WO2021030335A1 - A stereoisomerically pure nk-3 receptor antagonist and crystalline forms thereof - Google Patents

Abstract

A stereoisomerically pure NK-3 receptor antagonist is provided, including crystalline free base and salt forms thereof, as well as pharmaceutical compositions comprising the same. Also provided are methods for production of the stereoisomerically pure NK-3 receptor antagonist, as well as its use in the context of treating conditions for which antagonism of the NK-3 receptor is desired.

Description

A STEREOISOMERICALLY PURE NK-3 RECEPTOR ANTAGONIST AND

CRYSTALLINE FORMS THEREOF

BACKGROUND

Technical Field The invention relates to a stereoisomerically pure NK-3 receptor antagonist, including crystalline free base and salt forms thereof, as well as to pharmaceutical compositions comprising the same, and to methods for their production and use in the context of treating conditions for which antagonism of the NK-3 receptor is desired. Description of the Related Art

Neurokinins (also called tachykinins) are a class of peptide neurotransmitters that interact with three neurokinin G protein-coupled receptors involved with signaling, trafficking, and regulation of the neurokinin receptors. These three neurokinin receptors are known as neurokinin-1 (NK-1), neurokinin-2 (NK-2) and neurokinin-3 (NK-3), and preferentially bind the endogenous substance P (SP), neurokinin A (NKA) and neurokinin B (NKB), respectively. Among the three receptors, the NK-3 receptor (NK3R) has been reported as an important drug target due to its diverse physiological functions and possible role in central nervous system disorders, such as anxiety, depression, bipolar disorders, Parkinson's disease, schizophrenia and pain. NKB is known to be the most potent natural agonist for the NK-3 receptor.

European Patent No. 0 673 928 discloses a series of N-(3,4- dichlorophenyl-propyl)-piperidine derivatives as selective human NK-3 receptor antagonists. Among the disclosed NK-3 receptor antagonists, Osanetant, (R)-(+)-N-[[3-[1- benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl]prop-1-yl]-4-phenylpiperidin-4-yl]-N- methylacetamide, was selected and developed by Sanofi-Synthelabo as a potential treatment for schizophrenia. Following phase Ila clinical trials, osanetant had entered phase lib development in 2001. However, the development of osanetant was ceased in 2005.

U.S. Patent No. 8,507,535 discloses a series of methyl-pyrrolidine ether derivatives as NK-3 receptor antagonists for the treatment of depression, pain, psychosis, Parkinson's disease, schizophrenia, anxiety and attention deficit hyperactivity disorder (ADHD). The ’535 patent provides a process for preparing the methyl-pyrrolidine ether derivatives in racemic form. As noted in Scheme 1 of the ‘535 patent, a trans-isomer (II), (E)-2-methyl-3 -phenyl-acrylic acid ethyl ester, is employed as the starting material to produce the intended compound (I). Through the 1,3-dipolar cycloaddition between the trans-isomer (II) and the other starting material (III), the resulting compound (I) is formed into either a (3R,4R) or a (3S,4S) stereoisomer. For example, the (3R,4R) and (3S,4S) racemic mixture, ((3RS,4RS)-4-(4-chlorophenyl)-3-(((5-chloropyridin-2-yl)oxy)methyl)-3- methylpyrrolidin-1-yl)(6-methylpyridazin-4-yl)methanone, is described in Example 1 of the ’535 patent.

While advances have been made with regard to inhibition of the NK-3 receptor, there remains a need in the art for antagonists of NK-3 receptor, as well as the need to treat various conditions and/or disorders that would benefit from the same. The present invention fulfills that need and provides further related advantages as evident in the following disclosure.

BRIEF SUMMARY

In brief, a stereoisomerically pure NK-3 receptor antagonist and its crystalline free base and salt forms, and methods for its preparation and use in treating conditions for which antagonism of the NK-3 receptor is desired, are provided.

Accordingly, in some embodiments, 4-(4-chlorophenyl)-3-(((5- chloropyridin-2-yl)oxy)methyl)-3-methylpyrrolidin-1-yl)(6-methylpyridazin-4-yl)- methanone is provided as its (3R,4R) stereoisomer; namely, a stereoisomerically pure compound having the following structure (1) (also referred to herein as “Compound (1)”):

or a pharmaceutically acceptable salt, solvate, hydrate or isotope thereof. In more specific embodiments, the stereoisomerically pure compound is in the form of the free base. In other embodiments, the stereoisomerically pure compound is in the form of the pharmaceutically acceptable salt thereof, particularly, an HCl salt or a mesylate salt thereof.

In certain embodiments, Compound (1) is provided at a purity of at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, at least 99.5%, or at least 99.8% in terms of stereoisomeric excess.

Certain embodiments of the invention provide a crystalline form of the stereoisomerically pure compound. In a more specific embodiment, the crystalline form of Compound (1) can be characterized by an X-ray powder diffraction (XRPD) spectrum comprising peaks with the following diffraction angles (2q ± 0.5°): 6.3°, 12.6°, 16.6°, 21.5°, and 28.3°, which may further comprise peaks with the following diffraction angles (2q ± 0.5°): 17.2°, 18.8°, 19.0°, 25.4°, 27.5°, and 31.9°

In some embodiment, the invention provides a crystalline form of an HCl salt of the stereoisomerically pure compound. In a more specific embodiment, the crystalline form of the HCl salt of Compound (1) can be characterized by an X-ray powder diffraction (XRPD) spectrum comprising peaks with the following diffraction angles (2q ± 0.5°): 3.5°, 5.1°, 8.1°, 18.1°, and 19.6°, which may further comprise peaks with the following diffraction angles (2q ± 0.5°): 10.2°, 15.0°, 15.7°, 16.2°, 22.1°, and 22.7°

In some other embodiment, the invention provides a crystalline form of a mesylate salt of the stereoisomerically pure compound. In a more specific embodiment, the crystalline form of the mesylate salt of Compound (1) can be characterized by an X-ray powder diffraction (XRPD) spectrum comprising peaks with the following diffraction angles (2q ± 0.5°): 16.4°, 17.5°, 20.4° and 21.4°, which may further comprise peaks with the following diffraction angles (2q ± 0.5°): 19.8°, 24.7°, 26.3° and 28.1°.

In some embodiments, the invention provides a pharmaceutical composition comprising a stereoisomerically pure Compound (1), or a pharmaceutically acceptable salt, solvate, hydrate or isotope thereof, or a crystalline form thereof; and a pharmaceutically acceptable carrier.

In certain embodiments, the invention provides a method for inhibiting a NK-3 receptor, comprising contacting the receptor with an effective amount of a stereoisomerically pure Compound (1), or a pharmaceutically acceptable salt, solvate, hydrate or isotope thereof, or a crystalline form thereof, or a pharmaceutical composition comprising the same.

In more specific embodiments, the invention provides a method for treating a disease or condition for which NK-3 receptor antagonism is beneficial, treating a vasomotor symptom, or treating a psychological disorder, comprising administering to a subject in need thereof an effective amount of a stereoisomerically pure Compound (1), or a pharmaceutically acceptable salt, solvate, hydrate or isotope thereof, or a crystalline form thereof, or a pharmaceutical composition comprising the same.

In certain embodiments, the invention provides a method for increasing circulating leptin levels in a subject in need thereof, comprising administering to the subject an effective amount of a stereoisomerically pure Compound (1), or a pharmaceutically acceptable salt, solvate, hydrate or isotope thereof, or a crystalline form thereof, or a pharmaceutical composition comprising the same.

In more specific embodiments, the invention provides a method for treating a leptin-related disease, treating excess body fat, or preventing body fat gain in the subject, comprising administering to the subject an effective amount of a stereoisomerically pure Compound (1), or a pharmaceutically acceptable salt, solvate, hydrate or isotope thereof, or a crystalline form thereof, or a pharmaceutical composition comprising the same. The invention also provides processes of preparing a stereoisomerically pure Compound (1), and processes of preparing the crystalline free base or salt forms thereof.

These and other aspects of the invention will be apparent upon reference to the following detailed description. To this end, various references are set forth herein which describe in more detail certain background information, procedures, compounds and/or compositions, and are each hereby incorporated by reference in their entirety.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

Figure 1a shows the XRPD spectrum of an amorphous sample of Compound (1).

Figure 1b shows the DSC and TGA spectrums of an amorphous sample of

Compound (1).

Figure 2 shows the software-simulated single crystal structure of

Compound (1). Figure 3 shows the XRPD spectrum of the single crystal structure of

Compound (1).

Figure 4 shows the TGA spectrum of the single crystal structure of

Compound (1).

Figure 5 shows the DSC spectrum of the single crystal structure of Compound (1).

Figure 6 shows the XRPD spectrum of the crystalline HCl salt of

Compound (1).

Figure 7 shows the DSC and TGA spectrums of the crystalline HCl salt of

Compound (1). Figure 8 shows the XRPD spectrum of the crystalline mesylate salt of

Compound (1).

Figure 9 shows the DSC and TGA spectrums of the crystalline mesylate salt of Compound (1). Figure 10 shows the in vivo test results of the stereoisomerically pure

Compound (1).

DETAILED DESCRIPTION Unless the context requires otherwise, throughout this specification and claims, the words “comprise,” “comprising” and the like are to be construed in an open, inclusive sense; the words “a,” “an,” and the like are to be considered as meaning at least one and are not limited to just one; and the term “about” is to be construed as meaning plus or minus 10%. Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context.

The present invention provides stereoisomerically pure 4-(4-chlorophenyl)- 3-(((5-chloropyridin-2-yl)oxy)methyl)-3-methylpyrrolidin-1-yl)(6-methylpyridazin-4-yl)- methanone, particularly its (3R,4R) stereoisomer. Also provided are pharmaceutical compositions comprising the (3R,4R) stereoisomer, as well as methods for treating conditions for which antagonism of the NK-3 receptor is desired with the same, and processes for preparing the same. The present invention also provides crystalline forms of the (3R,4R) stereoisomer in either a free base or a salt form, pharmaceutical compositions comprising the same, methods of treating conditions for which antagonism of the NK-3 receptor is desired with the same, as well as processes for preparing such crystalline forms of the (3R,4R) stereoisomer.

