Solid form of thienopyrimidinedione ACC inhibitor and preparation method thereof

Abstract

The present invention provides solid forms of compounds useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, methods of making the same, and methods of treating ACC-mediated diseases using the same.

Description

[0001] This application is a divisional application of a Chinese patent application with application number 201780014543.0, invention name “Solid form of thienopyrimidinedione ACC inhibitor and preparation method thereof” and application date March 1, 2017 (PCT application number PCT / US2017 / 020271).

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 62 / 302,755, filed on March 2, 2016, and U.S. Provisional Application No. 62 / 303,237, filed on March 3, 2016, both of which are incorporated herein by reference. Background Art

[0004] Obesity is a health crisis for a large group of people. The health burden of obesity, measured by the quality-adjusted life-years lost per adult, has surpassed smoking to become the most serious, preventable cause of death. In the United States, about 34% of adults suffer from obesity, up from 31% in 1999 and about 15% from 1960 to 1980. Obesity increases the mortality rate caused by all causes in men and women of all ages and all races. Obesity also leads to social stigmatization and discrimination, which significantly reduces the quality of life. Chronic diseases caused by obesity cost the US economy more than $150 billion in weight-related medical bills each year. In addition, about half of the obese population and 25% of the general population suffer from metabolic syndrome, i.e., a condition associated with abdominal obesity, hypertension, increased plasma triglycerides, decreased HDL cholesterol and insulin resistance, which increases the risk of type 2 diabetes (T2DM), stroke and coronary heart disease. (Harwood, Expert Opin. Ther. Targets 9: 267, 2005).

[0005] Diet and exercise, even when used in conjunction with current drug therapies, do not provide the sustainable weight loss needed for long-term health benefits. Currently, only a few anti-obesity drugs are approved for use in the United States, the fat absorption inhibitor orlistat ( ), 5-HT2C antagonist lorcaserin (lorcaserin, ) and combination therapy phentermine / topiramate ( ). Unfortunately, poor efficacy and adverse gastrointestinal side effects limit the use of orlistat. Surgery may be effective, but is limited to patients with very high body mass index (BMI), and the low surgical throughput limits the impact of this approach to approximately 200,000 patients per year. Most obesity drugs in clinical development are designed to reduce caloric intake (e.g., anorectics and satiety agents) via central effects in the CNS. However, the FDA has taken an opposing stance towards CNS active agents due to their modest efficacy and observed / potential side effect profiles.

[0006] The persistent and growing problem of obesity and the current lack of safe and effective drugs to treat it highlight the urgent need for new drugs to treat this condition and its underlying causes.

[0007] Another ongoing problem is the lack of antifungal drugs that are active against a broad spectrum of fungal pathogens. Often, a given antifungal drug is active against one fungal species but lacks activity against other (even closely related) species such as Candida albicans, Candida krusei, and Candida parapsilosis. Summary of the invention

[0008] The compound, (R)-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2-methylpropanoic acid, referred to herein as Compound 1, has the formula:

[0009]

[0010] The present invention relates to various crystalline forms of Compound 1, methods of preparing Compound 1 and its various forms, and methods of using these forms.

[0011] Compound 1 is also provided in 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.”

[0012] Other crystalline forms of Compound 1 are further described herein.

[0013] In some embodiments, the crystalline form of Compound 1 may include a salt, a co-crystal, a solvate, or a hydrate of Compound 1.

[0014] In some embodiments, the crystalline form of Compound 1 may include a salt of Compound 1. In some embodiments, Compound 1 is provided in the 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.”

[0015] Some embodiments provide a method for preparing Compound 1, or a salt or co-crystal thereof, comprising:

[0016] (a) Compound G-2-a:

[0017]

[0018] Contacting with oxazole under conditions sufficient to form compound G-9-a:

[0019]

[0020] (b) contacting compound G-9-a with compound (R)-G-1-a under conditions sufficient to form compound G-4-a:

[0021]

[0022] and

[0023] (c) hydrolyzing compound G-4-a under conditions sufficient to form compound 1.

[0024] Some embodiments provide a method for preparing Compound 1 or a salt or co-crystal thereof, comprising:

[0025] (a) Compound (R)-G-5-a or its oxygen anion:

[0026]

[0027] contacting with a sulfonylating agent under conditions sufficient to form compound (R)-G-6-a:

[0028]

[0029] (b) contacting compound (R)-G-6-a with a bromide salt under conditions sufficient to form compound (R)-G-1-a:

[0030]

[0031] (c) Compound G-2-a:

[0032]

[0033] Contacting with oxazole under conditions sufficient to form compound G-9-a:

[0034]

[0035] (d) contacting compound G-9-a with compound (R)-G-1-a under conditions sufficient to form compound G-4-a:

[0036]

[0037] and (e) hydrolyzing compound G-4-a under conditions sufficient to form compound 1. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1A Depicted is an X-ray powder diffraction (XRPD) pattern of Form I of Compound 1.

[0040] Figure 1B Another X-ray powder diffraction (XRPD) pattern of Form I of Compound 1 is depicted.

[0041] Figure 2 An ellipsoid diagram of Form I of Compound 1 is depicted.

[0042] Figure 3A Depicted is a differential scanning calorimetry (DSC) curve of Form I of Compound 1.

[0043] Figure 3B Another differential scanning calorimetry (DSC) curve of Form I of Compound 1 is depicted.

[0044] Figure 4A Depicted is the thermogravimetric analysis (TGA) of Form I of Compound 1.

[0045] Figure 4B Another thermogravimetric analysis (TGA) of Form I of Compound 1 is depicted.

[0046] Figure 5 An X-ray powder diffraction pattern of Form II of Compound 1 is depicted.

[0047] Figure 6 An X-ray powder diffraction pattern of Form III of Compound 1 is depicted.

[0048] Fig. 7A An X-ray powder diffraction pattern of Form IV of Compound 1 is depicted.

[0049] Figure 7B Another X-ray powder diffraction pattern of Form IV of Compound 1 is depicted.

[0050] Figure 8The differential scanning calorimetry (DSC) curve of Form IV of Compound 1 is depicted.

[0051] Fig. 9 Depicted is the thermogravimetric analysis (TGA) of Form IV of Compound 1.

[0052] Fig.10 An X-ray powder diffraction pattern of Form V of Compound 1 is depicted.

[0053] Fig.11A An X-ray powder diffraction pattern of Form VI of Compound 1 is depicted.

[0054] Fig. 11B Another X-ray powder diffraction pattern of Form VI of Compound 1 is depicted.

[0055] Fig.12 The differential scanning calorimetry (DSC) curve of Form VI of Compound 1 is depicted.

[0056] Fig.13 Depicted is the thermogravimetric analysis (TGA) of Form VI of Compound 1.

[0057] Fig.14 An X-ray powder diffraction pattern of Form VII of Compound 1 is depicted.

[0058] Fig.15A An X-ray powder diffraction pattern of Form VIII of Compound 1 is depicted.

[0059] Fig. 15B Another X-ray powder diffraction pattern of Form VIII of Compound 1 is depicted.

[0060] Fig.16 Depicted is a differential scanning calorimetry (DSC) curve of Form VIII of Compound 1.

[0061] Fig.17 Depicted is the thermogravimetric analysis (TGA) of Form VIII of Compound 1.

[0062] Fig.18 An X-ray powder diffraction pattern of amorphous Compound 1 is depicted.

[0063] Fig.19 Depicted is an X-ray powder diffraction pattern of Compound 1 Sodium Form I.

[0064] Fig. 20 Depicted is the differential scanning calorimetry (DSC) curve of Compound 1 Sodium Form I.

[0065] Fig.21 Depicted is the thermogravimetric analysis (TGA) of Compound 1 Sodium Form I.

[0066] Fig. 22 Depicted is the X-ray powder diffraction pattern of Compound 1 Sodium Form II.

[0067] Fig.23 Depicted is the differential scanning calorimetry (DSC) curve of Compound 1 Sodium Form II.

[0068] Fig.24 Depicted is the thermogravimetric analysis (TGA) of Compound 1 Sodium Form II.

[0069] Fig.25 Depicted is the X-ray powder diffraction pattern of Compound 1 Calcium Form I.

[0070] Fig.26 Depicted is the differential scanning calorimetry (DSC) curve of Compound 1 Calcium Form I.

[0071] Fig. 27 Depicted is the thermogravimetric analysis (TGA) of Compound 1 Calcium Form I.

[0072] Fig.28 Depicted is an X-ray powder diffraction pattern of Compound 1 Magnesium Form I.

[0073] Fig.29 Depicted is a differential scanning calorimetry (DSC) curve of Compound 1 Magnesium Form I.

[0074] Fig.30 Depicted is the thermogravimetric analysis (TGA) of Compound 1 Magnesium Form I.

[0075] Fig.31 Depicted is an X-ray powder diffraction pattern of Compound 1 diethanolamine Form I.

[0076] Fig.32 Depicted is the differential scanning calorimetry (DSC) curve of Compound 1 diethanolamine Form I.

[0077] Fig.33 Depicted is the thermogravimetric analysis (TGA) of Compound 1 diethanolamine Form I.

[0078] Fig.34 An X-ray powder diffraction pattern of Compound 1 piperazine Form I is depicted.

[0079] Fig.35 Depicted is the differential scanning calorimetry (DSC) curve of Compound 1 piperazine Form I.

[0080] Fig.36 Depicted is the thermogravimetric analysis (TGA) of Compound 1 piperazine Form I.

[0081] Fig.37The differential scanning calorimetry (DSC) curve of Form II of Compound 1 is depicted.

[0082] Fig.38 The differential scanning calorimetry (DSC) curve of Form III of Compound 1 is depicted.

[0083] Fig.39 A differential scanning calorimetry (DSC) curve of Form V of Compound 1 is depicted.

[0084] Fig.40 The differential scanning calorimetry (DSC) curve of Form VII of Compound 1 is depicted.

[0085] DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0086] 1. General Description

[0087] U.S. Published Patent Application No. 2013 / 0123231A1, published on May 16, 2013, which is incorporated herein by reference in its entirety, discloses certain thienopyrimidinedione compounds that bind to and inhibit acetyl CoA carboxylase 1 and 2. These compounds include Compound 1:

[0088]

[0089] Compound 1, ((R)-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2-methylpropanoic acid), is referred to as Compound No. I-181, and the synthesis of Compound 1 is described in detail in Example 76 of U.S. Patent Publication No. 2013 / 0123231.

[0090] 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 a solid form of Compound 1 that imparts properties such as improved water solubility, stability, and ease of formulation.

[0091] Also disclosed are novel synthetic methods for preparing compound 1 and its analogs, as well as novel intermediates for synthesizing these compounds. Compared with the prior art, these methods and intermediates are suitable for large-scale production due to high yields, favorable physicochemical properties and reduced use of toxic reagents or solvents.

[0092] 2. Solid form of compound 1

[0093] In some embodiments, the present invention provides a solid form of Compound 1 or a salt, cocrystal, solvate or hydrate thereof. In some embodiments, the solid form of Compound 1 is a salt or cocrystal. In some embodiments, the salt or cocrystal is a pharmaceutically acceptable salt or cocrystal thereof. In some embodiments, 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 cocrystal thereof. In some embodiments, the present invention provides a solid form of Compound 1, or a pharmaceutically acceptable salt thereof, which is substantially free of impurities. As described herein, the term "substantially free of impurities" means that the compound does not contain a significant amount of foreign matter. Such foreign matter may include residual solvents, or any other impurities that may result from the preparation and / or isolation of Compound 1. In certain embodiments, there is at least about 95% by weight of Compound 1. In other embodiments of the present invention, there is at least about 99% by weight of Compound 1. In certain embodiments, there is at least about 95% by weight of Compound 1 as a salt or cocrystal thereof. In other embodiments of the present invention, there is at least about 99% by weight of Compound 1 as a salt or cocrystal thereof.

[0094] According to one embodiment, 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, wherein the percentage is based on the gross weight of the composition. According to another embodiment, relative to the total area of ​​the HPLC chromatogram, compound 1 contains no more than about 3.0 area % HPLC total organic impurities, and in certain embodiments, no more than about 1.5 area % HPLC total organic impurities. In other embodiments, relative to the total area of ​​the HPLC chromatogram, compound 1 contains no more than about 1.0% area % HPLC any single impurity, and in certain embodiments, no more than about 0.5 area % HPLC any single impurity.

[0095] In some embodiments, Compound 1 is present in an enantiomeric excess (ee) of about 90.0 to 99.95%. In some embodiments, Compound 1 is present in an enantiomeric excess (ee) 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,

[0096] 99.8, 99.9 or 99.95% enantiomeric excess (ee) is present. In some embodiments, Compound 1 is optically pure and substantially free of its (S)-enantiomer.

[0097] In some embodiments, Compound 1 exists as a free acid. In some embodiments, Compound 1 exists as a salt. In some embodiments, Compound 1 exists as a pharmaceutically acceptable salt.

[0098] In some embodiments, Compound 1 exists as a co-crystal.

[0099] In some embodiments, Compound 1 is an amorphous form of a salt or co-crystal of Compound 1.

[0100] In some embodiments, Compound 1 is a crystalline form of a salt or co-crystal of Compound 1. In some embodiments, the crystalline form of the salt or co-crystal of Compound 1 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 piperazine Form I.

[0101] The structure depicted for Compound 1 is also meant to include all tautomeric forms of Compound 1. The structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, a compound having the present structure, except for the replacement of hydrogen with deuterium or tritium, or with an isotopically enriched 13 C- or 14 C's carbon replacing carbon is within the scope of the present invention.

[0102] It has been found that compound 1 can exist in a variety of solid forms. These forms include polymorphs, solvates, hydrates and amorphous forms. All of these forms are within the scope of 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.

[0103] In some embodiments, Compound 1 is an amorphous solid. Fig.18 An X-ray powder diffraction pattern of amorphous Compound 1 is depicted. In certain embodiments, the present invention provides Compound 1 as an amorphous solid substantially free of crystalline Compound 1. As used herein, the term "substantially free of crystalline Compound 1" means that the compound does not contain a significant amount of crystalline Compound 1. In certain embodiments, at least about 95% by weight of amorphous Compound 1 is present. In other embodiments of the present invention, at least about 99% by weight of amorphous Compound 1 is present.

[0104] As used herein, the term "polymorph" refers to any of the different crystal structures in which a compound may crystallize. As used herein, the term "solvate" refers to a crystalline form that has a stoichiometric or non-stoichiometric amount of a solvent incorporated into the crystal structure. Similarly, the term "hydrate" specifically refers to a crystalline form that has a stoichiometric or non-stoichiometric amount of water incorporated into the crystal structure.

[0105] In certain embodiments, 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 does not contain a significant amount of amorphous Compound 1. In certain embodiments, at least about 95% by weight of crystalline Compound 1 is present. In other embodiments of the invention, at least about 99% by weight of crystalline Compound 1 is present.

[0106] In some embodiments, Compound 1 is substantially free of any water or other solvents. In some embodiments, Compound 1 is a pure crystalline form, so there is no water or other solvent incorporated into the crystal structure. It has now been discovered that Compound 1 can exist in at least one apparently pure (i.e., anhydrous, non-solvate) crystalline form. These pure crystalline forms of Compound 1 include Form I, Form VII, and Form VIII, each of which is described in detail herein.

[0107] In some embodiments, the present invention provides solvated crystalline forms of Compound 1. These 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).

[0108] In some embodiments, the present invention provides a crystalline form of compound 1 selected from any one of Form I, Form II, Form III, Form IV, Form V, Form VI, Form VII, or Form VIII. Methods for preparing any one of Forms I to VIII of compound 1 are described herein.

[0109] In some embodiments, the present invention provides a polymorph of Compound 1, referred to as Form I.

[0110] In some embodiments, the present invention provides Form I of Compound 1 having a powder X-ray diffraction pattern substantially similar to Figure 1A Depicted.

[0111] As used herein, the term "about", when used in relation to a 2θ value, refers to the stated value ± 0.1 degrees 2θ obtained under the sample preparation and data collection conditions described in the Examples. In some embodiments, the term "about", when used in relation to a 2θ value, refers to the stated value ± 0.2 degrees 2θ. One skilled in the art will appreciate that changes in specific XRPD acquisition parameters will affect the XRPD pattern and the specific values ​​of 2θ degrees obtained.

[0112] In some embodiments, Form I of Compound 1 is characterized in that it has one or more peaks in its powder X-ray diffraction pattern selected from Table 1 below.

[0113] Table 1: Compound 1 Form I XRPD Peaks

[0114] Position (°2θ) Height (cts) Relative strength (%) 8.73 1552 6.83 9.23 22736 100 12.13 1828 8.04 12.28 1818 8.00 12.51 609 2.68 13.74 1245 5.48 14.74 2776 12.21 14.89 3143 13.82 15.83 1881 8.27 15.92 1400 6.16 17.19 2164 9.52 17.87 1294 5.69 18.32 1466 6.45 18.44 1556 6.84 19.11 1171 5.15 19.29 621 2.74 19.60 2289 10.07 19.91 359 1.58 20.74 561 2.47 21.04 528 2.32 22.49 919 4.04 23.85 964 4.24 23.96 1534 6.75 25.58 1762 7.75 27.00 541 2.38 27.29 957 4.21 28.17 454 2.00 28.58 512 2.26 28.92 339 1.49 35.54 242 1.06 38.91 131 0.58

[0115] 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 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 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 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 Table 1. In some embodiments, Form I of Compound 1 is characterized in that it has 10 peaks in its X-ray diffraction pattern in Table 1. In some embodiments, Form I of Compound 1 is characterized in that it has 15 peaks in its X-ray diffraction pattern in Table 1. In some embodiments, Form I of Compound 1 is characterized in that it has 20 peaks in its X-ray diffraction pattern in Table 1. In some embodiments, Form I of Compound 1 is characterized in that it has all peaks in Table 1 in its X-ray diffraction pattern.

[0116] In some embodiments, Form I of Compound 1 is characterized in that it has one or more peaks in its powder X-ray diffraction pattern selected from the group consisting of: about 12.51, about 14.89, about 17.19, about 19.11, about 19.91, about 28.58, and about 38.91 degrees 2θ. 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 the group consisting of: about 12.51, about 14.89, about 17.19, about 19.11, about 19.91, about 28.58, and about 38.91 degrees 2θ. 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 the group consisting of: about 12.51, about 14.89, about 17.19, about 19.11, about 19.91, about 28.58, and about 38.91 degrees 2θ. 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 the group consisting of: about 12.51, about 14.89, about 17.19, about 19.11, about 19.91, about 28.58, and about 38.91 degrees 2θ. 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 the group consisting of: about 12.51, about 14.89, about 17.19, about 19.11, about 19.91, about 28.58, and about 38.91 degrees 2θ. 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 the group consisting of: about 12.51, about 14.89, about 17.19, about 19.11, about 19.91, about 28.58, and about 38.91 degrees 2θ. In some embodiments, Form I of Compound 1 is characterized in that it has all 7 peaks in its powder X-ray diffraction pattern selected from the group consisting of: about 12.51, about 14.89, about 17.19, about 19.11, about 19.91, about 28.58, and about 38.91 degrees 2θ.

[0117] In some embodiments, Form I of Compound 1 is characterized in that it has one or more peaks in its powder X-ray diffraction pattern selected from the group consisting of: about 9.2, about 15.8, about 19.6, about 24.0, about 25.6, about 28.6, and about 8.7 degrees 2θ. 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 the group consisting of: about 9.2, about 15.8, about 19.6, about 24.0, about 25.6, about 28.6, and about 8.7 degrees 2θ. 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 the group consisting of: about 9.2, about 15.8, about 19.6, about 24.0, about 25.6, about 28.6, and about 8.7 degrees 2θ. 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 the group consisting of about 9.2, about 15.8, about 19.6, about 24.0, about 25.6, about 28.6, and about 8.7 degrees 2θ. 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 the group consisting of about 9.2, about 15.8, about 19.6, about 24.0, about 25.6, about 28.6, and about 8.7 degrees 2θ. 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 the group consisting of about 9.2, about 15.8, about 19.6, about 24.0, about 25.6, about 28.6, and about 8.7 degrees 2θ. In some embodiments, Form I of Compound 1 is characterized by an X-ray diffraction pattern comprising peaks at about 9.2, about 15.8, about 19.6, about 24.0, about 25.6, about 28.6, and about 8.7 degrees 2Θ.

[0118] In some embodiments, Form I is characterized by an X-ray powder diffraction pattern comprising the following peaks: 9.3, 15.0, and 19.8 ° 2θ ± 0.2 ° 2θ using Cu-Kα radiation at The wavelength is measured by a diffractometer. In some embodiments, the diffraction pattern shown comprises additional peaks at 16.0, 24.0, 25.8, and 27.3° 2θ ± 0.2° 2θ. Compound 1 Form I is also characterized in that its X-ray diffraction pattern is substantially as follows Figure 1A Compound 1 Form I is also characterized by an X-ray diffraction pattern substantially as shown in Figure 1B shown.

[0119] Form I of Compound 1 has been characterized by single crystal analysis and the data are summarized in Table 2 and shown in Figure 2 Ellipsoid diagram.

[0120] Table 2. Crystallographic data and data collection parameters

[0121] Empirical C 28 H 31 N3O8S

[0122] Formula weight (g mol-1) 569.62

[0123] Temperature (K) 293(2)

[0124] wavelength 1.54184

[0125] Crystal system: orthorhombic

[0126] Space group C2221

[0127] Unit cell parameters

[0128] α=90°

[0129] β=90°

[0130] γ=90°

[0131] Unit cell volume 11191.1(3)

[0132] Cell formula unit, 16

[0133] Z

[0134] Calculated density (g cm-3) 1.352

[0135] Absorption coefficient (mm-1) 1.495

[0136] F(000) 4800

[0137] Crystal size (mm3) 0.19×0.13×0.06

[0138] Reflectometer for cell measurements 15725

[0139] The theta range of cell measurement is 3.5010°-77.2150°

[0140] Total reflections collected 29754

[0141] Index range: -18≤h≤18; -14≤k≤18; -63≤l≤58

[0142] The theta range for data collection was θmin = 3.414°, θmax = 77.642°

[0143] Integrity to theta maximum 98.2%

[0144] Completeness to θ = 67.684° 99.7%

[0145] Absorption Corrected Multiple Scan

[0146] Transmission coefficient range 0.918-1.000

[0147] Full matrix least squares of Fsqd by refinement method

[0148] Independent reflection 11199 [Rint=0.0330,Rσ=0.0361]

[0149] Reflection [I>2σ(I)] 9830

[0150] Reflection / Limitation / Parameters 11199 / 0 / 737

[0151] Goodness of fit for F2 S = 1.05

[0152] Final residual value [I>2σ(I)] R=0.0446,Rw=0.1187

[0153] Final residual value [total reflection] R = 0.0516, Rw = 0.1250

[0154] Maximum diffraction peak and hole 0.405, -0.297

[0155] Maximum / mean drift / standard uncertainty 0.001 / 0.000

[0156] Spend

[0157] Absolute structure determination Flack parameter: -0.007(8)

[0158] Hooft parameter: -0.011(7)

[0159] Friedel Coverage: 88.7%

[0160] In some embodiments, Form I of Compound 1 is characterized by a differential scanning calorimetry (DSC) curve comprising an endotherm at about 189° C. to about 193° C. Form I of Compound 1 is also characterized by a DSC curve substantially as follows Figure 3A In some embodiments, Form I of Compound 1 is further characterized in that its DSC curve is substantially as shown in Figure 3B shown.

[0161] In some embodiments, Form I of Compound 1 is characterized by a thermogravimetric analysis (TGA) curve substantially as follows Figure 4A In some embodiments, Form I of Compound 1 is characterized by a thermogravimetric analysis (TGA) curve substantially as shown in Figure 4B shown.

[0162] In some embodiments, 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.

[0163] In some embodiments, the crystalline form is at least about 85% Form I. In some embodiments, the crystalline form is at least about 90% Form I. In some embodiments, the crystalline form is at least about 95% Form I. In some embodiments, the crystalline form is at least about 99% Form I. In some embodiments, the crystalline form is at least about 99.5% Form I. In some embodiments, the crystalline form is at least about 99.9% Form I. In some embodiments, the crystalline form is at least about 99.99% Form I.

[0164] Some embodiments provide pharmaceutical compositions comprising Compound 1 in Form I. In one embodiment, the pharmaceutical composition comprises Compound 1, wherein at least about 85% of Compound 1 is in Form I. In one embodiment, the pharmaceutical composition comprises Compound 1, wherein at least about 90% of Compound 1 is in Form I. In one embodiment, the pharmaceutical composition comprises Compound 1, wherein at least about 95% of Compound 1 is in Form I. In one embodiment, the pharmaceutical composition comprises Compound 1, wherein at least about 99% of Compound 1 is in Form I. In one embodiment, the pharmaceutical composition comprises Compound 1, wherein at least about 99.5% of Compound 1 is in Form I. In one embodiment, the pharmaceutical composition comprises Compound 1, wherein at least about 99.9% of Compound 1 is in Form I. In one embodiment, the pharmaceutical composition comprises Compound 1, wherein at least about 99.99% of Compound 1 is in Form I.

[0165] In some embodiments, the present invention provides a crystalline form of solvated Compound 1, referred to as Form II. In some embodiments, the present invention provides Form II of Compound 1, which has a powder X-ray diffraction pattern substantially similar to Figure 5 In some embodiments, Form II of Compound 1 is characterized in that it has one or more peaks in its powder X-ray diffraction pattern selected from Table 3 below.

[0166] Table 3. Compound 1 Form II XRPD Peaks

[0167]

[0168]

[0169] 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 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 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 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 Table 3. In some embodiments, Form II of Compound 1 is characterized in that it has all peaks in Table 3 in its X-ray diffraction pattern.

[0170] In some embodiments, Form II of Compound 1 is characterized in that it has one or more peaks in its powder X-ray diffraction pattern selected from the group consisting of: 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 2θ. 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 the group consisting of: 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 2θ. 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 the group consisting of: 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 2θ. 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 the group consisting of: 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 2θ. 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 the group consisting of: 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 2θ. 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 the group consisting of: 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 2θ. In some embodiments, Form II of Compound 1 is characterized in that it has 7 or more peaks in its powder X-ray diffraction pattern selected from the group consisting of: 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 2θ. In some embodiments, Form II of Compound 1 is characterized in that it has all 8 peaks in its powder X-ray diffraction pattern selected from the group consisting of: 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 2θ.

[0171] In some embodiments, Form II of Compound 1 is characterized in that it has one or more peaks in its powder X-ray diffraction pattern selected from the group consisting of: about 12.2, about 12.8, about 17.0, about 19.6, about 21.0, and about 22.8 degrees 2θ.

[0172] In some embodiments, the present invention provides a crystalline form of solvated Compound 1, referred to as Form III. In some embodiments, the present invention provides Form III of Compound 1, which has a powder X-ray diffraction pattern substantially similar to Figure 6 In some embodiments, Form III of Compound 1 is characterized in that it has one or more peaks in its powder X-ray diffraction pattern selected from Table 4 below.

[0173] Table 4. Compound 1 Form III XRPD Peaks

[0174]

[0175]

[0176] 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 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 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 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 Table 4. In some embodiments, Form III of Compound 1 is characterized in that it has all peaks in Table 4 in its X-ray diffraction pattern.

[0177] In some embodiments, Form III of Compound 1 is characterized in that it has one or more peaks in its powder X-ray diffraction pattern selected from the group consisting of: about 6.27, about 18.02, about 21.61, and about 24.14 degrees 2θ. 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 the group consisting of: about 6.27, about 18.02, about 21.61, and about 24.14 degrees 2θ. 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 the group consisting of: about 6.27, about 18.02, about 21.61, and about 24.14 degrees 2θ. In some embodiments, Form III of Compound 1 is characterized in that it has all 4 peaks in its powder X-ray diffraction pattern selected from the group consisting of: about 6.27, about 18.02, about 21.61, and about 24.14 degrees 2θ.

[0178] In some embodiments, Form III of Compound 1 is characterized in that it has one or more peaks in its powder X-ray diffraction pattern selected from the group consisting of: about 6.3, about 8.5, about 12.2, about 15.9, and about 21.6 degrees 2θ.

[0179] In some embodiments, the present invention provides a crystalline form of solvated Compound 1, referred to as Form IV. In some embodiments, the present invention provides Form IV of Compound 1, which has a powder X-ray diffraction pattern substantially similar to Fig. 7A In some embodiments, the present invention provides Form IV of Compound 1 having a powder X-ray diffraction pattern substantially similar to Figure 7B In some embodiments, 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.

[0180] Table 5. Compound 1 Form IV XRPD Peaks

[0181] Position (°2θ) Height (cts) Relative strength (%) 8.60 18.2 4.2 8.73 19.6 4.5 9.73 147.8 34.0 9.88 435.1 100 10.56 183.9 42.3 10.70 127.6 29.3 11.86 107.8 24.8 11.97 58.2 13.4 13.50 139.5 32.1 14.54 126.5 29.1 15.80 29.7 6.8 16.46 19.2 4.4 16.62 41.5 9.5 17.74 46.1 10.6 19.30 120.7 27.7 20.36 253.3 58.2 21.30 24.6 5.7 21.94 385.6 88.6 23.90 30.7 7.1 25.61 55.5 12.8 26.72 405.3 93.2 28.28 41.3 9.5 29.02 43.2 9.9

[0182] In some embodiments, Form IV of Compound 1 is characterized in that it has two or more peaks in its powder X-ray diffraction pattern selected from 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 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 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 Table 5. In some embodiments, Form IV of Compound 1 is characterized in that it has all peaks in Table 5 in its X-ray diffraction pattern.

[0183] In some embodiments, Form IV of Compound 1 is characterized in that it has one or more peaks in its powder X-ray diffraction pattern selected from the group consisting of: 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 2θ. In some embodiments, Form IV of Compound 1 is characterized in that it has two or more peaks in its powder X-ray diffraction pattern selected from the group consisting of: 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 2θ. 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 the group consisting of: 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 2θ. 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 the group consisting of: 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 2θ. 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 the group consisting of 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 2θ. 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 the group consisting of 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 2θ. In some embodiments, Form IV of Compound 1 is characterized in that it has 7 or more peaks in its powder X-ray diffraction pattern selected from the group consisting of: 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 2θ.In some embodiments, Form IV of Compound 1 is characterized in that it has 9 or more peaks in its powder X-ray diffraction pattern selected from the group consisting of: 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 2θ. In some embodiments, Form IV of Compound 1 is characterized in that it has 10 or more peaks in its powder X-ray diffraction pattern selected from the group consisting of: 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 2θ. In some embodiments, Form IV of Compound 1 is characterized in that it has all 11 peaks in its powder X-ray diffraction pattern selected from the group consisting of 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 2θ.

[0184] In some embodiments, Form IV of Compound 1 is characterized in that it has one or more peaks in its powder X-ray diffraction pattern selected from the group consisting of: about 9.9, about 10.6, about 11.9, about 14.5, about 16.6, about 21.9, and about 26.7 degrees 2θ.

