OA21107A - Methods of manufacturing a bifunctional compound, ultrapure forms of the bifunctional compound, and dosage forms comprising the same.

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Abstract

Description

Claims

OA21107A

Publication number: OA21107A
Application number: OA1202200467
Authority: OA
Inventors: Hanqing Dong; Robert J. Duguid; Casey Keith JAGER; Aditya Mohan KAUSHAL; Samuel Elliott KENNEDY; Miranda Annell NEESER; Maxwell Marco REEVE; Joseph P. Reo; Mohammad Mehdi ZAHEDI; Venkata A. KATTUBOINA; Laura E.N. ALLAN; Chungpin Herman CHEN; John A. Grosso; III Royal J. HASKELL; Rhys LLOYD; Hayley REECE; Jerod ROBERTSON; Yuping Qiu
Original assignee: Arvinas Operations, Inc.
Priority date: 2020-05-09
Filing date: 2021-05-06
Publication date: 2023-11-13

The present disclosure relates to ultra-pure forms, polymorphs, amorphous forms, and formulations of N-[(1r,4r)-4-(3-chloro-4cyanophenoxy)cyclohexyl]-6-[4-({4-[2-(2,6dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro1H-isoindol-5-yl]piperazin-1-yl}methyl)piperidin-1yl]pyridazine-3-carboxamide, referred to herein as Compound A :

METHODS OF MANUFACTURING A BIFUNCTIONAL COMPOUND, ULTRAPURE FORMS OF THE BIFUNCTIONAL COMPOUND, AND DOSAGE FORMS

COMPRISING THE SAME

RELATED APPLICATIONS

[0001] This application claims priority to, and the benefît of, U.S. Provisional Application No.

63/022,475, filed May 9, 2020, U.S. Provisional Application No. 63/149,143, filed February 12, 2021, and U.S. Provisional Application No. 63/177,378, filed April 20, 2021. These applications are incorporated herein by reference in their entireties for ail purposes.

TECHNICAL FIELD

[0002] This application relates to a bifunctional compound that has been shown to be a useful modulator of targeted protein ubiquitination and dégradation via the ubîquîtin-proteasome system. In particular, the application relates to a process for manufacturing the bifunctional compound. The application further relates to crystalline forms, amorphous forms, ultrapure forms, and stable forms ofthe bifunctional compound. The application also relates to oral dosage forms (e.g., tablets) comprising the bifunctional compound and methods of making the same, along with methods of treating cancer (e.g., prostate cancer) comprising administering a therapeutically effective amount of a dosage form of the invention to a subject in need of such treatment.

STATEMENT REGARDING FEDERALLY FUNDED RESEARCH

[0003] This invention was made with government support under grant number 1R44CA20319920 01 by the National Cancer Instituts. The government has certain rights in the invention.

BACKGROUND

[0004] Most small molécule drugs bind to enzymes or receptors in tight and well-defined pockets. In contrast, protein-protein interactions are notoriously difficult to target using small molécules due to their large contact surfaces and the shallow grooves or fiat interfaces typically involved. E3 ubiquitin ligases (of which hundreds are known in humans) confer substrate spécifieity for ubiquitination, and therefore are attractive therapeutic targets due to their

speciflcity for certain protein substrates. The development of ligands of E3 ligases has proven chailenging, in part because they must disrupt protein-protein interactions. However, recent developments hâve provided spécifie ligands which bind to these ligases. For example, since the discovery of nutlins, the first small molécule E3 ligase inhibitors, additional compounds hâve been reported that target E3 ligases, though the field remains underdeveloped.

[0005] One E3 ligase with particular therapeutîc potential is cereblon, a protein that in humans is encoded by the CRBN gene. CRBN orthologs are highly conserved from plants to humans, indicating its physiologîcal importance. Cereblon fonns an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A), and regulatorof cullins I

1Ü (ROC 1 ). This complex ubîquitinates several other proteins. Through a mechanism not yet been completely elucidated, cereblon ubquitination of target proteins results in increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGFI0). FGF8, in turn, régulâtes several developmental processes, such as limb and auditory vesicle formation. The net resuit is that this ubiquitin ligase complex is important for limb outgrowth in embryos. In the absence of cereblon, DDB i forms a complex with DDB2, which functions as a DNA damagebinding protein.

[00061 Thalidomide, which has been approved for the treatment of a number of immunological indications, has also been approved for the treatment of certain neoplastic diseases, including multiple myeloma. In addition, thalidomide and several of its analogs are currently under investigation for use in treating a variety of other types of cancer. While the précisé mechanism of thalidomide’s anti-tumor activity is still emerging, it is known to inhibit angiogenesis. Recent literature discussing the biology of the imides includes Lu et al. Science 343, 305 (2014) and Krônke et al. Science 343, 301 (2014).

[0007] Significantly, thalidomide and its analogs, e.g. pomalidomide and lenalidomide, are known to bind cereblon, and to alter the spécifieity of the complex to induce the ubiquitination and dégradation of Ikaros (IKZF1) and Aiolos (IKZF3), which are transcription factors essential for multiple myeloma growth. Indeed, higher expression of cereblon has been linked to an increase in efficacy of imide drugs in the treatment of multiple myeloma.

[0008] Androgen receptor (AR) belongs to a nuclear hormone receptor family that is activated by androgens, such as testosterone and dihydrotestosterone (PharmacoL Rev. 2006, 58(4), 78297; Vitam. Horm. 1999, 55:309-52.). In the absence of androgens, AR is bound by Heat Shock

Protein 90 (Hsp90) in the cytosol. When an androgen binds AR, its conformation changes to release AR from Hsp90 and to expose the Nuclear Localization Signa! (NLS). The NLS enables AR to translocate into the nucléus where AR acts as a transcription factor to promote gene expression responsible for male sexual characteristics (Endocr. Rev. 1987, 8(I):l-28; Mol. Endocrinol. 2002, 16(10), 2181-7). AR deficiency leads to Androgen Insensitivity Syndrome, formerly termed testicular feminization.

[0009] While AR is responsible for development of male sexual characteristics, it is also a welldocumented oncogene in certain cancers including prostate cancer (Endocr. Rev. 2004, 25(2), 276-308). A commonly measured target of AR activity is the secreted Prostate Spécifie Antigen (PSA) protein. The current treatment regimen for prostate cancer involves inhibiting the androgen-AR axis by either of two methods. The first approach relies on réduction of androgens, while the second aitns to inhibit AR function (Nat. Rev. Drug Discovery, 2013, 12,823-824). Despite the development of effective targeted thérapies, most patients develop résistance and the disease progresses. An alternative approach for the treatment of prostate cancer may involve eliminating the AR protein. Because AR is a critical driver of tumorigenesis in many forms of prostate cancer, its élimination could lead to a therapeutically bénéficiai response.

[0010] The bifunctional compound made and used according to the present invention is Compound A having the molecular formula of C41H43CIFN9O6, and with the following structural formula:

[0011] Compound A is under development as a PROTAC® protein dégrader that targets AR for the potential treatment of men having metastatic, castration-résistant prostate cancer (mCRPC).

SUMMARY

[0012] The present disclosure provides ultra-pure forms, crystalline forms, amorphous forms, and formulations of N-[(l r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl]-6-[4-({4-[2-(2,6dioxopiperidin-3-yl)-6-fluoro-l,3-dioxo-2,3-dihydro-!H-isoindoi-5-yl]piperazin-l21107 yl}methyl)piperidin-l-yl]pyridazine-3-carboxamide, referred to herein as Compound A, and processes for manufacturîng Compound A:

(Compound A).

|0013] In one aspect, this application pertains to a method of treating prostate cancer in a subject 5 in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Compound A. In one embodiment, the method further comprises the administration of an additional anti-cancer agent.

[0014] In one aspect, this disclosure provides a crystalline form of Compound A having a powder x-ray diffraction pattern comprising peaks at 7.6° ± 0.2° 2Θ, 11.5° ± 0.2° 2Θ, and 17.6° ± 0.2° 20, 10 wherein said powder x-ray diffraction pattern is obtained using Cu Ka radiation at an x-ray wavelength of 1.5406 Â. This crystalline form is designated as “Form 2.”

[0015] In another aspect, this disclosure provides a crystalline form of Compound A having a powder x-ray diffraction pattern comprising peaks at 11.0° ± 0.2° 20, 16.1° ± 0.2° 20, and 17.9° ± 0.2° 26, wherein said powder x-ray diffraction pattern is obtained using Cu Ka radiation at an x15 ray wavelength of 1.5406 Â. This crystalline form is designated as “Form 4.”

[0016] In another aspect, this disclosure provides processes for manufacturîng Compound A, wherein the process comprises the reductive amination of N-((lr,4r)-4-(3-chloro-4cyanophenoxy)cyclohexyl)-6-(4-formylpiperidin-l-yl)pyridazine-3-carboxamide (Intermediate 3) with 2-(2,6-dioxopiperidtn-3-yl)-5-fluoro-6-(piperazin-l-y])isoindoline-l,3-dione 20 hydrochloride (Intermediate 5) and a reducing agent to provide Compound A:

Compound A

[0017] In another aspect, this disclosure provides an intermediate useful for the synthesis of Compound A which is 6-chloro-N-((lr,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyridazine3-carboxamide (Intermediate 4),

Intermediate 4

[0018] In another aspect, this disclosure provides an ultrapure fonn of Compound A having a purity greater than about 95 wt% .

[0019] In another aspect, this disclosure provides processes for manufacturing an amorphous form of Compound A wherein the process comprises the following steps;

(1) dissolving crystalline Compound A in a solvent to afford a solution of Compound A;

(2) introducing the solution of Compound A from step (1) into a spray dryer to create the amorphous form of Compound A; and (3) Drying the amorphous form of Compound A to remove residual solvent.

[0020) Alternative methods of preparing amorphous forms of Compound A may include lyophilization, hot-melt extrusion, milling, or high-shear mixing.

[0021J In another aspect, this disclosure provides an oral dosage form comprising one or more pharmaceutically acceptable excipients and Compound A, wherein the oral dosage form is selected from the group consisting of a tablet, a sachet, or a capsule.

[0022] In a preferred aspect, the oral dosage form comprises one or more pharmaceutically acceptable excipients and an ultrapure fonn of Compound A.

[0023] In another aspect, this disclosure provides processes of manufacturing a tablet Compound A comprising the following steps:

(1) blending a form of Compound A with at least one pharmaceutically acceptable excipient to create a powder;

(2) delumping the powder from step (1), adding at least one pharmaceutically acceptable excipient, and blending to create a first blend;

(3) granulating the blend from step (2) and passing the résultant powder through a screen to produce a plurality of granules;

(4) adding at least one pharmaceutically excipient to the at least one granule from step (3) and blending to produce a second blend; and (5) compressing the second blend from step (4) into one or more tablets.

[0024] In another aspect, this disclosure provides methods of treating cancer in a subject comprising administering to a subject in need of such treatment one or more unit dosage forms (e.g., tablets) of the present disclosure. In one embodiment, the method further comprises the administration of an additional anti-cancer agent.

[0025] The preceding general areas of utility are given by way of example only and are not întended to limit the scope of the present disclosure or appended claims. Additional objects and advantages associated with the compositions, methods, and processes of the present disclosure will be appreciated by one of ordinary skill in the art in light of the instant claims, description, and examples. For example, the various aspects and embodiments of the invention may be utilized in numerous combinations, ali of which are expressly contemplated by the present description. These additional advantages, objects, and embodiments are expressly included within the scope of the present disclosure. The publications and other materials used herein to iliuminate the background of the invention, and in particular cases, to provide additional details respecting the practice, are incorporated by reference.

[0026] Where applicable or not specifically disclaimed, any one of the embodiments described herein are contemplated to be able to combine with any other one or more embodiments, even though the embodiments are described under different aspects ofthe disclosure.

BRIEF DESCRIPTION OF THE DRAWINGS

[0027] FIG. 1 is a Differential Scanning Calorimetry plot for Compound A.

[0028] FIG. 2 is a dynamic vapor solution (DVS) isotherm plot of Compound A obtained on a laboratory batch of Compound A having the same powder x-ray diffraction pattern as in FIG. 3A. [0029] FIG. 3A is a powder X-ray diffraction pattern of Form 2 of Compound A and FIG. 3B is a table that includes the peak listings of the diffraction pattern in FIG. 3A.

[0030] FIG. 3C is a powder X-ray diffraction pattern of Form 4 of Compound A and FIG. 3D is a table that includes the peak listings of the diffraction pattern in FIG. 3C.

[0031] FIG. 4 is a 'H NMR Spectrum of Compound A in deuterated dimethylsulfoxide (DMSOd₆).

[0032] FIG. 5 is a ^l3C NMR Spectrum of Compound A in deuterated dimethylsulfoxide (DMSOd₆).

[0033] FIG. 6 is a high resolution mass spectrum of Compound A. High resolution mass spectrometry (MS) analyses of Compound A were conducted with flow injection analysis using positive ion electrospray [high-resolution electrospray ionization mass spectrometry (HR-ESI)] on a Thermo Orbitrap MS in Fourier Transform mode.

[0034] FIG. 7 shows the major peaks resulting from MS/MS fragmentation ofthe 812.308 parent ion from the high resolution mass spectrum of Compound A and FIG. 8A and FIG. 8B are an ion map and corresponding table showing the further fragmentation of the observed MS/MS ions (MS³).

[0035] FIG. 9 is an infrared spectrum of Compound A obtained on a Bomem MB-102 FTIR spectrometer equipped with a DuraSamplIR diamond ATR probe. Key features which lend further support to the structure for Compound A are bands at 2225 cm’¹, representing a nitrile stretch vibration, and five peaks between 1774 and 1594, which represent four imide carbonyl vibrations and an amide carbonyl stretch vibration.

[0036] FIG. 10 shows the size distribution, as determined by a sieve analysis, of the Tablets of

Pure Spray-dried Compound A.

[0037] FIG. 11 is a sériés of line graphs showing the dissolution of crystalline vs. amorphous Compound A API. API (l mg/mL) is present in gastric conditions (pH = 2), which is 2X diluted with FaSSIF at 30 minutes to increase the pH to 6.5. (API = active pharmaceutical ingrédient; FaSSIF = fasted state simulated intestinal fluid.)

[0038] FIG. 12 is a sériés of line graphs showing the non-sink dissolution of spray-dried amorphous Compound A produced at multiple scales. API (500 gg/mL) is present in gastric conditions (pH = 2), which is 2X Diluted with FaSSIF at 30 minutes to increase the pH to 6.5.

[0039] FIG. I3 is a sériés of line graphs showing the dissolution of prototype tablets in 900 mL of 37°C 50 mM Na2HPÛ4pH 6.5, 0.5% sodium lauryl sulfate both immediately after manufacture (t=0) and after 2 weeks storage at 50°C/75% RH Open. The dotted line represents accelerating the agitation from 75 to 250 RPM to simulate long-term dissolution. (N=2).

[0040] FIG. 14 is flow diagram of the manufacturing process of the amorphous Compound A spray-dried intermediate product.

[0041] FIG. 15 is a flow diagram ofthe manufacturing process of Compound A tablets.

[0042] FIG. 16A is a chromatogram of crude Compound A, as produced by the First-Generation synthesis. Column: Shim-pack XR-ODS, 2.2gm 3.0 x 50 mm. Mobile phase A: Water/0.05%TFA. Mobile phase B: Acetonitrile/0.05%TFA. Flow rate: 1.2 mL/min. Column temperature 40 °C. Detector, UV 254nm. FIG. 16B is the solvent gradient used to obtain the chromatogram in FIG. 16A. FIG. 16C is a chromatograph of Compound A following purification by prep-HPLC, as produced by the First-Generation synthesis. Column: Shim-pack XR-ODS, 2.2pm 3.0 x 50 mm. Mobile phase A: Water/0.05%TFA. Mobile phase B: Acetonitrile/0.05%TFA. Flow rate: 1.2 mL/min. Column temperature 40 °C. Detector, UV 254nm. FIG. 16D is the solvent gradient used to obtain the chromatogram in FIG. 16C

[0043] FIG. i 7A is a chromatogram of crude Compound A, as produced by the Second-Generation synthesis. Column: Atlantis T3, 3 gm, 4.6 x 150 mm. Mobile Phase A: 0.1% TFA in Water. Mobile Phase B:0.05% TFA in 75:25 ACN/MeOH. Flow Rate: 1.0 mL/min. Column temperature 45 °C. Detector: 260nm. FIG. 17B is a chromatogram of purified Compound A, as produced by the second-generation synthesis. Column: Atlantis T3, 3 gm, 4.6 x 150 mm. Mobile Phase A: 0.1% TFA in Water. Mobile Phase B:0.05% TFA in 75:25 ACN/MeOH. Flow Rate: 1.0 mL/min.

Column température 45 C. Detector: 260nm. FIG. 17C is the solvent gradient used to obtain the chromatogram in FIG. 17A and FIG. 17B.

[0044| FIG. ISA is a chromatogram of crude Compound A, as produced by the third-generation synthesis. Column: Atlantis T3, 3pm, 4.6 x 150 mm. Mobile Phase A: Water with 0.1% TFA. Mobile Phase B: 75:25 Acetonitrile/MeOH with 0.05% TFA. Column Température: 45 °C. Détection: 260 nm. FIG. 18B is the solvent gradient used to obtain the chromatogram în FIG. 18A. [0045] FIG. 19 is the 'H NMR spectrum of Intermediate 4, as produced by the second-génération synthesis, in deuterated dimethylsulfoxide (DMSO-dô).

[0046] FIG. 20 is an H'-NMR spectrum of Intermediate 8, produced by the second-generation synthesis, in deuterated dimethylsulfoxide (DMSO-dô).

[0047] FIG. 21 is an H'-NMR spectrum of Intermediate 9, produced by the second-generation synthesis, in deuterated dimethylsulfoxide (DMSO-dô).

[0048] FIG. 22 is an H'-NMR spectrum of Intermediate 5, produced by the second-generation synthesis, în deuterated dimethylsulfoxide (DMSO-dô).

[0049] FIG. 23 is an H'-NMR spectrum of Intermediate 2, produced by the third-generation synthesis, in deuterated dimethylsulfoxide (DMSO-dô).

[0050] FIG. 24 is an H'-NMR spectrum of Intermediate 3, produced by the third-generation synthesis, in deuterated dimethylsulfoxide (DMSO-dô).

[0051] FIG. 25 is an H'-NMR spectrum of Compound A, produced by the third-generation synthesis, in deuterated dimethylsulfoxide (DMSO-dô)·

[0052] FIG. 26 is a chromatogram of purified Compound A, as produced by the fifth-génération synthesis.

[0053] FIG. 27 shows a dissolution comparison between 5, 10, 20 and 40% SDI tablet formulations. The vertical line represents the point of an “infinity” spin, when the paddle speed ïncreased from 75 to 250 RPM.

[0054] FIG. 28 shows a dissolution comparison between 5% and 20% SDI loaded tablet formulations (Dl, D2, D3 and D4). The vertical line represents the point of an “infinity” spin, when the paddle speed ïncreased from 75 to 250 RPM.

[0055] FIG. 29 shows dissolution comparison between D2, GI * and G2* tablet compositions (525 mg tablet). Normal îzed for variable assay to the 90 minute time point. The vertical line represents the point of an “infinity” spin when the paddle speed increased from 75 to 250 RPM.

[0056] FIG. 30A and FIG. 30B show a comparison of granule size between the granules (A) and the final blend (B)

[0057] FIG. 31 shows a dissolution comparison between D2, and G2 pre-demo tablets compressed at 2.0 and 2.5 MPa tensile strength (525 mg tablet). Normalized for variable assay to the 90 minute time point.

[0058] FIG. 32 shows a comparison of granule size between Compound A final blend démonstration batch for 20% API and pre-demo batch.

[0059] FIG. 33 shows a dissolution comparison between 35 mg, 105 mg, and 140 mg démonstration batch tablets.

DETAILED DESCRIPTION

[0060] The present disclosure is related in certain aspects to US Patent Application Serial No. 15/730,728, issued as US Patent No. 10,584,101; US Patent Application Serial No. 16/577,901, îssued as US Patent No. 10,844,021; and US Provisional Patent Application Serial Nos. 62/528,385 and 62/406,888. The present disclosure is related in certain aspects to US Patent Application Serial No. 17/075,808, now published as US 2021/0113557, and Provisional Patent Application Serial Nos. US 62/924,655, 62/945,418, 63/028,843, and 63/032,453. Each of these applications are incorporated herein by reference in their entireties for ail purposes.

Définitions

[0061] Unless otherwise defined, ail technical and scientific ternis used herein hâve the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The terminology used in the description is întended to describe particular embodiments only, and is not întended to limit the scope of the invention.

[00621 Where a range of values is provided, it is understood that the range includes both of the endpoints with that range, as well as all intervening values.

[0063] The following terms are used to describe the present disclosure. In instances where a term is not specifically defined herein, that term is given an art-recognized meaning by those of ordinary skill applying that term in context to its use in describing the present invention.

[0064] The articles a and an as used herein and in the appended claims are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article unless the context clearly indicates otherwise. By way of example, an ultrapure form means one ultrapure form or more than one ultrapure form.

|0065] The phrase and/or, as used herein in the spécification and in the claims, should be understood to mean either or both. Other éléments may optionally be present other than the 5 éléments specifically identified by the and/or clause. Thus, as a non-limiting example, a reference to A and/or B, when used in conjunction with open-ended language such as comprising can refer, in one embodiment, to A only (optionally including éléments other than B); in another embodiment, to B only (optionally including éléments other than A); in yet another embodiment, to both A and B (optionally including other éléments).

[0066] As used herein in the spécification and in the claims, or should be understood to hâve the same meaning as and/or as defined above. For example, when separating items in a list, or or and/or shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of éléments, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as only one of or exactly one of, or, when used in 15 the claims, consisting of, will refer to the inclusion of exactly one element of a number or list of éléments. In general, the term or as used herein shall only be interpreted as indicating exclusive alternatives (i.e., one or the other but not both) when preceded by terms of exclusivity, such as either, one of, only one of, or exactly one of.

[0067] In the claims, as well as in the spécification, ail transitional phrases such as comprising, 20 including, carrying, having, containing, involving, holding, composed of, and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases consisting of and consisting essentially of shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

[0068] As used herein in the spécification and in the claims, the phrase at least one, in reference to a list of one or more éléments, means at least one element selected from any one or more of the éléments in the list of éléments, but not necessarily including at least one of each and every element specifically listed within the list of éléments and not excluding any combinations of éléments in the list of éléments. This définition also allows that éléments may optionally be present other than 30 the éléments specifically identified within the list of éléments to which the phrase at least one refers, whether related or unrelated to those éléments specifically identified. Thus, as a non21107

limiting example, at least one of A and B (or, equivalently, at least one of A or B, or, equivalently at least one of A and/or B) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including éléments other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present 5 (and optionally including éléments other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other éléments); etc.

[0069] It should also be understood that, in certain methods described herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the 10 order in which the steps or acts of the method are recîted unless the context indicates otherwise.

[0070] The terms co-administration and co-administering or “combination therapy” can refer to both concurrent administration (administration of two or more therapeutic agents at the same time) and time-varied administration (administration of one or more therapeutic agents at a time different from that of the administration of an additional therapeutic agent or agents), as long as the therapeutic agents are present in the patient to some extent, preferably at effective amounts, at the same time. In certain preferred aspects, one or more of the present compounds described herein, are co-administered in combination with at least one additional bioactive agent, especially including an anti-cancer agent. In particularly preferred aspects, the co-administration of compounds results in synergistic activity and/or therapy, such as, e.g., anti-cancer activity.

[00711 The term “effective” can mean, but is in no way limited to, that amount/dose of the active pharmaceutical ingrédient, which, when used in the context of its intended use, effectuâtes or is sufficient to prevent, inhibit the occurrence, ameliorate, delay or treat (alleviate a symptom to some extent, preferably ail) the symptoms of a condition, disorder or disease state in a subject in need of such treatment or receiving such treatment. The term “effective” subsumes ail other effective amount or effective concentration terms, e.g., “effective amount/dose,” “pharmaceutically effective amount/dose” or “therapeutically effective amount/dose,” which are otherwise described or used in the present application.

[0072] The effective amount dépends on the âge, weight, gender, previous patient history or family history, type and severity of disease, the composition used, the route of administration, the stage 30 of treatment, the type of mammal being treated, the physical characteristics of the spécifie mammal under considération, concurrent médication, and other factors which those skilled in the medical arts will recognize. The exact amount can be ascertainable by one skilled in the art using known techniques in view of clinical data and medical expérience (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and 5 Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0073] The terms “pharmacological composition,” “pharmaceutical composition,” “therapeutîc composition,” “therapeutîc formulation,” and “pharmaceutically acceptable formulation” are known in the art.

[0074] The terms pharmaceutically acceptable and “pharmacologically acceptable” are known 10 in the art.

[0075] The terms pharmaceutically acceptable carrier and “pharmacologically acceptable carrier” mean, but are not limited to, any and ail solvents, excipients, dispersion media, coatings, antibacterîal and antifungal agents, isotonie and absorption delaying agents, and the like, compatible with pharmaceutical administration. Suitable carriers are described in the most recent 15 édition of Remington's Pharmaceutical Sciences, a standard reference text in the field, which is incorporated herein by reference. Preferred examples of such carriers or diluents include, but are not limited to, water, saline, Ringer’s solution, dextrose solution, and 5% human sérum albumin. Liposomes and non-aqueous vehicles such as fixed oils may also be used. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any 20 conventional media or agent is incompatible with the active compound, use thereof în the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.

10076] The term “systemic administration refers to a route of administration that is, e.g., enterai or parentéral, and leads to systemic absorption or accumulation of drugs in the blood stream 25 followed by distribution throughout the entire body. Suitable forms, in part, dépend upon the use or the route of entry, for example oral, transdermal, or by injection. For example, pharmacological compositions injected into the blood stream should be soluble. Other factors to avoid include toxicity, and any forms which prevent the composition or formulation from exerting its effect. [0077] In one embodiment, Compound A may be solubilized în a vehicle suitable for parenieral 30 administration by using a cyclodextrin. Exemplary cyclodextrins suitable for this process include, without limitation, sulfobetylether-p-cyclodextrin and (2-hydroxypropyl)-p-cyclodextrin.