In some embodiments, the invention provides a stereoisomerically pure compound having the following structure (1) (also referred to herein as “Compound (1)”), or a pharmaceutically acceptable salt, hydrate, solvate, or isotope thereof:

As used herein, “stereoisomerically pure” means that the compound is substantially free of its other stereoisomers. As illustrated below, Compound (1) is in (3R,4R) stereometric form, and has the (3S,4S) stereoisomer as its enantiomer (shown with the plain double-headed arrow), and the (3S,4R) and (3R,4S) stereoisomers as its diastereomers (shown with the dashed double-headed arrows). In the context of the present invention, “stereoisomerically pure” means that Compound (1) is substantially free of its (3S,4S) enantiomer and (3S,4R) and (3R,4S) diastereomers.

“Stereoisomerically pure” may be further defined in terms of “stereoisomeric excess” (se), which is calculated from the ratio of the difference between the amounts of the respective stereoisomers present and the sum of these amounts, and expressed as a percentage. To illustrate, a mixture containing 95% of one stereoisomer and 5% of its other stereoisomers has a stereoisomeric excess (se) of (95-5)/(95+5)=90%. The “enantiomeric excess” (ee) is the analogous term for the difference between enantiomers, and the “diastereomeric excess” (de) is the analogous term for the difference between diastereomers. In the context of the present invention, “stereoisomerically pure” means that the stereoisomerically pure compound having the structure (1), or a pharmaceutically acceptable salt, hydrate, solvate, or isotope thereof, has a stereoisomeric excess of at least 80%. In further embodiments, the stereoisomerically pure compound, or a pharmaceutically acceptable salt, hydrate, solvate, or isotope thereof, has a stereoisomeric excess of at least 90%, at least 95%, at least 98%, at least 99%, at least 99.5%, or at least 99.8%.

The compounds of the present invention may generally be utilized as the free base or in the form of acid addition salts. In some embodiments, the invention provides stereoisomerically pure Compound (1) in the form of its free base. As used herein, the term “free base” refers to Compound (1) devoid, or essentially devoid, of addition of any salt.

In some embodiments, the invention provides stereoisomerically pure Compound (1) in the form of its pharmaceutically acceptable salt. A “salt” is well known in the art and includes an organic or inorganic compound in ionic form, capable of existing in combination with a counterion. A “pharmaceutically acceptable” salt is a salt formed from an ion that has been approved for animal (including human) consumption and is generally non-toxic; namely, it possess a toxicity profile within a range that affords utility in pharmaceutical applications.

Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acids. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, b-hydroxybutyric, salicylic, galactaric and galacturonic acid.

Non-limiting examples of potential salts of this disclosure include but are not limited to hydrochloride, citrate, glycolate, fumarate, malate, tartrate, mesylate, esylate, cinnamate, isethionate, sulfate, phosphate, diphosphate, nitrate, hydrobromide, hydroiodide, succinate, formate, acetate, dichloroacetate, lactate, p-toluenesulfonate, pamitate, pidolate, pamoate, salicylate, 4-aminosalicylate, benzoate, 4-acetamido benzoate, glutamate, aspartate, glycolate, adipate, alginate, ascorbate, besylate, camphorate, camphorsulfonate, camsylate, caprate, caproate, cyclamate, lauryl sulfate, edisylate, gentisate, galactarate, gluceptate, gluconate, glucuronate, oxoglutarate, hippurate, lactobionate, malonate, maleate, mandalate, napsylate, napadisylate, oxalate, oleate, sebacate, stearate, succinate, thiocyanate, undecylenate, and xinafoate.

In one specific embodiment, the invention provides stereoisomerically pure Compound (1) in the form of its HCl or mesylate salt.

In certain embodiments, the invention provides stereoisomerically pure Compound (1) in the form of its hydrate, solvate, or isotope.

A “hydrate” is a compound that exists in combination with water molecules. The combination can include water in stoichiometric quantities, such as a monohydrate or a dihydrate, or can include water in random amounts. As the term is used herein a “hydrate” refers to a solid form (i.e., a compound in a water solution, while it may be hydrated, is not a hydrate as the term is used herein since it is not in solid form).

A “solvate” is a similar combination except that a non-water solvent replaces the water. For example, methanol or ethanol can form an “alcoholate”, which can again be stoichiometric or non-stoichiometric. As the term is used herein, a “solvate” refers to a solid form (i.e., a compound in a solvent solution, while it may be solvated, is not a solvate as the term is used herein since it is not in solid form). Hydrates and solvates are held together by weak interactions that are generally broken upon dissolution, similar to salts. When a drug substance in such form is dissolved in the stomach, intestinal canal or blood of a subject, these hydrate/solvate forms will generally expose the subject to the same active moiety. It is well known in the art that hydrates and solvates are considered eligible for applications in the same way as salts are.

An “isotope” of a compound of the present invention is a compound having one or more atoms of the compound replaced by an isotope of such atom. For example, isotopes include compounds with deuterium in place of one or more hydrogen atoms. Other isotopic substitutions, which may be made in the formation of isotopes of the present invention, include non-radioactive (stable) atoms such as deuterium and carbon 13, as well as radioactive (unstable) atoms such as tritium, carbon 14, iodine 123, iodine 125, and the like.

As shown in Example 10, Compound (1) has been found to be potent and active on the NK-3 receptor, while its (3S,4S) enantiomer is inactive on the NK-3 receptor. Further, Compound (1) also shows better binding affinity against the NK-1 and NK-2 receptors as compared with its (3S,4S) enantiomer. The in vivo study noted in Example 11 further shows that Compound (1) can effectively modulate signaling via the hypothalamus-pituitary-gonadal (HPG) axis (HPG axis antagonism), demonstrated by inducing a reduction in serum testosterone in animal subjects.

In some embodiments, the invention provides a crystalline form of a compound having the following structure (1):

As used herein, “Compound (1)” is interchangeable with the term “a compound having the structure (1)”, and means the designated (3R,4R) stereoisomer in stereoisomerically pure form, unless otherwise specified.

As shown in the polymorph screening study noted in Comparative Example 1, it was found that Compound (1) tends to form amorphous solids or greasy, oily, or sticky substances. The crystalline form of Compound (1) is beneficial in large- scale production for being easier to handle and purify.

In some specific embodiments of the invention, the crystalline form of Compound (1) can be characterized by an X-ray powder diffraction (XRPD) spectrum comprising peaks with the following diffraction angles (2q ± 0.5°): 6.3°, 12.6°, 16.6°, 21.5°, and 28.3°. In further embodiments of the invention, the XRPD spectrum further comprises peaks with the following diffraction angles (2q ± 0.5°): 17.2°, 18.8°, 19.0°, 25.4°, 27.5°, and 31.9°

The values of the diffraction angle 2q peaks on a powder X-ray diffraction spectrum may vary slightly depending on measurement conditions of the used instrument and conditions of the sample being introduced. The 2q value deviation is generally considered to be ±0.5°. Crystals having 2q peaks within the deviation range are encompassed by the present invention. Specifically, a crystal showing the recited diffraction angles with a 2q value difference within a ±0.5° range is deemed to be the crystal of the present invention. In some instances, the measurement conditions are more ideal, and the 2q value deviation can be narrowed down to ±0.2°. Accordingly, the crystalline form of Compound (1) can be characterized by an X-ray powder diffraction (XRPD) spectrum comprising peaks with the following diffraction angles (2q ± 0.2°): 6.3°, 12.6°, 16.6°, 21.5°, and 28.3°. In further embodiments of the invention, such XRPD spectrum further comprises peaks with the following diffraction angles (2q ± 0.2°): 17.2°, 18.8°, 19.0°, 25.4°, 27.5°, and 31.9°. In certain embodiments of the invention, the crystalline form of Compound (1) can be characterized by an X-ray powder diffraction (XRPD) spectrum substantially as depicted in Figure 3.

In some embodiments of the invention, the crystalline form of Compound (1) can be characterized by showing almost no weight loss at the temperature up to about 130°C, about 150°C, or about 200°C, as measured by thermal gravimetric analysis (TGA). In a further embodiment of the invention, the crystalline form of Compound (1) can be characterized by a TGA spectrum substantially as depicted in Figure 4. The TGA analysis result indicates that the present crystalline form of Compound (1) may remain thermally stable at the temperature up to about 130°C, about 150°C, or about 200°C. In contrast, as shown in Figure 1b, the amorphous form of Compound (1) exhibits more significant weight loss (about 0.24% w/w) at about 90°C, as measured by TGA.

In certain embodiments of the invention, the crystalline form of Compound (1) can be characterized by a differential scanning calorimetry (DSC) thermogram having an onset peak at about 129°C and a peak temperature at about 133°C. In a further embodiment of the invention, the crystalline form of Compound (1) can be characterized by a DSC spectrum substantially as depicted in Figure 5. The DSC analysis result indicates that the crystalline form of Compound (1) has a melting point of higher than 120°C (onset melting point at about 129°C). In contrast, as shown in Figure 1b, the amorphous form of Compound (1) exhibits an onset peak at about 51°C and a peak temperature at about 57°C, as measured by DSC.

The superior thermal stability and higher melting point render the crystalline form of Compound (1) suitable and compatible to a wide range of formulation designs and corresponding preparation options.

In certain embodiments, the invention provides a crystalline form of an HCl salt of a compound having structure (1). In further embodiments of the invention, the crystalline HCl salt of Compound (1) can be characterized by an X-ray powder diffraction (XRPD) spectrum comprising peaks with the following diffraction angles (2q ± 0.5°): 3.5°, 5.1°, 8.1°, 18.1°, and 19.6°. In more specific embodiments of the invention, the XRPD spectrum further comprises peaks with the following diffraction angles (2q ± 0.5°): 10.2°, 15.0°, 15.7°, 16.2°, 22.1°, and 22.7°. As noted above, in some instances, the 2q value deviation can be narrowed down to ±0.2°. Accordingly, in some embodiments of the invention, the crystalline HCl salt of Compound (1) can be characterized by an X-ray powder diffraction (XRPD) spectrum comprising peaks with the following diffraction angles (2q ± 0.2°): 3.5°, 5.1°, 8.1°, 18.1°, and 19.6°. In more specific embodiments of the invention, the XRPD spectrum further comprises peaks with the following diffraction angles (2q ± 0.2°): 10.2°, 15.0°, 15.7°, 16.2°, 22.1°, and 22.7° In certain embodiments of the invention, the crystalline HCl salt of Compound (1) can be characterized by an X-ray powder diffraction (XRPD) spectrum substantially as depicted in Figure 6.