[0185] In some embodiments, Form IV of Compound 1 is characterized by an X-ray powder diffraction pattern comprising the following peaks: 9.9, 10.7, 19.5, 22.0, and 26.8 ° 2θ ± 0.2 ° 2θ using Cu-Kα radiation at The wavelength is determined by a diffractometer. The diffraction pattern shown contains additional peaks at 8.7, 12.0 and 14.7° 2θ ± 0.2° 2θ. Compound 1 Form IV is also characterized in that its X-ray diffraction pattern is substantially as follows Fig. 7A Compound 1 Form IV is also characterized by an X-ray diffraction pattern substantially as shown in Figure 7B shown.

[0186] In some embodiments, Form IV of Compound 1 is characterized by a differential scanning calorimetry (DSC) curve comprising endotherms at 85, 190, and 202° C. and an exotherm at 146° C. Form IV of Compound 1 is also characterized by a DSC curve substantially as Figure 8 shown.

[0187] In some embodiments, Form IV of Compound 1 is characterized by a thermogravimetric analysis (TGA) curve substantially as follows Fig. 9 shown.

[0188] In some embodiments, the present invention provides a crystalline form of solvated Compound 1, referred to as Form V. In some embodiments, the present invention provides Form V of Compound 1, which has a powder X-ray diffraction pattern substantially similar to Fig.10 In some embodiments, Form V of Compound 1 is characterized in that it has one or more peaks in its powder X-ray diffraction pattern selected from Table 6 below.

[0189] Table 6. Compound 1 Form V XRPD Peaks

[0190]

[0191]

[0192] In some embodiments, Form V of Compound 1 is characterized in that it has two or more peaks in its powder X-ray diffraction pattern selected from 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 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 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 Table 6. In some embodiments, Form V of Compound 1 is characterized in that it has all peaks in Table 6 in its X-ray diffraction pattern.

[0193] In some embodiments, Form V of Compound 1 is characterized in that it has one or more peaks in its powder X-ray diffraction pattern selected from 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 2θ. In some embodiments, Form V of Compound 1 is characterized in that it has two or more peaks in its powder X-ray diffraction pattern selected from 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 2θ. 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 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 2θ. 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 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 2θ. 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 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 2θ. In some embodiments, Form V of Compound 1 is characterized in that it has six or more peaks in its powder X-ray diffraction pattern selected from 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 2θ.In some embodiments, Form V of Compound 1 is characterized in that it has 7 or more peaks in its powder X-ray diffraction pattern selected from 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 2θ. In some embodiments, Form V of Compound 1 is characterized in that it has 8 or more peaks in its powder X-ray diffraction pattern selected from 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 2θ. In some embodiments, Form V of Compound 1 is characterized in that it has 9 or more peaks in its powder X-ray diffraction pattern selected from 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 2θ. In some embodiments, Form V of Compound 1 is characterized in that it has 10 or more peaks in its powder X-ray diffraction pattern selected from 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 2θ. In some embodiments, Form V of Compound 1 is characterized in that it has 11 or more peaks in its powder X-ray diffraction pattern selected from the group consisting of: 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 2θ. In some embodiments, Form V of Compound 1 is characterized in that it has 12 or more peaks in its powder X-ray diffraction pattern selected from the group consisting of: 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 2θ.In some embodiments, Form V of Compound 1 is characterized in that it has all 13 peaks in its powder X-ray diffraction pattern selected from the group consisting of: 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 2θ.

[0194] In some embodiments, Form V of Compound 1 is characterized in that it has one or more peaks in its powder X-ray diffraction pattern selected from the group consisting of: 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 2θ.

[0195] In some embodiments, the present invention provides a crystalline form of solvated Compound 1, referred to as Form VI. In some embodiments, the present invention provides Form VI of Compound 1, which has a powder X-ray diffraction pattern substantially similar to Fig.11A In some embodiments, the present invention provides Form VI of Compound 1 having a powder X-ray diffraction pattern substantially similar to Fig. 11B In some embodiments, Form VI of Compound 1 is characterized in that it has a peak in its powder X-ray diffraction pattern selected from Table 7 below.

[0196] Table 7. Compound 1 Form VI XRPD Peaks

[0197]

[0198] In some embodiments, Form VI of Compound 1 is characterized in that it has a peak in its powder X-ray diffraction pattern at approximately 10.19 degrees 2Θ.

[0199] In some embodiments, Form VI is characterized by an X-ray powder diffraction pattern comprising peaks at 18.0, 23.4, and 25.3 ° 2θ ± 0.2 ° 2θ using Cu-Kα radiation at The wavelength is determined by a diffractometer. The diffraction pattern shown contains additional peaks at 10.5, 14.2, 15.1 and 18.8° 2θ ± 0.2° 2θ. Compound 1 Form VI is also characterized in that its X-ray diffraction pattern is substantially as follows Fig.11A Compound 1 Form VI is also characterized in that its X-ray diffraction pattern is substantially as shown. Fig. 11B shown.

[0200] In some embodiments, Form VI of Compound 1 is characterized by a differential scanning calorimetry (DSC) curve comprising endotherms at 131° C., 193° C., and 205° C. Form VI of Compound 1 is also characterized by a DSC curve substantially as follows Fig.12 shown.

[0201] In some embodiments, Form VI of Compound 1 is characterized by a thermogravimetric analysis (TGA) curve substantially as follows Fig.13 shown.

[0202] In some embodiments, the present invention provides a polymorph of Compound 1, referred to as Form VII. In some embodiments, the present invention provides Form VII of Compound 1, which has a powder X-ray diffraction pattern substantially similar to Fig.14 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 Table 8 below.

[0203] Table 8. Compound 1 Form VII XRPD Peaks

[0204]

[0205] In some embodiments, Form VII of Compound 1 is characterized in that it has two or more peaks in its powder X-ray diffraction pattern selected from 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 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 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 Table 8. In some embodiments, Form VII of Compound 1 is characterized in that it has all peaks in Table 8 in its X-ray diffraction pattern.

[0206] 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 the group consisting of: about 8.94, about 17.90, and about 27.76 degrees 2θ in addition to one or more peaks selected from the group consisting of: 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 2θ. In some embodiments, Form VII of Compound 1 is characterized in that it has 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 2θ in its powder X-ray diffraction pattern, and has two or more peaks selected from about 8.94, about 17.90, and about 27.76 degrees 2θ. In some embodiments, Form VII of Compound 1 is characterized in that it has one or more peaks selected from about 8.94, about 17.90, and about 27.76 degrees 2θ in its powder X-ray diffraction pattern, in addition to a peak at about 25.96 degrees 2θ. In some embodiments, Form VII of Compound 1 is characterized in that it has one or more peaks selected from about 8.94 and about 27.76 degrees 2θ in its powder X-ray diffraction pattern in addition to a peak at about 25.96 degrees 2θ. In some embodiments, Form VII of Compound 1 is characterized in that it has all three peaks selected from about 8.94, about 27.76, and about 25.96 degrees 2θ in its powder X-ray diffraction pattern.

[0207] 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 the group consisting of: 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 2θ.

[0208] In some embodiments, the present invention provides a polymorph of Compound 1, referred to as Form VIII. In some embodiments, the present invention provides Form VIII of Compound 1, which has a powder X-ray diffraction pattern substantially similar to Fig.15A In some embodiments, the present invention provides Form VIII of Compound 1 having a powder X-ray diffraction pattern substantially similar to Fig. 15BIn some embodiments, Form VIII of Compound 1 is characterized in that it has one or more peaks in its powder X-ray diffraction pattern selected from Table 9 below.

[0209] Table 9. Compound 1 Form VIII XRPD Peaks

[0210]

[0211]

[0212] 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 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 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 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 Table 9. In some embodiments, Form VIII of Compound 1 is characterized in that it has all peaks in Table 9 in its X-ray diffraction pattern.

[0213] In some embodiments, Form VIII of Compound 1 is characterized in that it has one or more peaks in its powder X-ray diffraction pattern selected from the group consisting of about 5.50, about 10.31, about 18.77, about 22.23, and about 25.83 degrees 2θ. 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 the group consisting of about 5.50, about 10.31, about 18.77, about 22.23, and about 25.83 degrees 2θ. 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 the group consisting of about 5.50, about 10.31, about 18.77, about 22.23, and about 25.83 degrees 2θ. 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 the group consisting of: about 5.50, about 10.31, about 18.77, about 22.23, and about 25.83 degrees 2θ. In some embodiments, Form VIII of Compound 1 is characterized in that it has all 5 peaks in its powder X-ray diffraction pattern selected from the group consisting of: about 5.50, about 10.31, about 18.77, about 22.23, and about 25.83 degrees 2θ.

[0214] In some embodiments, Form VIII of Compound 1 is characterized in that it has one or more peaks in its powder X-ray diffraction pattern selected from the group consisting of: about 5.5, about 10.3, about 15.8, about 18.8, about 20.4, about 22.7, and about 25.8 degrees 2θ.

[0215] In some embodiments, Form VIII is characterized by an X-ray powder diffraction pattern comprising peaks at 16.0, 20.5, and 22.8 ° 2θ ± 0.2 ° 2θ using Cu-Kα radiation at The wavelength is determined by a diffractometer. The diffraction pattern shown contains additional peaks at 9.1, 10.5, 18.8 and 25.8° 2θ ± 0.2° 2θ. Compound 1 Form VIII is also characterized in that its X-ray diffraction pattern is substantially as follows Fig.15A Compound 1 Form VIII is also characterized by an X-ray diffraction pattern substantially as shown. Fig. 15B shown.

[0216] In some embodiments, Form VIII of Compound 1 is characterized by a differential scanning calorimetry (DSC) curve comprising an endotherm at 205° C. Form VIII of Compound 1 is also characterized by a DSC curve substantially as follows Fig.16 shown.

[0217] In some embodiments, Form VIII of Compound 1 is characterized by a thermogravimetric analysis (TGA) curve substantially as follows Fig.17 shown.

[0218] Some embodiments herein provide a crystalline form of the sodium salt or cocrystal of Compound 1, which is referred to as Compound 1 Sodium Form I. In some embodiments, Compound 1 Sodium Form I is characterized by an X-ray powder diffraction pattern comprising the following peaks: 7.5, 8.2, 20.4, and 20.9 ° 2θ ± 0.2 ° 2θ, which is measured using Cu-Kα radiation at The wavelength is determined by a diffractometer. The diffraction pattern shown contains additional peaks at 14.8, 17.5, 24.0 and 27.7° 2θ ± 0.2° 2θ. Compound 1 Sodium Form I is also characterized in that its complete X-ray diffraction pattern is substantially as follows Fig.19 shown.

[0219] In some embodiments, Compound 1 sodium Form I is characterized by a differential scanning calorimetry (DSC) curve comprising an endotherm at about 37° C. and an endotherm at about 283° C. Compound 1 sodium Form I is also characterized by a DSC curve substantially as Fig. 20 shown.

[0220] In some embodiments, Compound 1 Sodium Form I is characterized by a thermogravimetric analysis (TGA) curve substantially as follows Fig.21 shown.

[0221] Some embodiments herein provide a crystalline form of the sodium salt or cocrystal of Compound 1, which is referred to as Compound 1 Sodium Form II. In some embodiments, Compound 1 Sodium Form II is characterized by an X-ray powder diffraction pattern comprising the following peaks: 4.8, 6.7, 15.6, and 24.2° 2θ ± 0.2° 2θ, which is measured using Cu-Kα radiation at The wavelength is determined by a diffractometer. The diffraction pattern shown contains additional peaks at 17.9, 29.2, 32.5 and 38.0° 2θ ± 0.2° 2θ. Compound 1 Sodium Form II is also characterized in that its complete X-ray diffraction pattern is substantially as follows Fig. 22 shown.

[0222] In some embodiments, Compound 1 sodium Form II is characterized by a differential scanning calorimetry (DSC) curve comprising an endotherm at about 19° C., an endotherm at about 78° C., and an endotherm at about 136° C. Compound 1 sodium Form II is also characterized by a DSC curve substantially as Fig.23 shown.

[0223] In some embodiments, Compound 1 sodium Form II is characterized by a thermogravimetric analysis (TGA) curve substantially as follows Fig.24 shown.

[0224] Some embodiments herein provide a crystalline form of a calcium salt or cocrystal of Compound 1, which is referred to as Compound 1 Calcium Form I. In some embodiments, Compound 1 Calcium Form I is characterized by an X-ray powder diffraction pattern comprising the following peaks: 10.1, 14.3, and 20.4 ° 2θ ± 0.2 ° 2θ, which is measured using Cu-Kα radiation at The wavelength is determined by a diffractometer. The diffraction pattern shown contains additional peaks at 3.6, 7.8, 21.6, 27.3, 28.9° 2θ ± 0.2° 2θ. Compound 1 Calcium Form I is also characterized in that its complete X-ray diffraction pattern is substantially as follows Fig.25 shown.

[0225] In some embodiments, Compound 1 Calcium Form I is characterized by a differential scanning calorimetry (DSC) curve comprising 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. Compound 1 Calcium Form I is also characterized by a DSC curve substantially as Fig.26 shown.

[0226] In some embodiments, Compound 1 Calcium Form I is characterized by a thermogravimetric analysis (TGA) curve substantially as follows Fig. 27 shown.

[0227] Some embodiments herein provide a crystalline form of the magnesium salt or cocrystal of Compound 1, which is referred to as Compound 1 Magnesium Form I. In some embodiments, Compound 1 Magnesium Form I is characterized by an X-ray powder diffraction pattern comprising the following peaks: 8.2, 16.9, 19.1, and 21.2 ° 2θ ± 0.2 ° 2θ, which is measured using Cu-Kα radiation at The wavelength is determined by a diffractometer. The diffraction pattern shown contains additional peaks at 15.8, 24.1, 26.1 and 27.1° 2θ ± 0.2° 2θ. Compound 1 Magnesium Form I is also characterized in that its complete X-ray diffraction pattern is substantially as follows Fig.28 shown.

[0228] In some embodiments, Compound 1 Magnesium Form I is characterized by a differential scanning calorimetry (DSC) curve comprising an endotherm at about 53° C. Compound 1 Magnesium Form I is also characterized by a DSC curve substantially as Fig.29 shown.

[0229] In some embodiments, Compound 1 Magnesium Form I is characterized by a thermogravimetric analysis (TGA) curve substantially as follows Fig.30 shown.

[0230] Some embodiments herein provide a crystalline form of a diethanolamine salt or cocrystal of Compound 1, which is referred to as Compound 1 diethanolamine Form I. In some embodiments, Compound 1 diethanolamine Form I is characterized by an X-ray powder diffraction pattern comprising the following peaks: 5.1, 8.0, 17.0, 25.1 ° 2θ ± 0.2

[0231] °2θ, which uses Cu-Kα radiation in The wavelength is determined by a diffractometer. The diffraction pattern shown contains additional peaks at 13.4, 16.4, 20.4 and 22.6° 2θ ± 0.2° 2θ. Compound 1 diethanolamine Form I is also characterized in that its complete X-ray diffraction pattern is substantially as follows Fig.31 shown.

[0232] In some embodiments, Compound 1 diethanolamine Form I is characterized by a differential scanning calorimetry (DSC) curve comprising an endotherm at about 118° C. Compound 1 diethanolamine Form I is also characterized by a DSC curve substantially as Fig.32 shown.

[0233] In some embodiments, Compound 1 diethanolamine Form I is characterized by a thermogravimetric analysis (TGA) curve substantially as follows Fig.33 shown.

[0234] Some embodiments herein provide a crystalline form of a piperazine salt or cocrystal of Compound 1, which is referred to as Compound 1 piperazine Form I. In some embodiments, Compound 1 piperazine Form I is characterized by an X-ray powder diffraction pattern comprising the following peaks: 5.6, 8.0, 10.5, and 15.9 ° 2θ ± 0.2 ° 2θ, which is measured using Cu-Kα radiation at The wavelength is determined by a diffractometer. The diffraction pattern shown contains additional peaks at 13.3, 17.9, 22.1 and 24.3° 2θ ± 0.2° 2θ. Compound 1 Piperazine Form I is also characterized in that its complete X-ray diffraction pattern is substantially as follows Fig.34 shown.

[0235] In some embodiments, Compound 1 piperazine Form I is characterized by a differential scanning calorimetry (DSC) curve comprising an endotherm at about 27° C. and an endotherm at about 139° C. Compound 1 piperazine Form I is also characterized by a DSC curve substantially as Fig.35 shown.

[0236] In some embodiments, Compound 1 Piperazine Form I is characterized by a thermogravimetric analysis (TGA) curve substantially as follows Fig.36 shown.

[0237] 3. Compounds and Definitions

[0238] The compounds of the present invention include the compounds generally described above and are further described by the classes, subclasses and species disclosed herein. Unless otherwise indicated, the following definitions as used herein shall apply. For purposes of the present invention, the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th edition is used. th Ed) to identify chemical elements. In addition, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5 th Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0239] As used herein, the term "aliphatic" or "aliphatic group" refers to a straight chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or contains one or more unsaturated units, or a monocyclic hydrocarbon or bicyclic hydrocarbon (also referred to herein as "carbocycle", "alicyclic" or "cycloalkyl") that is completely saturated or contains one or more unsaturated units, but is not aromatic, and has a single point of attachment to the rest of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or contains one or more unsaturated units, but is not aromatic, and has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, straight or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl, and mixtures thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0240] The term "lower alkyl" refers to a C 1-4 Straight or branched chain alkyl. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.

[0241] The term "lower haloalkyl" refers to a C 1-4 Straight chain or branched chain alkyl.

[0242] The term "heteroatom" refers to 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, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (as in N-substituted pyrrolidinyl)).

[0243] As used herein, the term "unsaturated" means that a group has one or more units of unsaturation.

[0244] As used herein, the term "divalent C 1-8 (or C 1-6 ) saturated or unsaturated, straight or branched hydrocarbon chain” refers to straight or branched divalent alkylene, alkenylene and alkynylene chains as defined herein.

[0245] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n-, wherein n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2 or 2 to 3. The substituted alkylene chain is a polymethylene chain in which one or more methylene hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0246] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond and in which one or more hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0247] “Alkoxy” refers to the group “alkyl-O—.” Examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0248] The term "halogen" refers to F, Cl, Br or I.

[0249] The term "ring" refers to cycloalkyl or heterocycle as defined herein.

[0250] The term "aryl", used alone or as part of a larger group such as "aralkyl", "aralkyloxy", or "aryloxyalkyl", refers to a monocyclic or bicyclic ring system having a total of 5 to 14 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. The term "aryl" is used interchangeably with the term "aryl ring".

[0251] The term "aryl", used alone or as part of a larger group such as "aralkyl", "aralkyloxy" or "aryloxyalkyl", refers to monocyclic and bicyclic ring systems having a total of 5 to 10 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. The term "aryl" can be used interchangeably with the term "aryl ring". In certain embodiments of the present invention, "aryl" refers to an aromatic ring system, including (but not limited to) phenyl, biphenyl, naphthyl, anthracenyl, etc., which may bear one or more substituents. Also included within the scope of the term "aryl" as used herein are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimido, naphthimido, phenanthridinyl or tetrahydronaphthyl, etc.

[0252] The term "aralkyl" refers to an aryl-alkylene group wherein aryl and alkylene are as defined herein.

[0253] The term "aralkoxy" refers to an aryl-alkoxy group wherein aryl and alkoxy are as defined herein.

[0254] The term "aryloxyalkyl" refers to an aryl-O-alkylene group wherein aryl and alkylene are as defined herein.

[0255] The terms "heteroaryl" and "heteroar-", used alone or as part of a larger group such as "heteroaralkyl" or "heteroaralkoxy", refer to groups having 5 to 10 ring atoms, preferably 5, 6 or 9 ring atoms; having 6, 10 or 14 pi electrons shared in the ring array; and having 1 to 5 heteroatoms in addition to carbon atoms. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms "heteroaryl" and "heteroar-", as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic or heterocyclyl rings, wherein the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolyl, tetrahydroisoquinolyl and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. The heteroaryl group may be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring", "heteroaryl" or "heteroaromatic", any of which includes optionally substituted rings. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group, wherein the alkyl and heteroaryl moieties are independently optionally substituted.

[0256] As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic group" and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic group that is saturated or partially unsaturated and has one or more, preferably one to four, heteroatoms as defined above in addition to carbon atoms. The term "nitrogen" when used with respect to a ring atom of a heterocycle includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 atoms selected from oxygen, sulfur or nitrogen, nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or + NR (as in N-substituted pyrrolidinyl).

[0257] The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any ring atom may be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepine, oxazepine, thiazepine, morpholinyl, and quinuclidinyl. The terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety" and "heterocyclic radical" are used interchangeably herein and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl or alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring. The heterocyclyl group may be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl, wherein the alkyl and heterocyclyl portions are independently optionally substituted.

[0258] As used herein, the term "partially unsaturated" refers to a ring group that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl groups as defined herein.

[0259] As described herein, the compounds of the present invention may contain "optionally substituted" groups. In general, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the specified group are replaced by suitable substituents. Unless otherwise indicated, the "optionally substituted" group may have suitable substituents at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituents at each position may be the same or different. The combination of substituents envisioned by the present invention is preferably a combination that forms a stable or chemically feasible compound. As used herein, the term "stable" refers to a compound that does not change substantially when subjected to the conditions of its preparation, detection, and in certain specific examples, its recovery, purification, and use for one or more purposes disclosed herein.

[0260] Suitable monovalent substituents on the substitutable carbon atoms of an "optionally substituted" group are independently halogen; -(CH2) 0-4 R o ; -(CH2) 0-4 OR o ; -O-(CH2) 0-4 R o ; -O-(CH2) 0-4 C(O)ORo ; -(CH2) 0-4 CH(OR o )2; -(CH2) 0- 4SR o ; -(CH2) 0-4 Ph, which can be o Substitution; -(CH2) 0-4 O(CH2) 0-1 Ph, which can be o Substitution; -CH=CHPh, which can be R o Substitution; -(CH2) 0-4 O(CH2) 0-1 -pyridyl, which may be o Substitution; -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R o )2; -(CH2) 0-4 N(R o )C(O)R o ;-N(R o )C(S)R o ; -(CH2) 0-4 N(R o )C(O)NR o 2;-N(R o )C(S)NR o 2; -(CH2) 0-4 N(R o )C(O)OR o ;-N(R o )N(R o )C(O)R o ;-N(R o )N(R o )C(O)NR o 2;-N(R o )N(R o )C(O)OR o ; -(CH2) 0-4 C(O)R o ;-C(S)R o ; -(CH2) 0-4 C(O)OR o ; -(CH2) 0-4 C(O)SR o ; -(CH2) 0-4 C(O)OSiR o 3; -(CH2) 0-4 OC(O)R o ;-OC(O)(CH2) 0-4 SR-; -(CH2)0-4 SC(O)R o ; -(CH2) 0-4 C(O)NR o 2; -C(S)NR o 2; -C(S)SR o ;-SC(S)SR o ; -(CH2) 0- 4OC(O)NR o 2; -C(O)N(OR o )R o ; -C(O)C(O)R o ; -C(O)CH2C(O)R o ;-C(NOR o )R o ; -(CH2) 0-4 SSR o ; -(CH2) 0-4 S(O)2R o ; -(CH2) 0-4 S(O)2OR o ; -(CH2) 0-4 OS(O)2R o ; -S(O)2NR o 2; -(CH2) 0-4 S(O)R o ;-N(R o )S(O)2NR o 2;-N(R o )S(O)2R o ;-N(OR o )R o ; -C(NH)NR o 2;-P(O)2R o ;-P(O)R o 2;-OP(O)R o 2;-OP(O)(OR o )2;SiR o 3;-(C 1-4 Straight chain or branched alkylene)ON(R o )2; or-(C 1-4 Straight or branched alkylene)C(O)ON(R o )2, where each R o may be substituted as defined below and are independently hydrogen, C 1-6 Aliphatic groups, -CH2Ph, -O(CH2) 0-1Ph, -CH2-(5-6 membered heteroaryl ring) or a 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, notwithstanding the above definitions, two independent occurrences of R o Together with its intervening atoms it forms a 3-12 membered saturated, partially unsaturated or aromatic mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below.

[0261] R o (or two independent occurrences of R o Suitable monovalent substituents on the ring formed with its intervening atoms) are independently halogen, -(CH2) 0-2 R ● 、-(halogenated R ● )、-(CH2) 0-2 OH, -(CH2) 0-2 OR ● 、-(CH2) 0-2 CH(OR ● )2, -O(halogenated R ● )、-CN、-N3、-(CH2) 0-2 C(O)R ● 、-(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● 、-(CH2) 0-2 SR ● 、-(CH2) 0- 2SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR ● 、-(CH2) 0-2 NR ● 2. -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● 、-(C 1-4 Straight or branched alkylene)C(O)OR ● or -SSR ● ; Each R ● unsubstituted or, when the prefix "halo" is present, substituted only with one or more halogens, and independently selected from C 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. o Suitable divalent substituents on a saturated carbon atom of include =0 and =S.

[0262] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: =0, =S, =NNR * 2. =NNHC(O)R * 、=NNHC(O)OR * 、=NNHS(O)2R * , =NR * , =NOR * 、-O(C(R * 2)) 2-3 O-or-S(C(R * 2)) 2-3 S-, where each independent occurrence of R * is selected from hydrogen, C which may be substituted as defined below 1-6 an aliphatic group or an unsubstituted 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents for ortho-substitutable carbons of an "optionally substituted" group include: -O(CR * 2) 2-3 O-, where each independent occurrence of R * is selected from hydrogen, C which may be substituted as defined below 1-6 an aliphatic group or an unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0263] R * Suitable substituents on the aliphatic group include halogen, -R ● 、-(halogenated R ● ), -OH, -OR ● 、-O(halogenated R ● )、-CN、-C(O)OH、-C(O)OR ● 、-NH2、-NHR ● 、-NR ● 2 or -NO2, where each R ● unsubstituted or, when the prefix "halo" is present, substituted only with one or more halogens, and independently C 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0264] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include or Among them are independently hydrogen, C 1-6 an aliphatic group, an unsubstituted -OPh or an unsubstituted 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, notwithstanding the above definitions, two independent occurrences of Together with its intervening atoms, it forms an unsubstituted 3-12 membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0266] Suitable substituents on the aliphatic group are independently halogen, -R ● 、-(halogenated R ● ), -OH, -OR ● 、-O(halogenated R ● )、-CN、-C(O)OH、-C(O)OR ● 、-NH2、-NHR ● 、-NR ● 2 or -NO2, where each R ● unsubstituted or, when the prefix "halo" is present, substituted only with one or more halogens, and independently C 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0267] The term "co-crystal" refers to a molecular complex of ionized or non-ionized Compound 1 (or any other compound disclosed herein) and one or more non-ionized co-crystal formers (eg, pharmaceutically acceptable salts) linked by non-covalent interactions.

[0268] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reaction, and the like, within the scope of sound medical judgment, and are compatible with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, Handbook of Pharmaceutical Salts: Properties, Selection, and Use, 2 ndRevised Edition, P. Heinrich Stahl and Camille G. Wermuth, Eds. Wiley, April 2011, also described, each document is incorporated herein by reference. The pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids and bases. The example of pharmaceutically acceptable non-toxic acid addition salts is formed by inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or by 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) and the salt of the amino formed. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, 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, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.

[0269] Salts derived from appropriate bases include metal ions (including aluminum, zinc, alkali metals, alkaline earth metals), ammonium and N + (C 1–4 The salt of amine or ammonium includes but is not limited to arginine, betaine, hydrazine, choline, diethylamine, lysine, benzathine penicillin, 2-(diethylamino)-ethanol, ethanolamine, 1-(2-hydroxyethyl)-pyrrolidine, diethanolamine, ammonia, dimethylethanolamine, N-methyl-glucosamine, tromethamine, triethanolamine, 4-(2-hydroxyethyl)-morpholine, 1H-imidazole, ethylenediamine, piperazine, procaine and phenethylbenzylamine.

[0270] Unless otherwise stated, the structures depicted herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or configurational) isomer) forms of the structure; for example, R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E configurational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or configurational) isomer mixtures of the compounds of the present invention are within the scope of the present invention. Unless otherwise stated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention. In addition, unless otherwise stated, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, having a structure that includes the replacement of hydrogen with deuterium or tritium or with 13 C or 14 Compounds of the present structures in which a C-enriched carbon replaces a carbon are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, probes in biological assays, or therapeutic agents of the present invention.

[0271] The term "reaction conditions" refers to the physical and / or environmental conditions under which a chemical reaction is carried out. The term "under conditions sufficient to ..." or "under reaction conditions sufficient to ..." refers to reaction conditions under which a desired chemical reaction can be carried out. Examples of reaction conditions include, but are not limited to, one or more of the following: reaction temperature, solvent, pH, pressure, reaction time, molar ratio of reactants, presence of base or acid or catalyst, radiation, concentration, etc. The reaction conditions can be named after the specific chemical reaction using the conditions, such as coupling conditions, hydrogenation conditions, acylation conditions, reduction conditions, etc. The reaction conditions for most reactions are generally known to those skilled in the art or can be easily obtained from the literature. Exemplary reaction conditions sufficient for chemical transformations provided herein can be found throughout the text, especially in the following examples. It is also contemplated that the reaction conditions may include reagents other than those listed in the specific reaction.

[0272] 4. General Methods for Providing Compounds of the Invention

[0273] Can use the method disclosed herein and conventional improvement thereof to carry out the method of the present invention, according to the disclosure of this paper and method well known in the art, these modifications will be apparent.Except what is taught herein, conventional and well-known synthetic method can be used.The synthesis of typical compounds as described herein (for example, compounds with the structure described by compound 1 or other formulas or compounds disclosed herein (i.e., I, G-1, G-1-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-11, G-12, G-13, G-13-a, etc.)) can be completed as described in the following examples.If available, reagent can be purchased, for example, from Sigma Aldrich or other chemical suppliers.

[0274] Typical embodiments of compounds according to the present invention can be synthesized using the general reaction scheme described below. It will be apparent from the description herein that the general scheme can be changed by replacing the starting raw materials with other substances with similar structures, thereby generating corresponding different products. The description of synthesis provides a large number of examples below, illustrating how the starting raw materials change to provide corresponding products. Given the desired product in which the substituent is defined, the desired starting raw materials can usually be determined by inspection. The starting raw materials are usually obtained from commercial sources or synthesized using disclosed methods. In order to synthesize the compounds of the disclosed embodiments, the structure of the compound to be synthesized will provide the identification of each substituent. In view of the embodiments herein, the identification of the final product will usually show the identification of the desired starting raw materials through a simple inspection process.

[0275] Compounds of the present disclosure can be prepared from readily available starting materials using, for example, the following general methods and processes. It should be understood that, given typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.), other treatment and purification conditions may also be used unless otherwise indicated. Optimal reaction conditions may vary with the specific reactants or solvents used, but those skilled in the art may determine the conditions by conventional optimization procedures.