[0078] Administration routes which lead to systemic absorption are known and include, without limitations; intravenous, subeutaneous, intra-peritoneal, inhalation, oral, buccal, sublingual, transdermal, intra-ocular, intra-nasal, intra-pulmonary, rectal, vaginal, and intra-muscular. The rate of entry of a drug into the circulation is a function of molecular weight or size. The use of a 5 liposome or other drug carrier comprising Compound A may potentiaily localize the drug, for example, in certain tissue types, such as the tissues of the reticular endothélial system (RES). A liposome formulation which can facilitate the association of drug with the surface of cells, such as, lymphocytes and macrophages, may also be usefui.

[0079] The term “local administration refers to a route of administration in which the agent is 10 delivered to a site that is proximal, e.g., within about I0 cm, to the site of the lésion or disease.

(0080] The formulation of the present invention preferably provides “oral administration” as used herein refers to enterai, buccal, sublabial, or sublingual médications in the form of tablets, capsules, syrups, powders, granules, pastilles, solutions, tinctures, élixirs, émulsions, hydrogels, teas, films, dîsintegrating tablets, mouthwashes, and others.

[0081] Suitable forms for oral administration may include one or more pharmaceutically acceptable excipients, including, for example, carriers, fillers, surfactants, diluents, sweeteners, disintegrants, binders, lubricants, glidants, colorants, flavors, stabilizing agents, coatings, or any mixtures thereof.

[0082] Carriers include, pharmaceutically acceptable excipients and diluents and means a 20 material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject. Examples include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

[0083] Fillers include, but are not limited to, mannitol, sucrose, sorbitol, xylitol, microcrystalline cellulose, lactose, silicic acid, silicified microcrystalline cellulose, hydroxypropyl methyIcellulose, hydroxypropyl cellulose, starch, pullulan and fast dissolving carbohydrates such as Pharmaburst™ fast dîsintegrating tablets, mixtures thereof, and the like. For examples of fast-dissolving carbohydrates see, e.g., U.S. Patent No. 8,617,588, which is incorporated herein by reference.

|0084| Surfactants include, but are not limited to, non-ionic, anionic, cationic, amphoteric or zwitterionic surfactants. Examples of suitable non-ionic surfactants include ethoxylated triglycérides; fatty alcohol ethoxylates; alkylphenol ethoxylates; fatty acid ethoxylates; fatty amide ethoxylates; fatty amine ethoxylates; sorbitan alkanoates; ethylated sorbitan alkanoates; alkyl ethoxylates; Pluronics™; alkyl polyglucosides; stearol ethoxylates; alkyl polyglycosîdes. Examples of suitable anionic surfactants include alkylether sulfates; alkylether carboxylates; alkyl 5 benzene sulfonates; alkylether phosphates; dialkyl sulfosuccinates; sarcosinates; alkyl sulfonates;

soaps; alkyl sulfates; alkyl carboxylates; alkyl phosphates; paraffîn sulfonates; secondary n-alkane sulfonates; alpha-olefin sulfonates; isethionate sulfonates. Examples of suitable cationic surfactants include fatty amine salts; fatty diamine salts; quaternary ammonium compounds; phosphonium surfactants; sulfonium surfactants; sulfoxonium surfactants. Examples of suitable 10 zwitterionic surfactants include N-alkyl dérivatives of amino acids (such as glycine, betaine, aminopropionic acid); imidazoline surfactants; amine oxides; amidobetaines. Non-limiting examples of a surfactant that can be used în the ospemifene solid dispersions, include, for example. Tween 20, Tween 80, Span 20, Span 80, sodium docusate (e.g., AOT), sodium lauryl sulfate, and poloxamers (e.g., poloxamer 407, Kolliphor® EL, Pluronic F68). Poloxamers are also known by 15 the trade names Synperonics®, Pluronics®, and Kolliphor®/Cremophor®.

[0085] Diluents include, but are not limited to, carbohydrates such as monosaccharides like glucose, oligosaccharides like sucrose and lactose (including anhydrous lactose and lactose monohydrate), starch such as maize starch, potato starch, rice starch and wheat starch, pregelatinized starch, calcium hydrogen phosphate, and sugar alcohols like sorbitol, mannitol, 20 erythritol, and xylitol.

[0086] Swfeeteners include, but are not limited to, sucrose, high fructose corn syrup, fructose, glucose, aspartame, acesulfame K, sucralose, cyclamate, sodium saccharin, neotame, rebaudioside A, and other stevia-based sweeteners.

[0087] Disintegrants include, but are not limited to, sodium starch glycolate, sodium 25 carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, chitosan, agar, alginic acid, calcium alginate, methyl cellulose, microcrystalline cellulose, powdered cellulose, lower alkylsubstituted hydroxypropyl cellulose, hydroxyIpropy! starch, lowsubstituted hydroxypropylcellulose, polacrilin potassium, starch, pregelatinized starch, sodium alginate, magnésium aluminum silicate, polacrilin potassium, povidone, sodium starch glycolate, 30 mixtures thereof, and the like.

I6

[0088] Binders include, but are not limited to, hydroxypropylmethylcelluiose (HPMC), hydroxypropyl cellulose (HPC), povidone, copovidone (copolymers of vinylpyrrolidone with other vinyl derivatives), methyIceIlulose, powdered acacia, gelatin, gum arabicum, guar gum, carbomer such as carbopol, and polyméthacrylates.

[0089] Lubricants include, but are not limited to, calcium stéarate, glyceryl monostearate, glyceryl behenate, glyceryl palmitostearate, hexagonal boron nitride, hydrogenated vegetable oil, light minerai oil, magnésium stéarate, minerai oil, polyethylene glycol, poloxamer, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, zinc stéarate, mixtures thereof, and the like.

[0090] Glidants include, but are not limited to, Silicon dioxide, colloïdal Silicon dioxide, calcium silicate, magnésium silicate, magnésium trisilicate, talc, starch, mixtures thereof, and the like.

[0091] Flavors include, but are not limited to, menthol, peppermint oil, peppermint spirit, vanillin, and almond oil.

[0092] The term “Ubiquitin Ligase” refers to a family of proteins that facilitate the transfer of ubiquitin to a spécifie substrate protein, targeting the substrate protein for dégradation. For example, cereblon is an E3 Ubiquitin Ligase protein that alone or in combination with an E2 ubiquitin-conjugating enzyme causes the covalent attachment of several ubiquitin molécules to an available lysine residue on a target protein, thereby targeting the protein for dégradation b\ the protéasome. Thus, E3 ubiquitin ligase, alone or in complex with an E2 ubiquitin conjugating enzyme, causes the transfer of ubiquitin to targeted proteins. In general, the ubiquitin ligase is involved în polyubiquitinatîon such that a second ubiquitin is attached to the first; a third is attached to the second; and a fourth is attached to the third. Such polyubiquitination marks the protein for dégradation by the protéasome.

[0093] The ternis patient” and “subject” are used throughout this spécification to referto an animal, preferably a mammal, more preferably a human or a domesticated or companion animal, to whom treatment, including prophylactic treatment, with a composition according to the present disclosure, is provided. For treatment of those conditions or disease States spécifie for a spécifie type of animal, such as a human patient, the term “patient” refers to that spécifie type of animal, including a domesticated or companion animal such as a dog or cat, or a farm animai such as a horse, cow, sheep, etc. In general, in the present disclosure, the term “patient” refers to a human patient unless otherwise stated or implied from the context of the use of the term.

[0094] “Pharmaceutically acceptable sait”, as used herein with respect to a compound of the disclosure, means a sait form of that compound where the counterion is generaily regarded as safe for therapeutic administration to a patient or subject, or otherwise présents an acceptable risk/benefit profile permitting therapeutic administration to a patient or subject. The term 5 “pharmaceutically acceptable sait”, as used herein with respect to a compound may also include solvatés (e.g., hydrates) of such a sait, as well as cocrystals thereof.

[0095] Représentative pharmaceutically acceptable salts include, e.g., water-soluble and waterinsoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, 10 calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluoro phosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionale, lactate, lactobionate, laurate, magnésium, malate, maleate, mandelate, mesyîate, methy Ibromide, methyinitrate, methylsulfate, mucate, napsylate, nitrate, N15 methy Iglucamine ammonium sait, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate ( l, l-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate, phosphate/diphosphate, picrate, polygaiacturonate, propionate, p-toluenesulfonate, salicylate, stéarate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts.

[0096] Solvaté means a solvent addition form of Compound A that contains either a stoichîometric or non-stoichiometric amounts of solvent. Some compounds hâve a tendency to trap a fixed moiar ratio of solvent molécules in the crystalline solid state, thus forming a solvaté. Ifthe solvent is water the solvaté formed is a hydrate, when the solvent is alcohol, the solvaté formed is an alcoholate. Hydrates are formed by the combination of one or more molécules of water with 25 Compound A in which the water retains its molecular state as Η₂Ο, such combination being able to form one or more hydrates. In the hydrates, the water molécules are attached through secondary valencies by intermolecular forces, in particular hydrogen bridges. Solid hydrates contain water as so-called crystal water in stoichîometric ratios, where the water molécules do not hâve to be équivalent with respect to their binding state. Examples of hydrates are sesquihydrates, 30 monohydrates, dihydrates or trihydrates. Equally suitable are the hydrates of the pharmaceutically acceptable salts of Compound A.

[0097] Cocrystals represent novel forms of drug substances that would be suitable for incorporation in pharmaceutical solid dosage forms, and should enable formulation scientists to overcome a variety of problems that are encountered during development of traditional formulations. Cocrystals may be viewed as being an alternative to polymorphs, solvatomorphs, 5 and salts, as cocrystals represent a different approach to solve problems related to dissolution, crystallinity, and hygroscopicity, among others. For further discussions of cocrystals, see: Aitipaumula et al. “Polymorphs, Salts, and Cocrystals: What’s in a Name?” Crystal Growth Des. 2012, 12, 5, 2147-2152; and Brittain “Pharmaceutical Cocrystals: The Coming Wave ofNew Drug Substances” J. Pharm. Sci. 2013, 102, 2, 311-317; both of which are incorporated by reference 10 herein in their entîreties.

[0098] The term “powder X-ray diffraction pattern”, “PXRD pattern”, “PXRD”, “powder X-ray diffraction diagram”, “X-ray diffraction pattern”, or “XRPD” refers to the experimentally observed diffractogram or parameters derived therefrom. Powder X-ray diffraction patterns are characterized by peak position (abscissa) and peak intensities (ordinate).

[0099] The tenn “2 thêta value” or “2Θ” refers to the peak position in degrees based on the experimental setup of the X-ray diffraction experiment and is a common abscissa unit in diffraction patterns. The experimental setup requires that if a reflection is diffracted when the incoming beam forms an angle thêta (Θ) with a certain lattice plane, the reflected beam is recorded at an angle 2 thêta (2Θ). The reference herein to spécifie 20 values for a spécifie solid form is întended to mean the 2Θ values (in degrees) as measured using the X-ray diffraction experimental conditions as described herein.

[0100] Isotopic dérivative, as referred to herein, relates to Compound A that is isotopically enriched or labelled (with respect to one or more atoms of the compound) with one or more stable isotopes. Thus, in one embodiment, Compound A is isotopically enriched or labelled with one or 25 more atoms such as deuterium in place of one or more hydrogens.

[0101 ] Metastatic prostate cancer, or métastasés, refer to prostate cancer that has spread beyond the prostate to other parts or organs in the body, e.g., bones, lymph nodes, liver, lungs, brain.

[0102] Castrate-résistant prostate cancer, or castration-résistant prostate cancer, (or prostate cancer that is castrate- or castration-résistant), is a type of prostate cancer that continues to grow 30 even when the amount of testosterone in the body is reduced to very low levels.

[0103] Metastatic, castrate-resistant prostate cancer is a type of prostate cancer that has metastasized and continues to grow even when the amount of testosterone in the body is reduced to very low levels.

[0104] As used herein, ‘Treating”, “treatment”, and the like, describe the administration of a 5 pharmaceutical composition of the invention to a subject or patient for the purpose of combating a disease, condition, or disorder, which includes decreasing, mitigating or eliminating one or more symptoms or complications of the disease, condition or disorder, or decreasing, mitigating, or eliminating the disease, condition or disorder.

[0105] As used herein, “prevent”, “preventing” and the like describe stopping the onset of the 10 disease, condition or disorder, or one or more symptoms or complications thereof.

[0106] “C_max”, as used herein, refers to the observed maximum (peak) plasma concentration of a specified compound in the subject or patient after administration of a dose of that compound to the subject or patient.

[0107] “AUC”, as used herein, refers to the total area under the plasma concentration-time curve, 15 which is a measure of exposure to a compound of interest, and is the intégral of the concentration- time curve after a single dose or at steady state. AUC is expressed in units of ng*H/mL (ng x Η/mL), where “H” refers to hours.

[0108] “AUCmf”, as used herein, refers to the AUC from 0 hours to the end of a dosing interval.

[0109] “AUC0.24” means the AUC from 0 hours to 24 hours after administration of a single dose.

[0110] “Controlled release” or “CR” as used herein with respect to an oral dosage form refers to a compound of the disclosure that is released from the dosage form, other than in an immédiate release profile, according to a pre-determined profile that may include when and where release occurs after oral administration and/or a specified rate of release over a specified time period [OUI] “Controlled release agent” as used herein with respect to an oral dosage form of the 25 disclosure refers to one or more substances or materials that modify the release profile of a compound of the invention from the dosage form. Controlled release agents may be organic or inorganic, naturally occurring or synthetic, such as polymeric materials, triglycérides, dérivatives of triglycérides, fatty acids and salts of fatty acids, talc, boric acid, colloïdal silica, cellulosic dérivatives, and combinations thereof.

[0112] “Enteric coating” as used herein with respect to a dosage form of the disclosure refers to a pH-dependent material that surrounds a core comprising a compound of the disclosure and which romains substantially intact in the acid environment of the stomach, but which subsequently dissolves in the pH environment of the intestines,

[0113] “Gastro-résistant” or “GR” as applied to a CR oral dosage form described herein means that release ofa compound ofthe disclosure inthe stomach of a subject shall not exceed 5%, 2.5%, 1 % or 0.5% of the total amount of the compound of the disclosure in the dosage form.

[0114] “Loss on Drying” refers to the loss of weight expressed as percentage w/w/ resulting from water and volatile matter of any kind that can be driven off under specifîed conditions. Loss on Drying can be determined by persons of skill in the art using standard methods, including, for example, USP <731>.

[0115] The “Residue on Ignition” test (also known as the sulfated ash test) uses a procedure to measure the amount of residual substance not volatilized from a sample when the sample is ignited in the presence of sulfuric acid according to the procedure described below. This test is usually used for determinîng the content of inorganic impurities in an organic substance. Residue on Ignition can be determined by persons of skill in the art using standard methods, including, for example, USP <281>.

[0116|‘’COA” stand for certifîcate of analysis.

[0117] “Oral dosage form” as used herein refers to a pharmaceutical drug product that contains a specifîed amount (dose) of a compound of the disclosure as the active ingrédient, or a pharmaceutically acceptable sait and/or solvaté thereof, and inactive components (excipients), formulated into a particular configuration that is suitable for oral administration, such as an oral tablet, liquid, or capsule, in one embodiment, the oral dosage form comprises a tablet. In one embodiment, the oral dosage form comprises a tablet that can be scored. In one embodiment, the oral dosage form comprises a sublingual tablet. In one embodiment, the oral dosage form comprises a capsule, which can be taken intact or used as a sprinkle onto food (e.g., appiesauce or yogurt). In one embodiment, the oral dosage form comprises a sachet.

[0118] The term “about” and the like, as used herein, in association with numeric values or ranges, reflects the fact that there is a certain level of variation that is recognized and tolerated in the art due to practical and/or theoretîcal limitations. For example, minor variation is tolerated due to inhérent variances in the manner in which certain devices operate and/or measurements are taken. Thus, the term “about” is normally used to encompass values within standard error. In one embodiment, the term “about” as part of a quantitative expression such as “about X”, includes any value that is up to 10% higher or lower than X, and also includes any numerical value that fans between X-10% and X+10% (e.g., X-5% and X+5%, or X-3% and X+3%). Thus, for example, a weight of about 40 g may include a weight of between 36 to 44 g, inclusive of the endpoints; a température of about 100°C may include a température of 90°C to ] 10°C, inclusive of endpoints; and a température range of about 90 - i00°C, may include a range of 81 - 110°C, inclusive ofthe endpoints. Thus, for example, a percent composition of about 50% may include a percent composition of between 45% to 55%, inclusive of the endpoints.

[0119] As used herein, “about 0°C” includes a température of -2°C to 2°C, inclusive of endpoints. [0120] As used herein, the term “CDK inhibitor” refers to a compound that inhibits the enzymes in humans referred to as cyclin-dependent kinases (CDK). In one embodiment, the CDK inhibitor is a CDK4/6 inhibitor. As used herein, the term “CDK4/6 inhibitor” refers to a compound that inhibits CDK 4 and/or 6. Examples of a CDK inhibitor include, without limitation, SHR6390, trilaciclib, lerociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, palbociclib, or any pharmaceutically acceptable sait thereof. In one embodiment, the CDK inhibitor is palbociclib or a pharmaceutically acceptable sait thereof.

[0121] As used herein, the term “PARP inhibitor” refers to a compound that inhibits the enzymes in humans referred to as poly ADP ribose polymerase (PARP). Examples of a PARP inhibitor include, without limitation, olaparib, rucaparib, talazoparib, niraparib, veliparib, pamiparib, CEP 9722, E7016, 3-aminobenzamide, mefuparib, and AZD2281.

[0122] “Comprising” or “comprises” as applied to a particular dosage form, composition, use, method or process described or claimed herein means that the dosage form, composition, use, method, or process includes ail of the recited éléments in a spécifie description or claim, but does not exclude other éléments. “Consists essentially of’ and “consisting essentially of’ means that the described or claimed composition, dosage form, method, use, or process does not exclude other materials or steps that do not materially affect the recited physical, pharmacological, pharmacokinetic properties or therapeutic effects of the composition, dosage form, method, use, or process. “Consists of’ and “consisting of’ means the exclusion of more than trace éléments of other ingrédients and substantial method or process steps.

[0123] “Fasted condition” or “fasted State” as used to describe a subject means the subject has not eaten for at least 4 hours before a time point of interest, such as the time of administering

Compound A. In an embodiment, a subject in the fasted state has not eaten for at least any of 6, 8, or 12 hours prior to administration of a compound of the disclosure.

[0124] “Fed condition” or “fed State” as used to describe a subject herein means the subject has eaten less than 4 hours before a time point of interest, such as the time of administering a compound ofthe disclosure. In an embodiment, a subject in the fed state has eaten within at least any of 3, 2, I or 0.5 hours prior to administration of a compound of the disclosure.

[01251 “Antacid médication”, as used herein, refers to a substance that neutralîzes stomach acidity in the subject. Antacids include, without limitation, bismuth subsalîcylate, famotidine, and flavored liquids containing aluminum hydroxide and magnésium hydroxide (Maalox®). In one aspect, this application pertains to a subject who is administered Compound A, or a composition comprising Compound A, who is also taking, or being administered, an antacid médication.

[0126] Ail percentages provided herein are percentages by weight, and may be abbreviated wt% or (w/w), unless indicated otherwise,

[0127] In one embodiment, the term “ultrapure”, as used herein with reference to Compound A, refers to any of crystalline or amorphous forms of Compound A described herein that hâve a purity equal to or greater than about 95%, 96%, 97%, 98%, 99%, 99.5, or 99.9 wt%.

[0128] In one embodiment, the term “ultrapure”, as used herein with reference to Compound A, refers to any of crystalline or amorphous forms of Compound A described herein that contains less than about 5%, 4%, 3%, 2%, 1.9%, 1.8%, 1.7%, 1.6%, 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% of one or more impuritîes.

[0129] In one embodiment, the term “ultrapure”, as used herein with reference to Compound A, refers to any of crystalline or amorphous forms of Compound A described herein that hâve a purity equal to or greater than about 95%, 96%, 97%, 98%, 99%, 99.5, or 99.9 wt%, and also contains less than about 5%, 4%, 3%, 2%, 1.9%, 1.8%, 1.7%, 1.6%, 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% of one or more impuritîes.

[0130| As used herein, the term “impurity” refers to an unwanted compound, trace métal, or solvent that contaminâtes Compound A. In one embodiment, the impurity is a compound selected from the group consisting of Intermediate 2, Intermediate 3, Intennediate 5, Impurity l, Impurity 2, Impurity 3, and Impurity 4. In one embodiment, the impurity is a solvent that is selected from the group consisting of dîchloromethane, methanol, and acetonitrile.

[0131] “Stable,” as used herein with reference to Compound A, refers to forms of Compound A, including ultrapure forms, crystalline forms, ultrapure crystalline forms, amorphous forms, and ultrapure amorphous forms, that stably retain purity equal to, or greater than, 95%, 96%, 97%, 98%, 99%, 99.5, or 99.9% over a period of time (such as 6 months, 12 months, or 24 months) and under specified conditions (e.g., température and humidity) (such as 4 °C, 25 °C, or 40 °C).

[0132] Compound A refers to the compound: N-[(lr,4r)-4-(3-chloro-4cyanophenoxy)cyclohexyl]-6-[4-({4-[2-(2,6-dioxopiperidm-3-yl)-6-fluoro-l,3-dioxo-2,3dihydro-lH-isoindol-5-yl]piperazin-l-yl]methyl)piperidin-l-yl]pyridazine-3-carboxamide, that has a molecular formula of C41H43CIFN9O6, and has the following structural formula:

(Compound A).

[0133] Intermediate 1, as used herein, refers to the compound with the following structural formula:

Intermediate 1

[0134] Intermediate 2, as used herein, refers to the compound with the following structural formula:

Intermediate 2

[0135] Intermediate 3, as used herein, refers to the compound with the following structural formula:

[0136] Intermediate 4, as used herein, refers to the compound with the following structural formula:

Ck N, T ï ^h ° u Intermediate 4 5 |0137] Intennediate 5, as formula: o O _Cl- > ^V O Intermediate 5 [0138] Intermediate 6, as 10 formula: HO,. Tl ° 1 H Intermediate 6 [0139] Intermediate 7, as formula:

^.N '^^Xl used herein, refers to the compound with the following structural -NH used herein, refers to the compound with the following structural used herein, refers to the compound with the following structural

Intermediate 7

[0140] Intermediate 8, as used herein, refers to the compound with the following structural formula:

[01411 Intermediate 9, as used herein, refers to the compound with the following structural formula:

\ /=° O as used herein, refers to the compound with the following structural

OH

Intermediate 9

[0142] Intermediate 10_: formula:

HO

Intermediate 10

[0143] Impurity 1, as used herein, refers to the compound with the following structural formula:

Impurity 1

[0144] Impurity 2, as used herein, refers to the compound with the foilowing structural formula:

[0145] Impurity 3, as used herein, refers to the compound with the foilowing structural formula:

Impurity 3

[0146] Impurity' 4, as used herein, refers to the compound with the foilowing structural formula:

Compound A

The atoms in Compound A may be numbered as follows:

[0147] The centers carbon 10 and 7 are meso and by définition hâve no chirality and by définition are not stereogenic. The 1 A-trans relationship of the amide and ether on carbons 10 and 7,

respectively, is supported by 'H nuclear magnetic résonance (NMR.) in conjonction with 2-D nOe

NMR.

[0148] Compound A has a stereogenic center at carbon 36 (denoted by an * below). The starting materials for Compound A are sourced from racemic precursors, hence the molécule îs racemic.

Thus, Compound A, in one embodiment, refers to a 50/50 mixture of enantiomers - ent-1 and ent2 - which hâve the following structures:

[0149] As used herein, Compound A refers to a compound that is entirely ent-1, entirely ent-2, or 10 any mixture of ent-1 and ent-2, including, for example a 50/50 (racemic) mixture of ent-1 and ent2.

[0150] Compound A was originally disclosed in US Patent Application No. 15/730,728, which granted as US Patent No. 10,584,101 and which is incorporated by reference herein in its entirety.

I 5 MANUFACTURING PROCESSES OF COMPOUND A

[0151] First Génération Process

[0152] The first génération manufacturing process for Compound A was described in U.S. Patent No. 10,584,101, which is incorporated herein by reference. The process is summarized below in Scheme 1 and in the Examples section herein.

[0153] Scheme 1. First Génération Manufacturing Process of Compound A

Intermediate 2

Intermediate 3

Intermediate 5

Compound A

[0154J Second, Third, Fourth, and Fîfth Génération Processes.

|0155] The second, third, fourth, and fîfth génération processes are disclosed below and in the examples herein. These processes possess advantageous properties compared to the first génération synthesis. For example, the first génération process yielded Compound A with a purîty of about 98 %. In contrast, later-generation processes yield Compound A with higher purîty, e.g. greater than 98%, greater than 99%, greater than 99.5%, etc.

[0156] Second Génération Process

[0157] The second génération manufacturing process for Compound A is described below in Schemes 2-4 and in the Examples herein.

[0158] The synthesis used for the manufacture of Intermédiare 4 is shown below in Scheme 2.

[0159] Scheme 2. Synthetic Process for the Manufacture of Intennediate 4.

Intermediate 7

[0160] Step 1 involves an SnAr reaction between commercially-availabié 2,4- dichlorobenzonitrile and tert-butyl ((lr,4r)-4-hydroxycyclohexyl)carbamate in dimethylacetamide (DMA) with sodium hydrîde at 45° to afford Intermediate 1. The reaction is worked up with water and the precipitate dried to afford Intermediate L In the second step, the Boc protecting group is removed from Intermediate 1 by adding acetyl chloride in methanol at rt and the product is recrystallized in methyl tert-butyl ether to afford Intermediate 7. The third step involves amide coupling of Intermediate 7 and 6-chloropyridazine-3-carboxylic acid in ethyl acetate with triethylamine and propanephosphonic acid anhydride (T3P) to provide Intermediate 4. The reaction is quenched with 1 N aqueous HCl, and the crude Intermediate 4 is rinsed with ethyl acetate, fïltered and dried. Intermediate 4 is added to isopropyl acetate and dimethylacetamide, fïltered, and rinsed with IPAc.

[0161] The synthesis used for the manufacture of Intermediate 5 is shown below in Scheme 3.

[0162] Scheme 3. Synthetic Process for the Manufacture of intermediate 5.