In certain embodiments of the invention, the crystalline HCl salt of Compound (1) can be characterized by a differential scanning calorimetry (DSC) thermogram having two onset peaks at about 84 and 114oC, respectively; and two peak temperatures at about 88 and 124oC, respectively. In further embodiments of the invention, the crystalline HCl salt of Compound (1) can be characterized by a DSC spectrum substantially as depicted in Figure 7. The DSC analysis result indicates that crystalline HCl salt of Compound (1) has a melting point of higher than 80oC. In contrast, as shown in Figure 1b, the amorphous form of Compound (1) exhibits a melting point at around 50oC. In some embodiments, the invention provides a crystalline form of a mesylate salt of a compound having the structure (1). In further embodiments of the invention, the crystalline mesylate salt of Compound (1) can be characterized by an X-ray powder diffraction (XRPD) spectrum comprising peaks with the following diffraction angles (2q ± 0.5°): 16.4°, 17.5°, 20.4° and 21.4°. In more specific embodiments of the invention, the XRPD spectrum further comprises peaks with the following diffraction angles (2q ± 0.5°): 19.8°, 24.7°, 26.3° and 28.1°. As noted above, in some instances, the 2q value deviation can be narrowed down to ±0.2°. Accordingly, in some embodiments of the invention, the crystalline mesylate salt of Compound (1) can be characterized by an X-ray powder diffraction (XRPD) spectrum comprising peaks with the following diffraction angles (2q ± 0.2°): 16.4°, 17.5°, 20.4° and 21.4°. In more specific embodiments of the invention, the XRPD spectrum further comprises peaks with the following diffraction angles (2q ± 0.2°): 19.8°, 24.7°, 26.3° and 28.1°. In certain embodiments of the invention, the crystalline mesylate salt of Compound (1) can be characterized by an X-ray powder diffraction (XRPD) spectrum substantially as depicted in Figure 8. In certain embodiments of the invention, the crystalline mesylate salt of Compound (1) can be characterized by a differential scanning calorimetry (DSC) thermogram having an onset peak at about 144°C, and a peak temperature at about 155°C. In further embodiments of the invention, the crystalline mesylate salt of Compound (1) can be characterized by a DSC spectrum substantially as depicted in Figure 9. The DSC analysis result indicates that crystalline mesylate salt of Compound (1) has a melting point of higher than 140°C. In contrast, as shown in Figure 1b, the amorphous form of Compound (1) exhibits a melting point at around 50°C.

In some embodiments, the invention provides a crystalline form of Compound (1), or a pharmaceutically acceptable salt, hydrate, solvate, or isotope thereof, having a melting point of higher than about 80°C, about 120°C, or about 140°C.

In certain embodiments, the invention provides a pharmaceutical composition comprising Compound (1), or a pharmaceutically acceptable salt, hydrate, solvate, or isotope thereof, or a crystalline form thereof; and a pharmaceutically acceptable carrier. In a further embodiment, the present pharmaceutical composition comprises the free base form of Compound (1). In further embodiments, the present pharmaceutical composition comprises the HCl or mesylate salt of Compound (1).

Pharmaceutically acceptable carrier can be those familiar to persons skilled in the art. The particular carrier employed in these pharmaceutical compositions may vary depending upon the type of administration desired ( e.g . intravenous, oral, topical, suppository, or parenteral). For compositions formulated as liquid solutions, acceptable carriers include saline and sterile water, and may optionally include antioxidants, buffers, bacteriostats and other common additives. The compositions can also be formulated as pills, capsules, granules, or tablets which contain, in addition to Compound (1), excipients such as diluents, binders, and lubricants. One skilled in this art may further formulate Compound (1) in an appropriate manner, and in accordance with accepted practices, such as those disclosed in Remington: The Science and

Practice of Pharmacy, 22^nd Edition, Allen, Lloyd V., Jr. Ed. (2012) (incorporated herein by reference). For example, the compounds or crystalline forms of the invention will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which can be in the form of an ampoule, capsule, sachet, paper, or other container. When the compounds or crystalline forms of the invention is mixed with a carrier, or when the carrier serves as a diluent, it can be solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The compounds or crystalline forms of the invention can be adsorbed on a granular solid carrier, for example contained in a sachet. Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, poly hydroxy ethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrier can include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.

In certain embodiments, the invention provides a method for inhibiting a NK-3 receptor, comprising contacting the NK-3 receptor with an effective amount of Compound (1), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, or a crystalline form thereof, or a pharmaceutical composition comprising the same. In further embodiments, the present method comprises administering the free base form of Compound (1). In other embodiments, the present method comprises administering the HCl or mesylate salt of Compound (1).

“Inhibiting a NK-3 receptor” means diminishing and/or inactivating the ability or activity of the NK-3 receptor to transduce a signal. For example, many studies have shown that the regulation of NK-3 receptors may influence the release of biogenic amines, such as dopamine and serotonin, or intracellular calcium. NK-3 receptor antagonists could block the NK3R-mediated activation of these systems, thereby treating relevant medical conditions. The expression “effective amount”, when used to describe use of a compound or composition of the invention, refers to the amount of a compound or composition of the invention that is effective to bind to as an antagonist a NK-3 receptor. When applied in a subject and the NK-3 receptor is implicated in a medical disorder or condition, such binding occurs to an extent sufficient to produce a beneficial therapeutic effect on the subject. Similarly, as used herein, an “effective amount” of a compound or composition of the invention refers to an amount of the compound or composition that alleviates, in whole or in part, symptoms associated with the disorder or condition, or halts or slows further progression or worsening of those symptoms, or prevents or provides prophylaxis for the disorder or condition, in particular, refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result by acting as an antagonist against the NK-3 receptor. A therapeutically effective amount is also one in which any toxic or detrimental effects of compounds or compositions of the invention are outweighed by the therapeutically beneficial effects.

In more specific embodiments, the invention provides a method for treating a disease or condition for which NK-3 receptor antagonism is beneficial, comprising administering to a subject in need thereof an effective amount of Compound (1), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, or a crystalline form thereof, or a pharmaceutical composition comprising the same. In further embodiments, the present method comprises administering the free base form of Compound (1). In other embodiments, the present method comprises administering the HCl or mesylate salt of Compound (1).

“Treating” or “treatment” within the meaning herein refers to an alleviation of symptoms associated with a medical disorder or disease, or inhibition of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder.

Diseases, conditions or disorders, for which NK-3 receptor antagonism is beneficial or antagonism of the NK-3 receptor is desired, include diseases, conditions or disorders which can be eased, cured, or prevented through the effects of inhibiting the NK- 3 receptor. For example, these diseases, conditions or disorders include, but are not limited to, depression, anxiety, pyschosis, schizophrenia, psychotic disorders, bipolar disorders, cognitive disorders, Parkinson's disease, Alzheimer's disease, attention deficit hyperactivity disorder (ADHD), pain, convulsion, obesity, inflammatory diseases including irritable bowel syndrome and inflammatory bowel disorders, emesis, pre- eclampsia, airway related diseases including chronic obstructive pulmonary disease, asthma, airway hyperresponsiveness, bronchoconstriction and cough, reproduction disorders and sex hormone-dependent diseases including but not limited to benign prostatic hyperplasia (BPH), metastatic prostatic caminoma, testicular cancer, breast cancer, androgen dependent acne, male pattern baldness, endometriosis, abnormal puberty, uterine fibrosis, hormone-dependent cancers, hyperandrogenism, hirsutism, virilization, polycystic ovary syndrome (PCOS), HAIR-AN syndrome (hyperandrogenism, insulin resistance and acanthosis nigricans), ovarian hyperthecosis (HAIR-AN with hyperplasia of luteinized theca cells in ovarian stroma), other manifestations of high intraovarian androgen concentrations (e.g. follicular maturation arrest, atresia, anovulation, dysmenorrhea, dysfunctional uterine bleeding, infertility), androgen-producing tumor (virilizing ovarian or adrenal tumor), vasomotor symptoms, and leptin-related disease.

As used herein, “subject” means warm-blood animals, including, for example, humans; non-human primates, e.g. apes and monkeys; cattle; horses; sheep; and goats. “Administering” or “administration” can be conducted through any route of administration which effectively transports the active compound of the invention which inhibits the NK-3 receptor to the appropriate or desired site of action, such as oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal or parenteral, e.g., rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment, the oral route being preferred. The administration can be local or systemic, preferably, through the pharmaceutical compositions as discussed above. As used herein, systemic administration includes, for example, oral and parenteral methods of administration, subcutaneous, intramuscular, intracranial, intraorbital, ophthalmic, intraventricular, intracapsular, intraarticular, intraspinal, intraci sternal, intraperitoneal, intranasal, aerosol, intravenous, intradermal, inhalational, transdermal, transmucosal, and rectal administration.

In more specific embodiments, the invention provides a method for treating a vasomotor symptom, comprising administering to a subject in need thereof an effective amount of Compound (1), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, or a crystalline form thereof, or a pharmaceutical composition comprising the same. In further embodiments, the present method comprises administering the free base form of Compound (1). In other embodiments, the present method comprises administering the HCl or mesylate salt of Compound (1). In further embodiments of the present method of treatment, the vasomotor symptom is hot flashes or night sweats in menopausal women.