[0276] In addition, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent some functional groups from undesirable reactions. Suitable protecting groups for various functional groups and suitable conditions for protecting and deprotecting specific functional groups are well known in the art. For example, many protecting groups are described in TW Greene and GM Wuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York and the references cited therein.

[0277] In addition, the compounds of the present disclosure may contain one or more chiral centers. Therefore, if desired, the compound can be prepared as a pure stereoisomer, or separated into pure stereoisomers, i.e., as independent enantiomers or diastereomers or as a mixture enriched in stereoisomers. Unless otherwise indicated, all these stereoisomers (and enriched mixtures) are included within the scope of the present invention. For example, optional active starting materials or stereoselective reagents well known in the art can be used to prepare pure stereoisomers (or enriched mixtures). Alternatively, the racemic mixture of the compound can be separated using, for example, chiral column chromatography, chiral resolving agents, etc.

[0278] The starting materials for the following reactions are generally known compounds or can be prepared by known methods or obvious modifications thereof. For example, many 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 can be prepared by procedures described in standard references or obvious modifications thereof, such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 5 thEdition, 2001) and Larock's Comprehensive Organic Transformations (VCHPublishers Inc., 1989).

[0279] The term "solvent", "inert organic solvent" or "inert solvent" refers to a solvent that is inert under the reaction conditions described in conjunction therewith (including, for example, benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), 2-methyltetrahydrofuran ("MeTHF"), dimethylformamide ("DMF"), chloroform, dichloromethane, diethyl ether, methanol, 2-propanol, pyridine, etc.). Unless otherwise specified, the solvent used in the reaction of the present invention is an inert organic solvent, and the reaction is carried out under an inert gas, preferably nitrogen.

[0280] In each exemplary scheme, it may be advantageous to separate the reaction products from each other and / or from the starting materials. The desired product of each step or series of steps is separated and / or purified (hereinafter referred to as separation) to the desired degree of homogeneity by techniques common in the art. Typically, such separations include multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation or chromatography. Chromatography can include any number of methods, including, for example: reverse phase and normal phase chromatography; size exclusion chromatography; ion exchange chromatography; high, medium and low pressure liquid chromatography and equipment; small-scale analytical chromatography; simulated moving bed (SMB) and preparative thin layer or thick layer chromatography, as well as small-scale thin layer and flash chromatography techniques.

[0281] Another class of separation methods involves treating the mixture with a reagent that selectively binds to or separates from the product, unreacted starting material, reaction byproducts, etc. Such reagents include adsorbents or absorbents, such as activated carbon, molecular sieves, ion exchange media, etc. Alternatively, the reagent can be an acid (in the case of a basic substance), a base (in the case of an acidic substance), a binding agent such as an antibody, a binding protein, a selective chelating agent such as a crown ether, a liquid / liquid ion extraction reagent (LIX), etc.

[0282] The selection of an appropriate separation method depends on the properties of the substances involved. For example, boiling point and molecular weight in distillation and sublimation, the presence or absence of polar functional groups in chromatography, the stability of materials in acidic and basic media in multiphase extraction, etc. One skilled in the art will apply the technique most likely to achieve the desired separation.

[0283] A single stereoisomer, such as an enantiomer, which is substantially free of its stereoisomers, can be obtained by resolution of the racemic mixture using, for example, a method for forming diastereomers using an optically active resolving agent (Stereochemistry of Carbon Compounds, (1962), EL Elliel, McGraw Hill; Lochmuller, CH, (1975) J. Chromatogr., 113: (3) 283-302). The racemic mixture of the chiral compounds of the present invention can be separated and resolved by any suitable method, including: (1) forming ionic diastereomeric salts with chiral compounds and separating by fractional crystallization or other methods; (2) forming diastereomeric compounds with chiral derivatizing agents, separating diastereomers, and converting to pure stereoisomers; and (3) separating substantially pure or enriched stereoisomers directly under chiral conditions.

[0284] According to method (1), diastereomeric salts can be formed by reacting enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, α-methyl-β-phenylethylamine (amphetamine) etc. with an asymmetric compound having an acidic functional group such as carboxylic acid and sulfonic acid. Can be induced to separate diastereomeric salts by fractional crystallization or ion chromatography. In order to separate the optical isomers of amino compounds, chiral carboxylic acids or sulfonic acids are added, for example camphorsulfonic acid, tartaric acid, mandelic acid or lactic acid can cause the formation of diastereomeric salts.

[0285] Alternatively, by method (2), the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a diastereomeric pair (Eliel, E. and Wilen, S. (1994) Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., p. 322). Diastereomeric compounds can be formed by reacting an asymmetric compound with an enantiomerically pure chiral derivatizing agent such as a menthyl derivative, followed by separation of the diastereomers and hydrolysis to obtain a free enantiomerically enriched substrate. A method for determining optical purity comprises preparing a chiral ester of the racemic mixture, for example a menthyl ester such as (-) menthyl chloroformate, or the Mosher ester, α-methoxy-α-(trifluoromethyl)phenyl acetate (Jacob III. (1982) J. Org. Chem. 47:4165), in the presence of a base and analyzing the NMR spectrum of the two atropisomeric diastereomers present. Stable diastereomers of atropisomeric compounds can be separated and resolved by normal phase chromatography and reverse phase chromatography followed by a method for separating atropisomeric naphthyl-isoquinolines (Hoye, T., WO

[0286] 96 / 15111). According to method (3), the racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase (Chiral Liquid Chromatography (1989) WJ Lough, Ed. Chapman and Hall, New York; Okamoto, (1990) J. of Chromatogr.

[0287] 513:375-378). The 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.

[0288] In some embodiments, compounds of Formula I of the present invention (including, but not limited to Compound 1) can be generally prepared according to the methods described in 2013 / 0123231A1, which is incorporated herein by reference in its entirety.

[0289] In some embodiments, the present invention provides synthetic methods and synthetic intermediates for preparing compounds of formula I:

[0290]

[0291] or a pharmaceutically acceptable salt or an agriculturally acceptable salt thereof, wherein:

[0292] R ais an optionally substituted group selected from a 3-7 membered ring having 0-2 heteroatoms selected from nitrogen, oxygen and sulfur and a C 1-6 aliphatic groups;

[0293] R 2 is hydrogen or optionally substituted C 1-6 an aliphatic group; and

[0294] R 5 is hydrogen or halogen.

[0295] As generally defined above, R a is an optionally substituted group selected from a 3-7 membered ring and a C1-6 aliphatic group. a is an optionally substituted 3-7 membered ring. a is an optionally substituted 6-membered monocyclic ring. a is an optionally substituted 6-membered monocyclic heterocycle. a In some embodiments, R a In some embodiments, R a is an optionally substituted C 1-6 In some embodiments, R a is an optionally substituted C 1-6 alkyl.

[0296] As generally defined above, R 2 is hydrogen or optionally substituted C 1-6 In some embodiments, R 2 In some embodiments, R 2 is an optionally substituted C 1-6 In some embodiments, R 2 is an optionally substituted C 1-6 In some embodiments, R 2 C 1-6 In some embodiments, R 2 It is methyl.

[0297] As above, R is usually defined 5 is hydrogen or halogen. In some embodiments, R 5 In some embodiments, R 5 In some embodiments, R 5 For fluorine.

[0298] In some embodiments, the compound of Formula I is prepared according to the method described in Scheme 1, wherein R a , R e , R2 , R 5 Each is as defined in classes and subclasses (individually and in combination) herein.

[0299] Scheme 1. Synthesis of compounds of formula I.

[0300]

[0301]

[0302] As described in this article, R H In some embodiments, R H is a halogen or a sulfonate group. H In some embodiments, R H In some embodiments, R H In some embodiments, R H In some embodiments, R H In some embodiments, R H is methanesulfonate, trifluoromethanesulfonate, benzenesulfonate, toluenesulfonate, bromobenzenesulfonate or nitrobenzenesulfonate.

[0303] As described in this article, R e is a carboxyl protecting group. e -Si(R P )3 or optionally substituted C 1-6 aliphatic group; wherein each R P Independently for C 1-6 In some embodiments, R e -Si(R P )3. In some embodiments, R e is an optionally substituted C 1-6 In some embodiments, R e is an optionally substituted C 1-6 In some embodiments, R e In some embodiments, R e In some embodiments, R e In some embodiments, R e It is trityl.

[0304] In some embodiments, step S-1 comprises alkylating intermediate G-2 via intermediate G-1 to form intermediate G-3. A person skilled in the art will appreciate that a variety of leaving groups R HSuitable for achieving alkylation of G-2. In some embodiments, the alkylation is mediated by a base. In some embodiments, the base is an alkoxide base. In some embodiments, the base is an alkali metal alkoxide. In some embodiments, the base is potassium tert-butoxide. In some embodiments, the base is sodium tert-butoxide. In some embodiments, the base is potassium tert-amyl alcoholate. In some embodiments, the base is a carbonate base. In some embodiments, the carbonate base is an alkali metal carbonate. In some embodiments, the alkali metal carbonate is potassium carbonate or cesium carbonate. In some embodiments, the alkali metal carbonate is potassium carbonate, potassium bicarbonate, cesium carbonate, or cesium bicarbonate. In some embodiments, the alkali metal carbonate is potassium carbonate. In some embodiments, the alkali metal carbonate is potassium carbonate or potassium bicarbonate. In some embodiments, the alkali metal carbonate is cesium carbonate. In some embodiments, the alkali metal carbonate is cesium carbonate. In some embodiments, the alkali metal carbonate is cesium carbonate or cesium bicarbonate. In some embodiments, step S-1 is carried out in a polar solvent. In some embodiments, the polar solvent is a polar aprotic solvent. In some embodiments, 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, the crystalline intermediate G-3 is purified by crystallization.

[0305] In some embodiments, step S-2 comprises coupling intermediate G-3 with an oxazole synthon (oxazole) to form intermediate G-4. In some embodiments, the coupling is a metal-catalyzed coupling. In some embodiments, the metal-catalyzed coupling is a Negishi coupling. Those skilled in the art will understand that Negishi coupling is a cross-coupling of a transition metal-catalyzed organic halide or sulfonate compound with an organic zinc compound. In some embodiments, the oxazole synthon is an oxazole zincate. In some embodiments, the oxazole zincate is formed by metal exchange between 2-lithio-oxazole and a zinc salt. In some embodiments, the zinc salt is ZnCl2. In some embodiments, the 2-lithio-oxazole is formed by treating oxazole with n-butyllithium. In some embodiments, the 2-lithio-oxazole is formed at a temperature below -40°C. In some embodiments, the 2-lithio-oxazole is formed at a temperature below about -40°C. In some embodiments, the 2-lithio-oxazole is formed at a temperature below -60°C. In some embodiments, the 2-lithium-oxazole is formed at a temperature below about -60°C. In some embodiments, the metal catalyst is a palladium catalyst. In some embodiments, the palladium catalyst is Pd(PPh3)4. In some embodiments, the crystalline intermediate G-4 is purified by crystallization.

[0306] In some embodiments, the oxazole is treated with a metallizing agent selected from the group consisting of isopropylmagnesium chloride, isopropylmagnesium bromide, TMPZnCl-LiCl, TMPMgCl-LiCl, and isopropylmagnesium chloride / lithium chloride (wherein TMP refers to 2,2,6,6,-tetramethylpiperidine). In some embodiments, the metallizing agent is isopropylmagnesium chloride. In some embodiments, the oxazole is treated with isopropylmagnesium chloride (2M in THF). In some embodiments, the oxazole is treated with a metallizing agent at about -20°C to about -10°C. In some embodiments, the oxazole is treated with a metallizing agent at about -15°C. In some embodiments, the solvent is tetrahydrofuran, 2-methyltetrahydrofuran, or a mixture thereof. In some embodiments, the solvent is tetrahydrofuran and 2-methyltetrahydrofuran. In some embodiments, the reaction further comprises adding ZnCl2 to form oxazole zincate. In some embodiments, the reaction further comprises adding ZnCl2 as a solution in 2-methyltetrahydrofuran. In some embodiments, the catalyst used in the Negishi coupling is a palladium catalyst selected from Pd(PPh3)4, tBuXPhos Pd precatalyst, XPhos Pd precatalyst, RuPhos Pd precatalyst and Pd-PEPPSI-IPent (dichloro[1,3-di(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)). The precatalyst is described in, for example, Bruneau et al., ACS Catal., 2015, 5(2), pp.1386-1396. In some embodiments, the catalyst is Pd(PPh3)4. In some embodiments, the reaction mixture is heated to greater than about 50°C after the addition of ZnCl2. In some embodiments, the reaction mixture is heated to about 65°C.

[0307] In some embodiments, step S-3 comprises deprotecting the ester intermediate G-4 to provide a compound of Formula I. In some embodiments, wherein R eis benzyl or diphenylmethyl, and the deprotection is a catalytic hydrogenation using a hydrogen source. In some embodiments, the catalyst is a palladium catalyst. In some embodiments, the palladium catalyst is palladium carbon. In some embodiments, the hydrogen source is H2. In some embodiments, the residual hydrogen catalyst is removed by a palladium scavenger. In some embodiments, the palladium scavenger is a thiol. In some embodiments, the thiol is SiliaMetS thiol. In some embodiments, the deprotection is a hydrolysis reaction. In some embodiments, the hydrolysis is an acidic hydrolysis. In some embodiments, the acid is a strong protic acid. In some embodiments, the acid is sulfuric acid. In some embodiments, the acid is sulfuric acid, tetrafluoroboric acid, methanesulfonic acid, nitric acid or hydrochloric acid. In some embodiments, the reaction occurs in a cosolvent, wherein the cosolvent is an alcohol. In some embodiments, the cosolvent is 2-propanol, tert-butanol, tert-amyl alcohol or ethanol. In some embodiments, the cosolvent is 2-propanol, tert-butanol, tert-amyl alcohol, ethanol or acetonitrile.

[0308] In some embodiments, the temperature of the hydrolysis reaction is maintained at 5 to 10°C. In some embodiments, the temperature of the hydrolysis reaction is about 0 to about 20°C. In some embodiments, the temperature of the hydrolysis reaction is about 2 to about 8°C. In some embodiments, the temperature of the hydrolysis reaction is maintained at about 2 to about 10°C. In some embodiments, the product is purified by crystallization. In some embodiments, the product is crystallized from an alcoholic solution. In some embodiments, the alcoholic solution is a mixture of ethanol and water. In some embodiments, the product is crystallized from a mixture of acetonitrile and water.

[0309] In some embodiments, the intermediate of formula G-1 is prepared according to the method described in Scheme 2, wherein R a , R H , R 2 , R 5 Each is as defined in classes and subclasses (individually and in combination) herein.

[0310] Scheme 2. Synthesis of the intermediate of formula G-1

[0311]

[0312] In some embodiments, step S-4 comprises converting the hydroxyl group of intermediate G-5 into a leaving group, R H In some embodiments, intermediate G-5 is an alcohol or an oxyanion thereof. In some embodiments, wherein R HIn some embodiments, the sulfonate group is a sulfonate group, and G-5 is treated with a sulfonylating agent. In some embodiments, the sulfonate group is a methanesulfonate group, a trifluoromethanesulfonate group, a benzenesulfonate group, a toluenesulfonate group, a p-bromobenzenesulfonate group, or a nitrobenzenesulfonate group. In some embodiments, the sulfonylating agent is a sulfonyl halide. In some embodiments, the sulfonylating agent is a sulfonyl chloride. In some embodiments, the sulfonyl chloride is a methanesulfonyl chloride.

[0313] In some embodiments, wherein R H is a halogen, and the hydroxyl group is directly converted to a halogen by a halogenating agent. In some embodiments, the halogenating agent is a brominating agent.

[0314] In some embodiments, wherein R H In some embodiments, the first leaving group is a sulfonate group. In some embodiments, the sulfonate group is a methanesulfonate group, a trifluoromethanesulfonate group, a benzenesulfonate group, a toluenesulfonate group, a bromobenzenesulfonate group or a nitrobenzenesulfonate group. In some embodiments, the sulfonate group is a methanesulfonate group. In some embodiments, the methanesulfonate group is formed by treating G-5 with methanesulfonyl chloride. In some embodiments, the sulfonate group is formed in the presence of a base. In some embodiments, the base is an amine base. In some embodiments, the amine base is triethylamine, diisopropylethylamine (Hunig base), 1,8-diazabicyclo [5.4.0] 11-7-ene, pyridine or dimethylaminopyridine (DMAP). In some embodiments, the amine base is trimethylamine. In some embodiments, the amine base is triethylamine. In some embodiments, the solvent is 2-methyltetrahydrofuran, tetrahydrofuran, or dichloromethane. In some embodiments, the solvent is 2-methyltetrahydrofuran. In some embodiments, the reaction further comprises a promoter. In some embodiments, the promoter is NaI or tetrabutylammonium iodide. In some embodiments, the reaction occurs at about 20°C to about 30°C. In some embodiments, the reaction occurs at about 22°C.

[0315] In some embodiments, the first leaving group is further converted into a halogen by replacement with a halide. In some embodiments, the halide is a bromide. In some embodiments, the source of the halide is a metal halide. In some embodiments, the source of the bromide is a metal bromide. In some embodiments, the metal bromide is an alkali metal bromide. In some embodiments, the alkali metal bromide is LiBr. In some embodiments, the alkali metal bromide is NaBr. In some embodiments, the alkali metal bromide is KBr. In some embodiments, the replacement further includes a promoter. In some embodiments, the promoter is a phase transfer catalyst. The promoter may include, but is not limited to, tetramethylammonium bromide or tetrabutylammonium bromide. In some embodiments, the replacement occurs in a polar solvent. In some embodiments, the polar solvent is a polar aprotic solvent. In some embodiments, 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 (DMAc). In some embodiments, the polar aprotic solvent is ethyl acetate (EtOAc). In some embodiments, the reaction occurs at about 50°C to about 60°C. In some embodiments, the reaction occurs at about 55°C. In some embodiments, the leaving group formation step S-4 and the alkylation step S-1 are performed together without isolating the intermediate G-1.

[0316] In some embodiments, the intermediate of formula G-5 is prepared according to the method described in Scheme 3, wherein R a , R 2 , R 5 Each is as defined in classes and subclasses (individually and in combination) herein.

[0317] Scheme 3. Synthesis of intermediates of formula G-5

[0318]

[0319] In some embodiments, step S-5 comprises epoxidizing aldehyde G-6 to form an epoxide of formula rac-G-7. In some embodiments, the epoxidation is a Corey-Chaykovsky epoxidation. One skilled in the art will appreciate that Corey-Chaykovsky epoxidation is the conversion of a carbonyl compound to its corresponding epoxide using a sulfur ylide. In some embodiments, the sulfur ylide is formed from trimethylsulfonium or a trimethylsulfoxonium salt. In some embodiments, the sulfur ylide is formed from trimethylsulfoxonium iodide. In some embodiments, the sulfur ylide is formed from trimethylsulfoxonium mesylate.

[0320] In some embodiments, step S-6 comprises the step of a -OH alcohol undergoes epoxide ring opening to the intermediate rac-G-7, where R a As defined in the classes and subclasses herein, thereby forming the intermediate rac-G-5. In some embodiments, the epoxide ring opening is acid-catalyzed. In some embodiments, the acid is a Lewis acid. In some embodiments, the Lewis acid is a metal halide or a metal sulfonate. In some embodiments, the Lewis acid is an iron salt. In some embodiments, the Lewis acid is FeCl3. In some embodiments, step S-6 is carried out without additional solvent. In some embodiments, the Lewis acid is BF3-Et2O. In some embodiments, the solvent for step S-6 is toluene. In some embodiments, the acid is HBF4-OEt2, HBF4-water or camphorsulfonic acid. In some embodiments, the solvent for step S-6 is dichloromethane.

[0321] In some embodiments, step S-7 comprises selectively acylating the (R)-isomer of intermediate G-5 with an [acyl] donor, thereby preparing intermediate (R)-G-8 and residual (S)-G-5. In some embodiments, the [acyl] donor is a compound of formula R x C(O)OR y , where R x is an optionally substituted C 1-4 an aliphatic group; and R y is an optionally substituted C 1-4 An aliphatic group or an optionally substituted C 1-4 Acyl. In some embodiments, the [acyl] donor provides a C4-acyl. In some embodiments, the [acyl] donor is an optionally substituted 4-7 membered lactone or an optionally substituted 4-7 membered cyclic anhydride. In some embodiments, the [acyl] donor is an optionally substituted 4-7 membered cyclic anhydride. In some embodiments, the [acyl] donor is vinyl acetate, and the [acyl] is acetyl. In some embodiments, the [acyl] donor is vinyl butyrate, and the [acyl] is butyryl. In some embodiments, the [acyl] donor is succinic anhydride, and the [acyl] is succinyl.

[0322] In some embodiments, the acylation is a dynamic split. In some embodiments, the dynamic split is achieved by a lipase. In some embodiments, the lipase is Candida antarctica lipase B (CAL-B). In some embodiments, the lipase is Novozyme 435. In some embodiments, the acylation reaction is carried out in a THF solvent. In some embodiments, the acylation reaction is carried out in a toluene solvent. In some embodiments, the acylation reaction is carried out in a mixture of THF and toluene. In some embodiments, when [acyl] is succinyl, the unreacted intermediate G-5 is separated from (R)-G-8 by forming a succinate anion under aqueous alkaline conditions and extracting the unreacted neutral alcohol substance into an organic solvent.

[0323] In some embodiments, step S-8 comprises hydrolyzing the enantiomerically enriched intermediate (R)-G-8 to form (R)-G-5. In some embodiments, the hydrolysis is an aqueous hydrolysis. In some embodiments, the aqueous hydrolysis is an alkaline hydrolysis. In some embodiments, the aqueous hydrolysis is mediated by a hydroxide. In some embodiments, the aqueous hydrolysis is mediated by sodium hydroxide. In some embodiments, steps S-7 and S-8 are performed without isolating the intermediate (R)-G-8.

[0324] In some embodiments, (R)-G-8 is prepared with an enantiomeric excess of greater than 70%, 80%, 90%, 95%, 97%, 98%, 99%, or 99.5%.

[0325] In some embodiments, the compound of formula G-4 is prepared according to the method described in Scheme 4, wherein R a , R e , R H , R 2 , R 5 Each is as defined in classes and subclasses (individually and in combination) herein.

[0326] Scheme 4. Alternative Synthesis of Intermediates of Formula G-4

[0327]

[0328] In some embodiments, step S-9 comprises alkylating intermediate G-9 by alkyl halide G-1 to form intermediate G-4. In some embodiments, the alkylation is mediated by a base. In some embodiments, the base is an alkoxide base. In some embodiments, the base is an alkali metal alkoxide. In some embodiments, the base is potassium tert-butoxide. In some embodiments, the base is sodium tert-butoxide. In some embodiments, the base is potassium tert-amyl alcoholate. In some embodiments, the base is a carbonate base. In some embodiments, the carbonate base is an alkali metal carbonate. In some embodiments, the alkali metal carbonate is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, cesium bicarbonate, potassium phosphate or dipotassium hydrogen phosphate. In some embodiments, the alkali metal carbonate is potassium carbonate or cesium carbonate. In some embodiments, the alkali metal carbonate is potassium carbonate. In some embodiments, the alkali metal carbonate is potassium bicarbonate. In some embodiments, the alkali metal carbonate is cesium bicarbonate. In some embodiments, step S-9 is carried out in a polar solvent. In some embodiments, the polar solvent is a polar aprotic solvent. In some embodiments, 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, the reaction occurs at a temperature of about 90°C to about 100°C. In some embodiments, the reaction occurs at a temperature of about 100°C to about 140°C. In some embodiments, the reaction occurs at a temperature of about 115°C.

[0329] In some embodiments, compounds of formula G-2 and G-9 are prepared according to the method described in Scheme 5, wherein R e As defined in this article.

[0330] Scheme 5. Synthesis of intermediates of formula G-2 and G-9

[0331]

[0332] In some embodiments, step S-10 includes forming urea between intermediate G-10 (or its salt) and G-11 (or its salt), thereby forming formula G-12 intermediate. In some embodiments, the urea formation is carried out using a carbonyl source. In some embodiments, the carbonyl source is carbonyl diimidazole (CDI). In some embodiments, the carbonyl source is triphosgene. In some embodiments, the intermediate of formula G-11 is used with its hydrochloride. In some embodiments, another base is used. In some embodiments, the base is an amine base. In some embodiments, the amine base is triethylamine.

[0333] In some embodiments, step S-11 comprises brominating the intermediate of formula G-12 to form the intermediate of formula G-13. In some embodiments, the brominating agent is N-bromosuccinimide. In some embodiments, the bromination is carried out in a polar aprotic solvent. In some embodiments, the polar aprotic solvent is dimethylformamide (DMF).

[0334] In some embodiments, step S-12 comprises intramolecular cyclization of the intermediate of formula G-13 to form an intermediate of formula G-2. In some embodiments, the intramolecular cyclization is achieved by a strong base. In some embodiments, the strong base is an alkali metal alkoxide. In some embodiments, the alkali metal alkoxide is potassium tert-butoxide. In some embodiments, the intramolecular cyclization is carried out in an ether solvent. In some embodiments, the ether solvent is 1,4-dioxane.

[0335] In some embodiments, step S-13 comprises coupling intermediate G-2 with an oxazole synthon (oxazole or metallated oxazole) to form intermediate G-9. In some embodiments, the coupling is a metal-catalyzed coupling. In some embodiments, the metal-catalyzed coupling is a Negishi coupling. Those skilled in the art will understand that Negishi coupling is a cross-coupling of a transition metal-catalyzed organic halide or sulfonate compound with an organic zinc compound. In some embodiments, the oxazole synthon is an oxazole zincate. In some embodiments, the oxazole zincate is formed by metal exchange of 2-lithium-oxazole and a zinc salt. In some embodiments, the zinc salt is ZnCl2. In some embodiments, the 2-lithium-oxazole is formed by treating oxazole with n-butyllithium. In some embodiments, the 2-lithium-oxazole is formed at a temperature below -40°C. In some embodiments, the 2-lithium-oxazole is formed at a temperature below -60°C. In some embodiments, the transition metal catalyst is a palladium catalyst. In some embodiments, the palladium catalyst is Pd(PPh3)4. In some embodiments, the crystalline intermediate G-4 is purified by crystallization.

[0336] In some embodiments, the oxazole is treated with a metallizing agent selected from the group consisting of isopropylmagnesium chloride, isopropylmagnesium bromide, TMPZnCl-LiCl, TMPMgCl-LiCl, and isopropylmagnesium chloride / lithium chloride (wherein TMP refers to 2,2,6,6,-tetramethylpiperidine). In some embodiments, the metallizing agent is isopropylmagnesium chloride. In some embodiments, the oxazole is treated with isopropylmagnesium chloride (2M in THF). In some embodiments, the oxazole is treated with a metallizing agent at about -20°C to about -10°C. In some embodiments, the oxazole is treated with a metallizing agent at about -15°C. In some embodiments, the solvent is tetrahydrofuran, 2-methyltetrahydrofuran, or a mixture thereof. In some embodiments, the solvent is tetrahydrofuran and 2-methyltetrahydrofuran. In some embodiments, the reaction further comprises adding ZnCl2 to form oxazole zincate. In some embodiments, the reaction further comprises adding ZnCl2 as a solution in 2-methyltetrahydrofuran. In some embodiments, the catalyst used in the Negishi coupling is a palladium catalyst selected from Pd(PPh3)4, tBuXPhos Pd precatalyst, XPhos Pd precatalyst, RuPhos Pd precatalyst and Pd-PEPPSI-IPent (dichloro[1,3-di(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)). The precatalyst is described in, for example, Bruneau et al., ACS Catal., 2015, 5(2), pp.1386-1396. In some embodiments, the catalyst is Pd(PPh3)4. In some embodiments, the reaction mixture is heated to greater than about 50°C after the addition of ZnCl2. In some embodiments, the reaction mixture is heated to about 65°C.

[0337] Scheme 6. Synthesis of Intermediate G-13-a

[0338]

[0339] In some embodiments, step S-11 comprises chlorinating an intermediate of formula G-12 to form an intermediate of formula G-13-a. In some embodiments, the chlorinating agent is N-chlorosuccinimide. In some embodiments, G-13-a can be used in step S-12 instead of G-13 above to form a chloro analog of G-2, which can be used in step S-13 instead of G-2.

[0340] Some embodiments provide methods for preparing Compound 1:

[0341]

[0342] Comprising compound G-4-a:

[0343]

[0344] Contact with acids.

[0345] Some embodiments provide methods for preparing compound G-4-a:

[0346]

[0347] Comprising compound G-9-a:

[0348]

[0349] Contact with a compound of formula H-1:

[0350]

[0351] Where R H It is a halogen.

[0352] In some embodiments, R H For bromine.

[0353] Some embodiments provide methods for preparing Compound 1:

[0354]

[0355] Comprising a compound of formula G-4-b:

[0356]

[0357] Contacting with a hydrogen source and a palladium catalyst.

[0358] Some embodiments provide methods for preparing enantiomerically enriched compounds of formula (R)-G-5:

[0359]

[0360] Where 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 C 1-6 aliphatic groups;

[0361] R 2 is hydrogen or optionally substituted C 1-6 an aliphatic group; and

[0362] R 5 is hydrogen or halogen;

[0363] The following steps are involved:

[0364] The racemic compound of formula rac-G-5:

[0365]

[0366] Contacting with a lipase and an [acyl] donor to form a compound of formula (R)-G-8:

[0367]

[0368] wherein [acyl] is C1-C7 acyl; and

[0369] removal of [acyl] groups;

[0370] Thus, an enantiomerically enriched compound of formula (R)-G-5 is prepared.

[0371] In some embodiments, the compound of formula (R)-G-5 is:

[0372]

[0373] In some embodiments, the [acyl] donor is an optionally substituted 4-7 membered lactone or a 4-7 membered optionally substituted cyclic anhydride; or a x C(O)OR y A compound wherein R x is an optionally substituted C 1-4 an aliphatic group; and R y is an optionally substituted C 1-4 An aliphatic group or an optionally substituted C 1-4 Acyl.

[0374] In some embodiments, the [acyl] is a C4 acyl.

[0375] In some embodiments, the lipase is Candida antarctica lipase B.

[0376] Some embodiments provide methods for preparing compound G-9-a:

[0377]

[0378] Compound G-2-a:

[0379]

[0380] Contacting with oxazole under conditions sufficient to form compound G-9-a.

[0381] In some embodiments, the reaction conditions include a solvent, wherein the solvent is tetrahydrofuran, 2-methyltetrahydrofuran, or a mixture thereof. In some embodiments, the solvent is tetrahydrofuran and 2-methyltetrahydrofuran.