[0163] In the first step, commercially-available 4,5-difluorophthalic acid and 3-aminopiperidine2,6-dione are refluxed in acetic acid/acetate, and the reaction is quenched in water and the precipitate washed and dried to afford Intermediate 8. The second step in volves an SnAr reaction 5 between Intermediate 8 and commerciaily-avaiiable Boc-piperazine in N-methyl-2-pyrrolidone (NMP) with sodium bicarbonate at 90° to afford Intermediate 9. The reaction mixture is worked up with water/acetonitrile, filtered, washed with water, and dried to afford Intermediate 9. In the third step, the Boc protecting group is removed from Intermediate 9 with HCl in methanol and methylene chloride. The reaction mixture is filtered and rinsed with methanol and methylene 10 chloride to afford crude Intermediate 5 as a hydrochloride sait. Intermediate 5 is dissolved in water and dimethylacetamide, and recrystallized in isopropanol.

Scheme 4. Second Génération Manufacturing Process of Compound

Intermediate 3

Intermediate 5

Compound A

[0164] Step 1 in the process includes a SnAr reaction between Intermediate 4 and commercially available piperidin-4-y! methanol in dimethylacetamide (DMA) with N,N-diisopropylethy!amine 5 at 90 - 100°C to afford Intermediate 2. The reaction mixture is worked up with water and extracted with isopropylacetate (IPAc). The isopropylacetate layer is washed with water and concentrated to afford Intermediate 2 as an off white crystalline solid.

|0165] In some embodiments, Step 1 further comprises the step of purifying Intermediate 2 by recrystallization in an organic solvent. In some embodiments, the recrystallization further 10 comprises the following steps:

i) combining crude Intermediate 2 in an organic solvent with an agent that promûtes crystallization;

ii) reducing the volume of organic solvent;

iii) adding additional amounts ofthe organic solvent;

iv) stirring the mixture from part iii) at a température above 30 °C for about 30 to about minutes or longer;

v) cooling the mixture from part iii) to a température below 25 °C over about 30 to about minutes or longer;

vi) reducing the volume of organic solvent;

vii) stirring the mixture from part vi) at a température below 25 °C, for about 30 minutes, about 45 minutes, about 60 minutes, about 75 minutes, about 90 minutes, about 105 minutes, or about 120 minutes, or longer; and vii) filtering the mixture to obtain purified Intermediate 2.

[0166] In some embodiments, the organic solvent is isopropyl acetate. In some embodiments, the agent that promotes crystallization is a seed crystal of Intermediate 2. In some embodiments, the reducing ofthe volume oforganic solvent in step ii) is performed by vacuum distillation. In some embodiments, the température of step iv) is about 50 °C. In some embodiments, the température of step v) is about 20 °C. In some embodiments, the température of step vii) is about 10 °C.

[0167] Step 2 is an oxidation of Intermediate 2 with 0.01 équivalents of TEMPO (2,2.6,6tetramethylpiperidin-l-yl)oxyl and 1 équivalent of sodium hypochlorite (4.5 % aqueous solution) solution in dichloromethane at <I0°C to provide Intermediate 3. The réaction is quenched with 5% aqueous Na^SOs solution and the crude aldéhyde product is extracted into dichloromethane. The dichloromethane layer is distillatively exchanged with acetonitrile.

[0168] In some embodiments, Step 2 further comprises the step of purifying Intermediate 3 by recrystallization. For example, in one embodiment, addition of water to the acetonitrile solution afforded Intermediate 3 as a white crystalline solid. In some embodiments, the recrystallization occurs in the presence of a solvent and an anti-solvent. In some embodiments, the recrystallization comprises the foilowing steps:

i) combining crude Intermediate 3 with a mixture of solvent and anti-solvent;

ii) stirring the mixture of crude Intermediate 3, solvent, and anti-solvent; and iii) filtering the mixture to obtain purified Intermediate 3.

[0169| In some embodiments, the solvent in i) is a polar aprotic organic solvent and the antisolvent in i) is an aqueous solvent. In some embodiments, the solvent comprises acetonitrile. In some embodiments, the anti-solvent is water. In some embodiments, the ratio of solvent to antisolvent is about 1 : l (v/v). In some embodiments, the ratio of solvent to anti-solvent is about 1.04:1 (v/v). In some embodiments, step iî) is performed at a température between 15 °C and 20 °C. In some embodiments, step ii) is performed at a température of about 18 °C. In some embodiments, step ii) is performed at a température of about 20 °C. In some embodiments, the stirring of step ii) îs performed for at least 12 hours, at least 14 hours, at least 16 hours, or at least 18 hours. In some 5 embodiments, the stirring of step ii) is performed for about 18 hours.

[0170] Step 3 is a reductive amination of Intermediate 3 with Intermediate 5 in dimethylacetamide with sodium triacetoxyborohydride (STAB) and triethylamine at 5 - 10°C to afford Compound A. In some embodiments, the molar ratio of Intermediate 3 to Intermediate 5 is about 1.1:1. In some embodiments, the molar ratio of Intermediate 3 to Intermediate 5 is about 10 1.05:1. In some embodiments, the molar ratio of Intermediate 3 to Intermediate 5 is between about ] :1 and about 1.1:1. A mixture of éthanol and water is added to the crude réaction mixture and Compound A is precipitated as a yellow solid. Crude Compound A is dissolved in a mixture of dichloromethane:methanol (9:1). The product-rich solution is filtered and distillatively exchanged with éthanol. Crystallization from éthanol solution affords Compound A as a light yellow 15 crystalline solid which is dried in vacuo at 35 - 45°C.

[0171] Third Génération Process

[0172] The third génération manufacturîng process for Compound A is described below in Scheme and in the Examples that follow.

Scheme 5. Third Génération Manu fac tu ring Process of Compound A

Cûrapauqd A

[0173] In the first step, the coupling of Intermediate 10 and Intermediate 7 in DMAc with DIPEA, ethyl cyanohydroxyiminoacetate, and 1-Ethy 1-3-(3dimethylaminopropyl)carbodiimide (EDCI) at about 40°, followed by extraction with IPAc 5 and water, and then rinsing the organic layer with IPAc and drying affords Intermediate

2.

[0174] In some embodiments, the first step further comprises the step of purifying Intermediate 2 by recrystallization in an organic solvent. In some embodiments, the organic solvent is isopropyl acetate. In some embodiments, the recrystallization is 10 performed by réduction of the volume of the organic solvent. In some embodiments, the réduction of the volume ofthe organic solvent is performed by vacuum distillation.

[0175] Oxidation of Intermediate 2 with about 0.003 équivalents of TEMPO and about 1 équivalent of sodium hypochlorite (3.12 % aqueous solution) with sodium bicarbonate, sodium bromide, in dichloromethane and water at <5 °C affords Intermediate 3. The crude 15 Intermediate 3 is extracted with dichloromethane and distillatively exchanged with acetonitrile. Addition of water to the acetonitrile solution afforded Intermediate 3 as a white crystalline solid, Reductive amination of Intermediate 3 with Intermediate 5 in dimethylacetamide with sodium triacetoxyborohydride (STAB) at 5 - 10°C affords Compound A. In some embodiments, the molar ratio of Intermediate 3 to Intermediate 5 is 20 about 1.1:1. A mixture of éthanol and water is added to the crude reaction mixture and crude Compound A is precipitated. Crude Compound A is dissolved in a mixture of dichloromethane:methanol (9:1). The product-rich solution is filtered and distillatively exchanged with éthanol. Crystallization from éthanol solution affords Compound A as a light yellow crystalline solid which is dried in vacuo at 25°C.

[0176] In some embodiments, the oxidation of Intermediate 2 to afford Intermediate 3 occurs in the presence of an alcohol. In some embodiments, the oxidation of Intermediate 2 to afford Intermediate 3 occurs in the presence of a secondary alcohol. In some embodiments, the oxidation of Intermediate 2 to afford Intermediate 3 occurs in the presence of isopropanol. In some embodiments, the oxidation of Intermediate 2 to afford

Intermediate 3 occurs in the presence of 2-butanol. In some embodiments, the oxidation of Intermediate 2 to afford Intermediate 3 occurs in the presence of 2-pentanol. In some

embodiments, the oxidation of Intermediate 2 to afford Intermediate 3 occurs in the presence of 3-methyl 2 butanol,

[0177] In one embodiment, the second génération synthesis provides an ultrapure form of Compound A that has a purity of greater than about 95%. In certain embodiments, the ultrapure form of Compound A has a purity greater than about 96%, 97%, 98%, 99%, 99.5, or 99.9%.

[0178] In one embodiment, the third génération synthesis provides an ultrapure form of Compound A that has a purity of greater than about 95%. In certain embodiments, the ultrapure form of Compound A has a purity greater than about 96%, 97%, 98%, 99%, 99.5, 10 or 99.9%.

|0179] Fourth Génération Process

[0180] The fourth génération manufacturing process for Compound A is described below în Scheme 6 and in the Examples that follow.

Scheme 6. Fourth Génération Manufacturing Process of Compound A

Intermediate 10

Intermediate 7

nterm ediate 2 Interm ed tate 3

Compound A

[0181] In the first step, the coupling of Intermediate 10 with excess Intermediate 7 in DMAc with DIPEA, catalyzed by 2-pyridinol I-oxide (HOPO) and 1 -Ethyl-3-(3dimethylaminopropyl)carbodiimide (EDC1) at about 20 °C affords Intermediate 2. In some embodiments, the molar ratio of Intermediate 10 to Intermediate 7 is about 1.00:1.05.

[0182] In some embodiments, the first step further comprises the step of purifying Intermediate 2 by recrystallization in an organic solvent. In some embodiments, the organic solvent is isopropyl acetate. In some embodiments, the recrystallization is performed by cooling the organic solvent. In some embodiments, the organic solvent is cooled to a température between about 15 °C and about 25 °C. In some embodiments, the organic solvent is cooled to a température of about 20 °C.

[0183] Oxidation of Intermediate 2 with about 0.01 équivalents of TEMPO and about 1 équivalent of sodium hypochlorite with sodium bicarbonate, sodium bromide, in dichloromethane and water at 0 °C affords crude Intermediate 3. The crude Intermediate 3 was extracted with dichloromethane and dîstillatîvely exchanged with tetrahydrofuran. Addition of n-heptane to the tetrahydrofuran solution affords Intermediate 3 as a white crystalline solid.

[0184] In some embodiments, the oxidation of Intermediate 2 to afford Intermediate 3 occurs in the presence of an alcohol. In some embodiments, the oxidation of Intermediate 2 to afford Intermediate 3 occurs in the presence of a secondary alcohol. In some embodiments, the oxidation of Intermediate 2 to afford Intermediate 3 occurs in the presence of isopropanol. In some embodiments, the oxidation of Intermediate 2 to afford Intermediate 3 occurs in the presence of 2-butanol. In some embodiments, the oxidation of Intermediate 2 to afford Intermediate 3 occurs in the presence of 2-pentanoL In some embodiments, the oxidation of Intermediate 2 to afford Intermediate 3 occurs in the presence of 3-methyl 2 butanol.

[0185] Reductive amination of Intermediate 3 with Intermediate 5 in dimethylacetamide with sodium triacetoxyborohydride (STAB) and N-methylmorpholine at 0 °C affords Compound A. In some embodiments, the molar ratio of Intennediate 3 to Intermediate 5 is about 1.1:1. In some embodiments, the ratio of Intermediate 5 to N-methyl morpholine is between about 1.5:1 and about 2:1 (w/w). In some embodiments, the ratio of Intermediate 5 to N-methyl morpholine is about 1.7:1 (w/w). A mixture of éthanol and water is added to the crude reaction mixture and Compound A is precipitated. Crude Compound A is dissolved in a mixture of dichloromethane:methanol (17:1 w/w). The product-rich solution is filtered and dîstillatîvely exchanged with éthanol. Crystallization from éthanol solution affords Compound A as a light yellow crystalline solid which is dried in vacuo at 65°C.

[0186| In one embodiment, the fourth génération synthesis provides an uttrapure fonn of Compound A that has a purity of greater than about 95%. In certain embodiments, the ultrapure form of Compound A has a purity greater than about 96%, 97%, 98%, 99%, 99.5, or 99.9%.

[0187] Fifth Génération Process

[0188] The fifth génération manufacturing process for Compound A follows the same general scheme as the fourth génération process described above.

[0189] In the first step, the coupling of Intermediate 10 with excess Intermediate 7 in DMAc with DIPEA, catalyzed by 2-pyridinol 1-oxide (HOPO) and EDCI at about 20 °C affords Intermediate 2. In some embodiments, the molar ratio of Intermediate 10 to Intermediate 7 is about 1.00:1.02. In some embodiments, the précisé amount of Intermediate 7 is adjusted based on the purity and potency of the Intermediate 7 used. In some embodiments, the précisé amount of Intermediate 10 is adjusted based on the purity and potency of the Intermediate 10 used.

[0190] In some embodiments, the first step further comprises the step of purifying

Intermediate 2 by recrystallization in an organic solvent. In some embodiments, the organic solvent comprises tetrahydrofuran and n-heptane. In some embodiments, the organic solvent for the recrystallization of Intermediate 2 is seeded with crystals of pure Intermediate 2. In some embodiments, the recrystallization is performed by cooling the organic solvent. In some embodiments, the organic solvent is cooled to a température between about 15 °C and about 25 °C. In some embodiments, the organic solvent is cooled to a température of about 20 °C.

[0191] Oxidation of Intermediate 2 with about 0.01 équivalents of TEMPO and about 1.15 équivalents of sodium hypochlorite with sodium bicarbonate, sodium chloride, and 25 sodium bromide, in dichloromethane and water at 20 °C affords Intermediate 3. Addition of n-heptane and tetrahydrofuran to the solution affords Intermediate 3 as a white crystalline solid.

[0192] In some embodiments, the sodium hypochlorite is added to the reaction mixture rapidly. In some embodiments, the sodium hypochlorite is added over the course of less 30 than 60 minutes, less than 45 minutes less than 30 minutes, or less than 20 minutes. In some embodiments, the sodium hypochlorite is added over the course of between about 15 and about 45 minutes. In some embodiments, the sodium hypochlorite is added over the course of about 30 minutes. In some embodiments, the oxidation of Intermediate 2 to afford Intermediate 3 occurs in the presence of an alcohol. In some embodiments, the oxidation of Intermediate 2 to afford Intermediate 3 occurs in the presence of a secondary alcohol. In some embodiments, the oxidation of Intermediate 2 to afford Intermediate 3 occurs in the presence of isopropanol. In some embodiments, the oxidation of Intermediate 2 to afford Intermediate 3 occurs in the presence of 2-butanol. In some embodiments, the oxidation of Intermediate 2 to afford Intermediate 3 occurs in the presence of 2-pentanol. In some embodiments, the oxidation of Intermediate 2 to afford Intermediate 3 occurs in the presence of 3-methyl 2 butanol.

[0193] Reductive amination of Intermediate 3 with Intermediate 5 in dimethylacetamide with sodium triacetoxyborohydride (STAB) and N-methylmorpholine at 0 °C affords Compound A. In some embodiments, the molar ratio of Intermediate 3 to Intermediate 5 is about 1.1:1. In some embodiments, the ratio of Intermediate 5 to N-methyl morpholine is between about 1.5:1 and 2:1 (w/w). In some embodiments, the ratio of Intermediate 5 to N-methyl morpholine is about 1.7:1 (w/w). A mixture of éthanol and water is added to the crude reaction mixture and Compound A precipitated. Crude Compound A was dissolved în a mixture of dichloromethane:methanol (17:1 w/w). The product-rich solution is filtered and distillatively exchanged with éthanol. Crystallization from éthanol solution affords Compound A as a light yellow crystalline solid which is dried in vacuo at 65°C.

[0194] in the solvent swap from DCM into EtOH, auto-crystallization (self-seeding) occurs around a 1:1 ratio of DCM/EtOH content, which occurs shortly after 14 vol of EtOH hâve been dispensed (end of atmospheric distillation; solvent swap 1). To hâve a more uniform and consistent filtration of mother liquors and washes, it is proposed to control the crystallization with seeding. Experiments showed that at reflux conditions, the product solution is supersaturated at/around 67% DCM content. In some embodiments, the seeding protocol comprises the following steps:

• Distill to supersaturation point (7 vol EtOH added) • Remove sample for DCM content to ensure DCM < 67% (supersaturated) • Cool solution down to below reflux (-42 °C) to 35 °C • Charge 0.5 wt% seed (based on Intermediate 3 mput) at 35 C • Heat slurry back up to reflux and continue with remainder of solvent swap

[0195] In one embodiment, the fifth génération synthesis provides an ultrapure form of Compound A that has a purity of greater than about 95%. In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, 97%, 98%, 99%, 99.5, or 99.9%.

[0196] Purification of Compound A

[0197] In one embodiment, the purification of Compound A comprises the following steps:

(1) dissolving Compound A in about a mixture of dîchloromethane and methanol;

(2) filtering the solution comprising Compound A;

(3) distîllatively exchanging the solvent of the solution comprising Compound A with éthanol;

(4) crystallizing Compound A from the éthanol solution; and (5) drying the purified crystalline solid form of Compound A.

[0198] In one embodiment, the ratio of dîchloromethane to methanol in (1) is about 9:1 (w/w). In one embodiment, the ratio of dîchloromethane to methanol in (1) is about 10:1 (w/w)

[0199] In one embodiment, the purification of Compound A comprises dissolving compound A in a solvent of between about 95:5 (w/w) and about 80:20 (w/w) mixture of dîchloromethane and methanol.

[0200] In one embodiment, the purification of Compound A comprises dissolving compound A in about an 80:20 (w/w) mixture of dîchloromethane and methanol. In one embodiment, the purification of Compound A comprises dissolving compound A in about a 90:10 (w/w) mixture of dîchloromethane and methanol. In one embodiment, the purification of Compound A comprises dissolving compound A in about a 95:5 (w/w) mixture of dîchloromethane and methanol. In one embodiment, the purification of Compound A comprises dissolving compound A in about a 10:1 (v/v) mixture of dîchloromethane and methanol.

[0201] In one embodiment, the volume of éthanol in step (3) is between approximately 5 volumes and approximately 9 volumes relative to the amount of Intermediate 3 provided in the reductive amination step. In one embodiment, the volume of éthanol in step (3) is between approximately 6 volumes and approximately 8 volumes relative to the amount of Intermediate 3 provided in the reductive amination step. In one embodiment, the volume of éthanol in step (3) is approximately 7 volumes relative to the amount of intermediate 3 provided in the reductive amination step.

[0202] In some embodiments, the amount of éthanol in step (A3) is corrected for the éthanol content in the crude Compound A.

[0203] In one embodiment, drying of the purified crystalline solid form of Compound A is performed in vacuo. In some embodiments, the drying occurs at about 15 °C to about 30 °C, about 20 °C to about 30 °C, about 30 °C to about 40 °C, or about 35 °C to about 45 °C.

In some embodiments, the drying occurs at greater than about 50 °C, greater than about 60 °C, greater than about 70 °C, or greater than about 80 °C. In some embodiments, the drying occurs at between about 60 °C and about 70 °C. In some embodiments, the drying occurs at about 65 ^ÛC. In some embodiments, the drying occurs at between about 75 °C and about 85 °C.

[0204] In some embodiments, the drying occurs at about 80 °C.

[0205] Purification of Compound A

[0206] In the following embodiments, the percent purity of Compound A, and the percent composition of one or more impurities, reflects the purity on a w/w basis.

[0207] In some embodiments, the percent purity of Compound A, and the percent composition of one or more impurities, represents the purity as determined by HPLC (area %).

[0208] In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 1% of an impurity that is Intermediate 2.

[0209] In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 1% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 1% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, 30 and further comprises less than about 1% of an impurity that is Intennediate 2. In one embodiment, the ultrapure fonn of Compound A has a purity greater than about 99%, and further comprises less than about l% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.5% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity of greater than about 99.9%, and further comprises less than about 0.1% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity of about 99.9%, and further comprises less than about 0.1 % of an impurity that is Intermediate 2.

[0210] In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 0.5% of an impurity that is Intermediate 10 2.

[0211] In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 0.5% of an impurity that is Intermediate

2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 0.5% of an impurity that îs Intermediate 2. In one embodiment, the ultrapure fonn of Compound A has a purity greater than about 98%, and further comprises less than about 0.5% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 0.5% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.5% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity of greater than about 99.9%, and further comprises less than about 0.1% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity of about 99.9%, and further comprises less than about 0.1% of an impurity that is Intermediate 2.

[0212] In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 0.2% of an impurity that is Intermediate 2.

[0213] In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 0.2% of an impurity that is Intermediate

2. In one embodiment, the ultrapure form of Compound A has a purity greater than about

97%, and further comprises less than about 0.2% of an impurity that is Intermediate 2. In

one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 0.2% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 0.2% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.2% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity of greater than about 99.8%, and further comprises less than about 0.2% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity of about 99.8%, and further comprises less than about 0.2% of an impurity that is Intermediate 2.

[02141 In one embodiment, the ultrapure fonn of Compound A has a purity greater than about 95%, and further comprises less than about 0.1% of an impurity that is Intermediate 2.

[0215] In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 0.1% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 0.1% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 0.1% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 0.1% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.1% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.9%, and further comprises less than about 0.1% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity of about 99.9%, and further comprises less than about 0.1% of an impurity that is Intermediate 2.

[0216] In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 0.05% of an impurity that is Intermediate 30 2.

(0217] In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 0.05% of an impurity that is Intennediate 2, In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 0.05% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 0.05% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 0.05% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, 10 and further comprises less than about 0.05% of an impurity that is Intennediate 2. In one embodiment, the ultrapure form of Compound A has a purity of greater than about 99.9%, and further comprises less than about 0.05% of an impurity that is Intermediate 2. In one embodiment, the ultrapure form of Compound A has a purity of about 99.9%, and further comprises less than about 0.05% of an impurity that is Intermediate 2.

[0218] In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than 1% of an impurity that is Intermediate 3.

[0219] In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 1% of an impurity that is Intermediate 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 20 97%, and further comprises less than about 1% of an impurity that is Intermediate 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 1% of an impurity that is Intermediate 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 1% of an impurity that is Intermediate 3. In one 25 embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.5% of an impurity that is Intennediate 3. In one embodiment, the ultrapure form of Compound A has a purity of about 99.5%, and further comprises less than about 0.5% of an impurity that is Intermediate 3.

[0220] In one embodiment, the ultrapure form of Compound A has a purity greater than 30 about 95%, and further comprises less than about 0.5% of an impurity that is Intermediate 3.

|0221] In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 0.5% of an impurity that is Intermediate

3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 0.5% of an impurity that is Intermediate 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 0.5% of an impurity that is Intermediate 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 0.5% of an impurity that is Intermediate 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, 10 and further comprises less than about 0.5% of an impurity that is Intermediate 3. In one embodiment, the ultrapure form of Compound A has a purity of greater than about 99.9%, and further comprises less than about 0.1% of an impurity that is Intermediate 3. In one embodiment, the ultrapure form of Compound A has a purity of about 99.9%, and further comprises less than about 0.1% of an impurity that is Intermediate 3.

[0222] In one embodiment, the ultrapure form of Compound A has a purîty greater than about 95%, and further comprises less than about 0.2% of an impurity that is Intermediate 3.

[0223] In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 0.2% of an impurity that is Intermediate 20 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about

97%, and further comprises less than about 0.2% of an impurity that is Intermediate 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 0.2% of an impurity that is Intermediate 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and 25 further comprises less than about 0.2% of an impurity that is Intermediate 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.2% of an impurity that is Intermediate 3. In one embodiment, the ultrapure form of Compound A has a purity of greater than about 99.8%, and further comprises less than about 0.2% of an impurity that is Intermediate 3. In one 30 embodiment, the ultrapure form of Compound A has a purity of about 99.8%, and further comprises less than about 0.2% of an impurity that îs Intermediate 3.

[0224] In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 0.1% of an impurity that is Intermediate 3.

[0225] In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 0.1% of an impurity that is Intermediate 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 0.1% of an impurity that is Intermediate 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 0.1% of an impurity that is Intermediate 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 0.1% of an impurity that is Intermediate 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.1% of an impurity that is Intermediate 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.9%, and further comprises less than about 0.1% of an impurity that is Intermediate 3. In one embodiment, the ultrapure form of Compound A has a purity of about 99.9%, and further comprises less than about 0.1% of an impurity that is Intermediate 3.

[0226] In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 0.05% of an impurity that is Intermediate 20 3.

[0227] In one embodiment, the ultrapure fonn of Compound A has a purity greater than about 96%, and further comprises less than about 0.05% of an impurity that is Intermediate

3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 0.05% of an impurity that is Intermediate 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 0.05% of an impurity that is Intermediate 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 0.05% of an impurity that is Intermediate 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.05% of an impurity that is Intermediate 3. In one embodiment, the ultrapure fonn of Compound A has a purity of greater than about 99.9%, and further comprises less than about 0.05% of an impurity that is Intermediate 3. In one embodiment, the ultrapure form of Compound A has a purity of about 99.9%, and further comprises less than about 0.05% of an impurity that is Intermediate 3.

[0228] In one embodiment, the ultrapure form of Compound A has a purity greater than

95%, and further comprises less than about 1% of an impurity that is Intermediate 5.

[0229] In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 1% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 1% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 1% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 1% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.5% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity of greater than about 99.9%, and further comprises less than about 0.1% of an impurity' that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity of about 99.9%, and further comprises less than about 0.1% of an impurity that is Intermediate 5.

[0230] In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 0.5% of an impurity that is Intermediate 5.

[0231] In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 0.5% of an impurity that is Intermediate

5. In one embodiment, the ultrapure form of Compound A has a purity greater than about

97%, and further comprises less than about 0.5% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 0.5% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 0.5% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%,

and further comprises less than about 0.5% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity of about 99.5%, and further comprises less than about 0.5% of an impurity that is Intermediate 5.In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further 5 comprises less than about 0.2% of an impurity that is Intermediate 5.

[0232] In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 0.2% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 0.2% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 0.2% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 0.2% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.2% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity of greater than about 99.8%, and further comprises less than about 0.2% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity of about 99.8%, and further comprises less than about 0.2% of an impurity that is Intermediate 5.

[0233] In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 0.1% of an impurity that is Intermediate 5.

[0234] In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 0.1% of an impurity that is Intermediate

97%, and further comprises less than about 0.1% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 0.1% of an impurity that is Intennediate 5. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 0.1% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.1% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity of greater than about 99.9%, and further comprises less than about û.l% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity of about 99.9%, and further comprises less than about 0.1% of an impurity that is Intermediate 5.