“Vasomotor symptom(s)” or “VMS” means symptoms related to disturbances to normal homeostatic mechanisms controlling thermoregulation and vasomotor activity, including, but not limited to, hot flashes, flushing, insomnia, sleep disturbances, mood disorders, irritability, excessive perspiration, night sweats, fatigue, and the like. Vasomotor symptoms are known to be the most common symptoms associated with menopause, with an occurring rate of about 60% to 80% among women following natural or surgically-induced menopause. It is known in the art that the NK-3 antagonist can serve to effectively reduce the frequency, severity, bother, and interference of vasomotor symptoms in postmenopausal women (Julia K. Prague et al ., Menopause. 2018 Aug; 25(8): 862-869) (incorporated herein by reference).

“Hot flash” refers to an episodic disturbance in body temperature, typically consisting of a sudden skin flushing, usually accompanied by perspiration in a subject.

In certain embodiments, the invention also provides a method for treating a psychological disorder in a subject in need thereof, comprising administering to the subject an effective amount of Compound (1), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, or a crystalline form thereof, or a pharmaceutical composition comprising the same. In further embodiments, the present method comprises administering the free base form of Compound (1). In other embodiments, the present method comprises administering the HCl or mesylate salt of Compound (1). In some embodiments of the present method of treatment, the psychological disorder is anxiety, depressive mood or stress symptom occurring around menopause.

“Psychological disorder” means diseases, conditions or symptoms including, but not limited to, disorders of mood and affect, memory dysfunction, psychotic disorders, and anxiety disorders. In the context of the present invention, the psychological disorders particularly mean those disorders occurring around menopause, such as anxiety, stress, tension, depressive symptoms, schizophrenia, panic disorder, obsessive-compulsive disorder (OCD), and bipolar disorders. NK-3 antagonists’ application in treating psychological disorders can be further seen in, for example, U.S. Patent No. 8,507,535, U.S. Patent No. 7,834,008, U.S. Patent Application Pub. No. 2015/0315199, and U.S. Patent Application Pub. No. 2018/0194772 (all incorporated herein by reference).

In some embodiments, the invention further provides a method for increasing circulating leptin levels in a subject in need thereof, comprising administering to the subject an effective amount of Compound (1), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, or a crystalline form thereof, or a pharmaceutical composition comprising the same. In further embodiments, the present method comprises administering the free base form of Compound (1). In other embodiments, the present method comprises administering the HCl or mesylate salt of Compound (1).

As disclosed in PCT Patent Application Pub. No. WO 2016/146712, leptin is known to be the “satiety hormone” which enables to achieve energy homeostasis and is able to trigger impressive weight loss in some patients. The PCT ’712 application (incorporated herein by reference) further discloses that NK-3 antagonists can serve to increase the circulating leptin levels, thereby treating leptin- related diseases, treating excess body fat, or preventing body fat gain.

In some more specific embodiments, the invention provides a method for treating a leptin-related disease, comprising administering to a subject in need thereof an effective amount of Compound (1), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, or a crystalline form thereof, or a pharmaceutical composition comprising the same. In further embodiments, the present method comprises administering the free base form of Compound (1). In other embodiments, the present method comprises administering the HCl or mesylate salt of Compound (1). In some embodiments of the present method of treatment, the leptin-related disease is a metabolic disorder, a lipid regulation disorder, a congenital leptin deficiency, hypothalamic amenorrhea, or osteoporosis. In further embodiments of the present method of treatment, the metabolic disorder is diabetes.

“Leptin-related disease” means diseases or conditions include, but are not limited to, metabolic disorders such as diabetes, cardiovascular diseases or metabolic syndrome; lipid regulation disorders such as lipodystrophy, including congenital and acquired lipodystrophy, dyslipidemia, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis or hyperlipidemia; Congenital Leptin Deficiency; hypothalamic amenorrhea, including exercise-induced hypothalamic amenorrhea, Rabson-Mendenhall syndrome; and osteoporosis.

In certain embodiments, the invention also provides a method for treating excess body fat or preventing body fat gain in a subject in need thereof, comprising administering to the subject an effective amount of Compound (1), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, or a crystalline form thereof, or a pharmaceutical composition comprising the same. In further embodiments, the present method comprises administering the free base form of Compound (1). In other embodiments, the present method comprises administering the HCl or mesylate salt of Compound (1).

“Excess of body fat” in a subject should be understood as an undesirable excess body weight or fat accumulation which is or is not associated with pathological conditions or a growing burden of disease, such as glucose metabolism disorders, insulin resistance, metabolic syndrome, diabetes or vascular disorders. For example, the subject may be a human having a BMI from 18.5 to 25 kg/m².

In some embodiments, the invention provides a process to prepare a stereoisomerically enriched compound of Formula (A):

wherein

Q is the following structure (a), structure (b), or a cycloalkyl, optionally substituted by lower alkyl:

further wherein

Ar¹ is phenyl or a six membered heteroaryl;

X¹ is N or CH;

X² is N—R¹ or O;

R¹ is S(O)₂-lower alkyl, C(O)-cycloalkyl substituted by lower alkyl, or is C(O)- lower alkyl, lower alkyl, cyano, cycloalkyl or is a six membered heteroaryl substituted by lower alkyl, cyano, C(O)-lower alkyl, halogen, lower alkyl substituted by halogen or lower alkoxy; or is phenyl substituted by cyano or halogen; and

R² is lower alkyl, halogen, pyrazolyl, 3-methyl-[1,2,4]oxazolyl, 5-methyl-[1,2,4]oxadiazol-3-yl, pyridyl substituted by cyano, or is phenyl substituted by halogen, or is cyano, lower alkoxy, or is piperidin-2-one; according to the following General Scheme (I):

wherein B₁ and B₂ independently represents H, a lower alkyl, phenyl, benzyl, or alkyl phenyl group, further wherein at least one of B₁ and B₂ is not H; PG represents a protecting group; L represents a leaving group; and reagents and conditions (i) to (vii) are, for example, those noted in Example 1.

“Stereoisomerically enriched” means that the amount of the designated (3R, 4R) stereoisomer of structure (A) in the resulting mixture of the present manufacturing process is significantly greater than the amount of its other stereoisomers. Specifically, the resulting mixture of the present manufacturing process has a stereoisomeric excess of at least 20%, at least 40%, at least 50%, at least 80%, at least 85%, or at least 90%. In the context of preparing Compound (1), “stereoisomerically enriched” means that the amount of Compound (1) in the resulting mixture of the present manufacturing process is significantly greater than the amount of its other stereoisomers, including its (3S,4S) enantiomer and/or (3S, 4R) and (3R,4S) diastereomers. Specifically, the resulting mixture of the present process of preparing Compound (1) has a stereoisomeric excess of at least 20%, at least 40%, at least 50%, at least 80%, at least 85%, or at least 90%. More specifically, when the trans-isomer IM-2a is employed in the manufacturing process, the resulting mixture would contain either a (3R,4R) stereoisomer or a (3S,4S) stereoisomer. Accordingly, the resulting mixture of the present process of preparing a compound of structure (A) or Compound (1) has an enantiomeric excess of at least 20%, at least 40%, at least 50%, at least 80%, at least 85%, or at least 90% (the desired (3R,4R) stereoisomer and the undesired (3S,4S) stereoisomer are enantiomers).

“Cycloalkyl” means a monovalent saturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms, particularly a monovalent saturated monocyclic hydrocarbon group of 3 to 8 ring carbon atoms. Bicyclic means a structure consisting of two saturated carbocycles having one or more carbonatoms in common. Examples for monocyclic cycloalkyl are cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl or cycloheptyl. Examples for bicyclic cycloalkyl arebicyclo[2.2.1]heptanyl, or bicyclo[2.2.2]octanyl.

“Lower alkyl” means a straight or branched-hydrocarbon chain group containing from 1-8 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl and the like. Preferred lower alkyl groups are groups with 1-4 carbon atoms.

“Six membered heteroaryl” means a cyclic aromatic hydrocarbon radical which contains at least one N-heteroatom, for example, pyridinyl or pyridazinyl.

“Lower alkoxy” means a group of the formula — OR’, wherein R’ is a lower alkyl group as defined above. Examples of alkoxy moieties include methoxy, ethoxy, isopropoxy, and tert-butoxy.

“Alkyl phenyl” means a phenyl substituted by one or more alkyl groups of no more than 12 carbon atoms. Examples of these moieties include 2-phenylethyl, 3- phenyl propyl, 2-phenyl propyl, 1-methyl-2-phenylethyl, 5-phenylpentyl, 4-phenylhexyl and the like.

“Protecting group” means the group which selectively blocks one reactive site in a compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry. Exemplary protecting groups include, but are not limited to, trifluoroacetyl, acetamido, benzyl (Bn), benzyloxycarbonyl (carbobenzyloxy, CBZ), p- methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxy carbonyl (BOC), and the like.

“Leaving group” means a group of atoms that is displaced as stable species taking with it the bonding electrons when the carbon atom to which it is attached subject to nucleophilic attack. Exemplary leaving groups include, but are not limited to an anion (e.g. Cl-, I-, Br-, and ions of methyl sulfate, mesylate, trifluromethanesulfonate, and tosylate) or a neutral molecule (e.g. H₂O).

In more specific embodiments, the invention provides a process to prepare a stereoisomerically enriched compound of Formula (A), comprising providing a compound having the following structure (IM-3):

wherein B₁ and B₂ independently represents H, a lower alkyl, phenyl, benzyl, or alkyl phenyl group, further wherein at least one of B₁ and B₂ is not H; and converting the compound (IM-3) into the compound of Formula (A).

In further embodiments of the present process, B₁ is a phenyl, benzyl, methyl, or isopropyl group, and B₂ is H or a phenyl group. In certain embodiments of the present process, B₁ is a phenyl group, and B₂ is H.

In another embodiment of the present process, Q is a methylpyridazine group. As noted in Example 2, oxazolidinones, i.e., compound IM-2b, has been found capable of facilitating the formation of the desired stereoisomer; namely, the (3R,4R) intermediate IM-4. Specifically, the stereochemical configuration of compound IM-3 benefits the production of the (3R,4R) stereoisomer IM-4, thereby leading to the selective production of the compound of Formula (A) or Compound (1).

