, or a pharmaceutically acceptable composition thereof is administered in combination with one or more additional therapeutic agents, wherein at least one of the additional therapeutic agents is a transglutaminase inhibitor.
• the transglutaminase inhibitor precursor is mercaptamine.
• a provided compound, or a pharmaceutically acceptable composition thereof is administered in combination with one or more additional therapeutic agents, wherein at least one of the additional therapeutic agents is a transglutaminase inhibitor precursor.
• a provided compound, or a pharmaceutically acceptable composition thereof is administered in combination with one or more additional therapeutic agents, wherein at least one of the additional therapeutic agents is a PTPlb inhibitor.
• the PTPlb inhibitor is Al 19505, A220435, A321842, CPT633, ISIS-404173, JTT-551, MX-7014, MX-7091, MX-7102, NNC-521246, OTX-001, OTX-002, or TTP814.
• a provided compound, or a pharmaceutically acceptable composition thereof is administered in combination with one or more additional therapeutic agents, wherein at least one of the additional therapeutic agents is an ASK1 inhibitor.
• the ASK1 inhibitor is GS-4977 (also known as selonsertib).
• the one or more additional therapeutic agents are any suitable therapeutic agents.
• acetylsalicylic acid independently selected from acetylsalicylic acid, alipogene tiparvovec, aramchol, atorvastatin, BLX-1002, cenicriviroc, cobiprostone, colesevelam, emricasan, enalapril, GFT-505, GR-MD- 02, hydrochlorothiazide, icosapent ethyl ester (ethyl eicosapentaenoic acid), IMM-124E, KD- 025, linagliptin, liraglutide, mercaptamine, MGL-3196, obeticholic acid, olesoxime, peg- ilodecakin, pioglitazone, PX-102, remogliflozin etabonate, SHP-626, solithromycin, tipelukast, TRX-318, ursodeoxycholic acid,
• one of the one or more additional therapeutic agents is acetylsalicylic acid. In some embodiments, one of the one or more additional therapeutic agents is alipogene tiparvovec. In some embodiments, one of the one or more additional therapeutic agents is aramchol. In some embodiments, one of the one or more additional therapeutic agents is atorvastatin. In some embodiments, one of the one or more additional therapeutic agents is BLX-1002. In some embodiments, one of the one or more additional therapeutic agents is cenicriviroc. In some embodiments, one of the one or more additional therapeutic agents is cobiprostone. In some embodiments, one of the one or more additional therapeutic agents is colesevelam.
• one of the one or more additional therapeutic agents is emricasan. In some embodiments, one of the one or more additional therapeutic agents is enalapril. In some embodiments, one of the one or more additional therapeutic agents is GFT- 505. In some embodiments, one of the one or more additional therapeutic agents is GR-MD-02. In some embodiments, one of the one or more additional therapeutic agents is
• one of the one or more additional therapeutic agents is icosapent ethyl ester (ethyl eicosapentaenoic acid).
• one of the one or more additional therapeutic agents is IMM-124E.
• one of the one or more additional therapeutic agents is KD-025.
• one of the one or more additional therapeutic agents is linagliptin.
• one of the one or more additional therapeutic agents is liraglutide.
• one of the one or more additional therapeutic agents is mercaptamine.
• one of the one or more additional therapeutic agents is MGL-3196.
• one of the one or more additional therapeutic agents is obeticholic acid. In some embodiments, one of the one or more additional therapeutic agents is olesoxime. In some embodiments, one of the one or more additional therapeutic agents is peg-ilodecakin. In some embodiments, one of the one or more additional therapeutic agents is pioglitazone. In some embodiments, one of the one or more additional therapeutic agents is PX-102. In some embodiments, one of the one or more additional therapeutic agents is remogliflozin etabonate. In some embodiments, one of the one or more additional therapeutic agents is SHP-626. In some embodiments, one of the one or more additional therapeutic agents is solithromycin.
• one of the one or more additional therapeutic agents is tipelukast. In some embodiments, one of the one or more additional therapeutic agents is TRX-318. In some embodiments, one of the one or more additional therapeutic agents is ursodeoxycholic acid. In some embodiments, one of the one or more additional therapeutic agents is and VBY-376.