[0235] In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 0.05% of an impurity that is Intermediate 5.

[02361 In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 0.05% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 0.05% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 0.05% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 0.05% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.05% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity of greater than about 99.9%, and further comprises less than about 0.05% of an impurity that is Intermediate 5. In one embodiment, the ultrapure form of Compound A has a purity of about 99.9%, and further comprises less than about 0.05% of an impurity that is Intermediate 5.

[0237] In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about ]% of an impurity that is Impurity l,

[0238] In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about l% of an impurity that is Impurity l. In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about l% of an impurity that is Impurity 1. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and funher comprises less than about l%of an impurity that is Impurity 1. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 1% of an impurity that is Impurity 1. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.5% of an impurity that is Impurity 1. In one embodiment, the ultrapure form of Compound A has a purity of greater than about 99.9%, and further 5 comprises less than about 0.1% of an impurity that is Impurity 1. In one embodiment, the ultrapure form of Compound A has a purity of about 99.9%, and further comprises less than about 0.1% of an impurity that is Impurity 1.

[0239] In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 0.5% of an impurity that îs Impurity 1.

[0240] In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 0.5% of an impurity that is Impurity 1. In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 0.5% of an impurity that is Impurity 1. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 0.5% of an impurity that is Impurity 1. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 0.5% of an impurity that is Impurity 1. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.5% of an impurity that is Impurity 1. In one embodiment, the ultrapure form of Compound A has a purity of about 99.5%, and further comprises less than about 0.5% of an impurity that is Impurity 1 .In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 0.2% of an impurity that is Impurity 1.

[0241] In one embodiment, the ultrapure form of Compound A has a purity greater than 25 about 96%, and further comprises less than about 0.2% of an impurity that is Impurity 1.

In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 0.2% of an impurity that is Impurity 1. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 0.2% of an impurity that is Impurity I. In one 30 embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 0.2% of an impurity that is Impurity 1. In one

embodiment, the ultrapure fonn of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.2% of an impurity that is Impurity 1. In one embodiment, the ultrapure form of Compound A has a purity of greater than about 99.8%, and further comprises less than about 0.2% of an impurity that is Impurity 1. In one 5 embodiment, the ultrapure form of Compound A has a purity of about 99.8%, and further comprises less than about 0.2% of an impurity that is Impurity 1.

[0242] In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 0.1% of an impurity that is Impurity 1.

[0243] In one embodiment, the ultrapure form of Compound A has a purity greater than 10 about 96%, and further comprises less than about 0.1% of an impurity that is Impurity 1.

In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 0.1 % of an impurity that is Impurity 1. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 0.1% of an impurity that is Impurity 1. In one 15 embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 0.1% of an impurity that is Impurity 1. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.1% of an impurity that is Impurity 1. In one embodiment, the ultrapure form of Compound A has a purity of greater than about 99.9%, 20 and further comprises less than about 0.1% of an impurity that is Impurity 1. In one embodiment, the ultrapure fonn of Compound A has a purity of about 99.9%, and further comprises less than about 0.1% of an impurity that is Impurity 1.

[0244] In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 0.05% of an impurity that is Impurity 1. 25 [0245] In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 0.05% of an impurity that is Impurity 1. In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 0.05% of an impurity that is Impurity 1. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and 30 further comprises less than about 0.05% of an impurity that ts Impurity 1. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 0.0i% of an impurity that is Impurity 1. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.05% of an impurity that is Impurity 1. In one embodiment, the ultrapure fonn of Compound A has a purity of greater than about 99.9%, and further comprises less than about 0.05% of an impurity that is Impurity 1. In one embodiment, the ultrapure form of Compound A has a purity of about 99.9%, and further comprises less than about 0.05% of an impurity that is Impurity I.

[0246] In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 1% of an impurity that is Impurity 2.

[0247] In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 1% of an impurity that is Impurity 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 1% of an impurity that is Impurity 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 1 %of an impurity that is Impurity 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 1% of an impurity that is Impurity 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.5% of an impurity that is Impurity 2. In one embodiment, the ultrapure form of Compound A has a purity of greater than about 99.9%, and further comprises less than about 0.1% of an impurity that is Impurity 2. In one embodiment, the ultrapure form of Compound A has a purity of about 99.9%, and further comprises less than about 0.1% of an impurity that is Impurity 2.

[0248] In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 0.5% of an impurity that is Impurity 2.

[0249] In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 0.5% of an impurity that is Impurity 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 0.5% of an impurity that is Impurity 2. in one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 0.5% of an impurity that îs Impurity 2. In one

embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 0.5% of an impurity that is Impurity 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.5% of an impurity that is Impurity 2.In one 5 embodiment, the ultrapure form of Compound A has a purity of about 99.5%, and further comprises less than about 0.5% of an impurity that is Impurity 2.In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 0.2% of an impurity' that is Impurity 2.

[0250] In one embodiment, the ultrapure form of Compound A has a purity greater than 10 about 96%, and further comprises less than about 0.2% of an impurity that is Impurity 2.

In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 0.2% of an impurity that is Impurity 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 0.2% of an impurity that is Impurity 2. In one 15 embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 0,2% of an impurity that is Impurity 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.2% of an impurity that is Impurity 2. In one embodiment, the ultrapure form of Compound A has a purity of greater than about 99.8%, 20 and further comprises less than about 0.2% of an impurity that is Impurity 2. In one embodiment, the ultrapure form of Compound A has a purity of about 99.8%, and further comprises less than about 0.2% of an impurity that is Impurity 2.

[0251] In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 0.15% of an impurity that is Impurity 2.

(0252] In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 0.15% of an impurity that is Impurity 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 0.15% of an impurity that is Impurity 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and 30 further comprises less than about 0.15% of an impurity that is Impurity 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 0.15% of an impurity that is Impurity 2. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.15% of an impurity that is Impurity 2. In one embodiment, the ultrapure form of Compound A has a purity of greater than about 99.85%, and further comprises less than about 0.15% of an impurity that is Impurity 2. In one embodiment, the ultrapure form of Compound A has a purity of about 99.85%, and further comprises less than about 0.15% of an impurity that is Impurity 2.

[0253] In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 1% of an impurity that is Impurity 3.

[0254] In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 1% of an impurity that is Impurity 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 1% of an impurity' that is Impurity 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about l%of an impurity that is Impurity 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 1% of an impurity that is Impurity 3. In one embodiment, the ultrapure fonn of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.5% of an impurity that is Impurity 3. In one embodiment, the ultrapure form of Compound A has a purity of greater than about 99.9%, and further comprises less than about 0.1% of an impurity that is Impurity 3. In one embodiment, the ultrapure form of Compound A has a purity of about 99.9%, and further comprises less than about 0.1% of an impurity that is Impurity 3.

[0255] In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 0.5% of an impurity that is Impurity 3.

[0256] In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 0.5% of an impurity that is Impurity' 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 0.5% of an impurity that is Impurity 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 0.5% of an impurity that is Impurity 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 0.5% of an impurity that is Impurity 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.5% of an impurity that is Impurity 3. In one 5 embodiment, the ultrapure form of Compound A has a purity of about 99.5%, and further comprises less than about 0.5% of an impurity that is Impurity 3.In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 0.2% of an impurity that is Impurity 3.

[0257] In one embodiment, the ultrapure form of Compound A has a purity' greater than 10 about 96%, and further comprises less than about 0.2% of an impurity that is Impurity 3.

In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 0.2% of an impurity that is Impurity 3. In one embodiment, the ultrapure fonn of Compound A has a purity greater than about 98%, and further comprises less than about 0.2% of an impurity that is Impurity 3. In one 15 embodiment, the ultrapure form of Compound A has a purîty greater than about 99%, and further comprises less than about 0.2% of an impurity that is Impurity 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.2% of an impurity that is Impurity 3. In one embodiment, the ultrapure fonn of Compound A has a purity of greater than about 99.8%, 20 and further comprises less than about 0.2% of an impurity that is Impurity 3. In one embodiment, the ultrapure form of Compound A has a purity of about 99.8%, and further comprises less than about 0.2% of an impurity that is Impurity 3.

[0258] In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 0.15% of an impurity that is Impurity 3. 25 [0259] In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 0.15% of an impurity that is Impurity 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 0.15% of an impurity that is Impurity 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and 30 further comprises less than about 0.15% of an impurity' that is Impurity 3. In one embodiment, the ultrapure form of Compound A has a purity' greater than about 99%, and further comprises less than about 0.15% of an impurity that is Impurity 3. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.15% of an impurity that is Impurity 3. In one embodiment, the ultrapure fonn of Compound A has a purity of greater than about 99.85%, and further comprises less than about 0.15% of an impurity that is Impurity 3. In one embodiment, the ultrapure fonn of Compound A has a purity of about 99.85%, and further comprises less than about 0.15% of an impurity that is Impurity 3.

[0260] In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 1% of an impurity that is Impurity 4.

[0261] In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 1% of an impurity that is Impurity 4. In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 1% of an impurity that is Impurity 4. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 1 %of an impurity that is Impurity 4. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 1% of an impurity that is Impurity 4. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.5% of an impurity that is Impurity 4. In one embodiment, the ultrapure form of Compound A has a purity of greater than about 99.9%, and further comprises less than about 0.1% of an impurity that is Impurity 4. In one embodiment, the ultrapure form of Compound A has a purity of about 99.9%, and further comprises less than about 0.1% of an impurity that is Impurity 4.

[0262] In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 0.5% of an impurity that is Impurity 4.

[0263] In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 0.5% of an impurity that is Impurity 4. In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 0.5% of an impurity that is Impurity 4. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 0.5% of an impurity that is Impurity 4. In one

embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 0,5% of an impurity that is Impurity 4. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.5% of an impurity that is Impurity 4. In one 5 embodiment, the ultrapure form of Compound A has a purity of about 99.5%, and further comprises less than about 0.5% of an impurity that is Impurity 4. In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 0.2% of an impurity that is Impurity 4.

[0264] In one embodiment, the ultrapure form of Compound A has a purity greater than 10 about 96%, and further comprises less than about 0.2% of an impurity that is Impurity' 4.

In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 0.2% of an impurity that is Impurity 4. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 0.2% of an impurity that is Impurity 4. In one 15 embodiment, the ultrapure fonn of Compound A has a purity greater than about 99%, and further comprises less than about 0.2% of an impurity that is Impurity 4. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.2% of an impurity that is Impurity 4. In one embodiment, the ultrapure form of Compound A has a purity of greater than about 99.8%, 20 and further comprises less than about 0.2% of an impurity that is Impurity 4. In one embodiment, the ultrapure form of Compound A has a purity of about 99.8%, and further comprises less than about 0.2% of an impurity that is Impurity 4.

[0265] In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 0.15% of an impurity that is Impurity 4.

[0266] In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 0.15% of an impurity that is Impurity 4. In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 0.15% of an impurity that is Impurity 4. In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and 30 further comprises less than about 0.15% of an impurity that is Impurity 4. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 0.15% of an impurity that is Impurity 4. In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 0.15% of an impurity that îs Impurity 4. In one embodiment, the ultrapure form of Compound A has a purity of greater than about 99.85%, 5 and further comprises less than about 0.15% of an impurity that is Impurity 4. In one embodiment, the ultrapure form of Compound A has a purity of about 99.85%, and further comprises less than about 0.15% of an impurity that is Impurity 4.

[0267] In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 1%, 0.9%, 0.8%, 0.7%, 0.6%, or 0.5% in 10 total of at least two of the following impurities: Intermediate 2, Intermediate 3, Intermediate 5, Impurity 1, Impurity 2, Impurity 3, and Impurity 4.

[0268] In one embodiment, the ultrapure form of Compound A has a purity greater than about 95%, and further comprises less than about 1%, 0.9%, 0.8%, 0.7%, 0.6%, or 0.5% of each of at least two of the following impurities: Intermediate 2, Intermediate 3, 15 Intermediate 5, Impurity 1, Impurity 2, Impurity 3, and Impurity 4.

[0269] In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 1%, 0.9%, 0.8%, 0.7%, 0.6%, or 0.5% in total of at least two of the following impurities: Intermediate 2, Intermediate 3, Intermediate 5, Impurity 1, Impurity 2, Impurity 3, and Impurity 4.

[0270] In one embodiment, the ultrapure form of Compound A has a purity greater than about 96%, and further comprises less than about 1%, 0.9%, 0.8%, 0.7%, 0.6%, or 0.5% of each of at least two of the following impurities: Intermediate 2, Intermediate 3, Intermediate 5, Impurity l, Impurity 2, Impurity 3, and Impurity 4.

[0271] In one embodiment, the ultrapure form of Compound A has a purity greater than 25 about 97%, and further comprises less than about 1%, 0.9%, 0.8%, 0.7%, 0.6%, or 0.5% in total of at least two of the following impurities: Intermediate 2, Intermediate 3, Intermediate 5, Impurity l, Impurity 2, Impurity 3, and Impurity 4.

[0272] In one embodiment, the ultrapure form of Compound A has a purity greater than about 97%, and further comprises less than about 1%, 0.9%, 0.8%, 0.7%, 0.6%, or 0.5% 30 of each of at least two of the following impurities: Intermediate 2, Intermediate 3, Intermediate 5, Impurity 1, Impurity 2, Impurity 3, and Impurity 4.

[0273] In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 1%, 0.9%, 0.8%, 0.7%, 0.6%, or 0.5% in total of at least two of the following impurities: Intermediate 2, Intermediate 3, Intermediate 5, Impurity 1, Impurity 2, Impurity 3, and Impurity 4.

[0274] In one embodiment, the ultrapure form of Compound A has a purity greater than about 98%, and further comprises less than about 1%, 0.9%, 0.8%, 0.7%, 0.6%, or 0.5% of each of at least two of the following impurities: Intermediate 2, Intermediate 3, Intermediate 5, Impurity 1, Impurity 2, Impurity 3, and Impurity 4.

[0275] In one embodiment, the ultrapure form of Compound A has a purity' greater than 10 about 99%, and further comprises less than about 1% in total of at least two of the following impurities: Intermediate 2, Intermediate 3, Intermediate 5, Impurity 1, Impurity 2, Impurity 3, and Impurity 4.

[0276] In one embodiment, the ultrapure form of Compound A has a purity greater than about 99%, and further comprises less than about 1 % of each of at least two ofthe following 15 impurities: Intermediate 2, Intermediate 3, Intermediate 5, Impurity 1, Impurity 2, Impurity

3, and Impurity 4.

[0277] In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 1%, 0.9%, 0.8%, 0.7%, 0.6%, or 0.5% in total of at least two of the following impurities: Intermediate 2, Intermediate 3, 20 Intermediate 5, Impurity 1, Impurity 2, Impurity 3, and Impurity 4.

[0278] In one embodiment, the ultrapure form of Compound A has a purity greater than about 99.5%, and further comprises less than about 1%, 0.9%, 0.8%, 0.7%, 0.6%, or 0.5% of each of at least two of the following impurities: Intermediate 2, Intermediate 3, Intermediate 5, Impurity 1, Impurity 2, Impurity 3, and Impurity 4.

[0279] In one embodiment, the ultrapure fonn ofCompound A has a purity ofabout 99.9%, and further comprises less than about 1%, 0.9%, 0.8%, 0.7%, 0.6%, or 0.5% in total ofat least two of the following impurities: Intermediate 2, Intermediate 3, Intermediate 5, Impurity 1, Impurity 2, Impurity 3, and Impurity 4.

[0280] In one embodiment, the ultrapure form of Compound A has a purity of about 99.9%, 30 and further comprises less than about 1%, 0.9%, 0.8%, 0.7%, 0.6%, or 0.5% of each of at least two of the following impurities: Intermediate 2, Intermediate 3, Intermediate 3, Impurity 1, Impurity 2, Impurity 3, and Impurity 4.

[0281] In one embodiment, the ultrapure forms of Compound A as described herein are crystalline.

[0282] In one embodiment, the ultrapure forms of Compound A as described herein are amorphous.

Crystalline Forms of Compound A

[0283] In one aspect, this application pertains to a crystalline form of Compound A wherein Compound A is an ethanolate (i.e., an éthanol solvaté). The XRPD pattern corresponding to this crystalline form is referred to as Form 4, and is provided in FIG. 3C. [0284] The crystalline form of Compound A ethanolate, referred to as Form 4 and characterized by the XRPD pattern in FIG. 3C, has a powder x-ray diffraction pattern comprising at least one peak selected from the group consisting of 7.9° ± 0.2° 2Θ, 9.7° ± 0.2° 2Θ, 11.0° ± 0.2° 29, 11.3° ± 0.2° 29, 13.6°±0.2° 29, 16.1° ± 0.2° 2Θ, 17.2° ± 0.2° 29, 17.9° ± 0.2° 29 and 20.1° ± 0.2° 29, wherein said powder x-ray diffraction pattern is obtained using Cu Ka radiation at an x-ray wavelength of 1.5496 Â.

[0285] In one embodiment, this crystalline form of Compound A ethanolate, i.e. Form 4, has a powder x-ray diffraction pattern comprising peaks at 11.0° ± 0.2° 2Θ, 16.1⁰ ± 0.2° 29, and 17.9° ± 0.2° 29. In one embodiment, this crystalline form of Compound A ethanolate, i.e, Form 4, has a powder x-ray diffraction pattern further comprising a peak at 11.3° ± 0.2° 29. In one embodiment, this crystalline form of Compound A ethanolate, i.e. Form 4, has a powder x-ray diffraction pattern further comprising a peak at 17.2° ± 0.2° 29. In one embodiment, this crystalline form of Compound A ethanolate, i.e. Form 4, has a powder x-ray diffraction pattern further comprising a peak at 7.9° ± 0.2° 29. In one embodiment, this crystalline form of Compound A ethanolate, i.e. Form 4, has a powder x-ray diffraction pattern further comprising a peak at 20.1° ± 0.2° 29. In one embodiment, this crystalline form of Compound A ethanolate, i.e. Form 4, has a powder x-ray diffraction pattern further comprising a peak at 13.6° ± 0.2° 29. In one embodiment, this crystalline form of Compound A ethanolate, i.e. Form 4, has a powder x-ray diffraction pattern further comprising a peak at 9.7° ± 9.2° 29.

[0286] In one embodiment, the crystalline form of Compound A ethanolate, i.e. Form 4, has a powder x-ray diffraction pattern comprising peaks at 11.0° ± 0.2° 20, 11.3° ± 0.2° 20, 16.1° ± 0.2° 20, and 17.9° ± 0.2° 20. In one embodiment, the crystalline form of Compound A ethanolate, i.e. Fonn 4, has a powder x-ray diffraction pattern comprising peaks at 11.0° ± 0.2° 20, 11.3° i 0.2° 2Θ, 16.1° i 0.2° 20, 17.2° ± 0.2° 2Θ, and 17.9° ±0.2° 20. In one embodiment, the crystalline form of Compound A ethanolate, i.e. Form 4, has a powder x-ray diffraction pattern comprising peaks at 7.9° ± 0.2° 20,, 11.0° ± 0.2° 20, 11.3° ± 0.2° 20, 16.1° ± 0.2° 20, 17.2° ± 0.2° 20, and 17.9° ± 0.2° 20. In one embodiment, the crystalline form of Compound A ethanolate, i.e. Fonn 4, has a powder x-ray diffraction pattern comprising peaks at 7.9° ± 0.2° 20, 11.0° ± 0.2° 20, 11.3° ± 0.2° 20, 16.1° ± 0.2° 20, 17.2° ± 0.2° 20, 17.9° ±0.2° 20 and 20.1’±0.2° 20. In one embodiment, the crystalline fonn of Compound A ethanolate, i.e, Form 4, has a powder x-ray diffraction pattern comprising peaks at 7.9° ± 0.2° 20, 11.0° ± 0.2° 20, 11.3° ±0.2° 20, 13.6° ±0.2° 20, 16.1° ± 0.2’ 20, 17.2° ± 0.2° 2Θ, 17.9° ± 0.2° 2Θ and 20.1’ ± 0.2° 26.

[0287] In one embodiment, the crystalline form of Compound A ethanolate, i.e. Form 4, has a powder x-ray diffraction pattern comprising peaks at 7.9° ± 0.2° 20, 9.7° ± 0.2° 20, 11.0’± 0.2’20, 11.3°±0.2° 20, 13.6°±0.2° 2Θ, 16.1°±0.2° 2Θ, 17.2°±0.2° 20, 17.9°± 0.2° 20 and 20.1° ± 0.2° 20.

[0288] In one aspect, this application pertains to a crystalline form of Compound A characterized by the XRPD pattern in FIG. 3A, which is also referred to herein as Form 2. [0289] The crystalline form of Compound A, referred to as Form 2 and characterized by the XRPD pattern in FIG. 3A, has a powder x-ray diffraction pattern comprising at least one peak selected from the group consisting of 3.2° ± 0.2° 20, 7.6° ± 0.2° 20, 11.5° ± 0.2° 20, 17.6° ± 0.2° 20, 18.5° ± 0.2° 20, and 21.4° ± 0.2° 20, wherein said powder x-ray diffraction pattern is obtained using Cu K a radiation at an x-ray wavelength of 1.5406 Â. In one embodiment, this crystalline fonn of Compound A, i.e. Form 2, comprises peaks at 17.5°, 7.6°, and 11.5° ± 0.2° 20, wherein said powder x-ray diffraction pattern is obtained using Cu Ka radiation at an x-ray wavelength of 1.5406 Â. In one embodiment, this crystalline form of Compound A, i.e. Form 2, has a powder x-ray diffraction pattern further comprising a peak at 18.5° ± 0.2° 20. In one embodiment, this crystalline fonn of Compound A, i.e. Form 2, has a powder x-ray diffraction pattern further comprising a peak at 21.4° ± 0.2° 20. In one embodiment, this crystalline form of Compound A, i.e. Form 2, has a powder x-ray diffraction pattern further comprising a peak at 3.2° ± 0.2° 2Θ. In one embodiment, this crystalline form of Compound A, i.e. Form 2, comprises peaks at 7.6° + 0.2° 20, 11.5° ± 0.2° 2Θ, 17.6° ± 0.2° 20, and 18,5° ± 0.2° 20. In one embodiment, this crystalline form of Compound A, i.e. Form 2, comprises peaks at 7,6° ± 0.2° 20, 11.5° ± 0.2° 20, 17.6° ± 0.2° 20, 18.5° ± 0.2° 20, and 21.4° ± 0.2° 20. In one embodiment, this crystalline form of Compound A, i.e. Form 2, comprises peaks at 3.2° ± 0.2° 20, 7.6° ± 0.2° 2θ, I 1.5° ± 0.2° 20, 17.6° ± 0.2° 20, 18.5° ± 0.2° 20, and 21.4° ± 0.2° 20.

[0290] In one embodiment, the crystalline form of Compound A referred to as Form 2 and characterized by the XRPD pattern in FIG. 3A, serves as a convenient storage fonn for the préparation of the amorphous and/or ultrapure amorphous forms of Compound A and further used in the préparation ofpharmaceutical compositions ofthe disclosure, including, for example, tablets.

Amorphous Forms of Compound A and the Manufacturing Process of a SprayDried Intermediate Comprising an Amorphous Form of Compound A

[0291] This application further provides an amorphous form of Compound A, or a sait or soivate thereof.

[0292] In one embodiment, the amorphous form of Compound A is ultrapure.

[0293] In one embodiment, the amorphous form of Compound A îs characterized by a glass transition température, Tg, of about 146°C at 25°C and 0% relative humidity.

|0294| In one embodiment, the amorphous form of Compound A is characterized by a glass transition température, Tg, of about 103°C at 40°C and 75% relative humidity.

[0295] In one embodiment, the amorphous form of Compound A is characterized by a Dv(10) particle size of about 0.1-10 pm.

[0296] In one embodiment, the amorphous fonn of Compound A is characterized by a Dv(10) particle size of about 0.5-8 pm.

[0297] In one embodiment, the amorphous form of Compound A is characterized by a Dv( 10) particle size of about 0.6-7 pm.

[0298] In one embodiment, the amorphous form of Compound A is characterized by a

Dv( 10) particle size of about 0,7-6 μηι.

[0299] In one embodiment, the amorphous form of Compound A is characterized by a Dv(10) particle size of about 0.8-5 pm.

[0300] In one embodiment, the amorphous form of Compound A is characterized by a Dv(10) particle size of about 0.5, l, 2, 3, 4, 5, 6, 7, or 8 pm.

[0301] In one embodiment, the amorphous form of Compound A is characterized by a Dv(10) particle size of about 4 pm.

[0302] In one embodiment, the amorphous form of Compound A is characterized by a Dv(10) particle size of about 5 pm.

[0303] In one embodiment, the amorphous form of Compound A is characterized by a Dv(50) particle size of about 5-15 pm.

[0304] In one embodiment, the amorphous form of Compound A is characterized by a Dv(50) particle size of about 6-14 pm.

[0305] In one embodiment, the amorphous form of Compound A îs characterized by a Dv(50) particle size of about 7-13 pm.

[0306) In one embodiment, the amorphous form of Compound A is characterized by a Dv(50) particle size of about 8-12 pm.

[0307] In one embodiment, the amorphous form of Compound A is characterized by a Dv(50) particle size of about 9-11 pm.

[0308] In one embodiment, the amorphous form of Compound A is characterized by a Dv(50) particle size of about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 pm.

[0309] In one embodiment, the amorphous form of Compound A is characterized by a Dv(50) particle size of about 9 pm.

[0310] In one embodiment, the amorphous form of Compound A is characterized by a Dv(50) particle size of about 10 pm.

[0311] In one embodiment, the amorphous form of Compound A is characterized by a Dv(50) particle size of about 11 pm.

[0312] In one embodiment, the amorphous form of Compound A is characterized by a Dv(90) particle size of about 5-25 pm.

[0313] In one embodiment, the amorphous form of Compound A is characterized by a Dv(90) particle size of about 6-24 pm.

[0314] In one embodiment, the amorphous form of Compound A is characterized by a Dv(9û) particle size of about 7-23 pm.

[0315] In one embodiment, the amorphous form of Compound A is characterized by a Dv(90) particle size of about 8-22 pm.

[0316] In one embodiment, the amorphous form of Compound A is characterized by a

Dv(90) particle size of about 9-21 pm.

[0317] In one embodiment, the amorphous form of Compound A is characterized by a Dv(90) particle size of about 10-20 pm.

[0318] In one embodiment, the amorphous form of Compound A is characterized by a 10 Dv(90) particle size of about 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 pm.