In more specific embodiments of the present process, the oxazolidinone is in (S) form and has the following structure (S-IM-3):

In other embodiments of the present process, the oxazolidinone is in (R) form and has the following structure (R-IM-3):

In certain embodiments, the invention also provides a process to prepare a stereoisomerically pure compound having the structure (1), according to the following Scheme (I-1):

In more specific embodiments, the invention provides a process to prepare a stereoisomerically pure compound having the structure (1), comprising providing a compound having the following structure (IM-3-1):

and converting the compound (IM-3-1) into Compound (1). In further embodiments of the present process, the compound (IM-3-1) is in (S) form and has the following structure (S-IM-3-1):

In other embodiments of the present process, the compound (IM-3-1) is in (R) form and has the following structure (R-IM-3-1):

In some specific embodiments, when the compound IM-3-1 is employed in the present process to prepare Compound (1), the resulting mixture has an enantiomeric excess of at least 80%, at least 85%, or at least 90%.

EXAMPLES

In order that this invention may be more fully understood, the following examples are set forth. These examples are for the purpose of illustrating embodiments of this invention, and are not to be construed as limiting the scope of the invention in any way. The reactants used in the examples below may be obtained either as described herein, or if not described herein, are themselves either commercially available or may be prepared from commercially available materials by methods known in the art. X-ray Powder diffraction (XRPD) measurement method

The XRPD of samples was measured under the following conditions:

(1) XRPD conditions used in Comparative Example 2 and Example 4: Measurement instrument: PANalytical (Aeris);

Measurement conditions: Source Cu-Ka, Scan 3 to 40° 2q, Step 0.02° 2q, Generator 40 kV/7.5 mA.

(2) XRPD conditions used in Example 7 and Example 9: Measurement instrument: Bruker D8 advance;

Measurement conditions: Source Cu-Ka, Scan 3 to 40° 20, Step 0.02° 2q, Generator 40 kV/40 mA.

Differential scanning calorimetry (DSC) measurement method

The DSC of samples was measured under the following conditions: Instrument: Discovery DSC 250 (TA Instruments, US)

Heating rate: 10°C/min from 25°C to 250 or 300°C Purge gas: nitrogen

Thermal gravimetric analysis (TGA) measurement method

The TGA of samples was measured under the following conditions: Instrument: Discovery TGA 55 (TA Instruments, US)

Heating rate: 10°C/min from RT to 250 or 300°C Purge gas: nitrogen

Abbreviations t-BuOLi = Lithium tert-butoxide

THF = Tetrahydrofuran KOH = Potassium hydroxide LiCl = Lithium chloride

PivCl = Pivaloyl chloride TFA = Trifluoroacetic acid

L1BH₄ = Lithium borohydride EtOH = Ethanol t-BuOK = Potassium t-butoxide

DIEA = N,N-Diisopropylethylamine T₃P = Propylphosphonic anhydride DMF = Dimethylformamide n-BuLi = n-Butyl lithium MeOH = Methanol ACN = Acetonitrile MEK = Methyl ethyl ketone IPAC = Isopropyl acetate

IPA = Isopropyl alcohol EA = Ethyl acetate MTBE = Methyl tert-butyl ether HEP = Heptane RT = Room temperature

DCM = Dichloromethane DME = Dimethoxy ethane Me-THF = 2-Methyltetrahydrofuran h = Hour EXAMPLE 1

Preparation of Compound (1)

Step 1: Synthesis of (E)-3-(4-chlorophenyl)-2-methylacrylic acid (Compound IM-2a)

About 300 g compound IM-1a was dissolved in THF (3 L, 10 V), then IM-

1b (535.5 g, 1.05 eq) was added at 25°C. T-BuOLi (188.5 g, 1.1 eq.) was added with batches over 0.5 h at 25±5oC. The mixture was stirred at 25±5oC for 1 h. The HPLC showed that IM-1a < 0.5 %. Then KOH (300 g, 2.5 eq) in H2O (900ml) was added with one portion and stirred at 55oC for 2h. The resulting solution was cooled to RT, H2O (900mL) was added, and the resulting mixture was concentrated under reduced pressure.

The resulting mixture was extracted with MTBE (900ml). The water phase was adjusted to pH=3 with HCl. The resulting solid was filtered and washed with H₂O (2L) (PH=5). The filtrate was dried to give about 340 g compound IM-2a (82% yield, LCAP purity=97.5%). m/z: 196.03. ¹H NMR (300 MHz, Methanol-d4) d 7.65 (q, J = 1.5 Hz, 1H), 7.42 (d, J = 1.4 Hz, 4H), 2.07 (d, J =1.5 Hz, 3H). Step 2: Synthesis of (S,E)-3-(3-(4-chlorovhenyl)-2-methylacryloyl)-4-vhenyloxazolidin-2- one (Compound IM-3-1)

About 250 g compound IM-2a was dissolved in THF (6 L, 20 V), then TEA (322 g, 2.5 eq) was added. PivCl (168 g,1.05 eq) was added at -25°C and stirred for 1 hour (h) at -25°C. LiCl (58.9 g, 1.1 eq), (S)-oxazolidinone, i.e., compound IM-2b-1, (228.7g, 1.1 eq) was added at -25°C. The reaction mixture was warmed to 25°C and stirred for 3h. LCAP purity=86.9%. H₂O (6L, 20V) was added to the mixture, and stirred for lh at 10°C. The mixture was filtered and washed by IN HCl (100 ml), H₂O (2Lx3), until pH = 6-7, to give about 382 g crude compound IM-3-1 (88% yield, LCAP purity=97%). m/z:

341.08. ¹H NMR (400 MHz, Methanol-d4) d 7.58 - 7.23 (m, 8H), 7.01 (q, J = 1.6 Hz, 1H), 5.58 (dd, J = 8.8, 7.0 Hz, 1H), 4.83 (t, J = 8.8 Hz, 1H), 4.29 (dd, J = 8.7, 6.9 Hz, 1H), 2.10 (d, J = 1.5 Hz, 3H).

Step 3: Synthesis of (S)-3-((3R,4R)-1-benzyl-4-(4-chlorovhenyl)-3-methylvyrrolidine-3- carbonyl)-4-phenyloxazolidin-2-one ( Compound IM-4-1 )

About 100 g compound IM-3-1, was dissolved in toluene (2L, 20 V) then

TFA (3.4 g, 0.1 eq) was added. A-benzyl-1-methoxy-N-((trimethylsilyl (methyl) methanamine (139.1 g, 2.0 eq) was added at 10-15°C. The mixture was stirred for 2h and quenched by citric acid at pH=6. The organic phase was washed by NaHCO₃, brine and concentrated to give about 150 g crude compound IM-4-1 (82% yield, LCAP purity=93%). Chiral purity= 87% de. m/z: 474.17. ¹H NMR (300 MHz, Chloroform-d) d 7.59 - 7.17 (m, 15H), 5.54 (dd, J = 8.6, 4.3 Hz, 1H), 4.71 (t, J= 8.7 Hz, 1H), 4.24 (dd, J = 8.8, 4.3 Hz, 1H), 4.20 - 4.09 (m, 2H), 3.78 - 3.62 (m, 2H), 3.57 (d, J =11.1 Hz, 1H), 2.97 - 2.78 (m, 2H), 2.74 (dd, J = 9.2, 7.8 Hz, 1H), 1.11 (s, 3H). The solvent system can be replaced with DCM, THF, DME or Me-THF.

Step 4: Synthesis of ((3R,4R)-1-benzyl-4-(4-chlorophenyl)-3-methylpyrrolidin-3 - yl)methanol (Compound IM-5-1)

About 150g compound IM-4-1 was dissolved in DME (3L, 20V), EtOH (300ml, 2V). Then LiBH₄ (660 ml, 3.0 eq, 2 mol in THF) was added dropwise at 0-5°C and stirred for 2h. The reaction was quenched by 3N HCl under 0°C at pH=1-2. Then the resulting mixture was concentrated and EA (1500ml, 10V) was added. The mixture was stirred at 20°C for lh and filtered. The IM-5-1 HCl salt was dissociated by Na₂CO₃ to give about 46.5 g compound IM-5-1 (66% yield, LCAP purity=97%). Chiral purity= 94.1% ee. m/z: 315.14. ¹H NMR (400 MHz, Chloroform-d) d 7.41 - 7.32 (m, 4H), 7.33 - 7.26 (m, 3H), 7.23 - 7.15 (m, 2H),3.75 - 3.34 (m, 6H), 2.99 (d, J = 9.3 Hz, 1H), 2.64 (t, J = 9.1 Hz, 1H), 2.40 (dd, J = 9.3, 1.6 Hz, 1H),0.53 (s, 3H). The reaction solvent can be replaced with DME, MTBE, or toluene.

Step 5: Synthesis of 2-(((3R,4R)-1-benzyl-4-(4-chlorophenyl)-3-methylpyrrolidin-3- yl)methoxy)-5-chloropyridine (Compound IM-6-1)

About 20 g compound IM-5-1 was dissolved in THF (100ml, 5V), t-BuOK (8.5 g, 1.2 eq.) was added at 25°C. Then 5-chloro-2-fluoropyridine (9.2 g, 1.1 eq.) was added dropwise and stirred at 25°C for lh. Then the resulting mixture was quenched by H₂O (100 ml) and the organic phase was separated. The aqueous layer was extracted with EA (1 x 100ml). The organic phase was dried over anhydrous sodium sulfate and filtered, concentrated under vacuum to give about 28 g crude compound IM-6-1 (LCAP purity =95.7%). Chiral purity=94.1% ee. m/z: 426.13. ¹H NMR (300 MHz, Chloroform- d) d 8.12 (dd, J = 2.7, 0.6 Hz, 1H), 7.54 (dd, J = 8.8, 2.7 Hz, 1H),7.43 - 7.17 (m, 9H), 6.72 (dd, J = 8.8, 0.7 Hz, 1H), 4.21 (d, J = 2.6 Hz, 2H), 3.70 (d, J = 3.1 Hz, 2H),3.32 (t, J = 7.4 Hz, 1H), 3.06 (dd, J = 9.4, 7.5 Hz, 1H), 2.95 - 2.78 (m, 2H), 2.47 (d, J = 9.4 Hz, 1H),1.58 (s, OH), 1.40 (t, J = 7.1 Hz, OH), 0.77 (s, 3H).