• the anti-diabetic agent is an adenosine Ai receptor agonist (e.g. adenosine, CCPA, CVT-3619, GR-190718), an adenosine A 2 receptor antagonist (istradefylline, SCH-58261), an aldose reductase inhibitor, an a-amylase inhibitor (e.g.
• tendamistat tendamistat, treastatin, AL-3688
• an a-glucosidase inhibitor e.g. acarbose, camiglibose, diposine, emiglitate, miglitol, pradimicin-Q, sarbostatin, voglibose
• an amylin analog e.g. AC164209 and pramlintide
• an AMPK activator e.g.
• amibegron amibegron, AZ- 40140, CL-316,243, KRP-204, L-742,791, L-796,568, LY-368,842, LY-377,604, mirabegron, Ro 40-2148, solabegron, SWR-0342SA), a ⁇ -ketoacyl-acyl carrier protein synthase inhibitor, a biguanide (e.g. metformin, buformin, phenformin), a carnitine palmitoyl transferase inhibitor, a DGAT-2 inhibitor, a DPP -4 inhibitor (e.g.
• alogliptin anagliptin, dutogliptin, gemigliptin, linagliptin, omarigliptin, saxagliptin, sitagliptin, teneligliptin, trelagliptin, and vildagliptin
• an ERNl inhibitor a fatty acid oxidation inhibitor, a fatty acid synthase (FAS) inhibitor, an FGF21 derivative, a fructose 1,6-diphosphatase inhibitor, a GLP1 agonist (e.g.
• TAK-875 a GPR41 modulator, a GPR43 modulator, a GPR81 modulator, a GPR120 agonist, an HSL inhibitor, an ⁇ inhibitor, an ILI-beta modulator, insulin or an insulin analog (including, but not limited to, oral, inhaled or injectable formulations thereof), insulin-like growth factor (IGF-1) or an analog thereof, an insulin secretagogue, a JNK inhibitor (e.g. CC-359), a kappa opioid receptor modulator, LY3084077, a Kvl.3 inhibitor (e.g. ChTX, clofazmine, WIN-173173), a MAP4K4 inhibitor, an MCi or MC 4 agonist (e.g.
• afamelanotide BMS-470539, bremelanotide, Melanotan II, PF-00446687, PL-6983, setmelanotide, and THIQ
• a meglitinide e.g.
• repaglinide nateglinide, mitiglinide
• a mineralocorticoid receptor inhibitor a monoacylglycerol O-acyltransferase inhibitor, an NF- ⁇ inhibitor, a nicotinic acid receptor (HM74A) activator, a PDE-10 inhibitor, a PDHK2 inhibitor, a PDHK4 inhibitor, a PKC (including PKC-alpha, PKC- beta, and PKC-gamma) inhibitor, a PPARa/ ⁇ dual agonist, a PTPlb inhibitor (e.g.
• trodusquemine a retinol binding protein 4 inhibitor, a serine palmitoyl transferase inhibitor, an SGLT1 inhibitor (e.g. GSK1614235), a SIRT-1 inhibitor (e.g. resveratrol, GSK2245840, GSK184072), a somatostatin receptor inhibitor, a sulfonylurea (e.g. acetohexamide,
• chlorpropamide diabinese, glibenclamide, glipizide, glyburide, blimipiride, gliclazide, glipentide, gliquidone, glisolamide, tolazamide, tolbutamide), a thiazolidinedione (e.g.
• the one or more additional therapeutic agents is an anti -anti obesity agent.
• the anti-obesity agent is an apoB-MTP inhibitor (e.g. dirlotapide, JTT130, SLX4090, usistapide), a 3-adrenergic agonist (e.g.