[0382] In some embodiments, the reaction conditions include a metallizing agent. In some embodiments, the metallizing agent is selected from isopropylmagnesium chloride, isopropylmagnesium bromide, TMPZnCl-LiCl, TMPMgCl-LiCl and isopropylmagnesium chloride / lithium chloride (wherein TMP refers to 2,2,6,6,-tetramethylpiperidine). In some embodiments, the metallizing agent is isopropylmagnesium chloride. In some embodiments, the reaction conditions include contacting oxazole and the metallizing agent at about -20°C to -10°C or about -15°C.

[0383] In some embodiments, the reaction conditions include adding ZnCl2. In some embodiments, the catalyst is a palladium catalyst selected from Pd(PPh3)4, tBuXPhos Pd precatalyst, XPhos Pd precatalyst, RuPhos Pd precatalyst, and Pd-PEPPSI-IPent (dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)). In some embodiments, the catalyst is Pd(PPh3)4. In some embodiments, the reaction mixture is heated to greater than about 50°C after adding ZnCl2. In some embodiments, the reaction mixture is heated to about 60°C to about 70°C after adding ZnCl2.

[0384] Some embodiments provide methods for preparing compound (R)-G-1-a:

[0385]

[0386] include:

[0387] (a) Compound (R)-G-5-a or its oxygen anion:

[0388]

[0389] contacting with a sulfonylating agent under conditions sufficient to form compound (R)-G-6-a:

[0390]

[0391] (b) contacting compound (R)-G-6-a with a bromide salt under conditions sufficient to form compound (R)-G-1-a.

[0392] In some embodiments, the sulfonylating agent is methanesulfonyl chloride.

[0393] In some embodiments, the reaction conditions of step (a) include a base. In some embodiments, the base is triethylamine, diisopropylethylamine (Hunig base), 1,8-diazabicyclo [5.4.0] undec-7-ene, pyridine or dimethylaminopyridine (DMAP). In some embodiments, the base is triethylamine. In some embodiments, the reaction conditions of step (a) include a solvent selected from the following: 2-methyltetrahydrofuran, tetrahydrofuran and dichloromethane. In some embodiments, the solvent is 2-methyltetrahydrofuran. In some embodiments, the reaction conditions of step (a) include a promoter. In some embodiments, the promoter is NaI or tetrabutylammonium iodide. In some embodiments, the reaction conditions of step (a) include a temperature of about 20°C to about 30°C. In some embodiments, the reaction conditions of step (a) include a temperature of about 22°C.

[0394] In some embodiments, the bromide salt is LiBr, NaBr or KBr. In some embodiments, the bromide salt is LiBr. In some embodiments, the bromide salt is an ammonium salt. In some embodiments, the bromide salt is tetrabutylammonium bromide.

[0395] In some embodiments, the reaction conditions of step (b) include a solvent selected from the group consisting of N-methylpyrrolidone (NMP), dimethylformamide (DMF), and dimethylacetamide (DMAc). In some embodiments, the solvent is NMP. In some embodiments, in some embodiments, the reaction conditions of step (b) include a temperature of about 50°C to about 60°C. In some embodiments, in some embodiments, the reaction conditions of step (b) include a temperature of about 55°C.

[0396] Some embodiments provide methods for preparing Compound 1:

[0397]

[0398]

[0399] or a salt or co-crystal thereof, comprising:

[0400] (a) Compound G-2-a:

[0401]

[0402] Contacting with oxazole under conditions sufficient to form compound G-9-a:

[0403]

[0404] (b) contacting compound G-9-a with compound (R)-G-1-a under conditions sufficient to form compound G-4-a:

[0405]

[0406] and (c) hydrolyzing compound G-4-a under conditions sufficient to form compound 1.

[0407] In some embodiments, the reaction conditions of step (a) include a solvent, wherein the solvent is tetrahydrofuran, 2-methyltetrahydrofuran or a mixture thereof. In some embodiments, the solvent is tetrahydrofuran and 2-methyltetrahydrofuran.

[0408] In some embodiments, the reaction conditions of step (a) include a metallizing agent. In some embodiments, the metallizing agent is selected from isopropylmagnesium chloride, isopropylmagnesium bromide, TMPZnCl-LiCl, TMPMgCl-LiCl and isopropylmagnesium chloride / lithium chloride (wherein TMP refers to 2,2,6,6,-tetramethylpiperidine). In some embodiments, the metallizing agent is isopropylmagnesium chloride. In some embodiments, the reaction conditions of step (a) include contacting oxazole and the metallizing agent at about -20°C to -10°C or about -15°C.

[0409] In some embodiments, the reaction conditions of step (a) include adding ZnCl2. In some embodiments, the catalyst is a palladium catalyst selected from Pd(PPh3)4, tBuXPhos Pd precatalyst, XPhos Pd precatalyst, RuPhos Pd precatalyst and Pd-PEPPSI-IPent. In some embodiments, the catalyst is Pd(PPh3)4. In some embodiments, the reaction mixture is heated to greater than about 50°C after adding ZnCl2. In some embodiments, the reaction mixture is heated to about 60°C to about 70°C after adding ZnCl2.

[0410] In some embodiments, the reaction conditions of step (b) include a base. In some embodiments, the base is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, cesium bicarbonate, potassium phosphate or dipotassium hydrogen phosphate. In some embodiments, the base is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate or cesium bicarbonate. In some embodiments, the base is potassium carbonate. In some embodiments, the base is potassium carbonate or potassium bicarbonate.

[0411] In some embodiments, the reaction conditions of step (b) include a solvent selected from the group consisting of N-methylpyrrolidone (NMP), dimethylformamide (DMF) and dimethylacetamide (DMA). In some embodiments, the solvent is NMP.

[0412] In some embodiments, the reaction conditions of step (b) include a temperature of about 100° C. to about 140° C. In some embodiments, the reaction conditions of step (b) include a temperature of about 115° C.

[0413] In some embodiments, the reaction conditions of step (c) include an acid. In some embodiments, the acid is sulfuric acid, tetrafluoroboric acid, methanesulfonic acid, nitric acid, or hydrochloric acid. In some embodiments, the acid is sulfuric acid. In some embodiments, the acid is hydrochloric acid.

[0414] In some embodiments, the reaction conditions of step (c) include a cosolvent. In some embodiments, the cosolvent is an alcohol. In some embodiments, the cosolvent is 2-propanol, tert-butyl alcohol, tert-amyl alcohol, ethanol or acetonitrile.

[0415] In some embodiments, the reaction conditions of step (c) include a temperature of about 5 and 10° C. In some embodiments, the reaction conditions of step (c) include a temperature of about 0 to about 20° C. In some embodiments, the reaction conditions of step (c) include a temperature of about 2 to about 8° C.

[0416] Some embodiments provide a method for preparing Compound 1 or a salt or co-crystal thereof:

[0417]

[0418] include:

[0419] (a) Compound (R)-G-6-a:

[0420]

[0421] with a bromide salt under conditions sufficient to form compound (R)-G-1-a:

[0422]

[0423] (b) Compound G-2-a:

[0424]

[0425] Contacting with oxazole under conditions sufficient to form compound G-9-a:

[0426]

[0427] (c) contacting compound G-9-a with compound (R)-G-1-a under conditions sufficient to form compound G-4-a:

[0428]

[0429] and (d) hydrolyzing compound G-4-a under conditions sufficient to form compound 1.

[0430] In some embodiments, the bromide salt is LiBr, NaBr or KBr. In some embodiments, the bromide salt is LiBr. In some embodiments, the bromide salt is an ammonium salt. In some embodiments, the bromide salt is tetrabutylammonium bromide.

[0431] In some embodiments, the reaction conditions of step (a) include a solvent selected from the group consisting of N-methylpyrrolidone (NMP), dimethylformamide (DMF), and dimethylacetamide (DMAc). In some embodiments, the solvent is NMP. In some embodiments, in some embodiments, the reaction conditions of step (a) include a temperature of about 50°C to about 60°C. In some embodiments, in some embodiments, the reaction conditions of step (a) include a temperature of about 55°C.

[0432] In some embodiments, the bromide salt is LiBr, NaBr or KBr. In some embodiments, the bromide salt is LiBr. In some embodiments, the bromide salt is an ammonium salt. In some embodiments, the bromide salt is tetrabutylammonium bromide.

[0433] In some embodiments, the reaction conditions of step (b) include a solvent, wherein the solvent is tetrahydrofuran, 2-methyltetrahydrofuran or a mixture thereof. In some embodiments, the solvent is tetrahydrofuran and 2-methyltetrahydrofuran.

[0434] In some embodiments, the reaction conditions of step (b) include a metallizing agent. In some embodiments, the metallizing agent is selected from isopropylmagnesium chloride, isopropylmagnesium bromide, TMPZnCl-LiCl, TMPMgCl-LiCl and isopropylmagnesium chloride / lithium chloride (wherein TMP refers to 2,2,6,6,-tetramethylpiperidine). In some embodiments, the metallizing agent is isopropylmagnesium chloride. In some embodiments, the reaction conditions of step (b) include contacting oxazole and the metallizing agent at about -20°C to -10°C or about -15°C.

[0435] In some embodiments, the reaction conditions of step (b) include adding ZnCl2. In some embodiments, the catalyst is a palladium catalyst selected from Pd(PPh3)4, tBuXPhos Pd precatalyst, XPhos Pd precatalyst, RuPhos Pd precatalyst and Pd-PEPPSI-IPent. In some embodiments, the catalyst is Pd(PPh3)4. In some embodiments, the reaction mixture is heated to greater than about 50°C after adding ZnCl2. In some embodiments, the reaction mixture is heated to about 60°C to about 70°C after adding ZnCl2.

[0436] In some embodiments, the reaction conditions of step (c) include a base. In some embodiments, the base is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, cesium bicarbonate, potassium phosphate or dipotassium hydrogen phosphate. In some embodiments, the base is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, cesium bicarbonate, potassium phosphate or dipotassium hydrogen phosphate. In some embodiments, the base is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate or cesium bicarbonate. In some embodiments, the base is potassium carbonate. In some embodiments, the base is potassium carbonate or potassium bicarbonate.

[0437] In some embodiments, the reaction conditions of step (c) include a solvent selected from N-methylpyrrolidone (NMP), dimethylformamide (DMF) and dimethylacetamide (DMA). In some embodiments, the solvent is NMP.

[0438] In some embodiments, the reaction conditions of step (c) include a temperature of about 90° C. to about 100° C. In some embodiments, the reaction conditions of step (c) include a temperature of about 100° C. to about 140° C. In some embodiments, the reaction conditions of step (c) include a temperature of about 115° C.

[0439] In some embodiments, the reaction conditions of step (d) include an acid. In some embodiments, the acid is sulfuric acid, tetrafluoroboric acid, methanesulfonic acid, nitric acid, or hydrochloric acid. In some embodiments, the acid is sulfuric acid. In some embodiments, the acid is hydrochloric acid.

[0440] In some embodiments, the reaction conditions of step (d) include a cosolvent. In some embodiments, the cosolvent is an alcohol. In some embodiments, the cosolvent is 2-propanol, tert-butyl alcohol, tert-amyl alcohol, ethanol or acetonitrile.

[0441] In some embodiments, the reaction conditions of step (d) include a temperature of about 5 and 10° C. In some embodiments, the reaction conditions of step (d) include a temperature of about 0 to about 20° C. In some embodiments, the reaction conditions of step (e) include a temperature of about 2 to about 8° C.

[0442] Some embodiments provide a method for preparing Compound 1 or a salt or co-crystal thereof:

[0443]

[0444]

[0445] include:

[0446] (a) Compound (R)-G-5-a or its oxygen anion:

[0447]

[0448] contacting with a sulfonylating agent under conditions sufficient to form compound (R)-G-6-a:

[0449]

[0450] (b) contacting compound (R)-G-6-a with a bromide salt under conditions sufficient to form compound (R)-G-1-a:

[0451]

[0452] (c) Compound G-2-a:

[0453]

[0454] Contacting with oxazole under conditions sufficient to form compound G-9-a:

[0455]

[0456] (d) contacting compound G-9-a with compound (R)-G-1-a under conditions sufficient to form compound G-4-a:

[0457]

[0458] and (e) hydrolyzing compound G-4-a under conditions sufficient to form compound 1.

[0459] In some embodiments, the sulfonylating agent is methanesulfonyl chloride.

[0460] In some embodiments, the reaction conditions of step (a) include a base. In some embodiments, the base is triethylamine, diisopropylethylamine (Hunig base), 1,8-diazabicyclo [5.4.0] undec-7-ene, pyridine or dimethylaminopyridine (DMAP). In some embodiments, the base is triethylamine. In some embodiments, the reaction conditions of step (a) include a solvent selected from the following: 2-methyltetrahydrofuran, tetrahydrofuran and dichloromethane. In some embodiments, the solvent is 2-methyltetrahydrofuran. In some embodiments, the reaction conditions of step (a) include a promoter. In some embodiments, the promoter is NaI or tetrabutylammonium iodide. In some embodiments, the reaction conditions of step (a) include a temperature of about 20°C to about 30°C. In some embodiments, the reaction conditions of step (a) include a temperature of about 22°C.

[0461] In some embodiments, the bromide salt is LiBr, NaBr or KBr. In some embodiments, the bromide salt is LiBr. In some embodiments, the bromide salt is an ammonium salt. In some embodiments, the bromide salt is tetrabutylammonium bromide.

[0462] In some embodiments, the reaction conditions of step (b) include a solvent selected from the group consisting of N-methylpyrrolidone (NMP), dimethylformamide (DMF), and dimethylacetamide (DMAc). In some embodiments, the solvent is NMP. In some embodiments, in some embodiments, the reaction conditions of step (b) include a temperature of about 50°C to about 60°C. In some embodiments, in some embodiments, the reaction conditions of step (b) include a temperature of about 55°C.

[0463] In some embodiments, the reaction conditions of step (c) include a solvent, wherein the solvent is tetrahydrofuran, 2-methyltetrahydrofuran or a mixture thereof. In some embodiments, the solvent is tetrahydrofuran and 2-methyltetrahydrofuran.

[0464] In some embodiments, the reaction conditions of step (c) include a metallizing agent. In some embodiments, the metallizing agent is selected from isopropylmagnesium chloride, isopropylmagnesium bromide, TMPZnCl-LiCl, TMPMgCl-LiCl and isopropylmagnesium chloride / lithium chloride (wherein TMP refers to 2,2,6,6,-tetramethylpiperidine). In some embodiments, the metallizing agent is isopropylmagnesium chloride. In some embodiments, the reaction conditions of step (c) include contacting oxazole and the metallizing agent at about -20°C to -10°C or about -15°C.

[0465] In some embodiments, the reaction conditions of step (c) include adding ZnCl2. In some embodiments, the catalyst is a palladium catalyst selected from Pd(PPh3)4, tBuXPhos Pd precatalyst, XPhos Pd precatalyst, RuPhos Pd precatalyst and Pd-PEPPSI-IPent. In some embodiments, the catalyst is Pd(PPh3)4. In some embodiments, the reaction mixture is heated to greater than about 50°C after adding ZnCl2. In some embodiments, the reaction mixture is heated to about 60°C to about 70°C after adding ZnCl2.

[0466] In some embodiments, the reaction conditions of step (d) include a base. In some embodiments, the base is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, cesium bicarbonate, potassium phosphate or dipotassium hydrogen phosphate. In some embodiments, the base is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, cesium bicarbonate, potassium phosphate or dipotassium hydrogen phosphate. In some embodiments, the base is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate or cesium bicarbonate. In some embodiments, the base is potassium carbonate. In some embodiments, the base is potassium carbonate or potassium bicarbonate.

[0467] In some embodiments, the reaction conditions of step (d) include a solvent selected from N-methylpyrrolidone (NMP), dimethylformamide (DMF) and dimethylacetamide (DMA). In some embodiments, the solvent is NMP.

[0468] In some embodiments, the reaction conditions of step (d) include a temperature of about 90° C. to about 100° C. In some embodiments, the reaction conditions of step (d) include a temperature of about 100° C. to about 140° C. In some embodiments, the reaction conditions of step (d) include a temperature of about 115° C.

[0469] In some embodiments, the reaction conditions of step (e) include an acid. In some embodiments, the acid is sulfuric acid, tetrafluoroboric acid, methanesulfonic acid, nitric acid, or hydrochloric acid. In some embodiments, the acid is sulfuric acid. In some embodiments, the acid is hydrochloric acid.

[0470] In some embodiments, the reaction conditions of step (e) include a cosolvent. In some embodiments, the cosolvent is an alcohol. In some embodiments, the cosolvent is 2-propanol, tert-butyl alcohol, tert-amyl alcohol, ethanol or acetonitrile.

[0471] In some embodiments, the reaction conditions of step (e) include a temperature of about 5 and 10° C. In some embodiments, the reaction conditions of step (e) include a temperature of about 0 to about 20° C. In some embodiments, the reaction conditions of step (e) include a temperature of about 2 to about 8° C.

[0472] 5. Intermediate compounds

[0473] Some embodiments provided herein are intermediates useful for synthesizing Compound 1 or methods for preparing the intermediates.

[0474] Some embodiments provide compounds of formula G-4-a:

[0475]

[0476] Some embodiments provide compounds of formula G-4-b:

[0477]

[0478] Some embodiments provide compounds of formula (R)-G-8:

[0479]

[0480] in:

[0481] [Acyl] is R x C(O)-, where R x is an optionally substituted C 1-4 aliphatic groups;

[0482] 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 C 1-6 aliphatic groups;

[0483] R 2 is hydrogen or optionally substituted C 1-6 an aliphatic group; and

[0484] R 5 is hydrogen or halogen.

[0485] In some embodiments, R x is an optionally substituted C 3-4 Aliphatic group.

[0486] Some embodiments provide compounds of formula (R)-I-1:

[0487]

[0488] Where R x is an optionally substituted C 1-4Aliphatic group.

[0489] Some embodiments provide compounds of formula (R)-I-2:

[0490]

[0491] Where R x is an optionally substituted C 1-4 Aliphatic group.

[0492] Some embodiments provide compounds of formula (R)-G-1:

[0493]

[0494] in:

[0495] R H is the leaving group;

[0496] 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 C 1-6 aliphatic groups;

[0497] R 2 is hydrogen or optionally substituted C 1-6 an aliphatic group; and

[0498] R 5 is hydrogen or halogen.

[0499] Some embodiments provide compounds of formula H-1:

[0500]

[0501] Where R H For the leaving group.

[0502] Some embodiments provide compounds of formula H-2:

[0503]

[0504] Where R H For the leaving group.

[0505] In some embodiments, R H is a halogen or a sulfonate group. H In some embodiments, R H In some embodiments, [acyl] is succinyl. In some embodiments, the [acyl] donor is succinic anhydride.

[0506] Some embodiments provide compounds of the formula:

[0507] or a salt thereof.

[0508] Some embodiments provide compounds of the formula:

[0509] or a salt thereof.

[0510] 6. Use, preparation and administration and pharmaceutically acceptable compositions

[0511] According to another embodiment, the present invention provides a composition comprising a compound of the present invention or a pharmaceutically acceptable salt, ester, or ester salt thereof and a pharmaceutically acceptable carrier, excipient, or vehicle. Some embodiments provide a composition comprising a compound as described herein, or a pharmaceutically acceptable salt or cocrystal thereof, and a pharmaceutically acceptable carrier, excipient, or vehicle.

[0512] Some embodiments provide compositions comprising a crystalline form of Compound 1 described herein. The amount of the compound in the composition of the invention is an amount effective to inhibit ACC in a biological sample or in a patient to a measurable degree. In certain embodiments, the amount of the compound in the composition of the invention is an amount effective to inhibit ACC in a biological sample or in a patient to a measurable degree. In certain embodiments, the composition of the invention is formulated for administration to a patient in need of the composition. In some embodiments, the composition of the invention is formulated for oral administration to a patient.

[0513] The term "compound" as described herein refers to an ACC inhibitor of Formula I (including but not limited to Compound 1), or a solid form thereof. In some embodiments, the term "compound" as described herein refers to an ACC inhibitor of Formula I (including but not limited to Compound 1), or a salt or solid form thereof. In some embodiments, the compound is Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is the free acid of Compound 1. In some embodiments, the compound is a solid form of Compound 1. In some embodiments, the compound is a crystalline form of Compound 1. In some embodiments, the compound is Form I, Form II, Form III, Form IV, Form V, Form VI, Form VII, or Form VIII of Compound 1. In some embodiments, the compound is a polymorph of the free acid of Compound 1. In some embodiments, the compound is Form I, Form VII, or Form VIII of Compound 1. In some embodiments, the compound is a pseudopolymorph of the free acid of Compound 1. In some embodiments, the compound is Form I of Compound 1. In some embodiments, the compound is Form II of Compound 1. In some embodiments, the compound is Form III of Compound 1. In some embodiments, the compound is Form IV of Compound 1. In some embodiments, the compound is Form V of Compound 1. In some embodiments, the compound is Form VI of Compound 1. In some embodiments, the compound is Form VII of Compound 1. In some embodiments, the compound is Form VIII of Compound 1. In some embodiments, the compound is a solvate of Compound 1. In some embodiments, the compound is amorphous Compound 1. In some embodiments, the compound is a salt or cocrystal of Compound 1. In some embodiments, the compound is Compound 1 sodium Form I. In some embodiments, the compound is Compound 1 sodium Form II. In some embodiments, the compound is Compound 1 calcium Form I. In some embodiments, the compound is Compound 1 magnesium Form I. In some embodiments, the compound is Compound 1 diethanolamine Form I. In some embodiments, the compound is Compound 1 piperazine Form I.

[0514] The term "patient," as used herein, refers to an animal, preferably a mammal, and most preferably a human.

[0515] The term "pharmaceutically acceptable carrier, excipient or diluent" refers to a non-toxic carrier, excipient or vehicle that does not destroy the pharmacological activity of the compound formulated therewith. Pharmaceutically acceptable carriers, excipients or diluents that can be used in the compositions of the present invention include, but are not limited to, antiadhesives, binders, coatings, colorants, disintegrants, flavors, glidants, lubricants, preservatives, sorbents and vehicles. Examples of carriers, excipients 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 silicon dioxide; magnesium trisilicate; polyvinyl pyrrolidone; cellulose-based substances; polyethylene glycol; sodium carboxymethylcellulose; polyacrylates; waxes; polyethylene-polyoxypropylene-block polymers; polyethylene glycol and lanolin.

[0516] "Pharmaceutically acceptable derivative" refers to any non-toxic salt, ester, ester salt or other derivative of a compound of the invention which, when administered to a recipient, is capable of directly or indirectly providing a compound of the invention or its active metabolite or residue.

[0517] As used herein, the term "active metabolite or residue thereof that is inhibited" means that its metabolite or residue is also an ACC inhibitor. In some embodiments, the active metabolite or residue thereof that is inhibited is selected from the following:

[0518]

[0519] In some embodiments, the present invention provides a metabolite of Compound 1, wherein the metabolite is an M+ glucuronide conjugate. The M+ glucuronide conjugate has an IC of 50 In some embodiments, 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 IC of 50 In some embodiments, provided metabolites of Compound 1 are isolated.

[0520] The composition of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. The composition is preferably administered orally, intraperitoneally or intravenously. The sterile injectable form of the composition of the present invention may be an aqueous or oily suspension. These suspensions may be prepared using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injectable preparations may also be sterile injectable solutions or suspensions in parenterally acceptable nontoxic diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspension media.

[0521] For this purpose, any gentle fixed oil can be adopted, including synthetic monoglyceride or diglyceride.Oleic fatty acid and its glyceride derivative are suitable for preparing injectable as the acceptable oil of natural medicine (such as olive oil or castor oil, especially in its polyoxyethylated form).These oil solutions or suspensions can also contain long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersant that is usually used in preparing the acceptable dosage form (including emulsion and suspension) of medicine.For the purpose of preparation, other conventional surfactants (such as Tweens (Tweens), Spans (Spans)) and other emulsifiers or bioavailability enhancers that are usually used in making the acceptable solid, liquid or other dosage form of medicine can also be used.

[0522] The pharmaceutically acceptable compositions of the present invention can be orally administered in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, common carriers include lactose and corn starch. Lubricants such as magnesium stearate are also commonly added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with an emulsifier and a suspending agent. If necessary, certain sweeteners, flavorings or coloring agents may also be added.

[0523] In some embodiments, the pharmaceutically acceptable composition comprising a form of Compound 1 described herein is administered as a capsule. In some embodiments, the pharmaceutically acceptable composition comprising a form of Compound 1 described herein is administered as a tablet.

[0524] Alternatively, the pharmaceutically acceptable compositions of the present invention can be administered in the form of suppositories for rectal administration. These suppositories can be prepared by mixing the medicament with a suitable non-irritating excipient, which is solid at room temperature and liquid at rectal temperature and will therefore melt in the rectum to release the drug. The substances include cocoa butter, beeswax and polyethylene glycol.

[0525] The pharmaceutically acceptable compositions of the present invention can also be administered topically, especially when the target of treatment includes areas or organs easily reached by topical application (including diseases of the eye, skin, or lower intestinal tract). For each of these areas or organs, suitable topical formulations are readily prepared.

[0526] Topical application to the lower intestinal tract can be achieved in a rectal suppository formulation (see above) or in a suitable enema formulation.Topical transdermal patches may also be used.

[0527] For topical administration, the pharmaceutically acceptable compositions provided can be formulated in suitable ointments containing active ingredients suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutically acceptable compositions provided can be formulated in suitable lotions or creams containing active ingredients suspended or dissolved in one or more pharmaceutically acceptable carriers. 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.

[0528] For ophthalmic use, provided pharmaceutically acceptable compositions can be formulated as micronized sized suspensions in pH-adjusted isotonic sterile saline with or without a preservative such as benzylalkonium chloride, or preferably as solutions in pH-adjusted isotonic sterile saline. Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions can be formulated in an ointment such as petrolatum.

[0529] The pharmaceutically acceptable compositions of the present invention may also be administered by nasal aerosol or inhalation. The compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons and / or other conventional solubilizing agents or dispersants.

[0530] The pharmaceutically acceptable compositions of the present invention are most preferably formulated for oral administration. The preparation can be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of the present invention are not administered with food. In other embodiments, the pharmaceutically acceptable compositions of the present invention are administered with food.

[0531] The amount of the compound of the invention that can be combined with a carrier material to produce a composition in a single dosage form will vary depending on the subject being treated, the particular mode of administration. The provided compositions should preferably be formulated so that a dosage of 0.01-100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving these compositions.

[0532] It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, 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 specific disease being treated. The amount of the compound of the present invention in the composition will also depend on the specific compound in the composition.

[0533] In some embodiments, the crystalline form of Compound 1 is administered at a dose of about 2 mg to about 500 mg per day, about 2 mg to about 400 mg per day, about 2 mg to about 300 mg per day, about 2 mg to about 200 mg per day, or about 2 mg to about 100 mg per day. In some embodiments, the crystalline form of Compound 1 is administered at a dose of about 5 mg per day, about 6 mg per day, about 7 mg per day, about 8 mg per day, about 9 mg per day, about 10 mg per day, about 11 mg per day, about 12 mg per day, about 13 mg per day, about 14 mg per day, about 15 mg per day, 16 mg per day, 17 mg per day, 18 mg per day, 19 mg per day, 20 mg per day, 21 mg per day, 22 mg per day, 23 mg per day, 24 mg per day, or 25 mg per day.

[0534] In some embodiments, the crystalline form of Compound 1 is administered at a dose of greater than about 5 mg per day, greater than about 10 mg per day, greater than about 15 mg per day, greater than about 20 mg per day, greater than about 25 mg per day, greater than about 30 mg per day, greater than about 35 mg per day, greater than about 40 mg per day, greater than about 45 mg per day, or greater than about 50 mg per day. In some embodiments, the crystalline form of Compound 1 is administered at a dose of less than about 300 mg per day, less than about 275 mg per day, less than about 250 mg per day, less than about 225 mg per day, less than about 200 mg per day, less than about 175 mg per day, less than about 150 mg per day, less than about 125 mg per day, or less than about 100 mg per day.

[0535] In some embodiments, the crystalline form of Compound 1 is administered at a dose of about 5 mg once a day, about 20 mg once a day, about 30 mg once a day, about 50 mg once a day, about 80 mg once a day, about 100 mg once a day, about 150 mg once a day, about 200 mg once a day, about 500 mg once a day, about 800 mg once a day, or about 1000 mg once a day.

[0536] In some embodiments, the crystalline form of Compound 1 is administered at a dose of about 10 mg twice a day, about 25 mg twice a day, about 50 mg twice a day, or about 100 mg twice a day.

[0537] Drug Use

[0538] The terms "treatment", "treat" and "treating" as used herein refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder as described herein or one or more symptoms thereof. In some embodiments, treatment may be administered after one or more symptoms have occurred. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to susceptible individuals (e.g., based on a history of symptoms and / or based on genetics or other susceptibility factors) before the onset of symptoms. Treatment may also be continued after symptoms have resolved, for example, to prevent or delay their recurrence.

[0539] The term "therapeutically effective amount" refers to an amount of a compound described herein sufficient to achieve treatment as defined above when administered in one or more doses to a patient (particularly a human) in need of such treatment. The therapeutically effective amount will vary depending on the patient, the disease being treated, the patient's weight and / or age, the severity of the disease, or the mode of administration determined by a qualified prescriber or caregiver.

[0540] Acetyl-CoA carboxylase (ACC) catalyzes the ATP-dependent carboxylation of acetyl-CoA to form malonyl-CoA. This reaction, which is carried out in two half reactions, namely the biotin carboxylase (BC) reaction and the carboxyltransferase (CT) reaction, is the first key step in fatty acid (FA) biosynthesis and the rate-limiting reaction of this pathway. The product of the ACC-catalyzed reaction, malonyl-CoA, plays an important regulatory role in controlling mitochondrial FA absorption by allostatic inhibition of the enzyme carnitine palmitoyltransferase I (CPT-I), which catalyzes the first key step in mitochondrial FA oxidation. Therefore, malonyl-CoA is a key metabolic signal that controls FA production and utilization in response to changes in diet and nutritional requirements of animals during exercise, for example, and therefore plays a key role in controlling the conversion between carbohydrate and fat utilization in the liver and skeletal muscle (Harwood, 2005).

[0541] In mammals, ACC exists in 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 independent genes, exhibit different cellular distributions, and share 75% overall amino acid sequence identity except for an N-terminal extension of ACC2 that directs ACC2 to the mitochondrial membrane. ACC1, which lacks this targeting sequence, is localized to the cytoplasm. In the heart and skeletal muscle, which have limited capacity to synthesize fatty acids, malonyl-CoA formed by ACC2 functions to regulate FA oxidation. In the liver, malonyl-CoA formed in the cytoplasm by the action of ACC1 is used for FA synthesis and elongation, promoting triglyceride formation and VLDL production, while malonyl-CoA formed by ACC2 on the mitochondrial surface is used 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 decarboxylase (Cheng et al., J. Med. Chem. 49: 1517, 2006).