[0319] In one embodiment, the amorphous form of Compound A is characterized by a Dv(90) particle size of about 18 pm.

[0320] In one embodiment, the amorphous form of Compound A is characterized by a 15 Dv(90) particle size of about 19 pm.

[0321] In one embodiment, the amorphous form of Compound A is characterized by a Dv(90) particle size of about 20 pm.

[0322] In some embodiments, the particle size of the amorphous form of Compound A is determined by laser diffraction.

[0323] In one embodiment, the amorphous form of Compound A has a purity of greater than about 95%, 96%, 97%, 98%, 99%, 99.5, or 99.9%.

[0324] In one embodiment, the amorphous form of Compound A is characterized in that the amorphous form is stable for at least 1 month at 2-8°C; for 1 month at 25°C and 60% relative humidity; and for I month at 40°C and 75% relative humidity. In one embodiment, 25 the amorphous form of Compound A is characterized in that the amorphous form is stable for at least 6 months at 2-8°C; for 6 months at 25°C and 60% relative humidity; and for 6 months at 40°C and 75% relative humidity. In one embodiment, the amorphous form of Compound A is characterized in that the amorphous form is stable for at least 12 months at 2-8°C; for 12 months at 25°C and 60% relative humidity; and for 12 months at 40°C and 30 75% relative humidity. In one embodiment, the amorphous form of Compound A is characterized in that the amorphous form is stable for at least 24 months at 2-8^QC; for 24

months at 25°C and 60% relative humidity; and for 24 months at 40°C and 75% relative humidity. En one embodiment, the stability of Compound A is assessed by storing it in wire-tîed low-density polyethylene bags placed in beat-induction sealed, high-density polyethylene (HDPE) bottles containing a desiccant canister, and capped with a 5 polypropylene-lined closure.

[0325] This application also pertains to a method for manufacturing the amorphous fonn of Compound A, or a sait or solvaté thereof. In one embodiment, the amorphous form of Compound A prepared according to the methods described herein is ultrapure.

[0326] In one embodiment, the amorphous form of Compound A is manufactured by 10 taking an amount of Compound A, including any of the crystalline forms of Compound A, ultrapure forms of Compound A, and crystalline ultrapure forms ofCompound A described herein, and dissolving in an approprîate solvent until a clear solution is obtaîned. This solution of Compound A is introduced into a spray dryer and the damp solid output from the spray dryer is tray-dried to produce the amorphous solid form of Compound A, i.e., I5 “the spray-dried intermediate.” The spray-dried intermediate is checked for residual solvent before using in the préparation of pharmaceutical compositions comprising Compound A (e.g., tablets).

[0327] In one embodiment, the manufacturing process of an amorphous form of Compound A may be accomplished according to the flow diagram in FIG. 14.

[0328] In one embodiment, the amorphous form of Compound A prepared as described above is useful in the préparation of pharmaceutical compositions, e.g., tablets, comprising Compound A.

[0329] In one embodiment, for the process of preparing the amorphous form of Compound A described herein, Compound A is dissolved in méthanol, éthanol, isopropanol, l-butanol, 25 2-butanol, acetone, tert-butyl methyl ether, diethyl ether, ethyl acetate, chloroform, dîchloromethane, 2,2-dichlorethane, or any mixture thereof.

[0330] In one embodiment, forthe process of preparing the amorphous form ofCompound A described herein, Compound A is dissolved in a mixture of dîchloromethane and méthanol. In one embodiment, the mixture of dîchloromethane and méthanol is about 99/1 30 (w/w), about 95/5 (w/w). about 90/10 (w/w), about 85/15 (w/w), about 80/20 (w/w), about

70/30 (w/w), about 60/40 (w/w), about 50/50 (w/w), about 40/60 (w/w), about 30/70 (w/w), about 20/80 (w/w), about 10/90 (w/w), or about 1/99 (w/w). In a preferred embodiment, the mixture of dichloromethane and methanol is from about 70/30 (w/w) to about 95/5 (w/w), preferably about 90/10 (w/w), and most preferably about 93/7 (w/w).

[0331] In one embodiment, for the process of preparing the amorphous form of Compound

A described herein, the concentration of Compound A în solvent to be introduced into the spray drier is from about 1 mg/mL to about 100 mg/mL.

[0332] In one embodiment, for the process of preparing the amorphous form ofCompound A described herein, the concentration of Compound A in solvent to be introduced into the spray drier is from about 1 mg/mL to about 50 mg/mL. In one embodiment, for the process of preparing the amorphous form of Compound A described herein, the concentration of Compound A in solvent to be introduced into the spray drier is from about 1 mg/mL to about 25 mg/tnL. In one embodiment, for the process of preparing the amorphous form of Compound A described herein, the concentration of Compound A in solvent to be introduced into the spray drier is from about 1 mg/mL to about 10 mg/mL. In one embodiment, for the process of preparing the amorphous form of Compound A described herein, the concentration of Compound A in solvent to be introduced into the spray drier is from about 1 mg/mL to about 5 mg/mL. In one embodiment, for the process of preparing the amorphous form of Compound A described herein, the concentration of Compound A in solvent to be introduced into the spray drier is from about 2 mg/mL to about 5 mg/mL.

In one embodiment, for the process of preparing the amorphous form of Compound A described herein, the concentration of Compound A in solvent to be introduced into the spray drier is from about 2 mg/mL to about 4 mg/tnL In one embodiment, for the process of preparing the amorphous form of Compound A described herein, the concentration of Compound A in solvent to be introduced into the spray drier is from about 2 ing/mL to about 3 mg/mL.

10333] In one embodiment, for the process of preparing the amorphous fonn of Compound A described herein, the concentration of Compound A in solvent to be introduced into the spray drier is about 5 mg/mL, about 10 mg/mL, about 15 mg/mL, about 20 mg/mL, about 25 mg/mL, about 30 mg/mL, about 35 mg/mL, about 40 mg/mL, about 45 mg/mL, about

50 mg/mL, about 55 mg/mL, about 60 mg/mL, about 65 ing/mL, about 70 mg/mL, about

mg/mL, about 80 mg/mL, about 85 mg/mL, about 90 mg/mL, about 95 mg/mL, or about 100 mg/mL.

[0334] In one embodiment, for the process of preparing the amorphous form of Compound A described herein, the amount of Compound A in solvent that is introduced 5 into the spray drier is about l % (w/w), about 2 % (w/w), about 3 % (w/w), about 4 % (w/w), about 5 % (w/w), about 6 % (w/w), about 7 % (w/w), about 8 % (w/w), about 9 % (w/w), about ]0 % (w/w), about 11 % (w/w), about 12 % (w/w), about 13 % (w/w), about 14 % (w/w), or about 15 % (w/w). In one embodiment, for the process of preparing the amorphous form of Compound A described herein, the amount of Compound A in solvent 10 that is introduced into the spray drier is between about l and about 10 % (w/w), between about 3 and about 8 % (w/w), between about 5 and about 7 % (w/w), between about 5.5 and about 6.8 % (w/w), or preferably between about 5.8 and about 6.2 % (w/w).

[0335] In one embodiment, the process for manufacturing the amorphous form of Compound A comprises the following steps:

(I) dissolving crystalline and/or ultrapure Compound A in a solution of dichloromethane:methanol to afford a solution of Compound A;

(2) introducing the solution of Compound A from step (1) into a spray dryer;

(3) spraying the solution of Compound A from the spray dryer to create the amorphous form of Compound A; and (4) drying the amorphous form of Compound A to remove residual solvent.

[0336] In one embodiment, step (1) of the process for manufacturing the amorphous form of Compound A comprises dissolving Compound A in a solution of dichloromethane and methanol of about 95:5 (w/w) to about 80:20 (w/w).

[0337] In one embodiment, step (1) of the process for manufacturing the amorphous form 25 of Compound A comprises dissolving Compound A in an 80:20 (w/w) mixture of dichloromethane and methanol. In one embodiment, step (1) of the process for manufacturing the amorphous form of Compound A comprises dissolving Compound A in a 90:10 (w/w) mixture of dichloromethane and methanol. In one embodiment, step (1) of the process for manufacturing the amorphous form of Compound A comprises dissolving 30 Compound A in a 93:7 (w/w) mixture of dichloromethane and methanol. In one embodiment, step (1) of the process for manufacturing the amorphous form of Compound

A comprises dissolving Compound A in a 95:5 (w/w) mixture of dichloromethane and methanol.

[0338] In one embodiment, the température of the solution in step (l) is about 20 °C to about 40 °C prior to introducing the solution into the spray dryer. In one embodiment, the température of the solution in step (l) is about 25 °C to about 35 °C prior to introducing the solution into the spray dryer. In one embodiment, the température of the solution in step (l) is about 27.5 °C to about 32.5 °C prior to introducing the solution into the spray dryer. In one embodiment, the température ofthe solution in step (!) is about 30 °C prior to introducing the solution into the spray dryer.

[0339] The spray dryer used in the process for manufacturing the amorphous form of Compound A may be set at an appropriate température, gas flow rate, feed rated pressure as determined by one skilled in the art in view of this disclosure.

[0340] In one embodiment, the spray dryer used in the process for manufacturing the amorphous fonn of Compound A has an SK80-16 nozzle and is employed using the following conditions:

Dryer Inlet Température:	65-125°C;
Dryer Outlet Température:	32.5-42.5°C;
System Gas Flow:	1550-2150 g/min;
Liquid Feed Rate:	145-205 g/min; and
Liquid Feed Pressure:	300-600 psig.

[0341] In one embodiment, the spray dryer used in the process for manufacturing the amorphous form of Compound A has an SK80-16 nozzle and is employed using the following conditions;

Dryer Inlet Température:	about 95°C;
Dryer Outlet Température: System Gas Flow: Liquid Feed Rate:	about 37.5 °C; about 1850 g/min; about 180 g/min; and
Liquid Feed Pressure:	about 450 psig.

[0342] In one embodiment, the spray dryer used in the process for manufacturing the amorphous form of Compound A has an Schlick Model 121 nozzle and is employed using the following conditions:

Dryer Inlet Température:	46-96°C;
Dryer Outlet Température: System Gas Flow:	30-40°C; 60-100 kg/h;
Condenser Température: Liquid Feed Rate:	-10-0 °C 3.5-8.5 kg/h; and
Liquid Feed Pressure:	about 50 bar.

[0343] In one embodiment, the spray dryer used in the process for manufacturing the amorphous form of Compound A has an Schlick Model 121 nozzle and is employed using the following conditions:

Dryer Inlet Température: about 71°C;

Dryer Outlet Température: about 35 °C;

System Gas Flow: about 80 kg/h;

Condenser Température: about -5 °C

Liquid Feed Rate: about 6.0 kg/h; and

Liquid Feed Pressure: about 50 bar.

[03441 In one non-limiting embodiment, the amorphous form of Compound A is dried in 5 step (4) by tray drying. In one embodiment, the amorphous form of Compound A is dried in step (4) by filter drying. In one embodiment, the amorphous form of Compound A is dried in step (4) by tumble drying. In one embodiment, the amorphous form of Compound A is dried in step (4) by agitated conical drying. In one embodiment, the amorphous form of Compound A is dried in step (4) by fluid bed drying.

[0345] In one non-limiting embodiment, the amorphous fonn of Compound A is tray-dried in step (4) to remove any residual solvent from the spray drying process.

[0346] In one embodiment, the depth of the tray is about 2.5 cm.

[0347] In one embodiment, the tray containing the amorphous Compound A is dried in step (4) for a total of 1, 2,3,4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20,21, 15 22, 23, 24, 30, 36, or 48 hours either under reduced or at ambient pressure. In one embodiment, the tray containing the amorphous Compound A îs dried for about i to about 24 hours. In one embodiment, the tray containing the amorphous Compound A is dried for about 1 to about 10 hours. In one embodiment, the tray containing the amorphous

Compound A is dried for about 5 to about 10 hours. In one embodiment. the tray containing the amorphous Compound A is dried for about 5 to about 7 hours.

[0348] In one embodiment, the température during the tray drying procedure in step (4) is ramped from about 20°C up to about 3Û°C, up to about 40°C, up to about 50°C, up to about 60°C, up to about 70°C, or higher.

[0349] In one embodiment, the relative humidity during the tray drying procedure in step (4) îs ramped up from about !5% relative humidity (RH) to about 20% RH, to about 25% RH, to about 30% RH, to about 35% RH, to about 40% RH, to about 45% RH, to about 50% RH, or higher.

[0350] In one embodiment, the tray-dryîng procedure in step (4) involves no ramping of either the température or the relative humidity, i.e., the température and relative humidity are held constant.

[0351] In one embodiment, the tray-drying procedure in step (4) involves heating the product of step (3) in a bed depth of about 2.5 cm at about 40°C to about 60°C for about 6 hours to about 18 hours at from about 5% RH to about 35% RH, under reduced or ambient pressure, where the température and relative humidity are both held constant.

[0352] In one non-limiting embodiment, the amorphous form of Compound A is filterdricd to remove any residual solvent from the spray drying process.

[0353] In one embodiment, the amorphous form of Compound A is filter-dried for a total of 1, 2,3,4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22,23,24, 30, 36, or 48 hours under vacuum. In one embodiment, the amorphous form of Compound A is filter-dried for a total of from about 1 to about 50 hours. In one embodiment, the amorphous fonn of Compound A is filter-dried for a total of from about 12 to about 50 hours. In one embodiment, the amorphous form of Compound A is filter-dried for a total of from about 12 to about 36 hours. In one embodiment, the amorphous form of Compound A is filterdried for a total of from about 20 to about 30 hours.

[0354) lu one embodiment, the pressure during the filter drying procedure is below ambient pressure. In one embodiment, the pressure during the filter drying procedure is about 0.1 bar, about 0.2 bar, about 0.3 bar, about 0.4 bar, about 0.5 bar, about 0.6 bar, about 0.7 bar, about 0.8 bar, or about 0.9 bar. In one embodiment, the pressure during the filter drying procedure is about 0.9 bar below ambient pressure.

[0355] in one embodiment, the température during the filter drying procedure is ramped from about 20°C up to about 30°C, up to about 40°C, up to about 50°C, up to about 60°C, up to about 70°C, or higher.

Manufacturîng Process of Tablet Comprising the Spray-Dried Intermediate (Le., the ultrapure and stable amorphous form of Compound A)

[0356] In one aspect, this application provides tablets comprising Compound A, and processes for manufacturîng the same.

[0357] In certain embodiment, the tablets of the disclosure comprise the amorphous form of Compound A, i.e., the spray-dried form disclosed herein. In one embodiment, the tablets of the disclosure comprise the amorphous form of Compound A that is also ultrapure. In one embodiment, the tablets contain about 2.5% to about 50% (w/w) of Compound A.

[0358] Tablets of the disclosure may further comprise one or more pharmaceutically acceptable excipients, including, for example, carriers, fillers, surfactants, diluents, sweeteners, dis intégrants, binders, lubricants, glidants, colorants, flavors, stabilizing agents, coatings, or any mixtures thereof.

[0359] Fillers include, but are not limited to, mannitol, sorbitol, xylitol, microcrystailine cellulose, lactose, silicîfied microcrystalline cellulose, hydroxypropyl methylcellulose, hydroxy propyl cellulose, pullulan and fast dissolving carbohydrates such as Pharmaburst™, mixtures thereof, and the like. For examples of fast-dissolving carbohydrates, see U.S. Patent No. 8,617,588, which is incorporated herein by reference.

[0360] Glidants include, but are not limited to, Silicon dioxide, colloïdal Silicon dioxide, calcium silicate, magnésium silicate, magnésium trisilicate, talc, starch, mixtures thereof, and the like.

[0361] Lubricants include, but are not limited to, calcium stéarate, glyceryl monostearate, glyceryl behenate, glyceryl palm itostearate, hexagonal boron nitride, hydrogenated vegetable oil, light minerai oil, magnésium stéarate, minerai oil, polyethylene glycol, poloxamer, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, zinc stéarate, mixtures thereof, and the like.

[0362] Disintegrants include, but are not limited to, sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium,

crospovidone, chîtosan, agar, alginic acid, calcium alginate, methyl cellulose, microcrystalline cellulose, powdered cellulose, lower alkylsubstituted hydroxypropyl cellulose, hydroxy!propyl starch, low-substituted hydroxypropylcellulose, polacrilin potassium, starch, pregelatinized starch, sodium alginate, magnésium aluminum silicate, 5 polacrilin potassium, povidone, sodium starch glycolate, mixtures thereof, and the like.

[0363] In one embodiment, the tablets contain about 5% to about 95% w/w of one or more fillers, such as, e.g., about 75% to about 95% w/w, about 65% to about 85% w/w, about 55% to about 75% w/w, about 45% to about 65% w/w, about 35% to about 55% w/w, about 25% to about 45% w/w, about 15% to about 35% w/w, or about 5% to about 25% w/w of 10 one or more fillers.

[0364] In one embodiment, the tablets contain about 80% w/w of one or more fillers.

[0365] In one embodiment, the tablets contain about 1% to about 20% w/w dîsintegrant, such as, e.g., about 1% to about 15% w/w, about 1% to about 10% w/w, about 2% to about 9% w/w, about 3% to about 8% w/w, about 4% to about 7% w/w, or about 5% to about 7% 15 w/w dîsintegrant.

[0366] In one embodiment, the tablets contain about 0.20% to about 2.5% w/w lubricant, such as, e.g., about 0.2% to about 2.0% w/w, about 0.2% to about 1.8% w/w, about 0.2% to about 1.5% w/w, or about 0.25% to about 1.5% w/w lubricant.

[0367] In some embodiments, the tablets contain 0% to about 1% w/w glidant, such as, 20 e.g., about 0.25% to about 0.75% w/w, or about 0.25% to about 0.50% w/w glidant.

[0368] In one aspect, this application pertains to a process for manufacturing a tablet comprising Compound A.

[0369] In one embodiment, the process for manufacturing a tablet comprising Compound A comprises dry granulation. Dry granulation is a well-known pharmaceutical 25 manufacturing process. In general, API is combined with appropriate excipients, including lubricant, and then compacted to form a mass. This mass typically is then comminuted or milled, then sieved to obtain the desired size of particle. Extragranular excipients are then added and mixed in, and the granular product is then compressed into tablets, filled into capsules or otherwise formed into a unîtary dosage form in conventional fashion. In some 30 embodiments, high dosage tablets comprising Compound A are produced by this process.

In other embodiments, the granular product comprising high dosage Compound A is fïIled into capsules or otherwise formed into a unitary dosage form.

[0370] In one embodiment, the process for manufacturing a tabiet comprising Compound A comprises wet granulation. Wet granulation involves the formation of granules by the addition of a granulation liquid onto a powder bed of the API, which may be under the influence of an impeller, one or more screws, and/or air flow. After formation of the granules, the granulation liquid is removed by drying.

[0371] In one embodiment, the process for manufacturing a tabiet comprising Compound A comprises direct compression. In essence, direct compression bypasses the formation of a granule and involves the blending of an API with one or more phannaceutically acceptable carriers, diluents, and/or other excipients, followed by compression.

[0372] Compaction into a mass is accomplîshed using conventional equipment. Typically, the blended API and excipients are passed through a roller compacter or a Chilsonator® dry granulation roller/compactor apparatus for compaction. However, other means for compacting, e.g,, compaction into slugs (or “slugging”), the API/excipîent blend optionally are used. The compacted mass in turn is comminuted or milled, and then optionally sieved to produce the desired size granules.

[0373] A dry granulated composition comprising Compound A is defined as the product of a dry granulation process. Dry granulated compositions include the direct product of dry granulation, i.e., dry granules per se, as well as products made from such granules including tablets, capsules, suppositories and other pharmaceutical dosage forms.

[0374] In one aspect, this application pertaîns to a tabiet comprising one or more pharmaceutically acceptable excipients and Compound A, including ultrapure forms of Compound A as described herein.

[0375] In one embodiment, the tabiet comprises from about 5 to about 1000 mg of Compound A. In one embodiment, the tabiet comprises from about 5 to about 500 mg of Compound A. In one embodiment, the tabiet comprises from about 5 to about 250 mg of Compound A. In one embodiment, the tabiet comprises from about 25 to about 250 mg of Compound A. In one embodiment, the tabiet comprises from about 25 to about 200 mg of Compound A. In one embodiment, the tabiet comprises from about 25 to about 150 mg of Compound A. In one embodiment, the tabiet comprises from about 5 to about 50 mg of

Compound A. In one embodiment, the tablet comprises from about 30 to about 40 mg of

Compound A. In one embodiment, the tablet comprises from about 65 to about 70 mg of

Compound A. In one embodiment the tablet comprises from about 1Û0 to about 110 mg of Compound A. In one embodiment, the tablet comprises from about 135 to about 145 mg of Compound A.

[0376] In one embodiment, the tablet comprises about 5, !0, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, H5, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, i75, I80, 185, 190, 195,200,205,210,215,220, 225,230,235,240,

245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330,

335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420,

425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, or 500 mg of

Compound A.

[0377] In one embodiment, the tablet comprises about 5 mg of Compound A.

[0378] In one embodiment, the tablet comprises about 35 mg of Compound A, [0379] In one embodiment, the tablet comprises about 70 mg of Compound A.

[0380] In one embodiment, the tablet comprises about 105 mg of Compound A.

[0381] In one embodiment, the tablet comprises about 140 mg of Compound A.

[0382] In one embodiment, the tablet comprises about 175 mg of Compound A.

[0383] In one embodiment, the tablet comprises about 200 mg of Compound A.

[0384] In one embodiment, the tablet comprises about 210 mg of Compound A.

[0385] In one embodiment, the tablet comprises about 245 mg of Compound A.

[0386] In one embodiment, the tablet comprises about 280 mg of Compound A.

[0387] In one embodiment, the tablet comprises about 31 5 mg of Compound A. [0388] In one embodiment, the tablet comprises about 350 mg of Compound A.

[03891 In one embodiment, a tablet ofthe disclosure comprises about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7,0.8,0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7. 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7. 3.8, 3.9,4.0, 4.1, 4.2, 4.3, 4.4,4.5, 4.6, 4.7, 4.8,4.9,5.0,5.5,6.0,6.5,7.0,7.5,8.0,8.5,9.0,9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 15.5, 16.0, 16.5, 17.0, 17.5, 18.0, 18.5, 19.0, 19.5, 20.0, 20.5, 21.0, 21.5, 22.0, 22.5, 23.0, 23.5, 24.0, 24.5, 25.0, 25.5, 26.0, 26.5, 27.0, 27.5, 28.0, 28.5, 29.0, 29.5, 30.0, 30.5, 31.0, 31.5, 32.0, 32.5, 33.0, 33.5, 34.0, 34.5, 35.0, 35.5, 36.0, 36.5, 37.0,

37,5, 38.0, 38.5, 39.0, 39.5, 40.0, 40.5, 41.0, 41.5, 42.0, 42.5, 43.0, 43.5, 44.0, 44.5, 45.0,

45.5, 46.0, 46,5, 47.0, 47.5, 48.0, 48.5, 49.0, 49.5, or 50.0 % w/w of Compound A.

[03901 In one embodiment, a tablet ofthe disclosure comprises about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7,0.8,0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7. 1.8, 1.9,2.0,2.1,2.2, 2.3,2.4,2.5,2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7. 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4,4.5, 4.6, 4.7, 4.8,4,9,5.0,5.5,6.0, 6.5,7,0,7.5,8.0,8.5,9.0,9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 15.5, 16.0, 16.5, 17.0, 17.5, 18.0, 18.5, 19.0, 19.5, 20.0, 20.5, 21.0,

21.5, 22.0, 22.5, 23.0, 23.5, 24.0, 24.5, 25.0, 25.5, 26.0, 26.5, 27.0, 27.5, 28.0, 28.5, 29.0,

29.5, 30.0, 30.5, 31.0, 31.5, 32.0, 32.5, 33.0, 33.5, 34.0, 34.5, 35.0, 35.5, 36.0, 36.5, 37.0,

37.5, 38.0, 38.5, 39.0, 39.5, 40.0, 40.5, 41.0, 41.5, 42.0, 42.5, 43.0, 43.5, 44.0, 44.5, 45.0,

45.5, 46.0, 46.5, 47.0, 47.5, 48.0, 48.5, 49.0, 49.5, or 50.0 % w/w of an ultrapure form of Compound A.

[0391] In one embodiment, a tablet of the disclosure comprises about 1 % to about 5 % w/w of Compound A, about 2.5 % to about 7.5 % w/w of Compound A, about 10 % to about 15 % w/w of Compound A, about 12.5 % to about 17.5 % w/w of Compound A, about 15 % to about 20 % w/w of Compound A, about 17.5 % to about 22.5 % w/w of Compound A, about 20 % to about 25 % w/w of Compound A, about 22.5 % to about 27.5 % w/w of Compound A, about 25 % to about 30 % w/w of Compound A, about 27.5 % to about 32.5 % w/w of Compound A, or about 30 % to about 35 % w/w of Compound A. In one embodiment, a tablet of the disclosure comprises about 1 % to about 5 % w/w of an ultrapure form of Compound A, about 2.5 % to about 7.5 % w/w of an ultrapure fonn of Compound A, about 10 % to about 15 % w/w of an ultrapure form of Compound A, about 12.5 % to about 17.5 % w/w of an ultrapure form of Compound A, about 15 % to about 20 % w/w of an ultrapure form of Compound A, about 17.5 % to about 22.5 % w/w of an ultrapure form of Compound A, about 20 % to about 25 % w/w of an ultrapure fonn of Compound A, about 22.5 % to about 27.5 % w/w of an ultrapure form of Compound A, about 25 % to about 30 % w/w of an ultrapure form of Compound A, about 27.5 % to about 32.5 % w/w of an ultrapure form of Compound A, or about 30 % to about 35 % w/w of an ultrapure form of Compound A.

[0392] In one embodiment, a tablet of the disclosure comprises:

about 2.5 % to about 7.5 % w/w of Compound A;

about 42 % to about 47 % w/w microcrystalline cellulose;

about 42 % to about 47 % w/w lactose monohydrate;

about 1 % to about 5 % w/w croscarmellose sodium;

about 0.1 % to about 1.0 % w/w Silicon dioxide; and about 0.1 % to about 1.0 % w/w magnésium stéarate.