• amibegron amibegron, AZ-40140, CL-316,243, KRP-204, L-742,791, L-796,568, LY-368,842, LY- 377,604, mirabegron, Ro 40-2148, solabegron, SWR-0342SA), a bombesin receptor agonist, a BRS3 modulator, a CB1 receptor antagonist or inverse agonist, a CCKA agonist, ciliary neurotrophic factor (CNTF) or analog thereof (e.g. axokine, NT-501), ContraveTM
• a dopamine receptor agonist e.g. bromocriptine
• an 11 ⁇ - hydroxysteroid dehydrogenase ⁇ ⁇ -HSDl
• EmpaticTM pramlintide/metreleptin
• a 5- HT2C agonist e.g. lorcaserin
• a galanin antagonist e.g. a ghrelin agonist or antagonist
• a GLP1 agonist e.g. albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, taspoglutide
• MAR-701, ZP2929 a mixed glucagon receptor / GLP-1 agonist
• an H3 antagonist or inverse agonist a human agouti -related protein (AGRP) inhibitor, leptin or an analog thereof (e.g.
• a lipase inhibitor e.g. tetrahydrolipstatin
• an MCi or MC 4 agonist e.g.
• a melanocyte-stimulating hormone or analog thereof a MetAp2 inhibitor (e.g. ZGN-433), a monoamine reuptake inhibitor (e.g. buproprion, sibutramine, phentermine, tesofensine), a neuromedin U receptor agonist, an PY antagonist (e.g.
• velneperit an opioid receptor antagonist (e.g. naltrexone), an orexin receptor antagonist (e.g. almorexant, lemborexant, SB-334,867, SB-408,124, SB-649,868, suvorexant), oxyntomodulin or an analog thereof, PYY or an analog thereof (e.g. PYYi-36, PYY3-36), QsymiaTM
• phentermine/topiramate an RXR-alpha modulator, a stearoyl-CoA desaturase (SCD-1) inhibitor, or a sympathomimetic agent.
• SCD-1 stearoyl-CoA desaturase
• the lipid lowering agent is an acyl coenzyme A cholesterol acyl transferase (ACAT) inhibitor, a bile acid reabsorption inhibitor, a cholesterol ester transfer protein (CETP) inhibitor, a 5-LOX inhibitor (e.g. BAY X 1005), a FLAP inhibitor (e.g.
• AM-679 an HMG CoA synthase inhibitor, a lipoprotein synthesis inhibitor, a low-density lipoprotein receptor inducer, an LXR receptor modulator, a microsomal triglyceride transport inhibitor, niacin, a platelet aggregation inhibitor, a renin-angiotensin system inhibitor, a squalene epoxidase inhibitor, a squalene synthetase inhibitor, or a triglyceride synthesis inhibitor.
• At least one of the one or more additional therapeutic agents is an agent for treating a metabolic disorder.
• the agent for treating a metabolic disorder is an ABC transporter activator, ACT-434964 (Actelion), an ANG-5 inhibitor, an angiotensin II antagonist (e.g. MC4262), CCX-872, DUR-928 (Durect), ESP41091, F-652 (Generon), an FGF21 agonist (e.g. BMS-986036), fomepizole (Raptor), an FXR agonist, FXR/TGR5 dual agonist (e.g. INT-767), a ghrelin antagonist (e.g.
• TZP-301 a glucosylceramide synthase inhibitor, a GPR17 modulator, a GPR119 agonist, IG-MD-014 (Indigene), IMM-124E (Immuron), a lysosome pathway modulator (e.g. CAT5000), a melanin-concentrating hormone receptor 1 antagonist (e.g. KI-1361-17), an MCL1 inhibitor (e.g. CMPX-1023), an mTORCl inhibitor, an NaCT (e.g. SLC13A5) inhibitor, a HE3 inhibitor (e.g. RDX-011, tenapanor), P003 (Neuraltus), PBI-4050 (ProMetic), a proteostasis regulator (e.g.
• RG7652 a ROCK inhibitor
• SBC-104 Synageva BioPharma
• SPX-100 Spherix
• a stearoyl CoA desaturase inhibitor e.g. CVT-12805
• TRC150094 Torrent
• ZYH7 Zydus Cadila
• At least one of the one or more additional therapeutic agents is an agent for treating steatosis.
• the agent for treating steatosis is an adiponectin analog (e.g. PX 811013), aramchol (Galmed), an ASK1 inhibitor (e.g. GS-4977, GS-4997), AZD4076 (AstraZeneca), a bile acid sequestrant (e.g. obeticholic acid), BL-1060 (Galmed), BMS986171 (Bristol-Myers Squibb), a CCR5/CCR2 antagonist (e.g.