Step 6: Synthesis of 5-chloro-2-(((3R,4R)-4-(4-chlorovhenyl)-3-methylvyrrolidin-3- yl)methoxy)pyridine ( Compound IM-7)

About 1.2 g compound IM-6-1 was dissolved in toluene (6ml, 5V), and DIEA (0.6 g, 1.5 eq.) was added. 1-chloroethyl carbonochloridate (0.44 g, 1.1 eq.) was added dropwise at 0°C. The resulting mixture was stirred for 2h at 25°C. Then MeOH (6ml, 5V) was added and stirred for 2h at 25°C. The mixture was concentrated and washed by ACN to give about 0.7 g crude compound IM-7. Chiral purity=94.3% ee. m/z: 336.08. ¹H NMR (300 MHz, Methanol-d4) d 8.15 (dd, J = 2.7, 0.7 Hz, 1H), 7.76 (dd, J = 8.8, 2.7 Hz, 1H),7.49 - 7.36 (m, 2H), 7.33 - 7.23 (m, 2H), 6.94 (dd, J = 8.8, 0.7 Hz, 1H), 4.26 (d, J = 11.0 Hz, 1H),4.15 (d, J = 11.1 Hz, 1H), 3.90 - 3.69 (m, 3H), 3.62 (d, J = 12.0 Hz, 1H), 3.44 - 3.26 (m, 4H), 0.94 (s,3H).

Step 7: Synthesis of ((3R,4R)-4-(4-chlorovhenyl)-3-(((5-chloropyridin-2-yl)oxy)methyl)-3- methylpyrrolidin-1-yl)(6-methylpyridazin-4-yl)methanone ( Compound (1))

About 0.7 g compound IM-7, compound IM-8-1 (0.28g, 1.1 eq.), DIEA (0.61 g, 2.5eq.) were mixed in DMF (3.5ml, 5 V). Then T₃P (1.1 g, 1.05 eq.) was added dropwise. The reaction mixture was stirred at RT for 3 h to give about 0.5 g Compound (1) (LCAP purity=55%). Chiral purity= 94.3 % ee. m/z: 456.11. ¹H-NMR: 9.24, 9.18 (2H, d, J = 2 Hz, H-30); 8.12, 8.07 (2H, d, J = 2.4 Hz, H-18); 7.84, 7.77 (2H, d, J = 2 Hz, H-26); 7.71, 7.68 (2H, overlap, H-20); 7.37, 7.32 (4H, d, J = 8.4 Hz, H-2, 6); 7.29, 7.22 (4H, d, J = 8.4 Hz, H-3, 5); 6.87, 6.82 (2H, d, J = 8.4Hz, H-21); 4.28, 4.25, 4.17, 4.14, 4.12, 4.11, 4.10, 4.08, 3.89, 3.85, 3.82, 3.70, 3.68, 3.66, 3.49, 3.46 (14H, overlap, H-8, H-9a, 9b, H- 11a, 11b, H-14a, 14b ); 2.76, 2.75 (6H, overlap, H-31); 0.99, 0.86 (6H, s, H-13). ¹³C-NMR: 166.85, 166.71(C-23); 163.61, 163.51, 162.43, 162.40 (C-16); 148.03, 147.96, 146.22, 146.15, 140.33 (overlap, C-18, C-27, C-30); 137.24 (overlap, C-4); 136.41,

136.30 (C-20); 134.36 (overlap, C-24);131.46, 131.44 (overlap, C-1, C-3, 5); 129.67, 129.58 (C-26); 126.69, 125.87 (overlap, C-2, 6, C-19); 113.24 (overlap, C-21); 70.77, 70.66 (C-14); 58.71, 56.82 (C-9/C-11); 52.68, 51.12 (C-11/C-9); 48.38, 47.99 (overlap, C- 8); 47.44, 45.31(C-12); 22.04 (overlap, C-31); 18.12, 17.59 (C-13).

EXAMPLE 2

Selective Production by oxazolidinone Various oxazolidinones, i.e., compounds IM-2b, were tested to see their selectivity on the production of the desired stereoisomer, i.e., the (3R,4R) stereoisomer IM- 4. Comparative sample 1 was prepared based on the manufacturing process disclosed in U.S. Patent No. 8,507,535, with minor modifications. The resulting products were analyzed by HPLC to give the chiral purity {de %) in liquid chromatography area percent (LCAP). Results are listed in the following Table 1. As shown in Table 1, when ethyl (E)-3-(4-chlorophenyl)-2-methylacrylate was used as the starting material, the resulting product was in racemic form (comparative sample #1, chiral purity =1.5% de, where the ratio of the stereoisomers was 50.75:49.25, measured by supercritical fluid chromatography (SFC)). In contrast, when employing oxazolidinones according to the present manufacturing processes, the yield of the desired (3R,4R) stereoisomer IM-4 was significantly increased (samples #1-7, chiral purity = 21.7~86.9 % de). Table 1

Comparison of selective production

COMPARATIVE EXAMPLE 1

Polymorph Screening Study of Compound (1) Polymorph screening was performed using conventional evaporation, slurry, anti-solvent precipitation, and cooling crystallization techniques. All resulting samples were amorphous or in oil or sticky form. No single crystal of Compound (1) was uncovered during the Polymorph Screening Study.

Slow Evaporation Method About 30 mg of amorphous Compound (1) and 2 mL of one of Testing

Solvent System 1 were added into glass vials. Testing Solvent System 1 was selected from the group consisting of water, MeOH, ACN, MEK, IPAC, IPA, EA, EtOH, THF, MTBE, toluene, and HEP. After stirring for about 30 minutes, 1.5 mL of the suspensions/solutions were filtered, and the filtrates of the binary solvents were distributed into 96-well plate for slow evaporation study. The filtrates were used for single solvent evaporation study. The portions of suspensions were used for slurry study. Among 91 wells of 96-well plate, only 1 amorphous solid sample was obtained, and the other wells all contained samples in oil or glassy form. In the single solvent evaporation study, all samples were in oil form for 7 days at room temperature (RT). Cooling Crystallization About 20 mg of amorphous Compound (1) and 0.5 mL of one of Testing Solvent System 2 were added into vials, and held at 60°C until all solid dissolved, then cooled down to RT (~20°C). Testing Solvent System 2 was selected from the group consisting of MeOH-Water (2/1 ratio), Acetone-Water (6/5 ratio), EtOH-Water (5/6 ratio), THF-Water (6/5 ratio), IPA-Water (4/7 ratio), and ACN-Water (6/5 ratio). Concentration in each test was about 40 mg/ml. Some samples had very small peak in XRPD, but most were amorphous, where the small peaks may originate from the degradation of the Compound (1).

Anti-Solvent Precipitation

About 20 mg of amorphous Compound (1) was dissolved in 0.5 mL of a solvent, and then an anti-solvent was added (50 mL per time). The solvent systems (solventanti-solvent) used in this test included MeOH:Water, Acetone: Water, EtOEfWater, THF:Water, IPA:Water, ACN:Water, IPA:HEP; MTBE:HEP, Tolune:HEP, and Acetone:HEP. All resulting samples were amorphous or in sticky form.

Slurry in Sinsle or Binary Solvent at RT(~20°C)

About 20 mg of amorphous Compound (1) and 0.5 mL of one of Testing Solvent System 3 were added into glass vials. The mixtures were stirred at RT for 7 days. Testing Solvent System 3 was selected from the group consisting of Water, HEP, MTBE, MeOH-Water (1/1 ratio), Acetone-Water (1/2 ratio), EtOH-Water (1/2 ratio), THF-Water (1/2 ratio), IPA-Water (1/3 ratio), ACN-Water (1/3 ratio), IPA-HEP (1/6 ratio), MTBE- HEP (5/2 ratio), Toluene-HEP (1/2 ratio), and Acetone-HEP (1/5 ratio). Among the resulting samples, four were amorphous and the rest of them were all in sticky form.

Slurry in Sinsle or Binary Solvent at 50°C

About 20 mg of amorphous Compound (1) and 0.5 mL of one of Testing Solvent System 4 were added into glass vials. The mixtures were stirred at 50°C for 7 days. Testing Solvent System 4 was selected from the group consisting of Water, HEP, MTBE, MeOH-Water (1/1 ratio), Acetone-Water (1/2 ratio), EtOH-Water (1/2 ratio), THF-Water (1/2 ratio), IPA-Water (1/3 ratio), ACN-Water (1/3 ratio), IPA-HEP (1/3 ratio), MTBE-HEP (1/1 ratio), Toluene-HEP (1/2 ratio), and Acetone-HEP (1/5 ratio). Among the resulting samples, two had very small peak in XRPD, the rest of them were all in sticky or oil form.

Slurry in Single or Binary Solvent at 80°C

About 20 mg of amorphous Compound (1) and 0.1 mL of one of Testing Solvent System 5 were added into glass vials. The mixtures were stirred at 80°C for 5 days. Testing Solvent System 5 was selected from the group consisting of ACN-water (1/3 ratio), IPA-water (1/3 ratio), DMSO-water (1/2 ratio), DMF-water (1/2 ratio), HEP- Isobutanol (1/6 ratio), HEP-1,4-Dioxane (1/4 ratio), and HEP-toluene (1/5 ratio). Among the resulting samples, two had very small peak in XRPD, the rest of them were all in sticky or oil form.

Purity Check

Considering the peaks observed in the slurry tests at 50°C and 80°C, the purity of the selected samples was checked by LCMS. Based on LCMS test results, the purity decreased from 97% to 84% after the sample was treated in ACN/H₂O at 50°C for 7 days, and from 97% to 9% after treated in ACN/H₂O at 80°C for 5 days. Thus, the small peaks appeared on XRPD profiles were likely resulted from the degradation of Compound (1).