[0393] In one embodiment, a tablet of the disclosure comprises:

about 5 % w/w of Compound A;

about 45.5 % w/w microcrystalline cellulose;

about 45.5 % w/w lactose monohydrate;

about 3 % w/w croscarmellose sodium;

about 0.5 % w/w Silicon dioxide; and about 0.5 % w/w magnésium stéarate.

[0394] In one embodiment, a tablet of the disclosure comprises:

about 10 % w/w of Compound A;

about 57.3 % w/w microcrystalline cellulose;

about 28.7 % w/w lactose monohydrate;

about 3 % w/w croscarmellose sodium;

about 0.5 % w/w Silicon dioxide; and about 0.5 % w/w magnésium stéarate.

[0395] In one embodiment, a tablet of the disclosure comprises:

about 20 % w/w of Compound A;

about 50.7 % w/w microcrystalline cellulose;

about 25.3 % w/w lactose monohydrate;

about 3 % w/w croscarmellose sodium;

about 0.5 % w/w Silicon dioxide; and about 0.5 % w/w magnésium stéarate.

[0396] In one embodiment, a tablet of the disclosure comprises:

about 40 % w/w of Compound A;

about 37,3 % w/w microcrystalline cellulose;

about 18.7 % w/w lactose monohydrate;

about 3 % w/w croscarmellose sodium;

about 0.5 % w/w Silicon dioxide; and about 0.5 % w/w magnésium stearate.

[0397] In one embodiment, a tablet of the disclosure comprises:

about 2.5 % to about 7.5 % w/w of an ultrapure form of Compound A;

about 42 % to about 47 % w/w microcrystalline cellulose;

about 42 % to about 47 % w/w lactose monohydrate;

about l % to about 5 % w/w croscarmellose sodium;

about 0.1 % to about l .0 % w/w Silicon dioxide; and about 0.1 % to about 1.0 % w/w magnésium stearate.

[0398] In one embodiment, a tablet of the disclosure comprises:

about 5 % w/w of an ultrapure form of Compound A;

about 45.5 % w/w microcrystalline cellulose;

about 45.5 % w/w lactose monohydrate;

about 3 % w/w croscarmellose sodium;

about 0.5 % w/w Silicon dioxide; and about 0.5 % w/w magnésium stearate.

[0399| In one embodiment, a tablet ofthe disclosure comprises:

about 10 % w/w of an ultrapure form of Compound A;

about 57.3 % w/w microcrystalline cellulose;

about 28.7 % w/w lactose monohydrate;

about 3 % w/w croscarmellose sodium;

about 0.5 % w/w Silicon dioxide; and about 0.5 % w/w magnésium stearate.

[0400] In one embodiment, a tablet of the disclosure comprises:

about 20 % w/w of an ultrapure form of Compound A;

about 50.7 % w/w microcrystalline cellulose;

about 25.3 % w/w lactose monohydrate;

about 3 % w/w croscarmellose sodium;

about 0.5 % w/w Silicon dioxide; and about 0.5 % w/w magnésium stearate.

[0401 ] In one embodiment, a tablet of the disclosure comprises;

about 40 % w/w of an ultrapure form of Compound A;

about 37.3 % w/w microcrystalline cellulose;

about 18.7 % w/w lactose monohydrate;

about 3 % w/w croscarmellose sodium;

about 0.5 % w/w Silicon dioxide; and about 0.5 % w/w magnésium stéarate.

[0402] In some embodiments, a tablet of the disclosure comprises an intra-granular portion and an extra-granular portion. In some embodiments, the intra-granular portion comprises:

about 10 to about 40% w/w of Compound A;

about 35 to about 60% w/w microcrystalline cellulose;

about 15 to about 30% w/w lactose monohydrate;

about 1 to about 10% w/w croscarmellose sodium;

to about 1 % w/w Silicon dioxide; and to about 0.5% w/w magnésium stéarate.

[0403] In some embodiments, the intra-granular portion comprises:

about 10 to about 40% w/w of an ultrapure form of Compound A;

about 35 to about 60% w/w microcrystaliine cellulose;

about 15 to about 30% w/w lactose monohydrate;

about 1 to about 10% w/w croscarmellose sodium;

to about 1 % w/w Silicon dioxide; and to about 0.5% w/w magnésium stéarate.

[04041 In some embodiments, the extra-granular portion comprises:

about I to about 5% w/w croscarmellose sodium;

to about 1 % w/w magnésium stéarate; and to about 2 % w/w Silicon dioxide.

[0405] In one embodiment, the tablet of the disclosure comprises an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises:

about 10 to about 40% w/w of Compound A;

about 35 to about 60% w/w microcrystalline cellulose;

about 15 to about 30% w/w lactose monohydrate;

about 1 to about 10% w/w croscarmellose sodium;

to about 1 % w/w Silicon dioxide; and to about 0.5% w/w magnésium stéarate; and wherein the extra-granular portion comprises:

about 1 to about 5% w/w croscarmellose sodium;

to about 1 % w/w magnésium stéarate; and to about 2 % w/w Silicon dioxide.

[0406] In one embodiment, the tablet of the disclosure comprises an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises:

about 10 to about 40% w/w of an ultrapure form of Compound A;

about 35 to about 60% w/w microcrystalline cellulose;

about 15 to about 30% w/w lactose monohydrate;

about 1 to about 10% w/w croscarmellose sodium;

to about 1 % w/w Silicon dioxide; and to about 0.5% w/w magnésium stéarate;

and wherein the extra-granular portion comprises:

about 1 to about 5% w/w croscarmellose sodium;

to about 1 % w/w magnésium stéarate; and to about 2 % w/w Silicon dioxide.

[0407] In one embodiment, the tablet of the disclosure comprises an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises:

About 20% w/w of Compound A;

About 48.7% w/w microcrystalline cellulose;

About 24.3% w/w lactose monohydrate;

About 3% w/w croscarmellose sodium;

About 0.5 % w/w Silicon dioxide; and

About 0.25% w/w magnésium stéarate;

and wherein the extra-granular portion comprises:

About 2% w/w croscarmellose sodium;

About 0.5% w/w magnésium stéarate; and

About 0.25 % w/w Silicon dioxide.

[0408] In one embodiment, the tablet of the disclosure comprises an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises:

About 20% w/w of an ultrapure form of Compound A;

About 48.7% w/w microcrystalline cellulose;

About 24.3% w/w lactose monohydraîe;

About 3% w/w croscarmellose sodium;

About 0.5 % w/w Silicon dioxide; and

About 0.25% w/w magnésium stéarate;

and wherein the extra-granular portion comprises:

About 2% w/w croscarmellose sodium;

About 0.5% w/w magnésium stéarate; and

About 0.25 % w/w Silicon dioxide.

[0409] In some embodiments, the Silicon dioxide in the extra-granular portion comprises fumed silica. Fumed silica (also known as pyrogenic silica) can be produced from 15 compounds such as Silicon chloride (SiCk) by means of flame hydrolysis. Suppliers of fumed silica include Evonik (Aerosil®), Cabot Corporation (Cab-O-Sil®), Wacker Chemie (HDK®), Dow Corning, Heraeus (Zandosil®), Tokuyama Corporation (Reolosil®), OCI (Konasil®), Orisil (Orisil®) and Xunyuchem(XYSIL®). In some embodiments, the Silicon dioxide in the extra-granular portion comprises fumed silica after 20 treated with dimethyldichlorosilane. In some embodiments, the fumed silica comprises trimethylsilyl groups on the surface ofthe silica. In some embodiments, the Silicon dioxide in the extra-granular portion comprises fumed silica chemically modified with trimethylsilyl groups on the surface ofthe silica.

[0410] In one embodiment, the tablets of the disclosure are prepared according to the 25 procedures in the Examples.

[0411] In one embodiment, a dry granulation approach is used to produce Compound A tablets as follows: the spray-dried intermediate, i.e., the amorphous form of Compound A, is blended with at least one pharmaceutically acceptable excipient to create a powder. In one embodiment, Compound A is blended with one or more flllers, one or more 30 disintegrants, and one or more glidants. In one embodiment, Compound A is blended with two flllers, one disintegrant, and one glidant. In one embodiment, at least one filler is microcrystalline cellulose. In one embodiment, at least one filler is lactose monohydrade. In one embodiment, the disintegrant is croscarmellose sodium. In one embodiment, the glidant is Silicon dioxide. In one embodiment, Compound A is blended with microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, and Silicon dioxide in a suitable blender.

[0412] The resulting powder is delumped and a pharmaceutically acceptable excipient is added and blended. In one embodiment the pharmaceutically acceptable excipient is a lubricant. In one embodiment, the lubricant is magnésium stéarate.

[0413] The blend is granulated using a suitable roller compactor and passed through a screen for appropriate sizîng of granules.

[0414| In one embodiment, granules prepared according to this process are about 400 pm to about 600 μιη in diameter.

[0415] In one embodiment, granules prepared according to this process are about 450 pm to about 550 pm in diameter.

[0416] In one embodiment, granules prepared according to this process are about 575 pm to about 625 pm in diameter.

[0417] In one embodiment, granules prepared according to this process are about 590 pm to about 610 pm in diameter.

[0418] In one embodiment, granules prepared according to this process are about 595 pm to about 605 pm in diameter.

[0419] In one embodiment, granules prepared according to this process are about 598 pm to about 602 pm in diameter.

[0420] In one embodiment, granules prepared according to this process are about 450 pm in diameter, about 460 pm in diameter, about 470 pm in diameter, about 480 pm in diameter, about 490 pm in diameter, about 500 pm in diameter, about 510 pm in diameter, about 520 pm in diameter, about 530 pm in diameter, about 540 pm în diameter, or about 550 pm in diameter.

[0421] In one embodiment, granules prepared according to this process are about 500 pm in diameter.

[0422] At least one pharmaceutically acceptable excipient is added and the bulk powder is blended in a suitable blender. In one embodiment, the pharmaceutically acceptable excipient is a lubricant. In one embodiment the lubricant is extragranular magnésium stéarate.

[0423] The blend is compressed into tablets and the resulting tablets packaged in bulk containers. In some embodiments, the blend is compressed into tablets using a rotary press.

[0424] In one embodiment, the tablets of the disclosure are prepared according to the manufacturing process illustrated in the flow diagram in FIG. 15.

Methods Of Ubiquitinating/degrading A Target Protein In A Cell

[0425] The present disclosure further provides a method of ubiquitinating/degrading a target protein in a cell. The method comprises administering to a subject or patient in need 10 thereofany ofthe forms ofCompound A, or pharmaceutical compositions comprising any of these forms (e.g., tablets, capsules, parentéral solutions). Compound A comprises an E3 ubiquitin ligase (cereblon) binding moiety and an androgen receptor (AR) targeting moiety linked through a linker moiety, such that ubiquitination of AR will occur when the target protein is placed in proximity to the ubiquitin ligase, thereby triggering proteasomal 15 dégradation to control or reduce protein levels of AR, and inhibiting the effects of AR.

Methods Of Treatment

[0426] In one embodiment, the present disclosure is directed to a method of treating a subject in need of treatment for prostate cancer modulated through AR where the 20 ubiquitination and dégradation of the AR protein results in a therapeutic effect in that subject, the method comprising administering to the subject a therapeutically effective amount of Compound A or any of the forms of Compound A disclosed herein, or compositions (e.g., tablets, capsules, parentéral solutions) of any of these forms. The disease state or condition may be causally related to the expression or overexpression of 25 the AR protein.

[0427] In one aspect, the present application pertains to a method of treating cancer.

[0428] The methods of treating cancer described herein preferably resuit in a slowing or cessation of tumor growth, or more preferably a réduction in tumor size. The cancer may be metastatic cancer, and this method oftreatment may include inhibition of metastatic 30 cancer cell invasion.

[0429] In one embodiment, the cancer is prostate cancer.

[0430] In one embodiment, the cancer is metastatic prostate cancer.

[0431] In one embodiment, the cancer is castrate-resistant prostate cancer.

[0432] In one embodiment, the cancer is metastatic, castrate-resistant prostate cancer.

[0433] In one aspect, treating cancer results in a réduction in size of a tumor. A réduction in size of a tumor may also be referred to as tumor régression. Preferably, after one or more treatments, tumor size is reduced by about 5% or greater, e.g., about 5 to about 40%, relative to its size prior to treatment; more preferably, tumor size is reduced by about 10% or greater, e.g., about 10% to about 50%; more preferably, reduced by about 20% or greater, e.g., about 20% to about 60%; more preferably, reduced by about 30% or greater, e.g., about 30% to about 70%; more preferably, reduced by about 40% or greater, e.g, about 40% to about 80%; even more preferably, reduced by about 50% or greater, e.g., about 50% to about 90%; and most preferably, reduced by greater than about 75% or greater, e.g., about 75% to about 95% . Size of a tumor may be measured by any reproducible means of measurement. In a preferred aspect, size of a tumor may be measured as a diameter of the tumor.

[0434] In another aspect, treating cancer results in a réduction in tumor volume. Preferably, after treatment, tumor volume is reduced by about 5% or greater, e.g., about 5% to about 40%, relative to its volume prior to treatment; more preferably, tumor volume is reduced by about 10% or greater, e.g., about 10% to about 50%; more preferably, reduced by about 20% or greater, e.g., about 20% to about 60%; more preferably, reduced by about 30% or greater, e.g., about 30% to about 70%; more preferably, reduced by about 40% or greater, e.g., about 40% to about 80%; even more preferably, reduced by about 50% or greater, e.g., about 50% to about 90%; and most preferably, reduced by greater than about 75% or greater, e.g., about 75% to about 95%. Tumor volume may be measured by any reproducible means of measurement.

[0435] In another aspect, treating cancer results in a decrease in number of tumors. Preferably, after treatment, tumor number is reduced by about 5% or greater, e.g., about 5% to 40%, relative to number prior to treatment; more preferably, tumor number is reduced by about 10% or greater, e.g., about 10% to about 50%; more preferably, reduced by about 20% or greater, e.g., about 20% to about 60%; more preferably, reduced by about

30% or greater, e.g., about 30% to about 70%; more preferably, reduced by about 40% or greater, e.g., about 40% to about 80%; even more preferably, reduced by about 50% or greater, e.g., about 50% to about 90%; and most preferably, reduced by greater than about 75%, e.g., about 75% to about 95%. Number of tumors may be measured by any reproducible means of measurement. In a preferred aspect, number of tumors may be measured by counting tumors visible to the naked eye or at a specifîed magnification. In a preferred aspect, the specifîed magnification is about 2x, 3x, 4x, 5x, lOx, or 50x.

[0436] In another aspect, treating cancer results in a decrease in number of metastatic lésions in other tissues or organs distant from the primary tumor site. Preferably, after 10 treatment, the number of metastatic lésions is reduced by about 5% or greater, e.g., about

5% to about 40%, relative to number prior to treatment; more preferably, the number of metastatic lésions is reduced by about 10% or greater, e.g., about 10% to about 50%; more preferably, reduced by about 20% or greater, e.g., about 20 to about 60%; more preferably, reduced by about 30% or greater, e.g., about 30% to about 70%; more preferably, reduced 15 by about 40% or greater, e.g., about 40% to about 80%; even more preferably, reduced by about 50% or greater, e.g., 50% to about 90%; and most preferably, reduced by greater than about 75%, e.g., about 75% to about 95%. The number of metastatic lésions may be measured by any reproducible means of measurement. In a preferred aspect, the number of metastatic lésions may be measured by counting metastatic lésions visible to the naked eye or at a specifîed magnification. In a preferred aspect, the specifîed magnification is about 2x, 3x, 4x, 5x, lOx, or 50x.

[0437] In another aspect, treating cancer results in an increase in average survival time of a population of treated subjects in comparison to a population receiving carrier alone. Preferably, the average survival time is increased by more than about 30 days; more 25 preferably, by more than about 60 days; more preferably, by more than about 90 days; and most preferably, by more than about 120 days. An increase in average survival time of a population may be measured by any reproducible means. In a preferred aspect, an increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation or completion of treatment 30 with an active agent or compound of the disclosure. In another preferred aspect, an increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following a first round or completion of treatment with an active agent or compound of the disclosure.

[0438] In another aspect, treating cancer results in an increase in average survival time of a population of treated subjects in comparison to a population of untreated subjects. Preferably, the average survival time is increased by more than about 30 days; more preferably, by more than about 60 days; more preferably, by more than about 90 days; and most preferably, by more than about 120 days. An increase in average survival time of a population may be measured by any reproducible means. In a preferred aspect, an increase in average survival time of a population may be measured by calculating for a population the average length of survival following initiation of treatment with an active agent or compound of the disclosure. In another preferred aspect, an increase in average survival time of a population may be measured by calculating for a population the average length of survival following completion of a first round of treatment with a compound of the disclosure.

[0439] In another aspect, treating cancer results in a decrease in tumor growth rate. Preferably, after treatment, tumor growth rate is reduced by at least about 5%, e.g., about 5% to about 40%, relative to growth rate prior to treatment; more preferably, tumor growth rate is reduced by at least about 10%, e.g., about 10% to about 50%; more preferably, reduced by at least about 20%, e.g., about 20% to about 60%; more preferably, reduced by at least about 30%, e.g., about 30% to about 70%; more preferably, reduced by at least about 40%, e.g., about 40% to about 80%; more preferably, reduced by at least about 50%, e.g., about 50% to about 90%; even more preferably, reduced by at least about 60%, e.g., about 60% to about 95%; and most preferably, reduced by at least about 75%, e.g., about 75% to about 99%. Tumor growth rate may be measured by any reproducible means of measurement. In a preferred aspect, tumor growth rate is measured according to a change in tumor diameter per unit time.

[0440] In another aspect, treating cancer results in a decrease in tumor regrowth. Preferably, after treatment, tumor regrowth is less than about 5%; more preferably, tumor regrowth is less than about 10%; more preferably, less than about 20%; more preferably, less than about 30%; more preferably, less than about 40%; more preferably, less than about 50%; even more preferably, less than about 60%; and most preferably, less than about 75%. Tumor regrowth may be measured by any reproducible means of measurement. In a preferred aspect, tumor regrowth is measured by measuring an increase in the diameter of a tumor after a prior tumor shrînkage that followed treatment. In another preferred aspect, a decrease in tumor regrowth is indicated by failure of tumors to reoccur after 5 treatment has stopped.

[0441] The dosages ofthe compound of the disclosure for any of the methods and uses described herein vary depending on the Chemical agent, the âge, weight, and clinical condition of the récipient subject, and the expérience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage.

[0442] The therapeutically effective amount of the compound of the disclosure may be administered one or more times over a day for up to about 30 or more days, followed by 1 or more days of non-administration of the compound. This type of treatment schedule, i.e., administration of a the compound of the disclosure on consecutive days followed by nonadministration of the compound on consecutive days may be referred to as a treatment cycle. A treatment cycle may be repeated as many times as necessary to achieve the intended affect.

[0443] In some embodiments, the method comprises administering to the subject a therapeutically effective amount of any of the forms of Compound A disclosed herein, or compositions of any of these forms in combination with at least one other bioactive agent. 20 In some embodiments, the at least one other bioactive agent is an anti-cancer agent. In some embodiments, the anti-cancer agent is selected from a CDK inhibitor and a PARP inhibitor. In some embodiments, the anti-cancer agent is a CDK inhibitor. In some embodiments, the anti-cancer agent is a CDK 4/6 inhibitor. In some embodiments, the anticancer agent is a PARP inhibitor. In some embodiments, the anti-cancer agent is selected 25 from SHR6390, trilaciclîb, lerociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, palbociclib, olaparib, rucaparib, talazoparib, niraparib, veliparib, pamiparib, CEP 9722. E7016, 3-aminobenzainide, mefuparib, and AZD2281. In some embodiments, the anticancer agent is selected from SHR6390, trilaciclib, lerociclib, AT7519M, dinaciclib, ribociclib, abemaciclib, and palbociclib. In some embodiments, the anti-cancer agent is 30 selected from olaparib, rucaparib, talazoparib, niraparib, veliparib, pamiparib, CEP 9722, E7016, 3-aminobenzamide, mefuparib, and AZD2281. In soine embodiments, the anti21107 cancer agent is selected from olaparib, rucaparib, talazoparib, and niraparib. In some embodiments, the anti-cancer agent is olaparib.

EXAMPLES |0444] The disclosure is further illustrated by the following examples, which are not to be construed as limiting this disclosure in scope or spirit to the spécifie procedures herein described. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the disclosure is intended thereby. It is to be further understood that resort may be had to various other embodiments, 10 modifications, and équivalents thereof which may suggest themselves to those skilled in the art in view of the present disclosure, without departing from the spirit of the present disclosure and/or scope of the appended claims.

Example 1. General Properties of Compound A

[0445] The Chemical and physical characteristics of Compound A are presented in Table

L This batch was prepared for use in the 28-day good laboratory practice (GLP) toxicology studies using the same synthetic scheme and processing employed in préparation of active pharmaceutical ingrédient (API) to be used in the clinical drug product.

[0446] Table 1. General Properties of Compound A

Physical Parameters
Appearance	Off-white to yellow powder
Differential Scanning Calorimetry	FIG. 1 (Endotherm at 289-300 °C)
Hygroscopicity by Dynamic Vapor Sorption (DVS)¹	FIG. 2
Powder X-ray Diffraction	FIG. 3A
Powder X-ray Diffraction Peak Listing	FIG. 3B
Optical Rotation (c=l, DMSO)	0°
Solubility Parameters at 24°C ± 3°C
Solvent	Conc. (mg/mL), 24 h
Methanol	0.29

Acetonitrile	0.79
Dîchloromethane	25.1
Dichloromethane/methanol	100
Ethanol	0.08
Ethyl acetate	0.20
Propylene glycol	0.75
Polyethylene glycol-300	2.8
pKa	pKal = 6.8 pKa2 = 2.7
pl-l-Solubility Profile
Buffer	Concentration (gg/mL)	pH of solution
pH 1.2 HCl (aq)	397	1.2
pH 3 200 mM citrate buffer	15	3.0
pH 5 200 mM citrate buffer	0.5	5.0
pH 6.5 200 mM citrate buffer	0.3	6.5
Fasted state simulated intestinal fluid	1	6.5
Fed state simulated intestinal fluid	22	5.0
¹ The DVS was obtained on a laboratory	batch having the same powder x-ray diffraction

PXRD.

Example 2: First-Generation Synthesis of Compound A.

[0447] Step I: (tert-butyl N-[(lr,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl]carbamate) (Intermediate 1). Into a 50.0-mL round-bottom flask, was placed tert-butyl N-[(lr,4r)-4hydroxycyclohexyl]carbamate (500.0 mg, 2.32 mmol, 1.00 equiv), N,NdimethyIformamide (10.0 mL), sodium hydride (82.8 mg, 3.45 mmol, 1.50 equiv), 2chloro-4-fluorobenzonitrile (432.6 mg, 2.78 mmol, 1.20 equiv). The resulting solution was stirred for 2 hours at 0°C in a water/ice bath. The reaction was then quenched by the addition of 20.0 mL of water. The resulting solution was extracted with ethyl acetate (40.0 mL) and the organic layers combined. The resulting mixture was washed with sodium chloride (40.0 mL). The mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/2). The collected fractions were combined and concentrated under vacuum. This resulted in 470.0 mg (58%) of Intermediate 1 (tert-buty! N-[(lr,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl]carbamate) as yellow oil. LC-MS (ES⁺): m/z 295.0 [MH⁺], t_R = 1.199 min, (1.90 minute run).

Chemical formula: CieHsjClNzOîPSO.M].

|0448] Step 2: (4-(((lr,4r)-4-ammocyclohexyl)oxy)-2-chlorobenzonitrile) (Intermediate

7) . Into a 50.0-mL round-bottom flask, was placed Intermediate 1 (tert-buty! N-[(lr,4r)-4(3-chloro-4-cyanophenoxy)cyclohexyl]carbamate) (470.0 mg, 1.34 mmol, 1.00 equiv), methanol (5.0 mL), hydrogen chloride. The resulting solution was stirred for 2 hours at room température. The resulting mixture was concentrated under vacuum. This resulted in 340.0 mg (88%) of Intermediate 7 (2-chloro-4-[[(lr,4r)-4aminocyclohexyl]oxy]benzonitrile) hydrochloride as a yellow solid. LC-MS (ES⁺): m/z 250.90 [MH⁺], t_R = 0.537 min, (1.90 minute run). Chemical formula: Ci3Hi₅ClN₂O[250.09].

[0449] Step 3: (6-[4-(hydroxymethyl)piperidin-l-yl]-N-[(lr,4r)-4-(3-cMoro~4cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide) (Intermediate 2). Into a 100-mL round-bottom flask, was placed 6-[4-(hydroxymethyl)piperidin-l-yl]pyridazine-3carboxylic acid (1.0 g, 4.21 mmol, 1.00 equiv), Intermediate 7 (2-chloro-4-[(lr,4r)-4aminocyclohexyl]oxybenzonitrile hydrochloride) (1.2 g, 4.18 mmol, 1.00 equiv), N,N20 dimethyIformamide (30 mL), N,N,N',N’-Tetramethyl-O-(7-azabenzotriazol-l-yl)uronium hexafluorophospate (2.4 g, 6.31 mmol, 1.50 equiv), N,N-diisopropylethylamine (1.6 g, 12.38 mmol, 3.00 equiv). The resulting solution was stirred for 1 hour at room température. The reaction was then quenched by the addition of water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichioromethane/méthanol (v:v = 12:1). This resulted in 1.1 g (56%) of Intermediate 2 (6-[4-(hydroxymethyl)piperidin-I-yl]-N-[(lr,4r)-4-(3-chloro-4cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide) as yellow oil. LC-MS (ES’): m/z 470.0 [MH⁺], tu = 0.90 min (1.8 minute run).

[0450] Step 4: (6-(4-formylpiperidin-i-yl)-N-[(lr,4r)-4-(3-chloro-4-cyanophenoxy) cyclohexyl] pyridazine-3-carboxamide) (Intermediate 3). Into a 100-mL round-bottom flask, was placed Intermediate 2 (700.0 mg, 1.49 mmol, 1.00 equiv), dichloromethane (20 mL), (LLl-Triacetoxy)-l,l-dihydro-l,2-benziodoxoL3(lH)-one (947.2 mg, 2.23 mmol, 1.50 equiv). The resulting solution was stirred for 3 hours at room température. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (v: v = 1:3). This resulted in 390.0 mg (56%) of Intermediate 3 as a yellow solid. LC-MS (ES⁺): m/z 468.2 [MH⁴], tR =1.06 min (2.0 minute run).