[0542] Simultaneous inhibition of the enzymatic activity of ACC1 and ACC2 provides the ability to inhibit de novo FA production in lipogenic tissues (e.g., liver and adipose) while stimulating FA oxidation in oxidative tissues (e.g., liver and skeletal muscle), and therefore provides an attractive model for favorably affecting many cardiovascular risk factors associated with obesity, diabetes, insulin resistance, and metabolic syndrome in a synergistic manner.

[0543] Multiple lines of evidence strongly support the concept of directly inhibiting ACC activity as an important therapeutic target for the treatment of obesity, diabetes, insulin resistance, and metabolic syndrome.

[0544] Abu-Elheiga et al. (Proc. Natl. Acad. Sci. USA 100:10207-10212, 2003) demonstrated that ACC2 knockout mice exhibited decreased skeletal and cardiac malonyl-CoA, increased muscle FA oxidation, decreased liver fat, decreased total body fat, increased skeletal muscle uncoupling protein 3 (UCP3) (indicating increased energy expenditure), decreased body weight, decreased plasma free FA, decreased blood glucose, and decreased tissue glycogen, and were protected from diet-induced diabetes and obesity.

[0545] Savage et al. (J. Clin. Invest. 116:817, 2006) used ACC1 and ACC2 antisense oligonucleotides to demonstrate that FA oxidation in isolated rat hepatocytes and in rats fed a high-fat diet was stimulated, and liver triglycerides were reduced, insulin sensitivity was improved, liver glucose production was reduced, and UCP1 mRNA in high-fat fed rats was increased. These effects were higher when both ACC1 and ACC2 expression were inhibited than when ACC1 or ACC2 expression was inhibited alone.

[0546] Harwood et al. (J. Biol. Chem. 278:37099, 2003) demonstrated that ACC1 and ACC2 isolated from rats, mice, monkeys, and humans were equally inhibited. 50 = about 60 nM) without inhibiting pyruvate carboxylase or propionyl-CoA carboxylase isozyme non-selective ACC inhibitor CP-640186 reduces FA synthesis, triglyceride synthesis and secretion in Hep-G2 cells without affecting cholesterol synthesis, and reduces apoB secretion without affecting apoA1 secretion. CP-640186 also stimulates FA oxidation in C2C12 cells and in rat muscle slices, and increases CPT-I activity in Hep-G2 cells. In experimental animals, CP-640186 sharply reduces malonyl-CoA concentrations in lipogenic and oxidative tissues in the fed and fasted states, reduces liver and adipose tissue FA synthesis, and increases systemic FA oxidation. In sucrose-fed rats treated with CP-640186 for three weeks, CP-640186 reduced liver, muscle, and adipose triglycerides in a time- and dose-dependent manner, reduced body weight without reducing lean body mass due to selective fat loss, lowered leptin levels, alleviated hyperinsulinemia produced by a high-sucrose diet without changing blood glucose levels, and improved insulin sensitivity.

[0547] Saha et al. (Diabetes 55:A288, 2006) demonstrated that insulin sensitivity in muscle tissue of insulin-resistant rats was stimulated by CP-640186 within 30 minutes of compound administration, and studies by Furler et al. (Diabetes 55:A333, 2006) used dual-tracer analysis to show that acute (46 minutes) treatment of rats with CP-640186 stimulated FA clearance without reducing glucose clearance.

[0548] ACC is the rate-limiting enzyme in fatty acid synthesis, and its product malonyl CoA serves as an important regulator of fatty acid oxidation. Therefore, ACC inhibitors both reduce de novo lipid synthesis and promote the oxidation of existing fat. This dual action of lipid metabolism improves ACC inhibitors compared with other mechanisms and will substantially more effectively reduce the possibility of excess fat. In addition, ACC inhibitors will affect insulin sensitivity, blood plasma and tissue triglycerides and fasting plasma glucose, so whole body and tissue-specific fat mass reduction and do not need polypharmacy (poly-pharmacy).

[0549] For the treatment of obesity and other metabolic diseases, ACC inhibitors only need to approach the liver and muscle in the peripheral compartment. For tumor indications, tumor infiltration is also required. However, avoiding CNS will solve many side effects related to the late obesity program targeting CNS receptors. It is also expected that ACC inhibitors will have a safety profile that is superior to existing metabolic disease agents. For example, ACC inhibitors will be unlikely to contribute to life-threatening hypoglycemia as usually seen under insulin mimetics, insulin secretagogues and insulin degradation inhibitors. In addition, because ACC inhibitors will reduce whole body fat mass, they will be superior to glitazone (glitazone) that will increase whole body fat mass as a part of its mechanism of action.

[0550] The peripherally acting agents that cause significant weight loss and improve other metabolic endpoints fully meet the requirements of the U.S. FDA for the approval of new obesity agents. However, if the approval of obesity continues to be challenging within 5-7 years, ACC inhibitors may be approved for familial combined hyperlipidemia and non-alcoholic steatohepatitis (NASH). There are currently no commercially available ACC inhibitors, so in addition to other diseases mediated by the ACC enzyme, isozyme non-selective ACC inhibitors will represent the first-in-class therapy for the treatment of obesity and metabolic syndrome.

[0551] The activity of the compound used as an inhibitor of ACC or the treatment of obesity or metabolic syndrome in the present invention can be analyzed in vitro or in vivo. Animal models of obesity or metabolic syndrome (e.g., rodent or primate models) can be used to evaluate the in vivo efficacy of the compounds of the present invention. Cell-based analysis can be performed using, for example, cell lines isolated from tissues expressing ACC. In addition, analysis based on biochemistry or mechanism can be performed, such as transcription analysis, Northern blot, RT-PCR, etc. using purified proteins. In vitro analysis includes analysis of cell morphology, protein expression and / or cytotoxicity, enzyme inhibition activity, and / or subsequent functional consequences of cells treated with the compounds of the present invention. Alternative in vitro analysis quantifies the ability of an inhibitor to bind to a protein or nucleic acid molecule in a cell. Inhibitor binding can be measured by radiolabeling the inhibitor before binding, separating the inhibitor / target molecule complex, and determining the amount of the radiolabeled binding. Alternatively, inhibitor binding can be measured by performing a competition experiment, in which a new inhibitor is incubated with a purified protein or nucleic acid bound to a known radioligand. The detailed conditions for analyzing the compound used as an ACC inhibitor in the present invention are described in the following examples. The above assays are exemplary and are not intended to limit the scope of the invention. A skilled practitioner will appreciate that routine assays can be modified to develop equivalent assays that will achieve the same results.

[0552] The compounds or compositions thereof provided herein can be administered using any amount and any route of administration effective for treating or lessening the severity of metabolic disorders or conditions, cancer, bacterial infections, fungal infections, parasitic infections (e.g., malaria), autoimmune disorders, neurodegenerative or neurological disorders, schizophrenia, bone-related disorders, liver diseases, or cardiac disorders.

[0553] In some embodiments, the compounds or compositions thereof provided herein can be administered using any amount and any route of administration that is effective for treating a disease associated with ACC or alleviating its severity (Tong et al. "Acetyl-coenzyme Acarboxylase: crucial metabolic enzyme and attractive target for drug discovery" Cell and Molecular Life Sciences (2005) 62, 1784-1803).

[0554] In some embodiments, the compounds or compositions thereof provided herein can be administered using any amount and any route of administration that is effective in treating a metabolic disorder, disease or condition or reducing its severity. In some embodiments, the metabolic disorder is obesity; metabolic syndrome; diabetes or diabetes-related conditions, 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; complications of diabetes, 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. In some embodiments, the metabolic disorder, disease or condition is non-alcoholic fatty liver disease or hepatic insulin resistance. In some embodiments, the metabolic disease is non-alcoholic steatohepatitis.

[0555] Combination therapy

[0556] In some embodiments, the present invention provides a method for treating a metabolic disorder, disease or condition described herein, comprising administering the compounds of the present invention and one or more agents. Suitable agents that can be used in combination with the compounds of the present invention include anti-obesity agents (including appetite suppressants), antidiabetic agents, antihyperglycemic agents, lipid-lowering agents and antihypertensive agents.

[0557] Suitable lipid-lowering agents that can be used in combination with the compounds of the present invention include, but are not limited to, bile acid sequestrants, HMG-CoA reductase inhibitors, HMG-CoA synthetase inhibitors, cholesterol absorption inhibitors, acyl-CoA-cholesterol acyltransferase (ACAT) inhibitors, CETP inhibitors, squalene synthetase inhibitors, PPAR-α agonists, FXR receptor modulators, LXR receptor modulators, lipoprotein synthesis inhibitors, renin-angiotensin system inhibitors, PPAR-δ partial agonists, bile acid reabsorption inhibitors, PPAR-γ agonists, triglyceride synthesis inhibitors, microsomal triglyceride transport inhibitors, transcriptional regulators, squalene epoxidase inhibitors, low-density lipoprotein receptor inducers, platelet aggregation inhibitors, 5-LO or FLAP inhibitors, niacin and niacin-bound chromium.

[0558] Suitable antihypertensive agents that can be used in combination with the compounds of the present invention 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.

[0559] Suitable antidiabetic agents that can be used in combination with the compounds of the present invention include, but are not limited to, other acetyl-CoA carboxylase (ACC) inhibitors, DGAT-1 inhibitors, AZD7687, LCQ908, DGAT-2 inhibitors, monoacylglycerol O-acyltransferase inhibitors, PDE-10 inhibitors, AMPK activators, sulfonylureas (e.g., acetohexamide, chlorpropamide, diabinese, glibenclamide, glipizide, glyburide, glimepiride ...sulfonylureas (e.g., acetohexamide, chlorpropamide, diabinese, glibenclamide, glipizide, glyburide, glimepiride, glimepiride, glimepiride, glimepiride, glimepiride, glimepiride, glimepiride, glimepiride, glimepiride, glimepiride, glimepiride, glimepiride, glimepiride, sulfonylureas (e.g., acetohexamide, chlorpropamide, diabinese, glibenclamide, glibenclamide, glipizide, glyburide, glimepiride, glimepiride, glimepiride, glimepiride, glimepiride, glimepiride, glimepiride, glimepiride, iride), gliclazide, glipentide, gliquidone, glisolamide, tolazamide, tolbutamide), meglitinides, α-amylase inhibitors (e.g., tendamistat, treastatin, AL-3688), α-glucosidase inhibitors (e.g., acarbose), α-glucosidase inhibitors (e.g., adiposine, canagliflozin), camiglibose, emiglitate, miglitol, voglibose, pradimicin-Q, sarbostatin), PPAR-γ agonists (e.g., balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone, pioglitazone, rosiglitazon e), troglitazone), PPAR-α / γ agonists (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, incretin-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, GSK184072), DPP-IV inhibitors (e.g., sitagliptin, vildagliptin, alogliptin, dutogliptin, linagliptin, saxagliptin), insulin secretagogues, fatty acid oxidation inhibitors, A2 antagonists, JNK 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 (dapagliflozin, canagliflozin, BI-10733, tofogliflozin), ASP-194 1, 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 palmitoyltransferase inhibitors, fructose 1,6-bisphosphatase inhibitors, aldose reductase inhibitors, mineralocorticoid receptor inhibitors, TORC2 inhibitors, CCR2 inhibitors, CCR5 inhibitors, PKC (e.g., PKC-α, PKC-β, PKC-γ) inhibitors, fatty acid synthase inhibitors, serine palmitoyltransferase inhibitors, GPR81 modulators, GPR39 modulators, GPR43 modulators, GPR41 modulators, GPR105 modulators, Kv1.3 inhibitors, retinol binding protein 4 inhibitors, glucocorticoid receptor modulators, somatostatin receptors (e.g., SSTR1, SSTR2, SSTR3,SSTR5) inhibitors, PDHK2 inhibitors, PDHK4 inhibitors, MAP4K4 inhibitors, IL1-β modulators and RXR-α modulators.

[0560] Suitable anti-obesity agents include, but are not limited to, 11-β-hydroxysteroid dehydrogenase 1 inhibitors, stearoyl CoA desaturase (SCD-1) inhibitors, MCR-4 agonists, CCK-A agonists, monoamine reuptake inhibitors, sympathomimetic agents, β-3-adrenergic receptor agonists, dopamine receptor agonists (e.g., bromocriptine), melanocyte stimulating hormone and its analogs, 5-HT 2C agonists (e.g., lorcaserin / Belviq), melanin concentrating hormone antagonists, leptin, leptin analogs, leptin agonists, galanin antagonists, lipase inhibitors (e.g., tetrahydrolipstatin / orlistat), anorectics (e.g., bombesin agonists), NPY antagonists (e.g., velneperit, PYY 3-36 (and their analogs), BRS3 modulators, mixed opioid receptor antagonists, thyroxine mimetics, dehydroepiandrosterone, glucocorticoid agonists or antagonists, orexin antagonists, GLP-1 agonists, ciliary neurotrophic factor (e.g., Axokine), human gray-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 the glucagon, GIP, and GLP1 receptors (e.g., MA R-701, ZP2929); norepinephrine reuptake inhibitors, opioid antagonists (e.g., naltrexone), CB1 receptor antagonists or inverse agonists, gastric hormone agonists or antagonists, oxyntomodulin and its analogs, 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).

[0561] In some embodiments, the anti-obesity agent used in combination with the compounds of the present invention is selected from the group consisting of alimentary selective MTP inhibitors (e.g., dirlotapide, mitratapide, implitapide, R56918), CCK-A agonists, 5-HT 2C Agonists (e.g., lorcaserin / bevic), MCR4 agonists, lipase inhibitors (e.g., Cetilistat), PYY 3-36 (including its analogs and pegylated analogs), opioid antagonists (e.g., naltrexone), oleoyl estrone, obinepitide, pramlintide, tasofolcin, leptin, bromocriptine, orlistat, AOD-9604.

[0562] In some embodiments, the compounds and compositions according to the methods of the present invention can be administered using any amount and any route of administration effective to treat or lessen the severity of a LKB1 or Kras-related disease. In some embodiments, a LKB1 or Kras-related disease is selected from hepatocellular carcinoma, LKB1 mutant cancer, LKB1 heterozygosity loss (LOH) driven cancer, Kras mutant cancer, Peutz-Jeghers syndrome (PJS), Cowden's disease (CD) and tuberous sclerosis (TS) (Makowski et al., "Role of LKB1 in Lung Cancer Development" British Journal of Cancer (2008) 99, 683-688). In some embodiments, a LKB1 or Kras-related disease is a Kras-positive / LKB1-deficient lung tumor.

[0563] In some embodiments, the compounds and compositions according to the methods of the present invention can be administered using any amount and any route of administration effective for treating cancer or reducing its severity or inhibiting the growth of cancer cells or inducing apoptosis thereof (Wang et al., "Acetyl-CoA Carboxylase-alpha Inhibitor TOFA Induces Human Cancer Cell Apoptosis" Biochem Biophys Res Commun. (2009) 385(3), 302-306; Chajes et al., "Acetyl-CoA Carboxylase alpha Is Essential to Breast Cancer Cell Survival" Cancer Res. (2006) 66, 5287-5294; Beckers et al., "Chemical Inhibition of Acetyl-CoA Carboxylase Induces Growth Arrest and Cytotoxicity Selectivity in Cancer Cells" Cancer Res. (2007) 8180-8187; Brusselmans et al., "RNA Interference-Mediated Silencing of the Acetyl-CoA-Carboxylase-alpha Gene Induces Growth Inhibition and Apoptosis of Prostate Cancer Cells" Cancer Res. (2005) 65, 6719-6725; Brunet et al., "BRCA1 andAcetyl-CoA Carboxylase: The Metabolic Syndrom of Breast Cancer" Molecular Carcinogenesis (2008) 47, 157-163; Cairns et al., "Regulation of Cancer Cell Metabolism" (2011) 11, 85-95; Chiaradonna et al., "From Cancer Metabolism to New Biomarkers and Drug Targets" Biotechnology Advances (2012) 30, 30-51).

[0564] In some embodiments, the compounds and compositions according to the methods of the present invention can be administered using any amount and any route of administration effective to treat melanoma or reduce its severity. In some embodiments, the melanoma is a melanoma 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).

[0565] The compounds of the present invention are particularly suitable for triple-negative breast cancer because the tumor suppressor protein BRCA1 binds to the inactive form of ACC and stabilizes it, thereby regulating de novo lipid synthesis. The loss or mutation of this tumor suppressor protein leads to the loss of binding and stabilization of the inactive form of ACC, resulting in an increase in the ability of ACC-driven de novo lipogenesis, causing cancer cell proliferation. See Brunet et al., "BRCA1 and acetyl-CoA carboxylase: the metabolic syndrome of breast cancer" Mol. Carcinog. (2008) 47 (2), 157-163.

[0566] In some embodiments, the compounds and compositions according to the methods of the invention can be administered using any amount and any route of administration that is effective in treating liposarcoma or reducing its severity. Liposarcomas have been shown to be dependent on de novo long-chain fatty acid synthesis for growth, and inhibition of ACC by soraphen A inhibits lipogenesis and tumor cell growth (Olsen et al., "Fatty acid synthesis is atherapeutic target in human liposarcoma" International J. of Oncology (2010) 36, 1309-1314).

[0567] In some embodiments, the compounds and compositions according to the methods of the invention can be administered using any amount and any route of administration that is effective in treating liver disease or reducing its severity. In some embodiments, the liver disease is selected from alcoholic fatty liver disease (AFLD), familial mixed hyperlipidemia, hepatitis (including hepatitis A, B and C), hepatocellular carcinoma, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver cancer, liver fibrosis, liver inflammation, bile duct cancer, angiosarcoma, angiosarcoma and progressive familial intrahepatic cholestasis. In some embodiments, the liver disease is non-alcoholic steatohepatitis. In some embodiments, the liver disease is hepatocellular carcinoma.

[0568] Some embodiments provided herein provide methods of treating non-alcoholic steatohepatitis (NASH) comprising administering a therapeutically effective amount of a crystalline form of Compound 1 described herein or a composition described herein.

[0569] Some embodiments provided herein provide for use of a crystalline form of Compound 1 described herein or a composition described herein in treating non-alcoholic steatohepatitis (NASH).

[0570] Some embodiments provided herein provide 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.

[0571] Some embodiments provided herein provide use of Form I of Compound 1, or a composition comprising Form I of Compound 1, in treating non-alcoholic steatohepatitis (NASH).

[0572] Some embodiments provided herein provide a method for treating hepatocellular carcinoma (HCC), comprising administering a therapeutically effective amount of a crystalline form of compound 1 described herein or a composition described herein. Some embodiments provided herein provide the use of a crystalline form of compound 1 described herein or a composition described herein in the treatment of HCC. In some embodiments, the crystalline form of compound 1 is administered as an adjuvant therapy. In some embodiments, the crystalline form or composition of compound 1 described herein is administered after curative surgery, local ablation, or liver transplantation.

[0573] Some embodiments provided herein provide 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.

[0574] In some embodiments, the method of treating hepatocellular carcinoma (HCC) 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. In some embodiments, the method of treating hepatocellular carcinoma (HCC) 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 transplantation, radiofrequency ablation, percutaneous ethanol injection, transarterial embolization, radiation or chemotherapy.

[0575] In some embodiments, the compounds or compositions provided according to the methods of the present invention can be administered in combination with sorafenib for the treatment of hepatocellular carcinoma.

[0576] In some embodiments, the compounds and compositions according to the methods of the present invention may be administered using any amount and any route of administration effective to treat or lessen the severity of a bacterial infection or inhibit bacterial growth. In some embodiments, the bacterial infection is acne vulgaris.

[0577] In some embodiments, the compounds and compositions according to the methods of the present invention can be administered using any amount and any route of administration effective to treat or lessen the severity of fungal infection or inhibit the growth of fungal cells (Shen et al., "AMechanism for the Potent Inhibition of Eukaryotic Acetyl-Coenzyme ACarboxylase by Soraphen A, a Macrocyclic Polyketide Natural Product" Molecular Cell (2004) 16, 881-891).

[0578] In some embodiments, the compounds of the present invention inhibit one or more fungal species with a MIC of 2 μg / mL or less. In some embodiments, the compounds of the present invention inhibit at least one of Candida albicans, Candida krusei and Candida parapsilosis at a concentration of 2 μg / mL or less. In some embodiments, the compounds of the present invention inhibit at least one of Candida albicans / Candida krusei and Candida parapsilosis at a concentration of 1 μg / mL or less. In some embodiments, the compounds of the present invention inhibit at least two of Candida albicans, Candida krusei and Candida parapsilosis at a concentration of 2 μg / mL or less. In some embodiments, the compounds of the present invention inhibit at least two of Candida albicans, Candida krusei and Candida parapsilosis at a concentration of 1 μg / mL or less. In some embodiments, the compounds of the present invention inhibit each of Candida albicans, Candida krusei and Candida parapsilosis at a concentration of 2 μg / mL or less. In some embodiments, the compounds of the present invention inhibit each of Candida albicans, Candida krusei and Candida parapsilosis at a concentration of 1 μg / mL or less.

[0579] In some embodiments, the compounds of the present invention inhibit 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 μg / mL or less. In some embodiments, the compounds of the present invention inhibit 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 μg / mL or less. In some embodiments, the compounds of the present invention inhibit at least two of tomato gray mold, gramineous anthracnose, Maide shell color monoseptate spores, Fusarium moniliforme, soybean sudden death syndrome pathogen, pepper phytophthora, Rhizoctonia solani, and septoria at a concentration of 2 μg / mL or less. In some embodiments, the compounds of the present invention inhibit at least two of tomato gray mold, gramineous anthracnose, Maide shell color monoseptate spores, Fusarium moniliforme, soybean sudden death syndrome pathogen, pepper phytophthora, Rhizoctonia solani, and septoria at a concentration of 1 μg / mL or less. In some embodiments, the compounds of the present invention inhibit at least three of tomato gray mold, gramineous anthracnose, Maide shell color monoseptate spores, Fusarium moniliforme, soybean sudden death syndrome pathogen, pepper phytophthora, Rhizoctonia solani, and septoria at a concentration of 2 μg / mL or less. In some embodiments, the compounds of the invention inhibit at least three of Botrytis cinerea, Colletotrichum graminearum, Chlorella meyder, Fusarium moniliforme, Soybean sudden death syndrome, Phytophthora capsici, Rhizoctonia solani, and Septoria at a concentration of 1 μg / mL or less.

[0580] In some embodiments, the compounds and compositions according to the methods 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).

[0581] In some embodiments, the compounds and compositions according to the methods of the invention can be administered using any amount and any route of administration that is effective to treat or reduce the severity of a viral infection (Munger et al., Nat. Biotechnol. (2008) 26, 1179-1186). In some embodiments, the viral infection is hepatitis C. In some embodiments, the viral infection is hepatitis B. In some embodiments, the viral infection is hepatitis A.

[0582] In some embodiments, the compounds and compositions according to the methods of the present invention can be administered using any amount and any route of administration effective to treat or lessen the severity of a neurological disease (Henderson et al., Neurotherapeutics (2008) 5, 470-480; Costantini et al., Neurosci. (2008) 9 Suppl. 2: S16; Baranano et al., Curr. Treat. Opin. Neurol. (2008) 10, 410-419).

[0583] In some embodiments, the compounds and compositions according to the methods of the present invention can be administered using any amount and any route of administration effective to treat or lessen the severity of a parasitic infection or inhibit parasitic growth (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 gondiiis inhibited by aryloxyphenoxypropionate herbicides targeting acetyl-CoA carboxylase" PNAS (1999) 96 (23) 13387-13392).

[0584] In some embodiments, the compounds and compositions according to the methods of the invention can be administered using any amount and any route of administration that is effective in treating a cardiac disorder or reducing its severity. In some embodiments, the cardiac disorder is cardiac hypertrophy. In some embodiments, the cardiac disorder is treated or reduced in severity by a cardioprotective mechanism caused by increasing fatty acid oxidation via ACC inhibition (Kolwicz et al., "Cardiac-specific deletion of acetyl CoAcarboxylase 2 (ACC2) prevents metabolic remodeling during pressure-overload hypertrophy" Circ. Res. (2012); DOI: 10.1161 / CIRCRESAHA.112.268128).

[0585] In specific embodiments, the compounds and compositions according to the methods of the invention can be used as herbicides. In some embodiments, the invention provides a method of inhibiting plant growth or viability, comprising treating plants with the compounds of the invention. In some embodiments of the invention, the compounds of the invention can be used to inhibit the growth or viability of plants by inhibiting ACC. In some embodiments, the methods of the invention comprise using the compounds of the invention to inhibit fatty acid production or increase fatty acid oxidation in plants.

[0586] The exact amount required will vary between subjects, depending on the species, age, and overall condition of the subject, the severity of the infection, the specific agent, its mode of administration, and the like. The compounds of the present invention are preferably formulated in unit dosage form to achieve ease of administration and uniformity of dosage. The expression "unit dosage form" as used herein refers to a physically discrete unit of a medicament suitable for a patient to be treated. However, it should be understood that the total daily dosage of the compounds and compositions of the present invention will be determined by the attending physician within the scope of reasonable medical judgment. The specific effective dosage level for any particular patient or organism will depend on a variety of factors, including the condition being treated and the severity of the condition; the activity of the specific compound used; the specific composition used; the patient's age, weight, general health, sex, and diet; the administration time, route of administration, and excretion rate of the specific compound used; the duration of treatment; drugs used in combination or concomitantly with the specific compound used; and similar factors well known in the medical field.

[0587] The pharmaceutically acceptable compositions of the present invention may be administered to humans and other animals orally, rectally, parenterally, intracisternal, intravaginal, intraperitoneal, topically (e.g., by powder, ointment or drops), buccally, as an oral or nasal spray, etc., depending on the severity of the infection being treated. In a specific embodiment, the compounds of the present invention may be administered orally or parenterally at a dosage level of about 0.01 mg to about 50 mg per kilogram of subject body weight per day, and preferably about 1 mg to about 25 mg per kilogram of subject body weight, one or more times per day to obtain the desired therapeutic effect.

[0588] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage form may also contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitan fatty acid esters and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and aromatics.

[0589] Injectable preparations, such as sterile injectable aqueous or oily suspensions, can be prepared using suitable dispersants or wetting agents and suspending agents according to known techniques. Sterile injectable preparations can also be sterile injectable solutions, suspensions or emulsions in non-toxic parenteral acceptable diluents or solvents, such as in the form of solutions in 1,3-butanediol. Available acceptable vehicles and solvents include water, Ringer's solution, USP and isotonic sodium chloride solution. In addition, sterile fixed oils are routinely used as solvents or suspension media. For this purpose, any gentle fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids, such as oleic acid, are used in injectable preparations.

[0590] The injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter and / or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0591] In order to prolong the effect of the compounds of the present invention, it is usually necessary to slow down the absorption of the compounds from subcutaneous or intramuscular injections. This can be achieved using a liquid suspension of crystalline or amorphous materials with weak water solubility. The absorption rate of the compound depends on its dissolution rate, which can depend on crystal size and crystalline form. Alternatively, the absorption of the compound form for parenteral administration is delayed by dissolving or suspending the compound in an oil vehicle. Injectable reservoir forms are manufactured by forming a microcapsule matrix of the compound in a biodegradable polymer (such as polylactide-polyglycolide). Depending on the ratio of the compound to the polymer and the properties of the specific polymer used, the release rate of the compound can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable preparations are also prepared by embedding the compound in a liposome or microemulsion compatible with body tissues.

[0592] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of the invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity and releases the active compound.

[0593] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In the solid dosage form, 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 starch, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and gum arabic; c) humectants such as glycerol; d) disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) dissolution delay agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glyceryl monostearate; h) adsorbents such as kaolin and bentonite; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0594] Solid compositions of similar types can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose (lactose / milk sugar) and high molecular weight polyethylene glycol. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells (such as other coatings well-known in enteric coatings and pharmaceutical preparation technology). They can optionally contain opacifiers and can also have a composition that allows them to release the active ingredient only or preferentially in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used include polymers and waxes. Solid compositions of similar types can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose and high molecular weight polyethylene glycol.

[0595] The active compound can also be in the form of microcapsules with one or more excipients as shown above. The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells (such as enteric coatings, release control coatings and other coatings well-known in pharmaceutical formulation technology). In such solid dosage forms, the active compound can be mixed with at least one inert diluent (such as sucrose, lactose or starch). During normal practice, such dosage forms can also include other substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage form can also include a buffer. It can optionally contain an opacifier, and can also have a composition that allows it to release the active ingredient only in or preferentially in a certain part of the intestinal tract in a delayed manner. The example of the embedding composition that can be used includes polymers and waxes.

[0596] The dosage form for topical or transdermal administration of the compounds of the invention includes ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is mixed with a pharmaceutically acceptable carrier and any required preservatives or buffers as required under aseptic conditions. It is also expected that ophthalmic preparations, ear drops and eye drops are within the scope of the present invention. In addition, the present invention encompasses the use of transdermal patches, which have the additional advantage of providing controlled delivery of the compound to the body. The dosage form can be prepared by dissolving or dispersing the compound in an appropriate medium. Absorption enhancers can also be used to increase the flow of the compound through the skin. The rate can be controlled by providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0597] According to one embodiment, the present invention relates to a method for inhibiting ACC in a biological sample, comprising the step of contacting the biological sample with a compound of the present invention or a composition comprising the compound.

[0598] In a specific embodiment, the invention relates to a method of modulating fatty acid levels in a biological sample comprising the step of contacting the biological sample with a compound of the invention or a composition comprising the compound.

[0599] As used herein, the term "biological sample" includes, but is not limited to, cell cultures or extracts thereof; biopsy material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears or other body fluids or extracts thereof.

[0600] Inhibition of enzymes in biological samples is useful for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, biological analysis, gene expression studies, and biological target identification.

[0601] Another embodiment of the present invention is directed to a method of inhibiting ACC in a patient comprising the step of administering to said patient a compound of the present invention or a composition comprising said compound.

[0602] According to another embodiment, the present invention relates to a method for inhibiting fatty acid production, stimulating fatty acid oxidation, or both in a patient, comprising the following steps: administering to the patient a compound of the present invention or a composition comprising the compound. According to a specific embodiment, the present invention relates to a method for inhibiting fatty acid production, stimulating fatty acid oxidation, or both in a patient so as to reduce obesity or alleviate the symptoms of metabolic syndrome, comprising the following steps: administering to the patient a compound of the present invention or a composition comprising the compound. In other embodiments, the present invention provides a method for treating a condition mediated by ACC in a patient in need thereof, comprising the following steps: administering to the patient a compound according to the present invention or a pharmaceutically acceptable composition thereof. The condition is described in detail herein.

[0603] In some embodiments, the compounds and compositions of the present invention can be used to treat obesity or another metabolic disorder. In a specific embodiment, the compounds and compositions of the present invention can be used to treat obesity or other metabolic disorders in mammals. In a specific embodiment, the mammal is a human patient. In a specific embodiment, the compounds and compositions of the present invention can be used to treat obesity or other metabolic disorders in human patients.