• EpanovaTM EpanovaTM
• PX-102 Phenex
• PX-104 Phenex
• remogliflozin etabonate Kissei
• saroglitazar Zydus-Cadila
• SAR-548304 tipelukast
• ursodeoxycholic acid VK2809 (Viking)
• XL335 Exelixis
• At least one of the one or more additional therapeutic agents is an agent for treating inflammation.
• the agent for treating inflammation reduces the differentiation or activation of Thl7 cells.
• the agent for treating inflammation is a caspase inhibitor (e.g. emricasan), a TGF- ⁇ inhibitor, an IL- ⁇ inhibitor, an IL-6 inhibitor, an IL-17 inhibitor, an IL-17a inhibitor, an IL-17F inhibitor, an IL-21 inhibitor, an IL-23 inhibitor (e.g. guselkumab), IMM-124E, a RORyt inhibitor (e.g.
• At least one of the one or more additional therapeutic agents is an agent for treating fibrosis.
• the agent for treating fibrosis is
• cenicriviroc Tobira/Takeda
• CNX-014/023/024/025 Connexios
• an endothelin antagonist e.g. A192621, ambrisentan, atracentan, bosentan, BQ-123, BQ-788, macitentan, sitaxentan, tezosentan, zibotentan
• etanercept evitar
• AdeTherapeutics a fibroblast growth factor inhibitor
• galectin-3 inhibitor imatinib, IVA337 (Inventiva), N-acetylcysteine, nintedanib, pirfenidone, RG6069 (Roche), SP20102 (Sarfez), tipelukast (Kyorin), or XOMA 089 (Xoma).
• the non-alcoholic fatty liver disease is steatosis. In some embodiments, the non-alcoholic fatty liver disease is non-alcoholic steatohepatitis (NASH). In some embodiments, the non-alcoholic fatty liver disease is liver fibrosis caused by NASH. In some embodiments, the non-alcoholic fatty liver disease is liver cirrhosis caused by NASH. In some embodiments, the non-alcoholic fatty liver disease is hepatocellular carcinoma (HCC) caused by NASH.
• NASH non-alcoholic steatohepatitis
• HCC hepatocellular carcinoma
• Those additional agents may be administered separately from a provided compound or composition thereof, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a provided compound in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another, normally within five hours from one another.
• the term “combination,” “combined,” “in conjunction” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention.
• a provided compound may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.
• the present invention provides a single unit dosage form comprising a provided compound, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
• compositions of this invention should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of a provided compound can be administered.
• compositions which comprise an additional therapeutic agent that additional therapeutic agent and a provided compound may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions will be less than that required in a monotherapy utilizing only that therapeutic agent. In such compositions a dosage of between 0.01 - 100 ⁇ g/kg body weight/day of the additional therapeutic agent can be administered.
• the amount of additional therapeutic agent present in a composition comprising a provided compound will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent.
• the amount of additional therapeutic agent in a provided composition will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
• V volumes
• v/w volume/weight ratio
• v/v volume/weight ratio
• volume/volume ratio volume/volume ratio
• w/w weight/weight ratio
• amorphous Compound 1 prepared according to the method of Example 1, was slurried in acetone and subjected to temperature cycling from 40 °C to 25 °C, in 4 h cycles for 72 h. Solid Form I of Compound 1 was collected by filtration. Form I was determined to be an neat polymorph of Compound 1. Form I was determined to have poor aqueous solubility at pH 5.5 and below ( ⁇ 10 ⁇ g/mL), with a logD value of 1.06 at pH 7.4.
• the DSC curve of Form I of Compound 1 ( Figure 3 A and Figure 3B) indicates an endothermic transition with onset at about 189-193 °C attributed to a melt.
• the TGA curve of Form I of Compound 1 shows no significant weight loss up at about 150 °C, indicating an unsolvated phase.
• the moisture sorption curve of Form I of Compound 1 also indicates that Form I is slightly hygroscopic showing around a 0.45% weight gain at about 95% RH.
• An XRPD analysis of the sample after the DVS experiment shows that the material had not changed forms.
• a suitable single crystal was selected and analyzed by single-crystal X-ray diffractometry.