[0451] Step 5: (6-[4-([4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3-dioxo-2,3-dihydro-IHisoindol-5-yl]piperazin-1 -yl]methyl)plperidin-l -yl]-N-[(Ir, 4r)-4-(3-chloro- 410 cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide) (Compound A). Into a 100-mL round-bottom flask, was placed Intermediate 3 (180.0 mg, 0.38 mmol, 1.00 equiv), dichloromethane (10 mL), Intermediate 5 (2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6(piperazin-l-yl)-2,3-dihydro-lH-isoîndoIe-I,3-dione hydrochloride) (152.7 mg, 0.38 mmol, 1.00 equiv), sodium triacetoxyborohydride (244.6 mg, 3.00 equiv). The resulting solution was stirred for 3 hours at room température. The reaction was then quenched by water (30 mL), extracted with ethyl acetate (30 mL x 3), washed with brine (30 mL) and concentrated under reduced pressure. The solid was fîltered out. HPLC analysis revealed the crude product to be 81.5% pure by area, with 16.9% by area identified as unreacted Intermediate 5. See FIG. 16A. The crude product was purified by Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBD Column, 19* 150mm 5 uni; mobile phase, water (10 mmol/L ammonium bicarbonate) and acetonitrile (48.0% acetonitrile up to 73.0% in 8 min); Detector, UV 254nm. This resulted in 146.1 mg (47%) of Compound A as a yellow solid. HPLC-UV analysis showed the purified product to be 98% pure by area, with three impurities, quantified at 0.54%, 0.74% and 0.73% respectively. See FIG.

I6B Ή NMR (400 MHz, DMSO): δ 11.11 (s, IH), 8.58 (d, J = 8.2 Hz, IH), 7.86 (d, J = 8.8 Hz, 1 H), 7.81 (d, J = 9.5 Hz, 1 H), 7.73 (d, J = 11.4 Hz, 1 H), 7.46 (d, J = 7.4 Hz, IH), 7.39 (d, J = 2.4 Hz, IH), 7.34(d,J = 9.7 Hz, IH), 7.15-7.12 (m, IH), 5.13-5.08 (m, IH), 4.59-4.45 (m, 3H), 3.90-3.83 (m, IH), 3.27 (s, 4H), 3.03 (m, 2H), 2.97-2.82 (m, IH), 2.642.53 (m, 5H), 2.46 (m, 1 H), 2.23 (m, 2H), 2.14-2.09 (m, 2H), 2.07-2.02 (m, IH), 1.96-1.79 (m,5H), 1.65 (m, 2H), 1.52 (m, 2H), L 19-10.09 (m, 2H); LC-MS (ES⁴): m/z 812.25 [MH⁴], t# = 1.57 min (3.0 minute run). Chemical Formula: C41H43CIFN9O6 [811.30]. Total H count from HNMR data: 43.

Example 3: Second Génération Synthesis of Compound A

[04521 Step 1: N-((lr,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4(hydroxymethyl)piperidin-l -yl)pyridazine-3-carboxamide. To a clean, dry, 100-L jacketed, glass reactor equipped with a temperature controller, two pen chart recorder, and a nitrogen bleed was charged dimethylacetamide (24 L, 5 vol), Intermediate 4 (4800.5 g, 1 wt), piperidin-4-yl methanol (1699.9 g, 0.35 wt), and diisopropylethylamine (4759 g, 0.99 wt). The temperature ofthe batch was adjusted to 90 °C over 2 h, 7 min and the batch then held at 90 °C for an additional 15 h. The reaction was monitored by HPLC. The temperature of the batch was adjusted to 50 °C over 48 min then isopropyl acetate (48 L, 10 vol) added. The batch was split into two equal portions (each -42 L) for work-up.

|0453] Portion 1 Work-up. Portion Iwas charged to a clean, dry, 100-L, jacketed, glass reactor and heated to 50 °C. Purified water (36 L, 7.5 vol) was charged and the batch stirred at 50 °C for 5 min. The layers were allowed to separate and the lower aqueous layer was discarded to waste. Isopropyl acetate (12 L, 2.5 vol) and purified water (24 L, 5 vol) were charged and the batch temperature adjusted to 50 °C. The batch was stirred at 50 °C for 5 min, then the layers were allowed to separate, and the lower aqueous layer was discarded to waste. IPC: 'HNMR (TEST-2835) - % DMAc 8.7% relative to Intermediate 2.

[0454] Portion 2 Work-up. Portion 2 was charged to a clean, dry, 100-L, jacketed, glass reactor and heated to 50 °C. Purified water (36 L, 7.5 vol) was charged and the batch stirred at 50 °C for 5 min. The layers were allowed to separate and the lower aqueous layer was discarded to waste. Isopropyl acetate (12 L, 2.5 vol) and purified water (24 L, 5 vol) were charged and the batch temperature adjusted to 50 °C. The batch was stirred at 50 °C for 6 min, then the layers were allowed to separate, and the lower aqueous layer was discarded to waste. IPC: 'HNMR (TEST-2835) - % DMAc 2.8% relative to Intermediate 2.

[0455] The combined isopropyl acetate extracts were returned to the 100-L reactor.

Intermediate 2 Seeds (48.82 g, 0.01 wt,) were charged and the batch temperature adjusted to 15 °C over 2 h. The batch was distilled under vacuum (Jacket Temp. 35 °C) until 26 L, (5.4 vol) remained. Isopropyl acetate (46 L, 9.6 vol) was added and the batch température adjusted to 50 °C over 1 h. The batch was stirred at 50 °C for 36 min then cooled to 20 °C over 28 min. The batch was distilled under vacuum (Jacket Temp. 35 °C) until 28 L (5.8 vol) remained, then the température adjusted to 10 °C over 18 min, and stirred at this température for 1 h, 18 min. The precipitated solid was isolated by vacuum filtration on a 24 inch, polyethylene filter funnel. The reactor was rinsed with isopropyl acetate (24 L, 5 vol) and the rinse used to wash the filter cake. The wet cake was further washed with isopropyl acetate (24 L, 5 vol). After conditioning on the filter under nitrogen for 46 min, the wet-cake was transferred to eight glass drying trays (wet weight 6545.8 g) and dried in a vacuum oven at 45 °C for ~22 h until a constant weight was achieved. The isolated Intermediate 2 (4597.8 g, 79.7%) was packaged into two 3 mil LDPE bags and stored inside a fiber board drum. HPLC Analysis: 99.4%.

[0456] Step 2: N-((lr,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-formylpiperidinl-yl)pyridazine-3-carboxamide. To a clean, dry, 100-L, jacketed, glass reactor equîpped with a température controller, two pen chart recorder, and a nitrogen bleed was charged dîchloromethane (36 L, 7.9 vol), Intermediate 2 (4577.1 g, 1 wt), sodium bicarbonate (1222.0 g), sodium bromide (1097.5 g, 0.24 wt), and purified water (25 L, 5.5 vol). The biphasic mixture was cooled to 0 °C over I h 11 min then a solution of TEMPO (15.2 g, 0.0033 wt) in dîchloromethane (9 L, 2.0 vol) was added over 32 min while keeping the internai température at 0 ± 5 °C. Sodium hypochlorite solution (14353.4 g, 3.12 wt) was added over 45 min while maintaining the internai température at 0 ± 5 °C. The light yellow batch was stirred for an additional 46 min at 0 ± 5 °C. The reaction was monitored by HPLC. An additional portion of sodium hypochlorite solution (223.0 g, 0.05 wt) was added and the batch stirred for an additional 2 h at 0 ± 5 °C. Dîchloromethane (9 L, 2.0 vol) was added and the batch stirred for an additional 5 min. The layers were allowed to separate and the upper aqueous layer was discarded to waste. The organic phase was washed (5 min) with a solution of sodium sulfite (1222.2 g, 0.27 wt) in purified water (19 L, 4.2 vol). The layers were allowed to separate and the upper aqueous layer was discarded to waste. The organic phase was washed (10 min) with purified water (9 L, 2.0 vol). The layers were allowed to separate and the upper aqueous layer was discarded to waste. The product rich organic phase was charged to the 100-L reactor along with acetonitrile (19 L, 4.2 vol) and vacuum distilied (Jacket Temp. 45 °C) to a final volume of 26 L. During the vacuum distillation, additional acetonitrile (37 L, 8.1 vol) was added to the reactor. Acetonitrile (54 L, 11.8 vol) was added and the batch vacuum distilied (Jacket Temp. 45 °C) to a final volume of 26 L. The distillation was monitored by ’H NMR. Acetonitrile (22 L, 4.8 vol) and purified water (46 L, 10 vol) was charged and the batch température adjusted to 20 ’C. The batch was stirred for 1 h 26 min then the precîpitated solid was isolated by vacuum filtration on a 24-inch, polyethylene, filter funnel. The reactor was rinsed with acetonitrile/purified water 1:1 (23 L, 5 vol) and the rinse used to wash the filter cake. After conditioning on the filter under nitrogen for 31 min, the wet-cake was transferred to eight glass drying trays (wet weight 5456.9 g) and dried in a vacuum oven at 45 °C for ~44 h until a constant weight was achieved. The isolated Intermediate 3 (4129.8 g, 90.6%) was packaged into two 3 mil LDPE bags and stored inside a fiber board drum. HPLC Analysis: 96.7%.

[0457] Step 3: N-((lr,4r)-4-(3-chloro-4-cyanophenoxy)cycIohexyl)-6-(4-((4-(2-(2,6dioxopiperidin-3-yl)-6-fluoro-l, 3-dioxo isoindolin-5-yl)piperazin-1 -yl)methyl)piperidin-1 yl)pyridazine-3-carboxamide (CompoundA). To a clean, dry, 5 0-L, jacketed, glass reactor equipped with a température controller, two single pen chart recorders, and a nitrogen bleed was charged dimethylacetamide (4.3 L, 2.5 vol) and sodium triacetoxyborohydride (2020.4 g, 1.17 wt). The resulting suspension was cooled to 5 ± 5 °C over 22 min.

[0458] To a clean, dry, 22-L, jacketed, glass reactor equipped with a température controller, a two pen chart recorder, and a nitrogen bleed was charged dimethylacetamide (8.5 L, 4.9 vol), Intermediate 5 (1719.8 g, 1 wt), and Intermediate 3 (2134.0 g, 1.24 wt). The internai température was adjusted to 0 ± 5 °C over 39 min then triethylamine (1200 mL, 0.7 vol) was added over 38 min while maintaining the internai température <5 °C.

[0459] The contents of the reactor were transferred to a separate reactor over 1 h 25 min while maintaining an internai température of 5 ± 5 ’C. Once the transfer was complété, the first reactor was rinsed with dimethylacetamide (1.1 L, 0.64 vol) and the rinse transferred to the second reactor. The batch was stirred for an additional 61 min at 5 ± 5 °C. Reaction was monitored by HPLC.

[0460] To a clean, dry, 100-L, jacketed, glass reactor equipped with a température controller, a two pen chart recorder, and a nitrogen bleed was charged éthanol (21 L, 12.4 voi) and purified water (21 L, 12.4 vol). The internai température was adjusted to 10 ± 5 °C over 51 min. The contents of the reactor containing the reaction mixture were transferred to the glass reactor over 9 min while maintaining the internai température <20 °C. Once the transfer was complété, the former reactor was rînsed with dimethylacetamîde (1.1 L, 0.64 vol) and the rinse transferred to the glass reactor. The température of the batch was adjusted to 50 °C over 3 h and held at this température for an additional 33 min. The batch was cooled to 20 °C over 81 min, held at this température for 69 min, then the precipitated solid was isoiated by vacuum filtration on a 24-inch, polyethylene, filter funnel. The reactor was rinsed with ethanol/purified water 1:1 (2 χ 11 L, 2 * 6.4 vol) and the rinse used to wash the filter cake. The wet cake was further washed with éthanol (2 x 1 1 L, 2 x 6.4 vol). After conditioning on the filter under nitrogen for ~13 h, the wet-cake (crude Compound A) was transferred to seven glass drying trays (wet weight 11353 g) and dried in a vacuum oven at 25 °C for —I 15 h until a constant weight (3382.4 g) was achieved. HPLC purity: 99.60 area% (see FIG. 17A).

[0461] To a clean, dry, 100-L, jacketed, glass reactor equipped with a température controller, a two pen chart recorder, and a nitrogen bleed was charged dichloromethane (54.7 L, 16.2 vol), methanol (6 L, 1.8 vol), and crude Compound A (3375.5 g, 1 wt). The batch was stirred until complété dissolution was observed (27 min). The batch was clarified through a 0.4-micron, in-line filter then distilled under vacuum (jacket temp. 65 °C) while adding pre-filtered éthanol (27 L, 8 vol) at such a rate that a total volume of —67.5 L was maintained. Compound A seed crystals (8.4 g, 0.0025 wt) slurried in prefiltered éthanol (200 mL, C019788) were added to the batch. Distillation under vacuum (jacket temp. 65 °C) was continued while adding pre-filtered éthanol (54 L, 16 vol) at such a rate that a total volume of-67.5 L was maintained. Distillation was monitored by 'H NMR.. The batch was stirred at 20 ± 5 °C for 4 h, 30 min then the precipitated solid was isoiated by vacuum filtration on a 24-inch, polyethylene, filter funnel. The reactor was rinsed with éthanol ( 13.5 L, 4 vol) and the rinse used to wash the filter cake. The wet cake was further washed with purified water (2 x 13.5 L, 2 x 4 vol) and éthanol (2 x 13.5 L, 2 x 4 vol). After conditioning on the filter under nitrogen for 16 h, the wet-cake was

transferred to seven glass drying trays (wet weight 3336.4 g) and dried in a vacuum oven at 25 °C for -99.5 h untîl a constant weight was achieved and the dichloromethane level had dropped to an acceptable level (450 ppm). The isolated N-((lr,4r)-4-(3-chloro-4cy an ophenoxy)cyclohexy 1)-6-(4-( (4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l, 35 dioxoisoindolin-5-yl)piperazin-l-yl)methyl)piperidin-l-yl)pyridazine-3-carboxamide (Compound A) (3052.4 g, 87%) was packaged into two 3 mil LDPE bags and stored inside an HDPE drum. HPLC Analysis: 99.6 area% (see FIG. 17B).

Example 4: Controls of Critical Steps and Intermediates in the Manufacturing 10 Process for Compound A

[0462] At this stage of development, the in-process Controls consist of température monitoring and high performance liquid chromatography (HPLC) analysis of the reaction mixtures to déterminé the extent of the reaction. The transformations depicted in Scheme 4 are monitored by expected HPLC endpoints for consumption of the limiting reagent.

[0463] The critical in-process Controls and target limits for the synthesis of Compound A are provided in Table 2.

[0464] Table 2. Critical In-Process Control Points and Acceptance Limits

Step	In-Process Control	Acceptance Limit
1	Reaction température	90° to 100°C
Consumption of Intermediate 4	<1.0 % Intermediate 4 remaining
2	Reaction température	0° to 5°C
Consumption of Intermediate 2	<1.0% Intermediate 2 remaining
Drying température	50° to 60°C
3	Reaction température	0° to 5°C
Consumption of Intermediate 5	<2% Intermediate 5 remaining
Drying température	45° to 65°C
Level of residual solvent	ICHQ3C

[0465] The process development on Compound A includes development of the synthetic route and related processes on a laboratory-scale of 10 to 100 grams and transferred into the kilo-lab for préparation of 28-day toxicology supplies at 1.5 kilogram-scale. Compound A for use in the préparation of clinical supplies was prepared at a 3-kilogram scale using the same synthetic route and processes employed for the 28-day toxicology supply.

Example 5: Second Génération Synthesis of Intermediate 4

[0466] Step I: Tert-butyl ((lr,4r)-4-hydroxycyclohexyl)carbamate. A solution of K2CO3 (12 kg, 87 mol) in water (60 L) was added (Ir, 4r)-4-amînocyclohexanol hydrochloride (12.0 kg, 79.lmol) at 0-10°C. The mixture was stirred at 0-10°C for Ih. Di-tert-butyl dicarbonate (18.1 kg, 83.1 mol) was added to the mixture. The resulting mixture was stirred at ambient température ovemight (20 h). TLC (hexane/ethyl acetate=2/l, SM: Rt=0; Product: Rf=0.4) indicated the reaction was complété. The solid was collected by filtration and dried in oven to afford the title compound tert-butyl ((lr,4r)-4hydroxycyclohexyl)carbamate (Intermediate 6) (10.13 kg, 60% yield) as white solid.

'HNMR (400MHz, DMSO-d6): §(ppm) 1.08-1.20 (m,4H), 1.36 (s,9H), 1.70-1.78 (m, 4H),

3.14 (s, 1 H), 3.30 (s, 1H),4.48 (s, IH), 6.65 (d, J=4 Hz, IH).

[0467] Step 2: Tert-butyl ((lr,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl) carbamate.

NaH (60% in minerai oil, 1110 g, 27.8 mol) was added to a solution of Intermediate 6 tertbutyl ((Ir,4r)-4-hydroxycyclohexyl)carbamate (5 kg, 23mol) in DMF (65 L) at -10°C. The 20 mixture was stirred at -10°C for Ih. 2-Chloro-4-fluorobenzonitrile (3.6 kg, 23 mol) was added in portions. The resulting mixture was stirred at -10°C for 1 h. TLC (hexane/ethyl acetate=5/l, 2-Chloro-4-fluorobenzonitrile : Rf=0.7; Product: Rr =0.4) indicated the reaction was complété. The mixture was added to ice-water (200 kg) in portions and stirred at ambient température for 20h. The solid was collected by filtration and dried in oven to 25 afford Intermediate 1 (7.8 kg, 95% yield) as white solid. ‘HNMR (400MHz, DMSO):

5(ppm) 1.33-1.43(m, I3H), 1.79-1.82 (m, 2H),2.01-2.04 (m, 2H), 4.48-4.50 (m. 1 H), 6.85 (d, J=3.6Hz, IH), 7.11 (dd, J =8.8 Hz, J=2.4Hz, IH), 7.67 (d, J= 1.2 Hz, IH), 7.83 (d, J = 4.4 Hz, IH).

[0468] Step 3: 4-((( 1 r,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile hydrochloride. 30 Acetyl chloride ( 13.6 kg, 173mol) was added dropwise to methanol (35 L) at 0-20°C. After the addition was complété, the mixture was stirred at room température for 1 h. Intermediate (15.2 Kg) was added to the mixture and the resulting mixture was stirred at room température for 2h. TLC (hexane/ethyl acetate=5/l, SM; Ri=0.4; Product: R~0.1) indicated the reaction was complété. The mixture was concentrated in vacuo. The residue was taken into methyl tert-butyl ether (25 L) and stirred at ambient température ovemight (20 h). The solid was collected by filtration and dried in oven to afford 4-((( lr,4r)-4aminocyclohexyl)oxy)-2-chlorobenzonitrile hydrochloride (Intennediate 7) (11.7 kg, 95% yield). 'HNMR (400MHz, DMSO-d6): ô(ppm) 1.41-1.59 (m,4H), 2.00-2.11 (m, 4H), 3.05 (s, |H), 4.48-4.55 (m, IH), 7.14 (dd, J = 8 .8Hz, J=2.4Hz, IH), 7.41 (d, J=2.4Hz, IH), 7.85 (d, >8.8Hz, IH), 8.25 (s, 3H).

[0469] Step 4: 6-chloro-N-((Ir,4r)-4-(3-chloro-4-cyano_Phenoxy)cyclohexyi)pyridazine-3carboxamide. A 20-L, jacketed reactor was charged with 6-chloropyridazine-3-carboxylie acid (0.490 kg, 3.09 mol, 1.00 equiv), Intermediate 7 (0.888 kg, 3.09 mol, 1.00 equiv), and ethyl acetate (4.4 L, 9 vol). Triethylamine (1.565 kg, 15.5 mol, 5.0 equiv) was added over 47 min and the addition pump lines were rinsed with ethyl acetate (0.5 L, 1 vol). The batch température was adjusted to 15-25 °C and T3P (3.93 kg of 50% solution, 6.2 mol, 2.00 equiv) was dosed into the reaction over 70 min. The dosing pump was rinsed with ethyl acetate (0.5 L, 1 vol). The batch was aged at 19-20 °C for 30 min. The reaction was monitored by HPLC. The reaction was quenched by the addition of 1 N aqueous HCl (~5 L, 1.6 equiv) over 45 min. The slurry was stirred ovemight and then the batch was filtered in a Buchner funnel with filter paper. The kettle and filter cake were rinsed with water (2 x 2.4 L, 2 x 5 vol) and ethyl acetate (2 L, 4 vol). The wet cake was re-slurried in ethyl acetate (2.5 L, 5 vol) for 30 min at room température. The batch was filtered and was rinsed with ethyl acetate (1.5 L, 3 vol). However, in-process HPLC analysis ofthe wet cake showed no change to the level of N-((lr,4r)-4-(3-chloro-4cyanophenoxy)cyclohexyl)-6-hydroxypyridazine-3-carboxamide (the hydroxyl impurity). The wet cake (1055 g) was dried in a Iray drierat 40-50 °C to afford 0.96 kg of Intermediate 4 (79% yield). The water content of the batch was 0.17 wt % by KF titration. The IH NMR spectrum was consistent with the assigned structure and the HPLC purity was 97.3 area% with 2.4 area% of the hydroxyl impurity.

[0470| The impure Intermediate 4 (906 g) was charged to a 10-L reactor with DMAc (2.72

L, 3 vol) and the batch was warmed to 50.6 °C. IPAc (2.72 L, 3 vol) was added and the batch was maintained at 50 °C for 1 h. The température was adjusted to 20 °C over 1.5 h and then the batch was fïltered. The reactor and filter cake were rinsed with IPAc (3 x 1.8 L, 3 x 2 vol). The wet cake (1.3 kg) was dried in a tray drier at 30-35 °C to afford 0.772 kg of 6-chloro-N-((lr,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyridazine-35 carboxamide (Intermediate 4) (85% yield). The IH NMR spectrum was consistent with the assigned structure (see FIG. 20) and the HPLC purity was 98.6 area% with 1.3 area% ofthe hydroxyl impurity.

Example 6: Second Génération Synthesis of Intermediate 5

[0471 ] Step 1:2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione. A mixture of

4,5-difluorophthalic acid (9.81kg, l.Oeq.), 3-aminopiperidine-2,6-dione (10.38kg, L3eq.), CHjCOOH (49 kg , 5V) was degassed by purging with nitrogen for three times. Then CHîCOONa (5.375kg, 1.35eq) was added and degassed by purging with nitrogen for three times again. The resulting solution was stirred for 4 hrs at 117-120 °C . HPLC showed the reaction was complété. Then H₂O (147 L, 15V) was added to the mixture slowly at 90 °C] 20 °C. After cooling to 30 °C, the reaction mixture was fïltered and the filter cake washed with water (20L, 2Vj*2. The filter cake was collected and dried at 50 °C to get 12.6 kg 2(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-l,3-dione (Intennediate 8) as off-white solid with 88.2% yield. H^l-NMR conformed to reference spectrum (FIG. 19).

[0472] Step 2: tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3-dioxoisoindolin-5yl)piper azine-l-carboxylate. A 100-L, jacketed reactor was charged with Intermediate 8 (4.50 kg, 15.30 mol, 1.00 equiv), sodium bicarbonate (1.542 kg, 18.35 mol, 1.20 equiv), Boc-piperazine (3.134 kg, 16.82 mol, LIO equiv), and NMP (22.5 L, 5 vol). The batch was agitated at 125 rpm. The batch température was adjusted to 90 over 4 h. The batch was stirred at 90 °C for 16.5 h. The reaction was monîtored by HPLC. The batch was cooled over approximately 2 h to 24 °C. The cooled reaction mixture was removed from the reactor to a carboy, and the reactor was cleaned with methanol, acetone, and then water. The reactor was charged with water (43.2 L, 9.6 vol) and acetonitrile (1.8 L, 0.4 vol). The batch température was adjusted to 20 °C. The product mixture in the carboy was dosed to the quench solution over 2 h maintaining the température at 15—25 °C. The precipitated product slurry was transferred to a Nutsche filter. The reactor and filter cake were rinsed with water (2 χ 22.5 L, 2 χ 5 vol), and the filter cake was conditioned under nitrogen overnight. The wet cake (l 8.6 kg) was dried in a tray drier at 40—45 °C for 11 days to afford 7.05 kg of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-I,3-dioxoisoindolin-5yl)piperazine-l-carboxylate (Intermediate 9) (100% yield). The water content ofthe batch 5 was 0.6 wt % by KF titration and the 'H NMR potency (dô-DMSO) was 84.7 wt %. The 'H NMR spectrum was consistent with the assigned structure (see FIG. 21) and the HPLC purity was 98.6 area% .

[0473] Step 3: 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(piperazin-l-yl)isoindoHne-l,3dione hydrochloride. A 30-gallon, Pfaudler reactor was equipped with a sodium hydroxide 10 (2 M) scrubber. The reactor was charged with 3 M hydrochloric acid solution in methanol (70 L, 10 vol). The batch was agitated at 75 rpm. The batch température was adjusted to 31,7 °C over 30 min. Intermediate 9 (7.00 kg, 15.20 mol) and methylene chloride (28 L, 4 vol) were charged to a 40-L carboy. The slurry was stirred to dissolve the Intermediate 9. The solution of Intermediate 9 was charged to the 30-gallon reactor over 6.5 h maintaining 15 the température at 30-40 °C. The batch was aged at 35 °C for 21 h. The réaction was monitored by HPLC. The batch was cooled to 17.4 °C over approximately 30 min. The slurry was filtered in a Nutsche filter. The reactor and the filter cake were rinsed with a mixture of methanol (15.75 L) and methylene chloride (5.25 L). The wet cake (7.1 kg) was dried in a tray drier at 40-50 °C to afford 5.14 kg of product (85% yield). The water 20 content of the batch was 3.4 wt % by KF titration and the ’H NMR potency (dô-DMSO) was 92.4 wt %. The ¹H NMR spectrum was consistent with the assigned structure and the HPLC purity was 97.5 area% .