[0604] In some embodiments, the present invention provides a method for treating obesity or another metabolic disorder, which comprises administering a compound or composition of the present invention to a patient suffering from obesity or another metabolic disorder. In a specific embodiment, the method for treating obesity or another metabolic disorder comprises administering a compound and composition of the present invention to a mammal. In a specific embodiment, the mammal is a human being. In some embodiments, the metabolic disorder is dyslipidemia or hyperlipidemia. In some embodiments, obesity is a symptom of Prader-Willi syndrome, Bardet-Biedl syndrome, Cohen syndrome or MOMO syndrome. In some embodiments, obesity is a side effect of administering another drug, and the another drug includes but is not limited to insulin, sulfonylurea, thiazolidinedione, antipsychotic, antidepressant, steroid, anticonvulsant (including phenytoin and valproate), pizotifen or hormonal contraceptives.

[0605] In a specific embodiment, the present invention provides a method of treating cancer or another proliferative disorder comprising administering a compound or composition of the present invention to a patient suffering from cancer or another proliferative disorder. In a specific embodiment, the method of treating cancer or another proliferative disorder comprises administering a compound and composition of the present invention to a mammal. In a specific embodiment, the mammal is a human.

[0606] As used herein, the terms "inhibit cancer" and "inhibit cancer cell proliferation" refer to inhibiting the growth, division, maturation or viability of cancer cells, either alone or in aggregate with other cancer cells, or reducing their rate, and / or causing cancer cell death, by cytotoxicity, nutrient depletion or induction of apoptosis.

[0607] Examples of tissues containing cancer cells whose proliferation is inhibited by the compounds and compositions 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, gallbladder, rectum, salivary glands, adrenal glands, throat, esophagus, lymph nodes, sweat glands, sebaceous glands, muscle, heart, and stomach.

[0608] In some embodiments, the cancer treated with the compounds or compositions of the present invention is melanoma, liposarcoma, lung cancer, breast cancer, prostate cancer, leukemia, kidney cancer, esophageal cancer, brain cancer, lymphoma or colon cancer. In a specific embodiment, the cancer is primary effusion lymphoma (PEL). In certain preferred embodiments, the cancer to be treated with the compounds or compositions of the present invention is a cancer carrying an activated MAPK pathway. In some embodiments, the cancer carrying an activated MAPK pathway is a melanoma. In certain preferred embodiments, the cancer treated with the compounds or compositions of the present invention is a cancer associated with a BRCA1 mutation. In a particularly preferred embodiment, the cancer treated with the compounds or compositions of the present invention is triple-negative breast cancer.

[0609] In a specific embodiment, the disease that can be treated with the compounds of the present invention is a neurological disorder. In some embodiments, the neurological disorder is Alzheimer's Disease, Parkinson's Disease, epilepsy, ischemia, age-related memory impairment, mild cognitive impairment, Friedreich's Ataxia, GLUT1-deficient epilepsy, Leprechaunism, Rabson-Mendenhall Syndrome, coronary artery bypass graft dementia, anesthesia-induced memory loss, amyotrophic lateral sclerosis, glioma or Huntington's Disease.

[0610] In a specific embodiment, the disease that can be treated with the compounds of the present invention is an infectious disease. In some embodiments, the infectious disease is a viral infection. In some embodiments, the viral infection is a cytomegalovirus infection or an influenza infection. In some embodiments, the infectious disease is a fungal infection. In some embodiments, the infectious disease is a bacterial infection.

[0611] Depending on the specific condition or disease to be treated, additional therapeutic agents that are normally administered to treat that condition may be administered in combination with the compounds and compositions of the invention. As used herein, additional therapeutic agents that are normally administered to treat a specific disease or condition are referred to as "appropriate for the disease or condition being treated."

[0612] In a specific embodiment, the compounds of the invention or compositions thereof are administered in combination with one or more other antifungal (antifungal) agents for the treatment of fungal infections. In some embodiments, the one or more other antifungal (antifungal) agents are selected from polyene antifungal agents (including but not limited to amphotericin B (as amphotericin B deoxycholate, amphotericin B lipid complex or liposomal amphotericin B), candida albicans, filipin, hamycin, natamycin, nystatin and chelidoxime), azole antifungal agents (including but not limited to abafungin, albaconazole, bifonazole, butoconazole, clotrimazole, econazole, inaconazole, epoxyconazole, fenticonazole, fluconazole , isavuconazole, isoconazole, itraconazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, posaconazole, propiconazole, ravuconazole, sertaconazole, sulconazole, terconazole, tioconazole and voriconazole), allylamines (including but not limited to amorolfine, butenafine, naftifon and terbinafine), echinocandins (including but not limited to anidulafungin, caspofungin and micafungin), benzoic acid, ciclopirox, flucytosine, griseofulvin, haloprogin, tolnaftate, undecylenic acid and crystal violet.

[0613] In a specific embodiment, the compound or its composition provided is administered in combination with another ACC inhibitor or anti-obesity agent. In some embodiments, the compound or its composition provided is administered in combination with one or more other therapeutic agents. The therapeutic agent includes but is not limited to orlistat (Xenical), CNS stimulants, Qsymia or Belviq.

[0614] In specific embodiments, provided compounds or compositions thereof are administered to a patient in need thereof in combination with another anticancer drug, cytotoxin, or chemotherapeutic agent.

[0615] In a specific embodiment, the anticancer drugs or chemotherapeutic agents used in combination with the compounds or compositions of the present invention include, but are not limited to, metformin, phenformin, buformin, imatinib, nilotinib, gefitinib, sunitinib, carfilzomib, salinosporamide A, 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, Pacific Paclitaxel, docetaxel, irinotecan, topotecan, amsacrine, actinomycin, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, plicamycin, mitomycin (mitomycin), mitoxantrone, melphalan, busulfan, capecitabine, pemetrexed, epothilones, 13-cis-retinoic acid, 2-CdA, 2-chlorodeoxyadenosine, 5-azacitidine, 5-fluorouracil, 5-FU, 6-mercaptopurine, 6-MP, 6-TG, 6-thioguanine, Abraxane, Actinomycin-D, Aldesleukin, Alemtuzumab, ALIMTA, Alitretinoin, All-trans retinoic acid, interferon alpha, altretamine, amethopterin, amifostine, aminoglutethimide, anagrelide, Anastrozole, Arabinosylcytosine, Ara-C, Arsenic trioxide, Arzerra TM , asparaginase, ATRA, Azacitidine, BCG, BCNU, Bendamustine, Bevacizumab, Bexarotene, Bicalutamide, BiCNU, Bleomycin, Bortezomib, Busulfan, C225, Calcium Leucovorin, Camptothecin-11, Capecitabine, Carac TM , Carboplatin, Carmustine, Carmustine Chip, CC-5013, CCI-779, CCNU, CDDP, CeeNU, Cetuximab, Chlorambucil, Citrovorum Factor, Cladribine, Cortisone, CPT-11, Dacarbazine, Dacogen, Dactinomycin, Darbepoetin Alfa, Dasatinib, Daunomycin, Daunomycin hydrochloride, Daunomycin liposome, Decadron, Decitabine, Denileukin, Diftitox, DepoCyt TM , Dexamethasone, Dexamethasone acetate, Dexamethasone sodium phosphate, Dexasone, Dexrazoxane, DHAD, DIC, Diodex, Docetaxel, Doxorubicin, liposomal doxorubicin, Droxia TM ,DTIC, Eligard TM , Ellence TM , Eloxatin TM , Epirubicin, Epoetin Alfa, Erbitux, Erlotinib, Erwinia L-asparaginase, Estramustine, Ethyol, Etoposide, Etoposide phosphate, Everolimus, Exemestane, Filgrastim, Floxuridine, Fludarabine, Fluorouracil, Fluorouracil cream, Fluoxymesterone, Flutamide, Folinic acid, Fulvestrant, G-CSF, Gefitinib, Gemcitabine, Gemtuzumab, Ozogamicin, Gemzar Gleevec TM , Chip, GM-CSF, Goserelin, Granulocyte colony stimulating factor, Granulocyte macrophage colony stimulating factor, Hexadrol, Hexamethylmelamine, HMM, Hydrocort Hydrocortisone, Hydrocortisone Sodium Phosphate, Hydrocortisone Sodium Succinate, Hydrocortisone Phosphate, Hydroxyurea, Ibritumomab, Ibritumomab, Tiuxetan, Idarubicin IFN-α, Ifosfamide, IL-11, IL-2, Imatinib mesylate, Imidazole carboxamide, Interferon α, Interferon α-2b (PEG conjugate), Interleukin-2, Interleukin-11, Intron (interferon α-2b), Irinotecan, Isotretinoin, Ixabepilone, Ixempra TM , Lapatinib, L-asparaginase, LCR, Lenalidomide, Letrozole, Leucovorin, Leukeran, Leukine TM , Leuprolide, Leurocristine, Leustatin TM , Liposome Ara-C, Liquid Lomustine, L-PAM, L-Sarcolysin, Lupron Maxidex, Nitrogen mustard, Nitrogen mustard hydrochloride, Megestrol, megestrol acetate, melphalan, mercaptopurine, mesna, mesnex TM , Methotrexate, Methotrexate Sodium, Methylprednisolone, Mitomycin, Mitomycin-C, Mitoxantrone, MTC, MTX, Nitrogen mustard (Mustine), Mylocel TM , Nelarabine, Neulasta TM , Nilotinib, Nilutamide, Nitrogen Mustard, Nplate, Octreotide, Octreotide acetate, Ofatumumab, Onxal TM , Oprelvekin, Oxaliplatin, paclitaxel, protein-bound paclitaxel, pamidronate, panitumumab, Pazopanib, PEG interferon, Pegaspargase, Pegfilgrastim, PEG-INTRON TM , PEG-L-asparaginase, PEMETREXED, Pentostatin, Phenylalanine mustard, Prednisolone, Prednisone, Procarbazine, Prolifeprospan 20 and carmustine implants, Raloxifene, Rituximab, (interferon α-2a), Romiplostim, Rubidomycin hydrochloride, Sandostatin Sargramostim, Sorafenib, SPRYCELTM 、STI-571、Streptozocin、SU11248、Sunitinib、 Tamoxifen, Temozolomide, Temsirolimus, Teniposide, TESPA, Thalidomide, Thioguanine, Thioguanine Thiophosphoamide, Thiotepa Topotecan, Toremifene, Tositumomab, Trastuzumab, Tretinoin, Trexall TM , TSPA, VCR, Vectibix TM , Viadur TM , Vinblastine, Vinblastine Sulfate, Vincasar Vincristine, Vinorelbine, Vinorelbine tartrate, VLB, VM-26, Vorinostat, Votrient, VP-16, Zevalin TM , Zoledronic acid, Zolinza, Or a combination of any one of the above.

[0616] In a specific embodiment, the compounds or compositions of the present invention can be administered to a patient in need thereof together with a biguanide selected from metformin, phenformin or buformin. In a specific embodiment, the patient to whom the combination of the compounds of the present invention and the biguanide is administered suffers from cancer, obesity, liver disease, diabetes, or two or more of the foregoing.

[0617] In some embodiments, the compound or composition provided can be administered alone or with one or more other therapeutic agents for the treatment of acne vulgaris. In some embodiments, the one or more other therapeutic agents for the treatment of acne vulgaris are selected from topical anti-acne agents (e.g., retinoids, topical antibiotics, benzoyl peroxide) or systemic anti-acne agents (e.g., hormone therapy, oral antibiotics, isotretinoin). In some embodiments, the hormone therapy is an oral contraceptive or an androgen blocker. In some embodiments, the oral antibiotic is doxycycline, minocycline, tetracycline or erythromycin.

[0618] In some embodiments, provided compounds or compositions can be administered alone or with one or more additional therapeutic agents for treating seborrheic dermatitis. In some embodiments, provided compounds or compositions can be administered alone or with one or more additional therapeutic agents for treating seborrheic keratosis.

[0619] In specific embodiments, a combination of two or more therapeutic agents may be administered with the compounds of the invention. In specific embodiments, a combination of three or more therapeutic agents may be administered with the compounds of the invention.

[0620] Other examples of pharmaceutical agents with which the compounds of the invention may also be combined include, but are not limited to: vitamins and nutritional supplements; cancer vaccines; therapies for neutropenia (e.g., G-CSF, filgrastim, lenograstim); therapies for thrombocytopenia (e.g., blood transfusions, erythropoietin); PI3 kinase (PI3K) inhibitors; MEK inhibitors; AMPK activators; PCSK9 inhibitors; SREBP site 1 protease inhibitors; HMG CoA-reductase inhibitors; antiemetics (e.g., 5-HT3 receptor antagonists, dopamine antagonists, NK1 receptor antagonists, histamine receptor antagonists, cannabinoids, benzodiazepines or anticholinergic drugs); used in the treatment of Alzheimer's disease, such as and Therapies for Parkinson's disease, such as L-DOPA / carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; agents used to treat multiple sclerosis (MS), such as beta interferon (e.g. and ), and mitoxantrone; asthma treatments such as albuterol and Drugs used to treat schizophrenia, such as Zyprexa, Risperdal, Seroquel, and Haloperidol; anti-inflammatory agents, such as corticosteroids, TNF blockers, IL-1RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulators and immunosuppressants, such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, and sirolimus; mofetil), interferon, corticosteroids, cyclophosphamide, azathioprine and sulfasalazine; neurotrophic factors, such as acetylcholinesterase inhibitors, MAO inhibitors, interferon, anticonvulsants, ion channel blockers, riluzole and anti-Parkinson's disease agents; agents for the treatment of cardiovascular diseases, such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers and statins, fibrates, cholesterol absorption inhibitors, bile acid sequestrants and niacin; agents for the treatment of liver diseases, such as corticosteroids, cholestyramine, interferon and antiviral agents; agents for the treatment of blood disorders, such as corticosteroids, anti-leukemic agents and growth factors; drugs for the treatment of immune deficiency disorders and antidiabetic agents such as biguanides (metformin, phenformin, buformin), thiazolidinediones (rosiglitazone, pioglitazone, troglitazone), sulfonylureas (tolbutamide, acetophenonesulfonylcyclohexylurea, tolsulfenamide, chlorpropamide, glipizide, glibenclamide, glimepiride, gliclazide), meglitinides (repaglinide, nateglinide), alpha-glucosidase inhibitors (miglitol, acarbose), incretin mimetics (exenatide, liraglutide, tasiglutide), gastric inhibitory peptide analogs, DPP-4 inhibitors (vildagliptin, sitagliptin, saxagliptin, linagliptin, alogliptin), amylin analogs (pramlintide), and insulin and insulin analogs.

[0621] In specific embodiments, a compound of the invention or a pharmaceutically acceptable composition thereof is administered in combination with an antisense agent, a monoclonal or polyclonal antibody, or a siRNA therapeutic.

[0622] In some embodiments, the present invention provides a method for treating, stabilizing or reducing the severity or progression of non-alcoholic fatty liver disease (NAFLD), comprising administering to a patient in need thereof a combination of a provided compound or a pharmaceutically acceptable composition thereof and one or more other therapeutic agents. In certain embodiments, the one or more other therapeutic agents are independently selected from 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-acyltransferase 1 (DGAT1) inhibitors, dipeptidyl peptidase IV (DPPIV) inhibitors, farnesoid X receptor (FXR) agonists, FXR / TGR5 dual agonists, galectin-3 inhibitors, glucagon-like peptide 1 (GLP1) agonists, glutathione precursors, hepatitis C virus NS3 protease inhibitors, HMG CoA reductase inhibitors, 11β-hydroxysteroid dehydrogenase (11β-HSD1) inhibitors, IL-1β antagonists, IL-6 antagonists, IL-10 agonists, IL-17 antagonists, ileal sodium bile acid cotransporter inhibitors, leptin analogs, 5-lipoxygenase inhibitors, LPL gene stimulators, lysyl oxidase homolog 2 (LOXL2) inhibitors, PDE3 inhibitors, PDE4 inhibitors, phospholipase C (PLC) inhibitors, PPARα agonists, PPARγ agonists, PPARδ agonists, Rho-associated protein kinase 2 (ROCK2) inhibitors, sodium glucose transporter-2 (SGLT2) inhibitors, stearyl CoA desaturase-1 inhibitors, thyroid hormone receptor β agonists, tumor necrosis factor α (TNFα) ligand inhibitors, transglutaminase inhibitors, transglutaminase inhibitor pro, PTP1b inhibitors and ASK1 inhibitors.

[0623] In some embodiments, provided compounds, or pharmaceutically acceptable compositions thereof, are 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.

[0624] In some embodiments, provided compounds or pharmaceutically acceptable compositions thereof are administered in combination with one or more other therapeutic agents, wherein at least one of the other therapeutic agents is an angiotensin converting enzyme (ACE) inhibitor. In some embodiments, the ACE inhibitor is enalapril.

[0625] In some embodiments, provided compounds or pharmaceutically acceptable compositions thereof are administered in combination with one or more other therapeutic agents, wherein at least one of the other therapeutic agents is a caspase inhibitor. In some embodiments, the caspase inhibitor is enlicasin.

[0626] In some embodiments, provided compounds or pharmaceutically acceptable compositions thereof are administered in combination with one or more other therapeutic agents, wherein at least one of the other therapeutic agents is a cathepsin B inhibitor. In some embodiments, the cathepsin B inhibitor is a mixed cathepsin B / hepatitis C virus NS3 protease inhibitor. In some embodiments, the mixed cathepsin B / hepatitis C virus NS3 protease inhibitor is VBY-376.

[0627] In some embodiments, provided compounds or pharmaceutically acceptable compositions thereof are administered in combination with one or more other therapeutic agents, wherein at least one of the other therapeutic agents is a CCR2 chemokine antagonist. In some embodiments, the other therapeutic agent is a mixed CCR2 / CCR5 chemokine antagonist. In some embodiments, the mixed CCR2 / CCR5 chemokine antagonist is cenicriviroc.

[0628] In some embodiments, provided compounds, or pharmaceutically acceptable compositions thereof, are administered in combination with one or more other therapeutic agents, wherein at least one of the other therapeutic agents is a CCR5 chemokine antagonist.

[0629] In some embodiments, provided compounds or pharmaceutically acceptable compositions thereof are administered in combination with one or more other therapeutic agents, wherein at least one of the other therapeutic agents is a chloride channel stimulator. In some embodiments, the chloride channel stimulator is cobiprostone.

[0630] In some embodiments, provided compounds, or pharmaceutically acceptable compositions thereof, are administered in combination with one or more other therapeutic agents, wherein at least one of the other therapeutic agents is a cholesterol solubilizing agent.

[0631] In some embodiments, provided compounds or pharmaceutically acceptable compositions thereof are administered in combination with one or more other therapeutic agents, wherein at least one of the other therapeutic agents is a diacylglycerol O-acyltransferase 1 (DGAT1) inhibitor. In some embodiments, the DGAT1 inhibitor is LCQ908.

[0632] In some embodiments, provided compounds or pharmaceutically acceptable compositions thereof are administered in combination with one or more other therapeutic agents, wherein at least one of the other therapeutic agents is a dipeptidyl peptidase IV (DPPIV) inhibitor. In some embodiments, the DPPIV inhibitor is linagliptin.

[0633] In some embodiments, provided compounds or pharmaceutically acceptable compositions thereof are administered in combination with one or more other therapeutic agents, wherein at least one of the other therapeutic agents is a farnesoid X receptor (FXR) agonist. In some embodiments, the FXR agonist is INT-747 (obeticholic acid). In some embodiments, the FXR agonist is PX-102.

[0634] In some embodiments, provided compounds or pharmaceutically acceptable compositions thereof are administered in combination with one or more other therapeutic agents, wherein at least one of the other therapeutic agents is a FXR / TGR5 dual agonist. In some embodiments, the FXR / TGR5 dual agonist is INT-767.

[0635] In some embodiments, provided compounds or pharmaceutically acceptable compositions thereof are administered in combination with one or more other therapeutic agents, wherein at least one of the other therapeutic agents is a galectin-3 inhibitor. In some embodiments, the galectin-3 inhibitor is GR-MD-02.

[0636] In some embodiments, provided compounds or pharmaceutically acceptable compositions thereof are administered in combination with one or more other therapeutic agents, wherein at least one of the other therapeutic agents is a glucagon-like peptide 1 (GLP1) agonist. In some embodiments, the GLP1 agonist is liraglutide. In some embodiments, the GLP1 agonist is exenatide.

[0637] In some embodiments, provided compounds, or pharmaceutically acceptable compositions thereof, are administered in combination with one or more other therapeutic agents, wherein at least one of the other therapeutic agents is a glutathione precursor.

[0638] In some embodiments, provided compounds or pharmaceutically acceptable compositions thereof are administered in combination with one or more other therapeutic agents, wherein at least one of the other therapeutic agents is a hepatitis C virus NS3 protease inhibitor. In some embodiments, the hepatitis C virus NS3 protease inhibitor is a mixed cathepsin B / hepatitis C virus NS3 protease inhibitor. In some embodiments, the mixed cathepsin B / hepatitis C virus NS3 protease inhibitor is VBY-376.

[0639] In some embodiments, provided compounds or pharmaceutically acceptable compositions thereof are administered in combination with one or more other therapeutic agents, wherein at least one of the other therapeutic agents is an HMG CoA reductase inhibitor. In some embodiments, the HMG-CoA reductase inhibitor is a statin. In some embodiments, the HMG-CoA reductase inhibitor is atorvastatin.

[0640] In some embodiments, provided compounds or pharmaceutically acceptable compositions thereof are administered in combination with one or more other therapeutic agents, wherein at least one of the other therapeutic agents is an 11β-hydroxysteroid dehydrogenase (11β-HSD1) inhibitor. In some embodiments, the 11β-HSD1 inhibitor is RO5093151.

[0641] In some embodiments, provided compounds, or pharmaceutically acceptable compositions thereof, are administered in combination with one or more additional therapeutic agents, wherein at least one of the additional therapeutic agents is an IL-1β antagonist.

[0642] In some embodiments, provided compounds or pharmaceutically acceptable compositions thereof are administered in combination with one or more other therapeutic agents, wherein at least one of the other therapeutic agents is an IL-6 antagonist. In some embodiments, the IL-6 antagonist is a mixed IL-6 / IL-1β / TNFα ligand inhibitor. In some embodiments, the mixed IL-6 / IL-1β / TNFα ligand inhibitor is BLX-1002.

[0643] In some embodiments, provided compounds or pharmaceutically acceptable compositions thereof are administered in combination with one or more other therapeutic agents, wherein at least one of the other therapeutic agents is an IL-10 agonist. In some embodiments, the IL-10 agonist is peg-iloleukin.

[0644] In some embodiments, provided compounds or pharmaceutically acceptable compositions thereof are administered in combination with one or more other therapeutic agents, wherein at least one of the other therapeutic agents is an IL-17 antagonist. In some embodiments, the IL-17 antagonist is KD-025.

[0645] In some embodiments, provided compounds or pharmaceutically acceptable compositions thereof are administered in combination with one or more other therapeutic agents, wherein at least one of the other therapeutic agents is an ileal sodium bile acid cotransporter inhibitor. In some embodiments, the ileal sodium bile acid cotransporter inhibitor is SHP-626.

[0646] In some embodiments, provided compounds or pharmaceutically acceptable compositions thereof are administered in combination with one or more other therapeutic agents, wherein at least one of the other therapeutic agents is a leptin analog. In some embodiments, the leptin analog is metreleptin.

[0647] In some embodiments, provided compounds or pharmaceutically acceptable compositions thereof are administered in combination with one or more other therapeutic agents, wherein at least one of the other therapeutic agents is a 5-lipoxygenase inhibitor. In some embodiments, the 5-lipoxygenase inhibitor is a mixed 5-lipoxygenase / PDE3 / PDE4 / PLC inhibitor. In some embodiments, the mixed 5-lipoxygenase / PDE3 / PDE4 / PLC inhibitor is talukast.

[0648] In some embodiments, provided compounds or pharmaceutically acceptable compositions thereof are administered in combination with one or more other therapeutic agents, wherein at least one of the other therapeutic agents is an LPL gene stimulator. In some embodiments, the LPL gene stimulator is tipa aliporin.

[0649] In some embodiments, provided compounds or pharmaceutically acceptable compositions thereof are administered in combination with one or more other therapeutic agents, wherein at least one of the other therapeutic agents is a lysyl oxidase homolog 2 (LOXL2) inhibitor. In some embodiments, the LOXL2 inhibitor is an anti-LOXL2 antibody. In some embodiments, the anti-LOXL2 antibody is GS-6624.

[0650] In some embodiments, provided compounds or pharmaceutically acceptable compositions thereof are administered in combination with one or more other therapeutic agents, wherein at least one of the other therapeutic agents is a PDE3 inhibitor. In some embodiments, the PDE3 inhibitor is a mixed 5-lipoxygenase

[0651] / PDE3 / PDE4 / PLC inhibitors. In some embodiments, the mixed 5-lipoxygenase

[0652] The / PDE3 / PDE4 / PLC inhibitor is talukast.

[0653] In some embodiments, provided compounds or pharmaceutically acceptable compositions thereof are administered in combination with one or more other therapeutic agents, wherein at least one of the other therapeutic agents is a PDE4 inhibitor. In some embodiments, the PDE4 inhibitor is ASP-9831. In some embodiments, the PDE4 inhibitor is a mixed 5-lipoxygenase / PDE3 / PDE4 / PLC inhibitor. In some embodiments, the mixed 5-lipoxygenase / PDE3 / PDE4 / PLC inhibitor is talukast.

[0654] In some embodiments, provided compounds or pharmaceutically acceptable compositions thereof are administered in combination with one or more other therapeutic agents, wherein at least one of the other therapeutic agents is a phospholipase C (PLC) inhibitor. In some embodiments, the PLC inhibitor is a mixed 5-lipoxygenase / PDE3 / PDE4 / PLC inhibitor. In some embodiments, the mixed 5-lipoxygenase

[0655] The / PDE3 / PDE4 / PLC inhibitor is talukast.

[0656] In some embodiments, provided compounds or pharmaceutically acceptable compositions thereof are administered in combination with one or more other therapeutic agents, wherein at least one of the other therapeutic agents is a PPARα agonist. In some embodiments, the PPARα agonist is a mixed PPARα / δ agonist. In some embodiments, the mixed PPARα / δ agonist is GFT505.

[0657] In some embodiments, provided compounds or pharmaceutically acceptable compositions thereof are administered in combination with one or more other therapeutic agents, wherein at least one of the other therapeutic agents is a PPARγ agonist. In some embodiments, the PPARγ agonist is pioglitazone.

[0658] In some embodiments, provided compounds, or pharmaceutically acceptable compositions thereof, are administered in combination with one or more additional therapeutic agents, wherein at least one of the additional therapeutic agents is a PPARδ agonist.

[0659] In some embodiments, provided compounds or pharmaceutically acceptable compositions thereof are administered in combination with one or more other therapeutic agents, wherein at least one of the other therapeutic agents is a Rho-associated protein kinase 2 (ROCK2) inhibitor. In some embodiments, the ROCK2 inhibitor is KD-025.

[0660] In some embodiments, provided compound or its pharmaceutically acceptable composition is administered in combination with one or more other therapeutic agents, wherein at least one of the other therapeutic agents is a sodium glucose transporter-2 (SGLT2) inhibitor. In some embodiments, the SGLT2 inhibitor is regolifloxacin.

[0661] In some embodiments, provided compounds or pharmaceutically acceptable compositions thereof are administered in combination with one or more other therapeutic agents, wherein at least one of the other therapeutic agents is a stearyl CoA desaturase-1 inhibitor. In some embodiments, the stearyl CoA desaturase-1 inhibitor is aramchol. In some embodiments, the stearyl CoA desaturase-1 inhibitor is CVT-12805.

[0662] In some embodiments, provided compounds or pharmaceutically acceptable compositions thereof are administered in combination with one or more other therapeutic agents, wherein at least one of the other therapeutic agents is a thyroid hormone receptor beta agonist. In some embodiments, the thyroid hormone receptor beta agonist is MGL-3196.

[0663] In some embodiments, provided compounds, or pharmaceutically acceptable compositions thereof, are administered in combination with one or more additional therapeutic agents, wherein at least one of the additional therapeutic agents is a tumor necrosis factor alpha (TNFα) ligand inhibitor.

[0664] In some embodiments, provided compounds or pharmaceutically acceptable compositions thereof are administered in combination with one or more other therapeutic agents, wherein at least one of the other therapeutic agents is a transglutaminase inhibitor. In some embodiments, the transglutaminase inhibitor precursor is cysteamine.

[0665] In some embodiments, provided compounds, or pharmaceutically acceptable compositions thereof, are administered in combination with one or more other therapeutic agents, wherein at least one of the other therapeutic agents is a transglutaminase inhibitor precursor.

[0666] In some embodiments, provided compounds or pharmaceutically acceptable compositions thereof are administered in combination with one or more other therapeutic agents, wherein at least one of the other therapeutic agents is a PTP1b inhibitor. In some embodiments, the PTP1b inhibitor is A119505, A220435, A321842, CPT633, ISIS-404173, JTT-551, MX-7014, MX-7091, MX-7102, NNC-521246, OTX-001, OTX-002, or TTP814.

[0667] In some embodiments, provided compounds or pharmaceutically acceptable compositions thereof are administered in combination with one or more other therapeutic agents, wherein at least one of the other therapeutic agents is an ASK1 inhibitor. In some embodiments, the ASK1 inhibitor is GS-4977 (also known as selonsertib).

[0668] In some embodiments, the one or more additional therapeutic agents are independently selected from acetylsalicylic acid, tipaalipogin, aramchol, atorvastatin, BLX-1002, cenicriviroc, cobiprostone, colesevelam, enlicasen, enalapril, GFT-505, GR-MD-02, hydrochlorothiazide, icosapentaenoic acid ethyl (ethyl eicosapentaenoic acid), IMM-124E, KD-025, linagliptin, liraglutide, cysteamine, MGL-3196, obeticholic acid, olesoxime, peg-iloleukin, pioglitazone, PX-102, repagliflozin ectoate, SHP-626, solithromycin, talukast, TRX-318, ursodeoxycholic acid, and VBY-376.