• a colorless plate having approximate dimensions of 0.19 ⁇ 0.13 ⁇ 0.06 mm 3 , was mounted on a nylon loop in random orientation.
• Cell constants and an orientation matrix for data collection were obtained from least-squares refinement using the setting angles of 15725 reflections in the range 3.5010° ⁇ ⁇ ⁇ 77.2150°.
• the space group was determined by the program CRYSALISPRO to be C2221 (international tables no. 20). The data were collected to a maximum diffraction angle (2 ⁇ ) of 155.284° at room temperature.
• Form I is the most stable form of Compound 1.
• Aqueous solubility of Form VII was determined to be 0.109 mg/mL.
• XRPD analysis confirmed that prolonged exposure to water resulted in the conversion of Form VII to Form I.
• Form VII was determined to be chemically and physically stable following 7 days of storage at 40 °C and 75% RH. No change in form was observed, and the purity was determined to be 99.85%).
• Form VIII was produced.
• the NMR spectrum was found to be consistent with that of Compound 1, and HPLC analysis of Form VIII indicated a purity of 99.4%.
• Form VIII was also prepared by running 50 grams of anhydrous Form I of Compound 1 through a Leistriz twin screw extruder utilizing multiple heat zones of about 170 to about 193 °C and a screw speed of 30 rpms.
• DSC analysis of Form VIII showed the same sharp peak with onset at 204.7 °C (peak at 208.1 °C), corresponding to the melting point of Form VIII. Further DSC analysis of Form I indicate that cooling a melted sample of Form I, followed by a second heating event resulted in an endotherm with onset at 204.7 °C (peak at 208.1 °C), indicating that Form VIII is directly produced from Form I upon heating in that manner. [0477] The DSC curve shown in Figure 16 shows that Form VIII comprises an endotherm with onset at about 205 °C.
• Sodium Form I (hydrate) was prepared as follows. 3.48 g of anhydrous Form I of Compound 1 was placed in a beaker with 0.27 g of NaOH and 40 mL of water. The sample was heated and stirred until solution became clear. Next, the solution was filtered into a vial and placed in a vacuum centrifuge. The resulting solids were slurried in ethyl acetate and then washed with acetone, filtered, and dried. The XRPD pattern of Compound 1 Sodium Form I is shown in Figure 19. The DSC curve is shown in Figure 20 and indicates multiple endothermic transitions with onset at 37 °C and 283 °C.
• the TGA curve is shown in Figure 21 and displays a weight loss (4.1% RT to 175 °C) that was identified as water based on TGA-Mass Spectrometry (TGA-MS). Weight loss above 250 °C is attributed to decomposition.
• the dynamic vapor sorption curve indicates that the form absorbs about 32 weight % of water up to 95% RH (relative humidity) at 25 °C. The material was found to have deliquesced post experiment.
• Example 14 Production of Compound 1 Sodium Form II
• Compound 1 Sodium Form II (variable hydrate) was prepared as follows. 4.0 g of anhydrous Form I of Compound 1 was placed in a beaker with 0.4 g of NaOH and about 40 mL of water. The sample was heated and stirred until solution became clear. Next, the solution was filtered into a vial and placed in a vacuum centrifuge. The resulting solids from vacuum centrifuge were washed with 10% water in acetonitrile, and then the solids were dried and then slurried in ethyl acetate. The sample were sonicated for about 1 hour and then left to sit at room temperature. The solids were slurried in acetone and a portion was filtered to yield solids.
• the XRPD pattern of Compound 1 Sodium Form II is shown in Figure 22.
• the DSC curve is shown in Figure 23 and indicates multiple endothermic transitions with onset at about 19, about 78 and about 136 °C.
• the TGA curve is shown in Figure 24 and displays a weight loss (about 24% RT to about 150 °C) indicating a solvate that was identified as water based on TGA-MS.
• a second sample of Compound 1 Sodium Form II was prepared when 1092 mg of Form I of Compound 1 was placed in a vial with 76 mg of NaOH and 10 mL of water. Sample sonicated but solids till persisted. Another 45mg of NaOH as added with an additional 10 mL and the solution became clear.

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