COMPARATIVE EXAMPLE 2 XRPD. TGA and DSC Profiles of Amorphous Compound (1)

One amorphous sample of Compound (1) was subject to XRPD, TGA and DSC analysis according to the above noted measurement methods. The XRPD analysis result of the amorphous Compound (1) is shown in Figure 1a. The tested sample was light brown powder from visual observation. The TGA and DSC analysis results of the amorphous Compound (1) are shown in Figure 1b. As shown with the TGA curve, the amorphous Compound (1) experienced about 0.24% weight loss when heated to about 90°C. The DSC thermogram shows that the amorphous Compound (1) has an onset peak at about 51°C, and a peak temperature at about 57°C.

EXAMPLE 3 Preparation of Single Crystal of Compound (1)

Needle-like single crystal of Compound (1) was obtained in acetone through evaporation method. The solution was put into a vial covered with a film with several pinhole on it. Then the solution was allowed to evaporate at room temperature slowly. As shown in Table 2, various solvent systems and concentrations were tested, where only acetone was successfully used as the solvent system to produce the single crystal of Compound (1) (samples #1-2).

Table 2

Comparison between Various Crystallization Conditions

Analysis of Single Crystal of Compound (1)

Single crystal X-ray diffraction data of the crystalline Compound (1) was collected at 180 K on a Rigaku XtaLAB PRO 007HF(Mo) diffractometer, with Mo Ka radiation (l = 0.71073 Å). Data reduction and empirical absorption correction were performed using the CrysAlisPro program. The structure was solved by a dual- space algorithm using SHELXT program. All non-hydrogen atoms could be located directly from the difference Fourier maps. Framework hydrogen atoms were placed geometrically and constrained using the riding model to the parent atoms. Final structure refinement was done using the SHELXL program by minimizing the sum of squared deviations of F2 using a full-matrix technique. Single Crystal X-Ray Diffraction Analysis

The refined single crystal structure of Compound (1) is shown in Figure 2. The crystal structural data is summarized in Table 3.

Table 3 Crystal Data and Structure Refinement of Single Crystal of Compound (1)

XRPD, TGA and DSC Profiles of Crystalline Compound ( 1 ) The crystalline Compound (1) was subject to XRPD, TGA and DSC analysis according to the above noted measurement methods. The XRPD analysis result of the crystalline Compound (1) is shown in Figure 3. The crystalline Compound (1), in the XRPD spectrum, has peaks at diffraction angles 2q as listed in the following Table 4. The tested sample was off-white sloid from visual observation. The TGA and DSC analysis results of the crystalline Compound (1) are shown in Figures 4 and 5. As shown in Figure 4, the crystalline Compound (1) experienced almost no weight loss when the temperature reached at about 130°C. Such observation (no weight loss) remains till the test temperature reached to about 200°C (significant weight loss observed at the temperature of over 250°C). The DSC thermogram (Figure 5) shows that the crystalline Compound (1) has an onset peak at about 129°C, and a peak temperature at about 133°C. The TGA analysis result indicates that the thermal stability of Compound (1) is greatly improved when the compound is in the crystalline form (as compared with the TGA analysis result of the amorphous Compound (1) shown in Figure 1b). Further, the meting point of Compound (1) is greatly increased when the compound is in the crystalline form, as compared with the DSC analysis result of the amorphous Compound (1) shown in Figure 1b, i.e., from about 50°C to about 130°C.

Table 4

XRPD 2q Peak List of the Crystalline Compound (1)

EXAMPLE 5

Preparation of Single Crystal of Compound (1) in Large Scale About 1120 g Compound (1) was added into EtOH (2.20 L, 2V) and heated to reflux for 30 min, and then the solution was cooled slowly to RT and stirred overnight. The resulting solids were collected by filtration, washed with EtOH (550mL, 0.5 V) and dried under reduced condition to give about 1031 g crystalline Compound (1) as off-white solids. EXAMPLE 6

Preparation of Crystalline HCl salt of Compound (1)

Amorphous Compound (1) (about 20 mg) was added and dissolved into 0.2 mL ACN at RT. leq. HCl acid was added, and then stirred at RT for 2 hours. The resulting mixture was dried by evaporation to give a sticky or glassy sample. To the sample, 0.3 mL of EA was added, and stirred for 3 days to give the crystalline HCl salt of Compound (1).

EXAMPLE 7

Analysis of Crystalline HCl salt of Compound (1)

The crystalline HCl salt of Compound (1) obtained in Example 6 was subject to XRPD, TGA and DSC analysis according to the above noted measurement methods. The XRPD analysis result of the crystalline HCl salt of Compound (1) is shown in Figure 6. The TGA and DSC analysis results of the crystalline HCl salt of Compound (1) are shown in Figure 7. As shown with the TGA curve, the crystalline HCl salt of Compound (1) experienced about 2.9% weight loss at about 80-120°C. The DSC thermogram shows that the crystalline HCl salt of Compound (1) has two onset peaks at about 84 and 114°C, respectively; and two peak temperatures at about 88 and 124°C, respectively. The crystalline HCl salt of Compound (1) also exhibits higher melting point as compared with the amorphous form of Compound (1) (see from the comparison with Figure 1b). The diffraction angles (2q ± 0.5°) of the XRPD analysis result are listed in the following Table 5.

Table 5

XRPD 2q Peak List of the Crystalline HCl Salt of Compound ( 1)

EXAMPLE 8

Preparation of Crystalline Msylate Salt of Compound (1)

Amorphous Compound (1) (about 20 mg) was added and dissolved into 0.2 mL ACN at RT. 1eq. methanesulfonic acid was added. The resulting mixture was concentrated and dried. 0.1 mL EA and 0.1 mL n-heptane were induced to form a gel- like mixture. The mixture was stirred for 3 days to give a suspension. The solids were collected to give the crystalline mesylate salt of Compound (1).

EXAMPLE 9 Analysis of Crystalline Mesylate Ssalt of Compound (1)

The crystalline mesylate salt of Compound (1) obtained in Example 8 was subject to XRPD, TGA and DSC analysis according to the above noted measurement methods. The XRPD analysis result of the crystalline mesylate salt of Compound (1) is shown in Figure 8. The TGA and DSC analysis results of the crystalline mesylate salt of Compound (1) are shown in Figure 9. The DSC thermogram shows that the crystalline mesylate salt of Compound (1) has an onset peak at about 144°C, and a peak temperature at about 155°C. Similar to the crystalline free base and crystalline HCl salt of Compound (1), the crystalline mesylate salt of Compound (1) also exhibits a higher melting point as compared with the amorphous form of Compound (1) (see from the comparison with Figure 1b). The diffraction angles (2q ± 0.5°) of the XRPD analysis result are listed in the following Table 6.

Table 6

XRPD 2q Peak List of the Crystalline Mesylate Salt of Compound (1)

EXAMPLE 10

In Vitro Neurokinin Binging Assay of Compound (1)

Compound (1), its (3S,4S) enantiomer and reference compounds ([Sar⁹,Met(O₂)¹¹]-SP, [Nleu¹⁰]-NKA (4-10), SB 222200) were tested at several concentrations for IC₅₀ or EC₅₀ determination. The binding assays were conducted according to conventional methods (Aharony, D. et al. (1993), Mol. Pharmacol., 44 : 356- 363; Heuillet, E. et al. (1993), J. Neurochem., 60 : 868-876; Sarau, H.M. et al. (1997), J. Pharmacol. Exp. Ther., 281 : 1303-1311). The experimental conditions are listed in Table 7.

Table 7

In vitro Binding Assay Conditions

Compound binding was calculated as a % inhibition of the binding of a radioactively labeled ligand specific for each target. The results are expressed as a percent of control specific binding:

and as a percent inhibition of control specific binding:

obtained in the presence of the test compounds. The IC₅₀ values (concentration causing a half-maximal inhibition of control specific binding) and Hill coefficients (nH) were determined by non-linear regression analysis of the competition curves generated with mean replicate values using Hill equation curve fitting:

where Y = specific binding, A = left asymptote of the curve, D = right asymptote of the curve, C = compound concentration, C₅₀ = IC₅₀, and nH = slope factor. This analysis was performed using software developed at Cerep (Hill software) and validated by comparison with data generated by the commercial software SigmaPlot® 4.0 for Windows® (© 1997 by SPSS Inc.). The inhibition constants (Ki) were calculated using the Cheng Prusoff equation:

where L = concentration of radioligand in the assay, and K_D = affinity of the radioligand for the receptor. A scatchard plot is used to determine the K_D.

Assay results are listed in the following Table 8. Only the calculable IC₅₀ and EC₅₀ are reported below. As shown in Table 8, Compound (1) is potent and active on the NK-3 receptor, while its (3S,4S) enantiomer is inactive. Meanwhile, Compound (1) also shows better binding affinity against NK-1 and NK-2 receptors as compared with its (3S,4S) enantiomer.

Table 8

In vitro Assay Results of Compound (1). its (3S,4S) Enantiomer and Reference Compounds

> Cone.: IC₅₀ value above the highest test concentration. Concentration-response curve shows less than 50 % effect at the highest validated testing concentration.

N.C.: IC₅₀ value not calculable. Concentration-response curve shows less than 25% effect at the highest validated testing concentration.

EXAMPLE 11

In vivo Study of Compound (1)

The activity of Compound (1) in modulating signaling via the hypothalamus-pituitary-gonadal (HPG) axis was evaluated in dogs using testosterone as a biomarker of HPG axis antagonism. The objective of this study was to collect samples for the determination of the pharmacodynamic effects of Compound (1) following a single oral (PO) gavage administration of test article to dogs. A total of 20 male beagle dogs were assigned to study. The animals were not fasted prior to dosing. Each animal received a single PO gavage dose of the appropriate negative control, positive control, or Compound (1) formulation as outlined in the following Table 9. The gavage tube was rinsed with approximately 10 mL of tap water following dosing (prior to removal of the gavage tube). Blood samples were collected at various times after test article administration. Bioanalytical analysis to determine testosterone concentration in collected blood serum was conducted at the laboratory. The study results are shown in Figure 10. It can be seen from Figure 10 that Compound (1) administration was followed by a reduction in serum testosterone that was dose dependent and of a magnitude similar to a known NK- 3 receptor antagonist used as a positive control. Table 9

Study Design of NK3R Antagonism Test of Compound (1) on Dogs

The various embodiments described above can be combined to provide further embodiments. All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the Application Data Sheet are incorporated herein by reference, in their entirety. Aspects of the embodiments can be modified, if necessary to employ concepts of the various patents, applications and publications to provide yet further embodiments. These and other changes can be made to the embodiments in light of the above-detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.