[0669] In some embodiments, one of the one or more other therapeutic agents is acetylsalicylic acid. In some embodiments, one of the one or more other therapeutic agents is tipaliprin. In some embodiments, one of the one or more other therapeutic agents is aramchol. In some embodiments, one of the one or more other therapeutic agents is atorvastatin. In some embodiments, one of the one or more other therapeutic agents is BLX-1002. In some embodiments, one of the one or more other therapeutic agents is cenicriviroc. In some embodiments, one of the one or more other therapeutic agents is cobiprostone. In some embodiments, one of the one or more other therapeutic agents is colesevelam. In some embodiments, one of the one or more other therapeutic agents is enlicasin. In some embodiments, one of the one or more other therapeutic agents is enalapril. In some embodiments, one of the one or more other therapeutic agents is GFT-505. In some embodiments, one of the one or more other therapeutic agents is GR-MD-02. In some embodiments, one of the one or more other therapeutic agents is hydrochlorothiazide. In some embodiments, one of the one or more other therapeutic agents is ethyl eicosapentaenoate (ethyl eicosapentaenoic acid). In some embodiments, one of the one or more other therapeutic agents is IMM-124E. In some embodiments, one of the one or more other therapeutic agents is KD-025. In some embodiments, one of the one or more other therapeutic agents is linagliptin. In some embodiments, one of the one or more other therapeutic agents is liraglutide. In some embodiments, one of the one or more other therapeutic agents is cysteamine. In some embodiments, one of the one or more other therapeutic agents is MGL-3196. In some embodiments, one of the one or more other therapeutic agents is obeticholic acid. In some embodiments, one of the one or more other therapeutic agents is olesoxime. In some embodiments, one of the one or more other therapeutic agents is peg-iloleukin. In some embodiments, one of the one or more other therapeutic agents is pioglitazone. In some embodiments, one of the one or more other therapeutic agents is PX-102. In some embodiments, one of the one or more other therapeutic agents is reglipizide ectoate. In some embodiments, one of the one or more other therapeutic agents is SHP-626. In some embodiments, one of the one or more other therapeutic agents is solithromycin. In some embodiments, one of the one or more other therapeutic agents is talukast. 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 VBY-376.

[0670] In some embodiments, at least one of the one or more other therapeutic agents is an antidiabetic drug. In some embodiments, the antidiabetic drug is an adenosine A1 receptor agonist (e.g., adenosine, CCPA, CVT-3619, GR-190718), an adenosine A2 receptor antagonist (istradefylline, SCH-58261), an aldose reductase inhibitor, an α-amylase inhibitor (e.g., amylase inhibitor, treastatin, AL-3688), an α-glucosidase inhibitor (e.g., acarbose, canaglibose, diposine, acetylcholine, tadalafil ... glitate, miglitol, pramixin-Q, sarbostatin, voglibose), amylin analogs (e.g., AC164209 and pramlintide), AMPK activators, β3-adrenergic agonists (e.g., amibegron, AZ-40140, CL-316,243, KRP-204, L-742,791, L-796,568, LY-368,842, LY-377,604, mirabegron, Ro 40-2148, solabelon, SWR-0342SA), beta-ketoacyl-acyl carrier protein synthase inhibitors, biguanides (e.g., metformin, buformin, phenformin), carnitine palmitoyltransferase inhibitors, DGAT-2 inhibitors, DPP-4 inhibitors (e.g., alogliptin, alagliflozin, dutogliflozin, gemagliptin, linagliptin, omagliflozin, saxagliptin, sitagliptin, teneligliptin, trelagliptin, and vildagliptin) , ERN1 inhibitors, fatty acid oxidation inhibitors, fatty acid synthase (FAS) inhibitors, FGF21 derivatives, fructose 1,6-bisphosphatase inhibitors, GLP1 agonists (e.g., albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, taselolide), glucagon receptor modulators, mixed glucagon receptor / GLP-1 agonists (e.g., MAR-701, ZP2929), glucokinase inhibitors (e.g., such as TTP-399, TTP-355, TTP-547, AZD1656, ARRY403, MK-0599, TAK-329, AZD5658 and GKM-001), glycogen phosphorylase inhibitors (e.g., GSK1362885), GSK-3 inhibitors, GPR119 agonists (e.g., MBX-2982, GSK1292263, APD597, PSN821), GPBAR1 (TGR5) agonists (e.g., INT-777, XL-475), GPR39 modulators, GPR40 agonists (e.g., TAK-875), GPR41 modulators, GPR43 modulators, GPR81 modulators, GPR120 agonists, HSL inhibitors, IκB inhibitors, ILI-β modulators, insulin or insulin analogs (including, but not limited to, oral, inhaled or injectable formulations thereof),Insulin-like growth factor (IGF-1) or its analogs, insulin secretagogues, JNK inhibitors (e.g. CC-359), kappa opioid receptor modulators, LY3084077, Kv1.3 inhibitors (e.g. ChTX, clofazimine, WIN-173173), MAP4K4 inhibitors, MC1 or MC4 agonists (e.g. afamelanotide, BMS-470539, bremelanotide, melanotan II, PF-00446687, PL-6983, setmelanotide and THIQ), meglitinides (e.g. repaglinide, nateglinide, mitiglinide), mineralocorticoid receptor inhibitors, monoacylglycerol O-acyltransferase inhibitors, NF-κB inhibitors, nicotinic acid receptor (HM74A) activators, PDE-10 inhibitors, PDHK2 inhibitors, PDHK4 inhibitors, PKC (including PKC-α, PKC-β and PKC-γ) inhibitors, PPAR α / γ dual agonists, PTP1b inhibitors (e.g. trodusquemine), retinol binding protein 4 inhibitors, serine palmitoyltransferase inhibitors, SGLT1 inhibitors (e.g. GSK1614235), SIRT-1 inhibitors (e.g. resveratrol, GSK2245840, GSK184072), somatostatin receptor inhibitors, sulfonylureas (e.g. acetohexamide, chlorpropamide, terimin, glyburide, glipizide, glipizide benzamide, blimipiride, gliclazide, glitazone, gliquidone, glixolamide, tolazamide, tolbutamide), thiazolidinediones (e.g., ciglitazone, darglitazone, englitazone, lobeglitazone, MSDC-0602, netoglitazone, pioglitazone, rivoglitazone, rosiglitazone, and troglitazone), TORC2 inhibitors, urotensin II receptor agonists, vasopressin agonists (e.g., DDAVP, WAY-141608), or VPAC2 receptor agonists.

[0671] In some embodiments, at least one of the one or more other therapeutic agents is an anti-obesity drug. In some embodiments, the anti-obesity drug is an apoB-MTP inhibitor (e.g., dirlotapide, JTT130, SLX4090, usistapide), a β3-adrenergic agonist (e.g., 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 CCK Aagonists, ciliary neurotrophic factor (CNTF) or its analogs (e.g., axokine, NT-501), Contrave TM (buproprion / naltrexone), dopamine receptor agonists (such as bromocriptine), 11β-hydroxysteroid dehydrogenase (11β-HSD1) inhibitors, Empatic TM (Pramlintide / Metreleptin), 5-HT 2C agonists (e.g., lorcaserin), galantide antagonists, ghrelin agonists or antagonists, GLP1 agonists (e.g., albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, taselolide), mixed glucagon receptor / GLP-1 agonists (e.g., MAR-701, ZP2929), H3 antagonists or inverse agonists, human agouti-related protein (AGRP) inhibitors, leptin or its analogs (e.g., metreleptin), lipase inhibitors (e.g., tetrahydroleptin), MC1 or MC4 agonists (e.g., afamelanotide, BMS- 470539, bremelanotide, melanotan II, PF-00446687, PL-6983, setmelanotide and THIQ), melanocyte stimulating hormone or its analogs, MetAp2 inhibitors (e.g. ZGN-433), monoamine reuptake inhibitors (e.g. bupropion, phentermine, tesofensine), neuromedin U receptor agonists, NPY antagonists (e.g. velibactam), opioid receptor antagonists (e.g. naltrexone), orexin receptor antagonists (e.g. amorant, lemborexant, SB-334,867, SB-

[0672] 408,124, SB-649,868, Suvorexant), oxyntomodulin or its analogs, PYY or its analogs (e.g., PYY 1-36 ,PYY 3-36 ), Qsymia TM (phentermine / topiramate), RXR-α modulators, stearoyl-CoA desaturase (SCD-1) inhibitors, or sympathomimetics.

[0673] In some embodiments, at least one of the one or more other therapeutic agents is a lipid-lowering drug. In some embodiments, the lipid-lowering drug is an acyl-CoA cholesterol acyltransferase (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 transporter inhibitor, niacin, a platelet aggregation inhibitor, a renin-angiotensin system inhibitor, a squalene epoxidase inhibitor, a squalene synthase inhibitor, or a triglyceride synthesis inhibitor.

[0674] In some embodiments, at least one of the one or more other therapeutic agents is a drug for treating metabolic diseases. In some embodiments, the drug for treating metabolic diseases 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), FGF21 agonist (e.g., BMS-986036), methylpiperazole (Raptor), FXR agonist, FXR / TGR5 dual agonist (e.g., INT-767), ghrelin antagonist (e.g., TZP-301), glucosylceramide synthase inhibitor, GPR17 modulator, GPR119 agonist, IG-MD-014 (Indigene), IMM-124E (Immuron ), lysosomal pathway regulators (e.g. CAT5000), melanin concentrating hormone receptor 1 antagonists (e.g. KI-1361-17), MCL1 inhibitors (e.g. CMPX-1023), mTORC1 inhibitors, NaCT (e.g. SLC13A5) inhibitors, NHE3 inhibitors (e.g. RDX-011, tenapanor), NP003 (Neuraltus), PBI-4050 (ProMetic), protein homeostasis regulators (e.g. PTI-130, PTI-428, PTI-C1811), PS248288 (Pharmacopeia / Merck), PX-102 (Phenex), RG7410.RG7652, ROCK inhibitors, SBC-104 (Synageva BioPharma), SPX-100 (Spherix), a stearoyl-CoA desaturase inhibitor (e.g., CVT-12805), TRC150094 (Torrent), or ZYH7 (Zydus Cadila).

[0675] In some embodiments, at least one of the one or more additional therapeutic agents is a drug used to treat steatosis. In some embodiments, the drug used to treat steatosis is adiponectin analogs (e.g., PX 811013), aramchol (Galmed), ASK1 inhibitors (e.g., GS-4977, GS-4997), AZD4076 (AstraZeneca), bile acid sequestrants (e.g., obeticholic acid), BL-1060 (Galmed), BMS986171 (Bristol-Myers Squibb), CCR5 / CCR2 antagonists (e.g., cenicriviroc), cannabidiol, CER-209 (Cerenis), cysteamine analogs (e.g., RP-103, RP-104), DS102 (DS Biopharma), EGS21 (Enzo), elafibranor (Genfit), enlicasin (Idun), ethyl eicosapentaenoic acid (Mochida), FXR agonists, GPBAR1 agonists (e.g., RDX009), GR-MD-02 (Galectin Therapeutics), leucine / sildenafil / metformin (NuSirt), LCQ908 (Novartis), LJN452 (Novartis), LOXL2 inhibitors (e.g., simtuzumab), MAT-8800 (Matinas), MB-10866 (Metabasis), miR-103 / 107 inhibitors (e.g., RG-125), MK-4074 (Merck & Co.), nalmefene (Taiwan J), nivocasan (Gilead), NGM-282 (NGM Biopharmaceuticals), omega-3 carboxylic acids or mixtures thereof (e.g., Epanova TM ), PX-102 (Phenex), PX-104 (Phenex), repagliflozin ectoate (Kissei), saroglitazar (Zydus-Cadila), SAR-548304 (sanofi-aventis), talukast (Kyorin), ursodeoxycholic acid, VK2809 (Viking), or XL335 (Exelixis).

[0676] In some embodiments, at least one of the one or more other therapeutic agents is a drug for treating inflammation. In some embodiments, the drug for treating inflammation reduces T hIn some embodiments, the drug for treating inflammation is a caspase inhibitor (e.g., enlicasin), a TGF-β inhibitor, an IL-1β 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 RORγt inhibitor (e.g., JTE-151), a RORα inhibitor, solithromycin (Cempra), or a vascular adhesion protein-1 inhibitor (e.g., PXS-4728A).

[0677] In some embodiments, at least one of the one or more other therapeutic agents is a drug for treating fibrosis. In some embodiments, the drug for treating fibrosis is cenicriviroc (Tobira / Takeda), CNX-014 / 023 / 024 / 025 (Connexios), endothelin antagonists (e.g., A192621, ambrisentan, atracentan, bosentan, BQ-123, BQ-788, macitentan, sitaxentan, tezosentan, zibotentan), etanercept, evitar (AdeTherapeutics), fibroblast growth factor inhibitors, galectin-3 inhibitors, imatinib, IVA337 (Inventiva), N-acetylcysteine, nintedanib, pirfenidone, RG6069 (Roche), SP20102 (Sarfez), tipelukast (Kyorin) or XOMA 089 (Xoma).

[0678] In some embodiments, 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 cirrhosis caused by NASH. In some embodiments, the non-alcoholic fatty liver disease is hepatocellular carcinoma (HCC) caused by NASH.

[0679] Those additional agents may be administered separately from the compounds or compositions of the invention as part of a multiple dosing regimen. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of the invention in a single composition. If administered as part of a multiple dosing regimen, the two active agents may be provided simultaneously, sequentially, or within a certain time period (usually within five hours of each other).

[0680] As used herein, the terms "combination", "combined", "inconjunction" and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present invention. For example, a compound of the present invention can be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms or together in a single unit dosage form. Therefore, the present invention provides a single unit dosage form comprising a compound of the present invention, other therapeutic agents and a pharmaceutically acceptable carrier, excipient or vehicle.

[0681] The amount of both the compounds of the invention and other therapeutic agents (in those compositions comprising other therapeutic agents as described above) that can be combined with a carrier material to produce a single dosage form will vary depending on the subject being treated and the specific mode of administration. Preferably, the compositions of the invention should be formulated so that a dosage between 0.01 mg and 100 mg per kg of body weight per day can be administered.

[0682] In those compositions comprising other therapeutic agents, the other therapeutic agent and the compounds of the invention may act synergistically. Therefore, the amount of the other therapeutic agent in these compositions will be lower than the amount required in a monotherapy using only the therapeutic agent. In these compositions, the other therapeutic agent may be administered at a dose between 0.01 μg and 100 μg per kg of body weight per day.

[0683] The amount of the other therapeutic agent present in the compositions of the present invention will be no greater than the amount normally administered in a composition comprising the therapeutic agent as the sole active agent. Preferably, the amount of the other therapeutic agent in the compositions disclosed herein will be within the range of about 50% to 100% of the amount normally present in a composition comprising the agent as the sole therapeutically active agent. Example

[0684] As described in the following examples, in certain exemplary embodiments, compounds and solid forms are prepared according to the general procedures previously described. It should be understood that, although the general methods describe the synthesis of certain compounds of the present invention, the following methods and other methods known to those of ordinary skill in the art can be applied to all compounds and subclasses and each of these compounds, as described herein.

[0685] Experimental steps:

[0686] As used herein, "V" = volume, "v / w" = volume / weight ratio, "v / v" = volume / volume ratio, and "w / w" = weight / weight ratio.

[0687] Example 1. Preparation of amorphous compound 1

[0688] 1 gram of compound 1 prepared according to the method described in US2013 / 0123231 A1 was completely dissolved in 10 mL of dichloromethane. The dichloromethane solution was rapidly evaporated under vacuum at 40°C to obtain an amorphous compound 1 having Fig.18 XRPD pattern shown.

[0689] Example 2. Preparation of Form I of Compound 1

[0690] 50 mg of amorphous compound 1 prepared according to the method of Example 1 was slurried in acetone and subjected to a temperature cycle from 40° C. to 25° C., maintained for 72 h with a cycle of 4 h. Solid Form I of compound 1 was collected by filtration. Form I was determined to be a pure polymorph of compound 1. Form I was determined to have poor water solubility (<10 μg / mL) at pH 5.5 and below, and a logD value of 1.06 at pH 7.4.

[0691] DSC curve of Form I of Compound 1 ( Figure 3A and Figure 3B ) indicates an endothermic transition, which occurs at about 189-193°C, attributed to melting. The TGA curve of Form I of Compound 1 shows no significant weight loss up to about 150°C, indicating an unsolvated phase. The moisture sorption curve of Form I of Compound 1 also shows that Form I is slightly hygroscopic, showing a weight increase of about 0.45% at about 95% RH. XRPD analysis of the sample after the DVS experiment showed that the material did not change form.

[0692] Single crystals of Form I were obtained from attempted salt formation experiments. 0.5 mL of methyl ethyl ketone (MEK) was added to 40.5 mg of Compound 1 to form a suspension. In a separate vial, 10.2 mg of L-proline was dissolved in 0.1 mL of H2O and the solution was added to the Compound 1 suspension. The sample was slurried at about 60°C for about 5 days and a golden solution was formed. The solution was quenched to about 2-8°C and maintained at about 2-8°C for about 4 days, resulting in a golden solution with white oil. The sample was placed at room temperature and solids were observed in the solution after about 14 days.

[0693] Select a suitable single crystal and analyze it by single crystal X-ray diffraction. 3 The colorless plates were mounted on nylon rings in random orientation. Preliminary examination and data collection were performed on a Rigaku SuperNova diffractometer equipped with a copper anode microfocus sealed X-ray tube. The chromatogram was taken with a Dectris Pilatus 3R 200K hybrid pixel array detector. The cell constants and orientation matrices for data collection were obtained from least squares refinement using a set angle of 15725 reflections in the range of 3.5010° <θ < 77.2150°. The space group was determined to be C2221 (International Table No. 20) by the CRYSALISPRO program. Data were collected at room temperature to a maximum diffraction angle (2θ) of 155.284°.

[0694] The crystal system of Form I was found to be orthorhombic with a space group of C2221. The unit cell parameters and calculated volume are: α=90°, β=90°, γ=90°, Molecular weight is 569.62 g mol -1 , Z = 16, so the density is calculated to be 1.352 g cm -3 The standard uncertainty for the data is written in crystal bracket notation, e.g., 0.123(4) is equivalent to 0.123 ± 0.004. The quality of the obtained structure is high, as shown by the fit residual R of 0.0446 (4.46%). R factors in the range of 2-6% are cited as the most reliably determined structures.

[0695] Form I is expected to be the most stable form of Compound 1.

[0696] Example 3. Preparation of Form II of Compound 1

[0697] 100 mg of amorphous Compound 1 prepared according to the method of Example 1 was slurried in dimethylformamide (DMF) and subjected to a temperature cycle from 40°C to 25°C, with a cycle of 4h for 72h. Solid Form II of Compound 1 was collected by filtration. The DSC curve showed that the first endotherm was observed at about 74°C and the second endotherm was observed at above 180°C ( Fig.37 ).

[0698] Example 4. Preparation of Form III of Compound 1

[0699] 100 mg of amorphous compound 1 prepared according to the method of Example 1 was slurried in dimethyl sulfoxide (DMSO) and subjected to a temperature cycle from 40°C to 25°C, with a cycle of 4h for 72h. Solid Form III of compound 1 was collected by filtration. Thermogravimetric analysis of Form III showed a large steady-state weight loss, indicating that Form III may be a DMSO solvate of compound 1. No additional thermal events were observed above the solvent loss ( Fig.38 ).

[0700] Example 5. Preparation of Form IV of Compound 1

[0701] 500 mg of amorphous Compound 1 prepared according to the method of Example 1 was slurried in methanol and subjected to a temperature cycle from 40°C to 25°C, with a cycle of 4h for 48 hours. Solid Form IV of Compound 1 was collected by filtration. The DSC curve of Form IV includes endothermic transitions starting at 85°C, about 190°C, and about 202°C, and exothermic at 146°C.

[0702] Thermogravimetric analysis indicated a weight loss of 4.2% or 4.7% with a corresponding endotherm at 82-92°C, indicating that Form IV is a methanol solvate of Compound 1. After the sample was further heated to 120°C, XRPD analysis confirmed that the sample had converted to Form I.

[0703] Example 6. Preparation of Form V of Compound 1

[0704] 100 mg of amorphous Compound 1 prepared according to the method of Example 1 was slurried in N-methyl-2-pyrrolidone (NMP) and subjected to a temperature cycle from 40°C to 25°C, with a cycle of 4h for 72h. Solid Form V of Compound 1 was collected by filtration. Thermogravimetric analysis of Form V showed a large steady-state weight loss of 13.5%, indicating that Form V may be an NMP solvate of Compound 1. No additional thermal events were observed above the solvent loss ( Fig.39 ).

[0705] Example 7. Preparation of Form VI of Compound 1

[0706] 100 mg of amorphous Compound 1 prepared according to the method of Example 1 was dissolved in toluene and the toluene was quenched or evaporated at -18°C. In both cases, solid Form VI of Compound 1 was collected by filtration. XRPD analysis indicated a unique toluene solvate form of Compound 1.

[0707] Example 8. Preparation of Form VII of Compound 1

[0708] 100 mg of Form IV of Compound 1 prepared according to the method of Example 5 was heated to 80° C. in an oven. Form VII was confirmed to be a desolvated form of Form IV produced by drying the methanol solvate Form IV. XRPD analysis showed that although Form VII had a diffraction pattern similar to Form I, there were many different peaks between the two forms, which confirmed that they were different crystalline forms. Differential Scanning Calorimetry (DSC) Results ( Fig.40) is consistent with thermogravimetric analysis. The occurrence of the first endothermic event was observed at 133.7°C (peak at 141.4°C), and the exothermic peak was at 151.6°C. A major sharp endotherm was observed with an onset temperature of 192.3°C (peak at 195.0°C). A smaller endotherm with a peak at 207.0°C may indicate the formation of a crystalline form with a higher melting point. Dynamic vapor sorption (DVS) analysis of Form VII showed that the material had moderate hygroscopicity (water absorption>4% at 90% RH), and post-DVS analysis showed no change in form. Absorption between 40% and 70% RH may indicate hydrate formation (temporarily designated name Form IX). Karl-Fischer analysis showed a water content of 0.503%, consistent with observations of ambient humidity measured during DVS analysis. NMR and IR data confirmed the structural integrity of the compound 1 present. The water solubility of Form VII was determined to be 0.109 mg / mL. XRPD analysis confirmed that long-term exposure to water resulted in the conversion of Form VII to Form I. However, after storage at 40°C and 75% RH for 7 days, Form VII was determined to be chemically and physically stable. No changes in form were observed, and the purity was determined to be 99.85%.

[0709] Example 9. Preparation of Form VIII of Compound 1

[0710] 100 mg of anhydrous Form VII of Compound 1 was heated to 195°C. Consistent with the DSC analysis of Form VII, XRPD analysis of the resulting solid showed the production of Form VIII of Compound 1. 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 using multiple heating zones from about 170 to about 193°C with a screw speed of 30 rpms.

[0711] DSC analysis of Form VIII showed the same sharp peak with an onset temperature of 204.7°C (peak at 208.1°C), corresponding to the melting point of Form VIII. Further DSC analysis of Form I showed cooling of a melted sample of Form I followed by a second heating event resulting in an endotherm with an onset temperature of 204.7°C (peak at 208.1°C), indicating that Form VIII was generated directly from Form I upon heating in this manner.

[0712] Fig.16 The DSC curve shown in shows that Form VIII contains an endotherm with an onset of about 205 °C.

[0713] Example 10. Competitive slurrying of Form I and Form VII

[0714] Competitive slurrying of Form I and Form VII in acetone, acetonitrile:water (10%), ethanol, and ethyl acetate at ambient temperature and 60°C resulted in conversion to Form I as confirmed by XRPD and DSC.

[0715] Example 11. Competitive slurrying of Form I and Form VIII

[0716] Competitive slurrying of Form I and Form VIII in acetone, acetonitrile:water (10%), ethanol, and ethyl acetate at ambient temperature and 60°C resulted in conversion to Form I as confirmed by XRPD and DSC.

[0717] Example 12. Competitive slurrying of Form I and Form VIII

[0718] Competitive slurrying of Form I and Form VIII in a 1:1 ratio in a solution of 6:4 ethanol:water at room temperature for approximately two weeks resulted in conversion to Form I as confirmed by XRPD.

[0719] The results of the competitive slurry analysis indicated that Form I is the more thermodynamically stable form between 22-60° C. Form VIII may be the more stable form at high temperatures.

[0720] Example 13. Preparation of Compound 1 Sodium Form I

[0721] 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 the solution became clear. Next, the solution was filtered into a vial and placed in a vacuum centrifuge. The resulting solid was slurried in ethyl acetate, then washed with acetone, filtered and dried. The XRPD pattern of Compound 1 Sodium Form I is shown at Fig.19 The DSC curve is shown in Fig. 20 In Figure 2, multiple endothermic transitions starting at 37°C and 283°C are shown. The TGA curve is shown in Fig.21 The results are shown in Table 1 and show a weight loss identified as water (4.1% RT to 175°C) based on TGA-mass spectrometry (TGA-MS). The weight loss above 250°C is attributed to decomposition. The dynamic vapor sorption curve shows that this form absorbs about 32% by weight of water up to 95% RH (relative humidity) at 25°C. The material was found to have deliquesced after the experiment.

[0722] Example 14. Preparation of Compound 1 Sodium Form II

[0723] Compound 1 sodium form II (variable hydrate) is prepared as follows. 4.0 g of anhydrous form I of compound 1 is placed in a beaker with 0.4 g of NaOH and about 40 mL of water. The sample is heated and stirred until the solution becomes clear. Next, the solution is filtered into a vial and placed in a vacuum centrifuge. The solid obtained by the vacuum centrifuge is washed with a 10% water solution in acetonitrile, and the solid is then dried and then slurried in ethyl acetate. The sample is ultrasonically treated for about 1 hour and then allowed to stand at room temperature. The solid is slurried in acetone and a portion is filtered to obtain a solid. The XRPD pattern of compound 1 sodium form II is shown at Fig. 22 The DSC curve is shown in Fig.23 In the graph, multiple endothermic transitions are shown, starting at about 19, about 78, and about 136°C. The TGA curve is shown in Fig.24 In, and shows weight loss (about 24%RT to about 150°C), indicating that it is a solvate, identified as water based on TGA-MS. When 1092mg of Form I of Compound 1 was placed in a vial containing 76mg NaOH and 10mL of water, a second sample of Compound 1 Sodium Form II was prepared. The sample was sonicated but the solid remained. Another 45mg NaOH was added, and 10mL was added, and the solution became clear. The sample was then centrifuged and evaporated over the weekend to obtain a dry solid. These solids were then slurried in EtOAc for about 10 days. The resulting solid had the same XRPD pattern as Compound 1 Sodium Form II, and was found to have only about 10.4% weight loss up to about 175°C. This may indicate that this form can have about 4-10 moles of water. Weight losses above about 250°C are attributed to decomposition. The dynamic vapor sorption curve shows that the form absorbs about 35% by weight of water at about 25°C up to 95%RH. It was found that the material had deliquesced after the experiment.

[0724] Example 15. Preparation of Compound 1 Calcium Form I

[0725] Compound 1 calcium form I (hydrate) is prepared as follows. 4.47 g of anhydrous form I of compound 1 is placed in a beaker with 0.4 g KOH and about 25 mL of water. The sample is heated and stirred until the solution becomes clear. Next, 0.5 g of calcium chloride is added, the sample is cooled to room temperature and stirred for several hours. The sample is then filtered and slurried in an acetonitrile solution of about 20% water to obtain a turbid solution. The sample is ultrasonically treated for about 1 hour to produce a slurry. The sample is then filtered and dried in a nitrogen box at 5 psi. The XRPD pattern of compound 1 calcium form I is shown at Fig.25 The DSC curve is shown in Fig.26 and shows multiple endothermic transitions, starting at about 17, about 72, about 180, and about 202°C. The TGA curve is shown in Fig. 27The DVS experiment was performed in 1% RH and showed a weight loss (about 6.0% RT to about 200°C), which was identified as water based on TGA-MS. The weight loss above about 250°C was attributed to decomposition. The dynamic vapor sorption curve showed that the form absorbed about 9% by weight of water at about 25°C up to about 95% RH. XRPD analysis of the sample after the DVS experiment showed that the material did not change form.

[0726] Example 16. Preparation of Compound 1 Magnesium Form I

[0727] Compound 1 Magnesium Form I (hydrate) was prepared as follows. 987.6 mg of anhydrous Form I of Compound 1 was placed in a vial with 156 mg of KOH and about 10 ml of water. The sample was sonicated and heated until the solution became clear. Next, 130 mg of magnesium acetate tetrahydrate was added and the sample was stirred at room temperature for about 3 days and then separated. The XRPD pattern of Compound 1 Magnesium Form I is shown at Fig.28 The DSC curve is shown in Fig.29 In the figure, a single endotherm is shown starting at about 53°C. The TGA curve is shown in Fig.30 The DVS experiment was performed in 1% RH and showed a weight loss (about 13.8% RT to about 150°C), which was identified as water based on TGA-MS. The weight loss above about 250°C was attributed to decomposition. The dynamic vapor sorption curve showed that the form absorbed about 8% by weight of water at about 25°C up to about 95% RH. XRPD analysis of the sample after the DVS experiment showed that the material did not change form.

[0728] Example 17. Preparation of Compound 1 Diethanolamine Form I

[0729] Compound 1 diethanolamine Form I (hydrate) was prepared as follows. 106.9 mg of anhydrous Form I of Compound 1 was dissolved in about 3 mL of acetone. 20 μL of diethanolamine was added, and the sample was sonicated for about 2 hours. An additional about 40 μL of diethanolamine was then added, and the sample was further slurried at room temperature and then separated. The XRPD pattern of Compound 1 diethanolamine Form I is shown at Fig.31 The DSC curve is shown in Fig.32 The TGA curve shows an endothermic transition starting at about 118°C. Fig.33 The DVS experiment was performed in 1% RH and showed a weight loss (about 2.7% RT to about 150°C) which was identified as water based on TGA-MS. The weight loss above about 250°C was attributed to decomposition. The dynamic vapor sorption curve showed that the form absorbed about 14% by weight of water at about 25°C up to about 95% RH. XRPD analysis of the sample after the DVS experiment showed that the material did not change form.

[0730] Example 18. Preparation of Compound 1 Piperazine Form I

[0731] Compound 1 piperazine form I (hydrate) was obtained as follows: Anhydrous form I of compound 1 was placed in a centrifuge tube and 1 molar ratio of piperazine was also added. Next, 30 μl of MeOH was added to the powder and the sample was sonicated for about 30 minutes. The sample tube was then opened and dried in a nitrogen box. The XRPD pattern of compound 1 piperazine form I is shown at Fig.34 The DSC curve is shown in Fig.35 and shows multiple endothermic transitions starting at about 27 and about 139 °C. The TGA curve is shown in Fig.36 The DVS experiment was performed on a 100°C, 10% RH, 0.1% RH, and showed a weight loss identified as water based on TGA-MS (about 7.3% RT to about 100°C). Weight loss above about 250°C is attributed to decomposition. The dynamic vapor sorption curve showed that the form absorbed about 1.5% by weight of water up to about 95% RH at about 25°C. XRPD analysis of the sample after the DVS experiment showed that the material did not change form.

[0732] Example 19. X-ray powder diffraction (XRPD) analysis method A

[0733] XRPD analysis of the amorphous form and Forms II, III, IV, V, VI, VII, and VIII of Compound 1 was performed by a Siemens D5000 diffractometer, scanning the samples at 3 to 30 degrees 2θ. The material was gently pressed onto a glass plate inserted into the sample holder. The sample was then loaded into the diffractometer operating in reflection mode and analyzed using the following experimental conditions.

[0734]

[0735] Example 20. X-ray powder diffraction (XRPD) analysis method B

[0736] XRPD analysis of Compound 1 Form I was performed on a PANalytical Cubix Pro diffractometer. The sample was placed in the sample holder so that the sample of Compound 1 was flush with the zero height of the instrument. The following parameters were used to obtain the XRPD pattern of Compound 1 Form I.

[0737]

[0738]

[0739] Example 21. X-ray Powder Diffraction (XRPD) Analysis Method C

[0740] X-ray powder diffraction (XRPD) analysis of 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 piperazine form I is carried out using copper radiation (CuKα, λ=1.541874) on a diffractometer (PANalytical XPERT-PRO, PANalytical BV, Almelo, Netherlands). The sample is evenly coated on a zero background sample plate. The generator is operated at a voltage of 45kV and a current of 40mA. The slit is Soller 0.02rad, anti-scattering 1.0° and divergence. Scanning is performed from 2 to 40°2θ with a step size of 0.0167. Data analysis is performed using X'Pert Data Viewer V1.2d (PANalytical BV, Almelo, Netherlands).

[0741] Example 22. Thermogravimetric / differential thermal analysis (TG / DTA)

[0742] For each analysis as discussed in Examples 3 to 6 and 8, 5 mg of material was weighed into an open aluminum pan and loaded into the simultaneous TG / DT analyzer and maintained at room temperature. The sample was then heated from 25°C to 300°C at a rate of 10°C / min, during which the change in sample weight and any differential thermal events (DTA) were recorded. Nitrogen was used as the purge gas at a flow rate of 100 cm 3 / min.

[0743] For Examples 2, 5, 7, 9, and 13 to 18, TGA was used to evaluate the sample weight loss as a function of temperature by loading 1-10 mg of material onto an aluminum weigh pan (TA Instruments, New Castle, DE) and heating the sample to 350° C. or higher at a rate of 10° C. / min. The sample and reference pans were run at 60 mL / min and 40 mL / min nitrogen purges, respectively. Data analysis was completed using Universal Analysis 2000 Version 4.7A (TA Instruments, New Castle, DE).

[0744] Example 23. Differential Scanning Calorimetry (DSC)

[0745] For each analysis as discussed in Examples 8 to 11, 5 mg of material was weighed into an aluminum DSC pan and sealed non-hermetically with a perforated aluminum lid. The sample pan was then loaded into a Seiko DSC6200 (equipped with a chiller) and cooled to and held at 25°C. Once a stable heat flow response was obtained, the sample and reference were heated to approximately 280°C (or the degradation temperature observed by TG / DTA) at a scan rate of 10°C / min and the resulting heat flow response was recorded.

[0746] For Examples 2, 5, 7, 9, and 13 to 18, DSC was performed by loading 1 to 5 mg of material into a crimped Tzero standard aluminum pan and heating the sample at 10°C / min from 20 to 300°C or higher. The sample and reference pans were run under a 50 mL / min nitrogen purge. Data analysis was completed using Universal Analysis 2000 Version 4.7A (TA Instruments, New Castle, DE).

[0747] Example 24. Karl-Fischer Coulometric Titration (KF)

[0748] Before analyzing the compound samples, a blank sample containing only methanol was analyzed using a Mettler Toledo C30 compact titrator to determine the blank water content. About 10-15 mg of solid material was accurately weighed into a vial. The material was then dissolved in methanol and the amount added was recorded. The resulting material was then manually introduced into the titration cell of the instrument. The water content was calculated as a percentage and the value was recorded.

[0749] Example 25. Infrared Spectrometer (IR)

[0750] Infrared spectroscopy was performed on a Bruker ALPHA P spectrometer. Sufficient material was placed in the center of the spectrometer plate and the spectra were acquired using the following parameters.

[0751] <![CDATA[Resolution (cm -1 )]]> 4 Background scan time (scan) 16 Sample scan time (scan) 16 <![CDATA[Data collection range (cm -1 )]]> 4000-400 Results spectrum Transmittance software OPUS v.6

[0752] Example 26. Dynamic Vapor Sorption (DVS)

[0753] For DVS analysis as discussed in Example 8, approximately 10 mg of sample was placed in a mesh vapor sorption balance pan and loaded into a DVS-1 dynamic vapor sorption balance (Surface Measurement Systems). The sample was subjected to a gradual increase in relative humidity (RH) from 0-90% in 10% increments, holding the sample at each step until a stable weight was reached (99.5% step completion). After the sorption cycle was complete, the sample was dried using the reverse procedure, reducing the RH to 0%. The weight change during the sorption / desorption cycle was plotted.

[0754] For Examples 2, 5, 7, 9, and 13 to 18, hygroscopicity was studied using dynamic vapor sorption (DVS, TA Q5000 SA, TA Instruments, New Castle, DE or DVS, DVS Intrinsic, Surface Measurement Systems, London, UK). The samples (2-20 mg) were placed in an aluminum DVS pan and loaded on the sample side of a double pan balance. Water adsorption and desorption were studied as a function of relative humidity (RH) at 25°C. The relative humidity was increased from 5% RH to 95% RH in 10% RH increments and then decreased to 5%. Each relative humidity increment had an equilibrium time of 180 minutes unless the weight change% was less than 0.002% within 30 minutes. Data analysis was performed using Universal Analysis 2000 Version 4.7A (TA Instruments, New Castle, DE) for TA DVS runs and Microsoft Excel for SMSDVS runs.

[0755] Example 27. High Performance Liquid Chromatography-Ultraviolet Detection (HPLC-UV).

[0756] Purity and concentration analysis was performed using the following methods:

[0757]

[0758] Example 28. pKa Measurement

[0759] pKa analysis was performed using a UV metrology method. Samples were titrated in triplicate (pH 12.1 to pH 2) at concentrations from 32 to 20 μM under methanol-water cosolvent conditions (methanol concentration varied from 53 to 30% (v / v)). pKa was determined using spectral data by Yasuda-Shedlovsky extrapolation of each titration result.

[0760] Example 29. LogP and LogD determination

[0761] LogP analysis was performed using a potentiometric (pH-metric) method. The samples were titrated with various ratios of octanol / water to cover the pH range of 1.9 to 12.0 in two titrations at concentrations of 1.0 to 0.6 mM. The shift in the aqueous pKa in the presence of octanol was used to determine the logP of neutral and anionic species. From this information, a lipophilicity curve was constructed so that the logD at a given pH could be determined.

[0762] Example 30. Pharmaceutical composition

[0763] A pharmaceutical composition comprising Form I of Compound 1 is prepared comprising the following ingredients.

[0764]

[0765] The pharmaceutical composition was prepared as follows.

[0766] Example 31. Micronization

[0767] Crystalline Compound 1 (Form I) was continuously fed into a 2-inch vertical annular jet mill. The compressed air supply was high purity nitrogen with an inlet pressure of at least 110 psi. The propeller nozzle and grinder nozzle pressures were maintained at 80 psi throughout the grinding process. The feed rate was controlled by a vibrating feeder with an equipment set point of 3. About 800 grams of material was produced in this way over the course of about 5 hours. The material was then collected in a single container and mixed, and then hot melt particles were incorporated at 10 mg, 50 mg, and 200 mg dosage strengths.

[0768] Example 32. Hot Melt High Shear Granulation, Grinding and Mixing

[0769] Granules were prepared in a jacketed 4L bowl on a Vector GMX Lab-Micro High Shear granulator. The bowl was jacketed with 60°C water. Approximately half of the lactose monohydrate, cross-linked sodium carboxymethylcellulose, and micronized Compound 1 drug substance were added to the bowl. The remaining lactose was then used to dry wash the Compound 1 drug substance transfer container before adding it to the bowl. The dry solid components were then mixed until the mixture reached 55°C. After reaching this temperature, the Gelucire 50 / 13 melted, and as the Gelucire 50 / 13 melted, the granules continued to mix until the product temperature dropped. The granules continued to mix until the product temperature returned to 55°C to ensure that the Gelucire 50 / 13 was completely melted and mixed. The granulated product was then cooled to room temperature. The cooled granules were ground using a Quadro Comil 197S equipped with a 1905μm screen and a circular impeller.

[0770] Example 33. Capsule Preparation

[0771] The powder prepared in Example 22 was encapsulated in size 0 white opaque gelatin capsules using a Profill apparatus and then dusted. The final capsule drug product had a fill weight of 450 mg, of which 90 mg was Gelucire 50 / 13, 22.5 mg was croscarmellose sodium, and the remaining weight consisted of lactose monohydrate and micronized Compound 1 drug substance. The amounts of lactose monohydrate and Compound 1 were each dependent on the dosage strength, and their total weight was equal to 337.5 to achieve a total fill weight of 450 mg. 100% weight sorting was performed and the final product was packaged in white opaque HDPE bottles and then induction sealed.

[0772] Example 34. Synthesis of intermediate (R)-G-1-a

[0773]

[0774] Step 1. Synthesis of rac-G-7-a

[0775] 330 kg DMSO was added to a 1000 L reactor, and potassium tert-butoxide (30 kg, 1.22 eq) was added at 10-25 ° C. Trimethylsulfoxonium iodide (58 kg, 1.2 eq) was added in portions at 18-25 ° C, and the mixture was stirred for 2 hours in this temperature range. 2-Methoxybenzaldehyde (30.15 kg, 1.0 eq) was added in portions while maintaining the reactor temperature between 18-25 ° C. The mixture was stirred at a temperature of 18-25 ° C until less than 0.5% of 2-methoxybenzaldehyde was present as determined by HPLC (usually 1-2 hours), and then 300 kg of water was added to quench the reaction, keeping the temperature below 25 ° C. The reaction mixture was extracted with heptane (204 kg of 3 parts), and the heptane extracts were combined, washed with water (300 kg of 3 parts), and then washed with brine (300 kg). The organic layer was concentrated in vacuo at 40-45 °C to give rac-G-7-a (18.55 kg, 56% isolated yield, HPLC purity 96.6% at 220 nm, 94% wt. by NMR) as an oil which was used in the next step without any further purification.

[0776] Alternative Step 1: Synthesis of rac-G-7-a

[0777] Trimethylsulfonium methyl sulfate (1.08 eq) was added to 2-methoxybenzaldehyde (1 eq), followed by dichloromethane (about 75.5 mL), and the resulting mixture was stirred. About 50 wt% aqueous NaOH solution was added to the mixture in portions and stirred at a temperature range of about 28°C to about 22°C for about 2.5 hours. Additional water was added, and the mixture was cooled to a temperature of about 17°C. Dichloromethane was added to the mixture and stirred. The mixture was separated, and the organic layer was concentrated in vacuo to provide rac-G-7-a. 1 H NMR (400MHz, CDCl3): δ7.28-7.25 (m, 1H), 7.15 (d, J=7.5Hz, 1H), 6.94 (t, J=7.5Hz, 1H), 6.88 (d, J= 8.2Hz, 1H), 4.21 (t, J=2.9Hz, 1H), 3.87 (s, 3H), 3.14 (t, J=4.9Hz, 1H), 2.71 (dd, J=5.6, 2.4Hz, 1H).

[0778] Step 2. Synthesis of rac-G-5-a

[0779] Tetrahydro-2H-pyran-4-ol (16.3 kg, 4.0 eq) was loaded into a 50 L reactor, and FeCl3 (225 g, 0.035 eq) was then added. Intermediate rac-G-7-a (6.0 kg, 1.0 eq) was added dropwise, maintaining the temperature between -10 and 10 ° C. The reaction was stirred at 0-10 ° C until the starting epoxide was shown to be present at less than 0.5% by HPLC (usually 0.5-1 hour). Once the reaction was judged to be complete, the reaction mixture was diluted with toluene (240 L), and the toluene solution was extracted with water (3 portions of 24 kg) and then with brine (12 kg). The organic layer was concentrated in vacuo at 40-45 ° C to give rac-G-5-a (19.64 kg, 47% yield) as an oil.

[0780] Alternative Step 2: Synthesis of rac-G-5-a

[0781] Toluene was charged into the reactor, and then tetrahydro-2H-pyran-4-ol (4eq), BF3-Et2O (0.005v / w) were added. Intermediate rac-G-7-a (1.0eq) was added dropwise, maintaining the temperature between 0 and 10°C. The reaction was stirred at a temperature of 0 to 10°C for about 1 hour. The solution was combined with toluene (about 8v / w) at about 15 to 25°C and washed with water for about 3 times. The aqueous layers were combined, washed with MTBE, and the MTBE layer was washed with water for about 2 times. The organic layers were then combined and concentrated in vacuo. THF was added to the resulting residue, and the mixture was concentrated in vacuo to give rac-G-5-a as a stock solution.

[0782] Step 3. Synthesis of (R)-G-5-a

[0783] Toluene (5.0 v / w) was added to a 50 L glass reactor, followed by a one-time addition of rac-G-5-a (6.2 kg, 1.0 eq). The solution was warmed to 40 ° C until the mixture became a clear solution, then cooled to 25 ° C. Vinyl butyrate (0.5 eq) was added to the above solution in a one-time manner, and the mixture was stirred at a temperature of 25-30 ° C for 0.5 hours until a clear solution was obtained. CAL-B lipase (1.5% w / w) was added to the reactor in a one-time manner and the mixture was stirred at 22-26 ° C until the reaction was considered complete, at which point IPC showed that the ratio of (S)-G-5-a / (R)-G-5-a was 96:3.5 and the ee of (R)-G-8-a was 97.9% (usually 4 hours). CAL-B was filtered out, and the filter cake was washed with THF (11.6 L). The filtrate was mixed with another batch of the same scale, and the combined filtrate was concentrated in vacuo at 35-40 ° C until 13 L of residue was retained. Add petroleum ether (5.0v / w), and the mixture was stirred for 30 minutes. Precipitated (S)-G-5-a is filtered, and filter cake is washed with petroleum ether (2.0v / w). Filtrate is concentrated in vacuo at temperature 40-45°C, to obtain a crude oil. Toluene (3.0v / w) is added to a 50L glass reactor, then the oil of the previous step is added. Add succinic anhydride (0.25eq.) and dimethylaminopyridine (DMAP, 0.02eq.), and the mixture is heated to 70-80°C and stirred for 2 hours, periodic sampling is performed until the amount of remaining (S)-G-5-a is measured by HPLC and is no more than 0.5%. Then the mixture is cooled to 10-20°C and washed with saturated sodium bicarbonate aqueous solution (two 1.0v / w). HPLC analysis of the organic layer shows that the amount of (S)-G-5-a present is less than 0.1%. The organic solvent is concentrated to obtain an oil (9.9kg, 53.6% yield, 89% purity, 97%ee), which is used for the next step without further purification. Methanol (40L) is added to a 100L reactor, followed by the oil of the previous step, followed by water (30kg, 3.0w / w). Sodium hydroxide (1.23kg) is added in multiple portions while maintaining the temperature between 10-25°C. The reaction is stirred at this temperature until HPLC analysis indicates that butyrate is completely consumed. pH is adjusted to 7 with a 3N HCl aqueous solution, and the mixture is concentrated in vacuo at 40-45°C until 30 volumes remain. The mixture is filtered and filter cake is collected to obtain a crude material (R)-G-5-a (9.0kg, 96% purity, 96.8%ee). Ethyl acetate (4.3L) and petroleum ether (26L) are added to the reactor, followed by the crude product of the previous step. The mixture is stirred at a temperature of 10-25°C for 1 hour, then filtered.The collected solid was dried in a vacuum oven at 40-45 °C to afford pure (R)-G-5-a (5.2 kg, 70% yield for this step, 99% purity, 96% ee) as an off-white solid.

[0784] Alternative Step 3: Alternative Synthesis of (R)-G-5-a

[0785]

[0786] THF (29 L) was added to a 50 L glass reactor, followed by a single addition of rac-G-5-a (5.8 kg, 1.0 eq). Succinic anhydride (2.3 kg, 1.0 eq) was added to the above solution in a single addition, and the mixture was stirred at a temperature of 25-30 ° C for 0.5 hours until a clear solution was obtained. CAL-B lipase (406 g, 7% w / w) was added to the reactor in a single addition, and the mixture was stirred at 25-30 ° C until the reaction was considered complete (when the ratio of G-5-a to (R)-G-8-b was 51:49 by IPC (usually 24 hours)). CAL-B was filtered out, and the filter cake was washed with THF (11.6 L). The filtrates were combined and concentrated in vacuo at 35-40 ° C. The resulting residue was diluted with ethyl acetate (58 L) at 15-25 ° C, and the ethyl acetate was washed with saturated sodium bicarbonate (four portions of 23 L) at 15-25 ° C. A sample from the ethyl acetate layer was analyzed by HPLC, which indicated that the ratio of (R)-G-8-b to G-5-a was no more than 1:99. The aqueous layers were combined and washed with ethyl acetate (three portions of 29 L each). A sample from the aqueous layer was analyzed by HPLC, which indicated that the ratio of (R)-G-8-b to G-5-a was greater than 99.5:0.5. Sodium hydroxide (5.8 kg) was added to the aqueous layer in multiple portions at a temperature of 15-25° C. The reaction was stirred at this temperature for 0.5-1 hour until HPLC analysis indicated that the ratio of (R)-G-8-b to (R)-G-5-a was no more than 1:99. The reaction mixture was filtered and the filter cake was washed with water (5.8 L). The filter cake was dried at 40-45° C. to constant weight to give 2.4 kg of crude material (R)-G-5-a with 96% purity and 98.9% ee. The crude material from multiple batches was purified by recrystallization as follows. To a 100L reactor comprising ethyl acetate (72L, 6 volumes), crude (R)-G-5-a (12kg) was added, and the mixture was warmed to 30-35°C and stirred for 1 hour. The solution was filtered to remove undissolved solids, and the filtrate was concentrated in vacuo at 40-45°C until about 2 volumes of solvent remained. Heptane (120L, 10 volumes) was added to the solution, and the mixture was heated to reflux to obtain a clear solution. The solution was gradually cooled to a temperature between 15-20°C over 8 hours, and stirred at this temperature for 12 hours. The resulting solid was collected by filtration, and the filter cake was washed once with a solution of ethyl acetate / heptane (1:5, 12L). The filter cake was collected and dried to constant weight at 40-45°C to obtain 10.2kg (R)-G-5-a (99.2% purity, 99.8%ee determined by HPLC), which was an off-white solid.

[0787] The synthesis of (R)-G-5-a was also carried out by a method similar to that described above, using Novozyme 435 instead of CAL-B lipase.

[0788] Step 4. Synthesis of (R)-G-6-a

[0789] To a 100L glass reactor under nitrogen, dichloromethane (58L) was added, followed by (R)-G-5-a (5794g, 1.0eq.) and triethylamine (4.8L), and the reaction mixture was cooled to 0-10°C. Methanesulfonyl chloride (3160g) was added over 35 minutes, keeping the reaction temperature no higher than 25°C. The mixture was then stirred at 20-30°C for 18 hours, at which point the amount of (R)-G-5-a remaining was determined to be no more than 1%. Purified water (58L) was added, and the mixture was transferred to a 200L glass reactor and stirred for at least 1 hour. The phases were separated and the organic layer was transferred to a 100L reactor and washed with 2N HCl (29L), then with 10% aqueous sodium bicarbonate solution (29L), and the organic layer was concentrated at 70°C in vacuo to a volume of 29L. Isopropanol (58L) was added and the mixture was concentrated at 70°C in vacuo to a volume of 29L. Isopropyl alcohol (58L) was added again, and the mixture was concentrated to a final volume of 28L. Purified water (29L) was added, and the mixture was heated to 50-60°C under stirring until complete dissolution was observed. The mixture was then cooled to 0-10°C and stirred for at least 14 hours. The resulting solid was collected by filtration, washed with purified water (12L), and dried in a vacuum oven at 25°C for at least 12 hours. The isolated intermediate (R)-G-6-a (6962g) was used in the next step without further purification.

[0790] Alternative Step 4. Synthesis of (R)-G-6-a

[0791] 2-Methyltetrahydrofuran (1300 mL) was added to a reactor containing (R)-G-5-a (200 g, 1.0 eq.), followed by trimethylamine (120 g, 1.5 eq.). The contents were cooled to 5 °C (2 to 8 °C) and methanesulfonyl chloride (109 g, 1.2 eq.) was added while maintaining the reaction contents at no more than about 25 °C.

[0792] ℃. 2-Methyltetrahydrofuran (120mL) is used to wash the methanesulfonyl chloride forward, and the reaction is warmed to about 22 ℃ and stirred until the reaction is complete. Then water (1600mL) is slowly added so that the internal temperature is less than about 40 ℃, and the solution is stirred for about 30 minutes. Stop stirring and settle the solution. Remove the bottom water layer and the organic layer is washed with HCl aqueous solution (about 160g concentrated HCl in 664g water) at about 22 ℃. Stirring stops again and the solution is settled. Remove the bottom water layer and the organic layer is then washed with sodium bicarbonate aqueous solution (about 72g NaHCO3 in 776g water) at about 22 ℃. Stirring stops again and the solution is settled. Remove the bottom water layer and the organic layer is then washed with water (800mL, about 4.0v / w (R)-G-5-a). Stirring stops again and the solution is settled. Remove the bottom water layer. The organic layer is vacuum distilled to about 3V tank volume. 2-propanol (1200mL, about 6.0v / w (R)-G-5-a) was added and the reaction was distilled to about 6V tank volume twice. Water (1000mL, about 5.0v / w (R)-G-5-a) was then added and the solution was warmed to about 55°C to about 65°C. The solution was then cooled to about 22°C (19 to 25°C) and (R)-G-6-a seeds (prepared according to the method or from a previous alternative approach as described herein) (0.6g, about 0.003w / w (R)-G-6-a) were added, the solution was cooled to about 5°C and filtered. The filter cake was washed with water (about 400mL, 2.0v / w (R)-G-6-a) and dried to obtain (R)-G-6-a. 1 H NMR (400MHz, CDCl3): δ7.48 (d, J=7.6Hz, 1H), 7.33 (t, J=8.0Hz, 1H), 7.02 (t, J=7 .6Hz, 1H), 6.91 (d, J=8.0Hz, 1H), 5.21 (d, J=8.0Hz, 1H), 4.34 (d, J=10.8Hz, 1H), 4.19 (dd, J=8.0, 10.8Hz), 4.01 (m, 1H), 3.90 (m, 1H), 3.87 (s, 3H), 3.55 (m, 1H), 3 .40(dq, J=9.8, 2.2Hz, 2H), 3.04(s, 3H), 2.02(m, 1H), 1.82(m, 1H), 1.66(m, 2H).

[0793] Step 5. Synthesis of (R)-G-1-a

[0794] N-methylpyrrolidone (NMP, 14 L) was added to a 100 L reactor under nitrogen, and the reactor was cooled to 0-10 ° C. Lithium bromide (9189 g) was added to the reactor in three portions over 1 hour, and the temperature was restored to 0-10 ° C after each addition. The mixture was heated to 55-65 ° C. (R)-G-6-a (6962 g) was combined with NMP (14 L) in a 72 L reactor and stirred at 30-40 ° C until completely dissolved. The solution was transferred to a 100 L reactor containing a lithium bromide solution, and the mixture was stirred at 50-60 ° C for 18 hours, sampling every hour for HPLC analysis until the amount of the remaining (R)-G-6-a did not exceed 1%. The contents of the 100 L reactor were cooled to 15-25 ° C and transferred to a 200 L glass reactor with purified water (70 L) and ethyl acetate (70 L), and the mixture was stirred for at least 15 minutes, then separated. The aqueous phase was extracted with ethyl acetate (35 L) under stirring for at least 15 minutes. The combined organic phases were washed with two portions of brine (35 L each) and two portions of purified water (35 L each), then concentrated to dryness in vacuo at 40-50° C. to afford (R)-G-1-a (6691 g, 92% yield) as an oil.

[0795] Alternative synthesis of (R)-G-1-a

[0796] 1-Methyl-2-pyrrolidone (NMP) (148 g, about 2.4 v / w) was added to the reactor, stirred, and adjusted to about 5°C. Lithium bromide (26.4 g, about 0.44 w / w (R)-G-6-a, 1.67 equiv) was then added to the reactor in batches and stirred for about 30 minutes. Once the temperature reached about 5°C, the next addition of lithium bromide (2...

Claims

1. Crystalline form of compound 1: or a salt, co-crystal, hydrate or solvate thereof.

2. Crystalline form of compound 1: (Compound 1 Form I), characterized by an X-ray powder diffraction pattern comprising peaks at 9.3, 15.0, and 19.8° 2θ ± 0.2° 2θ using Cu-Kα radiation at The wavelength is measured by a diffractometer.

3. The crystalline form of claim 2, wherein the diffraction pattern comprises one or more additional peaks located at: 16.0, 24.0, 25.8 and 27.3° 2θ ± 0.2° 2θ.

4. Crystalline form of compound 1: Features It has in its powder X-ray diffraction pattern one or more peaks selected from the group consisting of peaks located at about 9.2, about 15.8, about 19.6, about 24.0, about 25.6, about 28.6, and about 8.7 degrees 2θ.

5. The crystalline form of claim 2, characterized by a differential scanning calorimetry (DSC) curve comprising an endotherm at about 189°C to about 193°C.

6. The crystalline form of claim 2, wherein the crystalline form is at least about 85% Form I.

7. Crystalline form of compound 1: or a pharmaceutically acceptable salt or co-crystal thereof, It is selected from: 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, 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.

8. Amorphous compound 1:

9. The amorphous form of Compound 1 according to claim 8, wherein the form is substantially free of crystalline Compound 1.

10. A pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of Compound 1 according to any one of claims 1 to 7, and a pharmaceutically acceptable carrier, excipient or diluent.

11. A pharmaceutical composition comprising a therapeutically effective amount of the amorphous compound 1 according to claim 9 or 10, and a pharmaceutically acceptable carrier, excipient or diluent.

12. A method of treating an ACC-mediated disease comprising administering to a patient in need thereof the crystalline form of any one of claims 1 to 7, the amorphous compound of claim 8 or 9, or the pharmaceutical composition of claim 10 or 11.

13. The method according to claim 12, wherein the ACC-mediated disease is non-alcoholic fatty liver disease.

14. The method according to claim 13, wherein the non-alcoholic fatty liver disease is non-alcoholic steatohepatitis.

15. The method of claim 12, wherein the ACC-mediated disease is acne vulgaris.

16. A method for preparing compound 1 or its salt or co-crystal: Comprising compound G-4-a: Contact with acids.

17. Method for preparing compound G-4-a: Comprising compound G-9-a: Contact with compound H-1: Where R H It is a halogen.

18. The method of claim 7, wherein R H For bromine.

19. Method for preparing compound 1: Comprising compound G-4-b: Contacting with a hydrogen source and a palladium catalyst.

20. A method for preparing an enantiomerically enriched compound of formula (R)-G-5: Where 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 C 1-6 aliphatic groups; R 2 is hydrogen or optionally substituted C 1-6 an aliphatic group; and R 5 is hydrogen or halogen; Includes the following step: c) the racemic compound of formula rac-G-5 Contacting with a lipase and an [acyl] donor to form a compound of formula (R)-G-8: wherein [acyl] is C1-C7 acyl; and d) removal of the [acyl] group; Thus, an enantiomerically enriched compound of formula (R)-G-5 is prepared.

21. The method of claim 20, wherein the compound of formula (R)-G-5 is (R)-G-5-a:

22. The method of claim 20 or 21, wherein the [acyl] donor is an optionally substituted 4-7 membered lactone or a 4-7 membered optionally substituted cyclic anhydride; or a x C(O)OR y A compound wherein R x is an optionally substituted C 1-4 an aliphatic group; and R y is an optionally substituted C 1-4 An aliphatic group or an optionally substituted C 1-4 Acyl.

23. The method of any one of claims 20-22, wherein [acyl] is a C4 acyl group.

24. The method of any one of claims 20-23, wherein the lipase is Candida antarctica lipase B.

25. Compounds of the formula:

26. Compounds of the formula:

27. Compound of formula (R)-G-8: in [Acyl] is R x C(O)-, where R x is an optionally substituted C 1-4 aliphatic groups; 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 C 1-6 aliphatic groups; R 2 is hydrogen or optionally substituted C 1-6 an aliphatic group; and R 5 is hydrogen or halogen.

28. The compound of claim 27, wherein R x is an optionally substituted C 3-4 Aliphatic group.

29. The compound of claim 27 or 28, wherein the compound is of formula (R)-I-1:

30. The compound of claim 27, wherein the compound is of formula (R)-I-2:

31. Compound of formula (R)-G-1: in R H is the leaving group; 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 C 1-6 aliphatic groups; R 2 is hydrogen or optionally substituted C 1-6 an aliphatic group; and R 5 is hydrogen or halogen.

32. The compound of claim 31, wherein the compound is of formula H-1:

33. The compound of claim 31, wherein the compound is of formula H-2:

34. The compound of any one of claims 31-33, wherein R H It is a halogen or a sulfonate group.

35. The compound of any one of claims 31-33, wherein R H For bromine.

36. The compound of any one of claims 31-33, wherein R H It is a methanesulfonate group.

37. The method of any one of claims 20 or 21, wherein [acyl] is succinyl.

38. The method of any one of claims 20-22, wherein the [acyl] donor is succinic anhydride.

39. The compound of claim 27, wherein the compound is of the formula: or a salt thereof.

40. The compound of claim 27, wherein the compound is of the formula: or a salt thereof.

41. The method of any one of claims 17-18, wherein preparing compound G-9-a comprises reacting compound G-2-a: Contacting with oxazole under conditions sufficient to form compound G-9-a.

42. A method for preparing compound 1 or its salt or co-crystal: include: (a) Compound G-2-a: Contacting with oxazole under conditions sufficient to form compound G-9-a: (b) contacting compound G-9-a with compound (R)-G-1-a under conditions sufficient to form compound G-4-a: (c) hydrolyzing compound G-4-a under conditions sufficient to form compound 1.

43. The method of claim 42, wherein preparing compound (R)-G-1-a comprises: (d) Compound (R)-G-5-a or its oxygen anion: contacting with a sulfonylating agent under conditions sufficient to form compound (R)-G-6-a: (e) contacting compound (R)-G-6-a with a bromide salt under conditions sufficient to form compound (R)-G-1-a.

44. A method for preparing compound 1 or its salt or co-crystal: include: (a) Compound (R)-G-5-a or its oxygen anion: contacting with a sulfonylating agent under conditions sufficient to form compound (R)-G-6-a: (b) contacting compound (R)-G-6-a with a bromide salt under conditions sufficient to form compound (R)-G-1-a: (c) Compound G-2-a: Contacting with oxazole under conditions sufficient to form compound G-9-a: (d) contacting compound G-9-a with compound (R)-G-1-a under conditions sufficient to form compound G-4-a: and (e) hydrolyzing compound G-4-a under conditions sufficient to form compound 1.

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