U.S. Provisional Application 62/885,741, filed August 12, 2019 is incorporated herein by reference, in its entirety.

Claims

CLAIMS What is claimed is:

1. A stereoisomerically pure compound having the following structure

(1):

or a pharmaceutically acceptable salt, hydrate, solvate, or isotope thereof.

2. The stereoisomerically pure compound of claim 1, wherein the compound is in the form of the free base.

3. The stereoisomerically pure compound of claim 1, wherein the compound is in the form of the pharmaceutically acceptable salt thereof.

4. The stereoisomerically pure compound of claim 1, wherein the compound is in the form of the hydrate, solvate, or isotope thereof.

5. The stereoisomerically pure compound of claim 3, wherein the pharmaceutically acceptable salt is an HCl salt.

6. The stereoisomerically pure compound of claim 3, wherein the pharmaceutically acceptable salt is a mesylate salt.

7. The stereoisomerically pure compound of any one of claims 1-6, wherein the compound, or the pharmaceutically acceptable salt, hydrate, solvate, or isotope thereof, has a stereoisomeric excess of at least 80%.

8. The stereoisomerically pure compound of any one of claims 1-6, wherein the compound, or the pharmaceutically acceptable salt, hydrate, solvate, or isotope thereof, has a stereoisomeric excess of at least 90%.

9. The stereoisomerically pure compound of any one of claims 1-6, wherein the compound, or the pharmaceutically acceptable salt, hydrate, solvate, or isotope thereof, has a stereoisomeric excess of at least 95%.

10. The stereoisomerically pure compound of any one of claims 1-6, wherein the compound, or the pharmaceutically acceptable salt, hydrate, solvate, or isotope thereof, has a stereoisomeric excess of at least 98%.

11. The stereoisomerically pure compound of any one of claims 1-6, wherein the compound, or the pharmaceutically acceptable salt, hydrate, solvate, or isotope thereof, has a stereoisomeric excess of at least 99%.

12. The stereoisomerically pure compound of any one of claims 1-6, wherein the compound, or the pharmaceutically acceptable salt, hydrate, solvate, or isotope thereof, has a stereoisomeric excess of at least 99.5%.

13. The stereoisomerically pure compound of any one of claims 1-6, wherein the compound, or the pharmaceutically acceptable salt, hydrate, solvate, or isotope thereof, has a stereoisomeric excess of at least 99.8%.

14. A crystalline form of a compound having the following structure

(1):

15. The crystalline form of claim 14 having an X-ray powder diffraction (XRPD) spectrum comprising peaks with the following diffraction angles (2q ± 0.5°): 6.3°, 12.6°, 16.6°, 21.5°, and 28.3°

16. The crystalline form of claim 15, wherein the XRPD spectrum further comprises peaks with the following diffraction angles (2q ± 0.5°): 17.2°, 18.8°, 19.0°, 25.4°, 27.5°, and 31.9°

17. The crystalline form of claim 14 having an X-ray powder diffraction (XRPD) spectrum comprising peaks with the following diffraction angles (2q ± 0.2°): 6.3°, 12.6°, 16.6°, 21.5°, and 28.3°

18. The crystalline form of claim 17, wherein the XRPD spectrum further comprises peaks with the following diffraction angles (2q ± 0.2°): 17.2°, 18.8°, 19.0°, 25.4°, 27.5°, and 31.9°

19. The crystalline form of claim 14 having a XRPD spectrum substantially as depicted in Figure 3.

20. The crystalline form of claim 14 having a differential scanning calorimetry (DSC) thermogram having an onset peak at about 129 °C and a peak temperature at about 133 °C.

21. The crystalline form of claim 14 having a DSC spectrum substantially as depicted in Figure 5.

22. A crystalline form of an HCl salt of a compound having the following structure (1):

23. The crystalline form of claim 22 having an X-ray powder diffraction (XRPD) spectrum comprising peaks with the following diffraction angles (2q ± 0.5°): 3.5°, 5.1°, 8.1°, 18.1°, and 19.6°

24. The crystalline form of claim 23, wherein the XRPD spectrum further comprises peaks with the following diffraction angles (2q ± 0.5°): 10.2°, 15.0°, 15.7°, 16.2°, 22.1°, and 22.7°

25. The crystalline form of claim 22 having a XRPD spectrum substantially as depicted in Figure 6.

26. A crystalline form of a mesylate salt of a compound having following structure (1):

27. The crystalline form of claim 26 having an X-ray powder diffraction (XRPD) spectrum comprising peaks with the following diffraction angles (2q ± 0.5°): 16.4°, 17.5°, 20.4° and 21.4°

28. The crystalline form of claim 27, wherein the XRPD spectrum further comprises peaks with the following diffraction angles (2q ± 0.5°): 19.8°, 24.7°, 26.3° and 28.1°

29. The crystalline form of claim 26 having a XRPD spectrum substantially as depicted in Figure 8.

30. A pharmaceutical composition comprising a stereoisomerically pure compound of any one of claims 1-13, or a crystalline form of any one of claims 14- 29, and a pharmaceutically acceptable carrier.

31. A method for inhibiting a NK-3 receptor, comprising contacting the receptor with an effective amount of a stereoisomerically pure compound of any one of claims 1-13, a crystalline form of any one of claims 14-29, or a pharmaceutical composition of claim 30.

32. A method for treating a disease or condition for which NK-3 receptor antagonism is beneficial, comprising administering to a subject in need thereof an effective amount of a stereoisomerically pure compound of any one of claims 1-13, a crystalline form of any one of claims 14-29, or a pharmaceutical composition of claim 30.

33. A method for treating a vasomotor symptom, comprising administering to a subject in need thereof an effective amount of a stereoisomerically pure compound of any one of claims 1-13, a crystalline form of any one of claims 14-29, or a pharmaceutical composition of claim 30.

34. The method of claim 33, wherein the vasomotor symptom is hot flashes or night sweats in menopausal women.

35. A method for treating a psychological disorder, comprising administering to a subject in need thereof an effective amount of a stereoisomerically pure compound of any one of claims 1-13, a crystalline form of any one of claims 14-29, or a pharmaceutical composition of claim 30.

36. The method of claim 35, wherein the psychological disorder is anxiety, depressive mood or stress symptom occurring around menopause.

37. A method for increasing circulating leptin levels in a subject in need thereof, comprising administering to the subject an effective amount of a stereoisomerically pure compound of any one of claims 1-13, a crystalline form of any one of claims 14-29, or a pharmaceutical composition of claim 30.

38. A method for treating a leptin-related disease, comprising administering to a subject in need thereof an effective amount of a stereoisomerically pure compound of any one of claims 1-13, a crystalline form of any one of claims 14-29, or a pharmaceutical composition of claim 30.

39. The method of claim 38, wherein the leptin-related disease is a metabolic disorder, a lipid regulation disorder, a congenital leptin deficiency, hypothalamic amenorrhea, or osteoporosis.

40. The method of claim 39, wherein the metabolic disorder is diabetes.

41. A method for treating excess body fat or preventing body fat gain in a subject in need thereof, comprising administering to the subject an effective amount of a stereoisomerically pure compound of any one of claims 1-13, a crystalline form of any one of claims 14-29, or a pharmaceutical composition of claim 30.

42. A process for preparing a stereoisomerically enriched compound of

Formula (A):

wherein

Q is the following structure (a), structure (b), or a cycloalkyl, optionally substituted by lower alkyl:

further wherein

Ar¹ is phenyl or a six membered heteroaryl; X¹ is N or CH;

X² is N—R¹ or O;

R¹ is S(O)₂-lower alkyl, C(O)-cycloalkyl substituted by lower alkyl, or is C(O)-lower alkyl, lower alkyl, cyano, cycloalkyl or is a six membered heteroaryl substituted by lower alkyl, cyano, C(O)-lower alkyl, halogen, lower alkyl substituted by halogen or lower alkoxy; or is phenyl substituted by cyano or halogen; and

R² is lower alkyl, halogen, pyrazolyl, 3-methyl-[1,2,4]oxazolyl, 5- methyl-[1,2,4]oxadiazol-3-yl, pyridyl substituted by cyano, or is phenyl substituted by halogen, or is cyano, lower alkoxy, or is piped din-2-one; according to the following scheme:

wherein B₁ and B₂ independently represents H, a lower alkyl, phenyl, benzyl, or alkyl phenyl group, further wherein at least one of B₁ and B₂ is not H; PG represents a protecting group; and L represents a leaving group.

43. The process of claim 42, employing the compound (IM-3) having the following structure (IM-3):

wherein B₁ and B₂ independently represents H, a lower alkyl, phenyl, benzyl, or alkyl phenyl group, further wherein at least one of B₁ and B₂ is not H; and converting the compound (IM-3) into the compound of Formula (A).

44. The process of claim 43, wherein B₁ is a phenyl, benzyl, methyl, or isopropyl group, and B₂ is H or a phenyl group.

45. The process of claim 44, wherein B₁ is a phenyl group and B₂ is H.

46. The process of any one of claims 42-45, wherein Q is a methylpyridazine group.

47. The process of any one of claims 42-46, employing a compound having the following structure (S-IM-3) as compound (IM-3):

48. The process of any one of claims 42-46, employing a compound having the following structure (R-IM-3) as compound (IM-3):

49. A process for preparing a stereoisomerically pure Compound 1 according to the following scheme:

50. The process of claim 49, wherein compound (IM-3-1) is in the (S) form and has the following structure (S-IM-3-1):

51. The process of claim 49, wherein compound (IM-3-1) is in the (R) form and has the following structure (R-IM-3-1):