[0474] The batch was then re-purified. To a 100-L, jacketed reactor was charged the previous product (4.95 kg, 12.5 mol) and dimethylacetamide (15.0 L, 3 vol). The batch 25 température was adjusted to 55 °C. Water (8.4 L, 1.7 vol) was charged in one portion to the batch and the température was re-adjusted 55-65 °C. The mixture was stirred for 44 min to obtaîn a clear solution. To the batch was charged 2-propanol (40 L, 8 vol) over 1 h maintaining the température above 45 °C. The batch was seeded at 55 °C with Intermediate 5 seeds (5 g). The batch was held at 45-55 °C for 20 min and was cooled over l h to 25 30 °C. The batch was aged for 17.5 h at 20-25 °C. The slurry was filtered in a Nutsche filter.

The reactor and filter cake was rinsed with 2-propanol (25 L, 5 vol). The filter cake was

100 washed again with 2-propanol (25 L, 5 vol). The wet cake (5.8 kg) was dried in a tray drier at 40-50 °C to afford 3.95 kg of product (79% recovery). The water content of the batch was 2.1 wt % by KF titration and the Ή NMR potency (d_é-DMSO) was 98.2 wt %. The 'H NMR spectrum is shown in FIG. 22 and the HPLC purity was 99.8 area%.

THIRD GENERATION SYNTHESIS

Example 7: Third Génération Synthesis of Compound A

[0475] Step 1: 6-(4-(hydroxymethyl)piperidin-l-yl)pyridazine-3-carboxylic acid (Intermediate 10). The synthetic route to Intermediate 10 is shown below in Scheme 7.

Scheme 7. Synthetic route to Intermediate 10

[0476] Step 2 N-((lr, 4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4(hydroxymethyl)piperidin-l-yl)pyridazine-3-carboxamide. In a 30-L jacketed reactor 15 equipped with a mechanical stirrer, thermoineter and nitrogen bleed was added 6-(4(hydroxymethyl)piperidin-l-yl)pyridazine-3-carboxylic acid (Intermediate 10) (500 g, 2.11 mol, 1 eq), 4-(((lr,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile hydrochloride (Intermediate 7) (654 g, 2.28 mol, 1.08 eq) and DMAc (2.5 L, 5 vol). To the mixture was added DIPEA (1.092 Kg, 8.43 mol, 4 eq) and ethyl cyanohydroxyiminoacetate (314 g, 2.21 20 mol, 1.05 eq). To the slurry was added 1-Ethy 1-3-(3-dimethylaminopropyl)carbod timide (EDCI) (525 g, 2.74 mol, 1.3 eq) at once. The température of the reaction mixture was increased to -40 °C. The reaction mixture was kept at internai température of ~40 °C for ~3 h. The reaction was monitored by IPC.

ΙΟΙ

[0477] The reaction mixture was diluted with IPAc (5 L, 10 vol) and H₂O (Dl, 5 L, 10 vol). The internai temperature was adjusted to 50±5 °C while the biphasic mixture was mixing vigorously. The mixture was kept at 50 °C for 15 minutes while mixing. The aqueous phase was drained and the organic phase was washed with H₂O (3 x 5 L, 3 x I0 vol) at 50 °C. The organic phase was drained in to a carboy. The aqueous phase was transferred in to the reactor and washed with IPAc (2.5 L, 5 vol) at 50±5 °C. Ail organic phases were combined and transferred in to the reactor (initiai KF value: 19754 ppm). The organic phase was concentrated down to -3 L (KF value: 4436 ppm). To the mixture was added IPAc (5 L, 10 vol) and distillation was continued to the final volume of 3 L (KF value: 1169 ppm, <3000 ppm). A thick solid residue was precipitated from the mixture. The thick slurry mixture was stirred at room temperature for the additional 18 hours. The slurry was filtered and the wet cake was rinsed with IPAc (2 x 5 L, 2 x 2.5 vol). The cake was aged under vacuum for 1.5 hours. The cake was further dried in vacuum oven at 35 °C to con stant we ight. N -(( l r,4r)-4-(3 -ch loro-4-cyano phenoxy)cyc lohexy 1)-6-(4(hydroxymethyl)pipendin-l-yl)pyridazine-3-carboxamide (Intermediate 2) (830 g, 84% isolated yield, 99.2% HPLC purity, RRT 1.11: -0.13%). The ‘HNMR. spectrum is shown in FIG. 23

[04781 Step 3: N-((Ir,4r)M-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-formylpiperidinl-yl)pyridazine-3-carboxamide. In a 30-L jacketed reactor equipped with a mechanical stirrer, thermometer and nitrogen bleed was added Intermediate 2 (700 g, 1.49 mol, 1 eq) followed by DCM (5.6 L. 8 vol). To the clear solution was added NaHCOj (189 g, 2.25 mol, 0.27 wt%), NaBr (168 g, 1.63 moi, 0.24 wt%) and water (DI, 3.5 l, 5 vol) at room temperature. The biphasic mixture was cooled down to <5 °C. To the reaction mixture was added solution of TEMPO (23 g, 0.015 mol, 0.0033 wt%) in DCM (1.4 L, 2 vol) at once (no exotherm was observed). To the reaction mixture was added NaOCl solution (2.18 Kg, 3.12 wt%) in portions while keepingthe internai temperature <5 °C. The reaction was monitored by IPC and HPLC. Extra portion of NaOCl (0.293 Kg, 0.5 wt%) was added to the reaction mixture.

[0479] The agitation was stopped and the layers were separated. The organic phase was drained and collected in a clean carboy. The aqueous phase was back extracted using DCM (1.4 L, 2 vol) and the organic was collected. The aqueous phase was discarded. The

102 organic phase was transferred in to the reactor and washed with Na₂SO3 solution (0.5 M, 2.94 L, 4.2 vol). A thick émulsion was formed. To the mixture was added brine (1 L). A partial séparation of the aqueous phase was observed. The clear aqueous phase was removed and to the émulsion was added THF (1.3 L, 10% with respect to the émulsion volume). The stirring was stopped after 10 min and the layers were separated. The aqueous phase was back extracted using DCM (1.4 L, 2 vol). The organic phase was collected and the aqueous phase was discarded. All organic phases were transferred into the reactor. To the reactor was added ACN (2.94 L4.2 vol) and the mixture was distilled under reduced pressure to the final volume of 4.5 L. To the reactor was charged ACN (5.7 L, 8.1 vol) and distillation was continued. An IPC of the sample showed 7 wt% of DCM with respect to Intermediate 3 remaîned. To the reactor was added ACN (4.2 L, 6 vol) and distillation was continued to the final volume of 4 L. Distillation was monitored by IPC. The batch température was adjusted to 18 °C. To the batch was added ACN (3 L, 4.2 vol) total ACN volume of 7 L (10 vol). To the mixture was added water (DI, 7 L, 10 vol) and the mixture was stirred at 18 °C for 18 hours before filtration. The product was filtered on a Buckner funnel and the wet cake was aged under vacuum for 45 min. The cake was transferred into a glass tray and dried further in vacuum ovenat35±5 °C to the constant weight. N~((lr,4r)4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-formylpiperidin-l-yI)pyridazine-3carboxamide (Intermediate 3) (676 g, 96% yield, 0.96 wt% ACN content, 94 wt% potency, 96% HPLC purity, 1.93 % Intermediate 2). The ’HNMR spectrum is shown in FIG. 24.

[0480] Step 4: N-((lr,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(2-(2,6dioxopiperidin-3-yl)-6-fluoro-l,3-dioxoisoindolin-5-yl)piperazm-l-yl)methyl)piperidin-lyl)pyridazme-3-carboxamide. To a clean, dry, 10-L, jacketed, glass reactor equipped with a température controller, thermometer, mechanical stirrer and a nitrogen bleed was charged dimethylacetamide (1.24 L, 2.75 vol) and sodium triacetoxyborohydride (528 g, 2.42 eq). The resulting suspension was cooled to 5 ± 5 °C.

[0481] To a clean, dry, 30-L, jacketed, glass reactor equipped with a température controller, a thermometer, mechanical stirrer and a nitrogen bleed, was charged dimethy lacetam ide (2.2 L, 4.9 vol), Intermediate 5 (450 g, 90.7 wt%), and Intermediate 3 (563 g, 94 wt%, l.ieq). The internai température was adjusted to 0 ± 5 ° then trimethylamine (315 mL) was added over 40 min while maintaining the internai

103 température <5 °C. The contents ofthe reactor containing Intermediate 5 and Intermediate 3 were transferred to the reactor containing the sodium triacetoxyborohydride over 40 min while maintaining an internai température ofto 5 ± 5 °C. Once the transfer was complété, the reactor was rinsed with dimethylacetamide (DMAC) (225 mL, 0.5 vol) and the rinse transferred to the other reactor. The batch was stirred for an additional Ihour at 5 ± 5 °C. The reaction was monitored by IPC.

|0482] To a clean, dry, 30-L, jacketed, glass reactor equipped with a température controller, thermometer and a nitrogen bleed was charged éthanol (5.5 L, 12.1 vol) and purified water (5.6 L, 12.4 vol). The internai température was adjusted to 15 ± 5 °C. The contents ofthe reactor containing the process mixture were transferred to the new reactor over 1 hour while maintaining the internai température <20 ’C. Once the transfer was complété, the former reactor was rinsed with DMAC (200 mL, 0.5 vol) and the rinse transferred to the latter reactor. The température of the batch was adjusted to 50 °C and held at this température for an additional 1 hour. The batch was cooled to 20 °C over 81 min, held at this température for 1, then the precîpitated solid was isolated by vacuum filtration. The reactor was rinsed with ethanol/purified water 1:1 (2 x 2.9 L, 2 x 6.4 vol) and the rinse used to wash the filter cake. The wet cake was further washed with éthanol (2 x 2.9 L, 2 x 6.4 vol). After conditioning on the filter Ihour, the wet-cake (crude Compound A) was transferred to three glass drying trays dried in a vacuum oven at 50 °C for 3 days. Constant weight was not achieved.

[0483| To a clean, dry, 30-L, jacketed, glass reactor equipped with a température controller, a thermometer, mechanical stîrrer, condenser, vacuum controller and a nitrogen bleed was charged dichloromethane (15 L, 16.2 vol), methanol (1.66 L, 1.8 vol), and crude Compound A (925 g, 1 wt). The batch was stirred until complété dissolution was observed. The batch was clarified through a 0.4 micron in-line filter then distilied under vacuum (jacket temp. 65 °C) while adding éthanol (5.6 L, 8 vol) at such a rate that a total volume of -18.5 L was maintained. Compound A seed crystals (1.85 g, 0.0025 wt) slurried in éthanol (120 mL) were added to the batch. Distillation under vacuum (jacket temp. 65 °C) was continued while adding éthanol (10 L, 10 vol) at such a rate that a total volume of -18 L was maintained. Distillation was monitored by IPC. The batch was stirred at 20 ± 5 °C for 18 hours then

104 the precipitated solid was isolated by vacuum filtration. The wet cake was further washed with purified water (2 x 2 L, 2 x 2 vol) and éthanol (2 x 2 L, 2 x 2 vol). The wet-cake was dried in a vacuum at 25 °C for ~24 h until a constant weight was achieved. The isolated N-((1r,4r)-4-(3-ch !oro-4-cyanophenoxy)cyclohexy 1)-6-(4-((4-(2-(2,6-dioxopiperidin-35 yl)-6-fluoro-l,3-dioxoisoindolin-5-yl)piperazin-l-yl)methyl)piperidin-l-yl)pyridazine-3carboxamide (Compound A) (850 g, 100%) HPLC Analysis: 99.22 area% (FIG. 18). The 'HNMR spectrum is shown in FIG. 25.

Example 8. Elucidation of Structure and Other Physical Characteristics of 10 Compound A

[0484] Scheme 8. Numbered Carbon Atoms of Compound A.

[0485] There is a single stereogenic center in the Compound A molécule at carbon 36. The 15 starting materials for Compound A are sourced from achiral precursors, hence the molécule is racemic.

[0486] The centers carbon 10 and 7 are meso and by définition hâve no chirality. The 1,4trans relationship of the amide and ether on carbons 10 and 7, respectively, is supported by ¹H nuclear magnetic résonance (NMR) in conjunction with 2-D nOe NMR.

[0487] The drug substance has been characterized by application of various spectroscopic techniques (*HNMR, ^l3C NMR, mass spectrometry (MS), and Infrared spectroscopy (IR)), all of which support the Chemical structure.

[04881 NMR Spectroscopy

[0489] The ’H and ¹³C NMR reference spectra of Compound A were taken in the NMR 25 solvent deuterated dimethyIsulfoxide (DMSO-dô). The spectra were obtained on a Bruker

500 MHz spectrometer. The *H NMR spectrum is presented in FIG. 4. The ¹³C NMR spectrum for Compound A is presented in FIG. 5. Chemical shift assignments for both spectra are also provided in Table 3.

105

[0490] The résonances in both the Ή and ^l3C spectra were assigned based on 'H-'H COSY, 'H-^C edited HSQC and 'H-^l3C HMBC experiments. Ail NMR data acquired support the structure of Compound A.

[0491] Table 3. 'H and ¹³C NMR: Chemical Shifts of Compound A

Position⁸	Ή Chemical Shift^b’ ^e, Integ., multiplicity, J (Hz)^d	^l3C Chemical Shift^b, J (Hz)
l	—	161.7
2	7.37, IH, d(2.39)	116.8
3	—	137.0
4	—	103.2
5	7.84, IH, d (8.77)	135.7
6	7.12, IH, dd (8.80,2.39)	115.4
7	4.51, IH, m	75.6
8, 12	1.50, 2H, m; 2.09, 2H, br d (l 0.14)	29.8
9, l ]	1.63, 2H, aq; 1.88, 2H, overlapping br ad	29.4
10	3.85, IH, m	47.0
10-NH	8.56, IH, d(8.21)	—
I3	—	162.5
14	—	144.2
15	7.79, IH, d (9.55)	126.2
16	7.32, IH, d(9.71)	112.3
17	—	159.9
18, 22	4.47, 2H, brd (12.97); 3.01, 2H, t (11.78)	44.4
19, 21	1.82,2H, brd (11.49); 1.12,2H,m	29.8
20	1.90, 1 H, overlapping br ad	32.6
23	2.21, 2H, d (7.04)	63.6
24,27	2.53, 4H, brs	52.8
25,26	3.24, 4H, brs	49.6
28	—	145.3 (²Jc-f=8.55)
29	7.44, IH, d (⁴Jh-f = 7.38)	113.5
30	—	128.7
31	—	166.6

I06

Position’'	’H Chemical Shift”’ ^c, Integ., multiplicity, J (Hz)^d	¹³C Chemical Shift”, J (Hz)
32	—	166.1
33	—	123.3 (³Jc-f = 9.61)
34	7.71, IH,d(³J_H._F= 11.43)	111.9 (²Jc-f = 24.92) ____
35	—	157.3 (’Jc-f = 253.69)
36	5.10, IH, dd (12.87, 5.41)	49.0
37	—	169.9
37-NH	11.09, IH, s	—
38		172.7
39	2.59, IH, m; 2.88, IH,m	30.9
40	2.02, IH, m;2.5l, IH, overlapping m;	22.1
41	—	116.4

NMR = nuclear magnetic résonance a

The numbering used in the structure is for convenience and may not be consistent with IUPAC nomenclature.

’H and ^l3C NMR Chemical shifts were referenced to the résonances due to the NMR solvent at 2.49 and 39.5 ppm, respectively.

d = doublet, dd = doublet of doublet, m = multiplet, s = singlet, t = triplet, br = broad, aq = apparent quartet, ad = apparent doublet.

1H-1H coupling constants in Hertz are given in parenthesis.

[0492] Mass Spectrometry

[0493] High resolution mass spectrometry (MS) analyses of Compound A were conducted with flow injection analysis using positive ion electrospray [high-resolution electrospray îonization mass spectrometry (HR-ESI)] on a Thermo Orbitrap MS in Fourier Transform mode.

[0494] The high resolution mass spectrum of Compound A is presented in FIG. 6, and the major peaks resulting from MS/MS fragmentation ofthe 812.308 parent ion are presented in FIG. 7.

[0495] Further fragmentation of the observed MS/MS ions (MS³) was carried out, yielding the ion map provided in FIG. 8. Ail ions observed were within 4 ppm oftheory by accurate mass, and the ion map serves to further confirm the structure of Compound A.

[0496] Infrared Spectrometry

107

[0497] An infrared spectrum of Compound A was obtained on a Bornera MB-102 FT1R spectrometer equipped with a DuraSamplIR diamond ATR probe. The spectrum is shown in FIG. 9, along with a listing of peaks observed. Key features which lend further support to the structure for Compound A are bands at 2225 cm^-1, representîng a nitrile stretch 5 vibration, and five peaks between 1774 and 1594, which represent four imide carbonyl vibrations and an amide carbonyl stretch vibration. The fingerprint région from 1500 800 cm'¹ provides a distinct signature from which to identify Compound A.

Example 9: Summary of Studies to Détermine the Particle Size Distribution of 10 Compound A

[0498] The particle size statistics for Batch I2070-C-01-72-01 of Compound A which will be used în préparation of drug product for use in the clinic are shown in Table 4.

[0499] Table 4. Particle Size Distribution of Compound A

Batch	D (4,3) pm	D (10) gm	D (50) iirn	D (90) μικ
12070-C-01-72-01	43	6	24	__93________

Example 10. Impurities in the Second-Generation Manufacturîng Process for Compound A

[0500] Batches of Compound A drug substance contain low levels of impurities. The structure and origin of each known impurity are provided in Table 5. The residual levels of solvents used in the last steps of the synthesis are within the limits as per International 20 Conférence on Harmonisation (ICH) Q3C: “Impurities; Guidelines for Residual

Solvents.” Residual eiemental metals meet the limits as described in the United States Pharmacopeia (USP) <232/233> for drug product and follows the principles described in Food and Drug Administration (FDA) and ICH Guidelines for Eiemental Impurities (ICHQ3D).

[0501] Table 5. Process Related Impurities in the Compound A Drug Substance

108

Impurity 1

Origin

LJnreacted starting material from Step 3 (reductive amination)

A process impurity in intermediate 3 and can be formed as a by-product of the reductive amination in Step 3. This impurity is also a metaboiîte in female mouse liver microsornes

A process impurity resulting from over oxidation of Intermediate 2 in Step 2. This impurity is also a métabolite in male human, monkey, dog, rat, and mouse liver microsornes and hépatocytes

109

Compound	Structure	Orîgin
Intermediate 5	o z — M o Π g——/ _oX_zX_oex o	Unreacted starting material from Step 3 (reductive amination).

Example 11. Analytical Procedures for Compound A Manufacturing Process

[0502] Summaries of the compound spécifie analytical methods for Compound A are presented below.

[0503] HPLC for Identity, Assay and Impurities

[0504] This is a reverse phase high performance liquid chromatography (HPLC) method devised to détermine the assay and impurity profile of Compound A for release and stability testing. The method was qualîfied for its intended uses. Forced dégradation 10 studies were performed and used to qualify this method as stability indicating. The HPLC parameters are listed below in Table 6.

[0505] Table 6. HPLC Parameters

Column:	Waters Atlantis T3, 4.6 x 150 mm, 3 pm
Column Température;	45 °C
Sample Température:	ambient
Détection:	220 nm and 260 nm
Mobile Phase A:	0.1% TFA in Water
Mobile Phase B:	0.05% TFA in 75/25 Acetonitrile/methanol
Flow Rate;	1.0 mL/minute
Injection Volume:	10.0 pL
Data Collection Time:	36 minutes
Analysis Time:	28 minutes

[0506] Gradient:

Time (minutes)	% A	%B
0	95.0	5.0
1.00	95.0	5.0
10.0	55.0	45.0

110

20.10	45.0	55.0
24.10	5.0	95.0
28.00	5.0	95.0
28.01	95.0	5.0
36.00	95.0	5.0

[0507] GC Method

[0508] This is a gas chromatography (GC) method used to déterminé the residuai solvents in Compound A drug substance. The chromatographie parameters are listed in Table 7.

[0509] Table 7. GC Parameters for Method Number

Column	DB-624 (60 m x 0.32 mm ID x 1.8 pm)
Carrier Gas	n₂
FID Temperature	280°C
Makeup (N₂) Flow	30 mL/min
H 2 Flow	40 mL/min
Air Flow	400 mL/min
Control Mode	Linear Velocity
Column Temperature Program	Ramp	Temp. (°C)	Hold Time
-	45	5 min
10°C/min	220	3 min
Injector Temperature	200°C
Split Ratio	10:1
Diluent	NMP
Run Time	25.5 min

FID = flame ionization detector; GC = gas chromatography; Temp. = temperature

[0510] The analytical procedures for the détermination of assay, impurities, and residuai solvents in Compound A drug substance hâve been qualified. The qualification criteria are provided within the methods. Qualification for high performance liquid chromatography (HPLC) Method was designed to ensure that the HPLC method is suitable for its intended use of assay and impurity détermination. The method was qualified for specificity, limit 10 of détection (LOD), limit of quantification (LOQ), linearity, précision and solution stability. Acceptance criteria were established for each studied parameter. Forced

dégradation studies determined that method TM05187 is stability indicating and suitable to monitor the assay and impurity détermination of Compound A during stability studies.

Qualification of the gas chromatographie (GC) Method was designed to ensure that the method is suitable for its intended use for residual solvent détermination. The method was 5 qualified for specificity, sensitivity, linearity, and repeatability.

Example 12. Stability Studies with Compound A

[0511] An exploratory stability study on Compound A is on-going. The stability of Compound A will be studied at 5°C, 25°C/60%RH, and 40°C/75%RH with sampling 10 points at 1, 2, 3, and 6 months. Samples will be analyzed using the stability indicating method TEST-05187 (high performance liquid chromatography (HPLC)).

|0512] The critical quality attributes of the drug substance Compound A that will be monitored are appearance, purity, assay (wt%), impurities, water content, and x-ray powder diffraction (XRPD). The container and closure system for the stability study consists of 15 double plastic (PE) bags placed inside an high-density polyethylene (HDPE) container.

Data from this study are shown in Tables 8, 9, and 10.

[0513] Table 8. Stability Data for Compound A Storage at 5°C +/- 3°C

Test	At Date of Manufacture:	Initial Date¹	Initial Date + 1 Month	Initial Date + 2 Months
Appearance	Yellow Solid	Yellow Solid	Yellow Solid	Yellow Solid
Water Content (wt%)	0.27	0.86	0.85	LO
HPLC Assay (wt%)	97.7	99.5	97.4	97.4
HPLC Purity (%)	98.0	98.4	98.4	98.4
HPLC Impurities (%)
RRT 0.50 (Intermediate 5)	0.06	0.06	0.05	0.05
RRT 0.89	0.07	0.08	0.07	0.07
RRT 0.90	ND	<QL	<QL	<QL
RRT 0.92	0.07	0.06	<QL	0.06
RRT 0.94	ND	ND	ND	<QL
RRT 0.96 (Intermediate 2)	0.16	0.18	0.18	0.17

112

RRT 1,02	0.39	0.38	0.33	0.29
RRT 1.04 (Intennediate 3)	0.12	0.11	0.09	<QL
RRT 1.05 (Impurity 1)	<QL	ND	ND	ND
RRT 1.07	0.19	0.15	0.15	0.15
RRT 1.23	0.06	0.06	0.05	<QL
RRT 1.32	ND	ND	ND	0.05
RRT 1.36 (Intermediate 9)	0.05	ND	<QL	<QL
RRT 1.39	0.67	0.45	0.58	0.61
RRT 1.54	ND	<QL	<QL	<QL
Total Impuritîes (%)	2.0	1.3	1.5	1.5
XRPD	Crystalline	Crystalline	Crystalline	Crystalline

'about 3 months after date of manufacture

HPLC = high performance liquid chromatography; ND = <_0.02 % ; QL = 0.05 %; XRPD = x-ray powder diffraction

[0514] Table 9, Stability Data for Compound A Storage at 25°C + 2°C/60 % RH ±5%

Test	At Date of Manulactu re:	Initial Date¹	Initial Date + 1 Month	Initial Date + 2 Months
Appearance	Yellow Solid	Yellow Solid	Yellow Solid	Yellow Solid
Water Content	0.27	0.86	0.93	1.2
HPLC Assay (wt%)	97.7	99.5	97.3	97.5
HPLC Purity (%)	98.0	98.4	98.3	98.3
HPLC Impuritîes (%)
RRT 0.50 (Intermediate 5)	0.06	0.06	0.05	0.05
RRT 0.89	0.07	0.08	0.07	0.07
RRT 0.90	ND	<QL	<QL	<QL
RRT 0.92	0.07	0.06	0.07	0.06
RRT 0.94	ND	ND	ND	<QL

113

RRT 0.96 (Intermediate 2)	0.16	0.18	0.18	0.17
RRT 1.02	0.39	0.38	0.34	0.28
RRT 1.04 (Intermediate 3)	0.12	0.11	0.07	<QL
RRT 1.05 (Impurity 1)	<QL	ND	ND	ND
RRT 1.07	0.19	0.15	0.15	0.15
RRT 1.23	0.06	0.06	0.05	0.05
RRT 1.32	ND	ND	ND	<QL
RRT 1.36 (Intermediate 9)	0.05	ND	<QL	ND
RRT 1.39	0.67	0.45	0.57	0.65
RRT 1.54	ND	<QL	<QL	<QL
Total Impurities (%)	2.0	1.3	1.6	1.5
XRPD	Crystalline	Crystalline	Crystalline	Crystalline

¹ about 3 months after date of manufacture

HPLC = high performance liquid chromatography; ND = < 0.02 % ; QL = 0.05 %; XRPD = x-ray powder diffraction

[0515] Table 10. Stability Data for Compound A Storage at 40°C + 2°C/75% RLI + 5%

Test	At Date of Manufacture:	Initial Date¹	Initial Date + 1 Month	Initial Date + 2 Months
Appearance	Yellow Solid	Yellow Solid	Yellow Solid	Yellow Solid
Water Content	0.27	0.86	1.0	1.3
HPLC Assay (wt%)	97.7	99.5	97.3	97.2
HPLC Purity (%)	98.0	98.4	98.3	98.3
HPLC Impurities (%)
RRT 0.50 (Intermediate 5)	0.06	0.06	0.05	0.06
RRT 0.89	0.07	0.08	0.06	0.06
RRT 0.90	ND	<QL	<QL	<QL
RRT 0.92	0.07	0.06	0.07'	0.07

114

RRT 0.94	ND	ND	ND	<QL
RRT 0.96 (Intermediate 2)	0.16	0.18	0.18	0.18
RRT 1.02	0.39	0.38	0.34	0.28
RRT 1.04 (Intermediate 3)	0.12	0.11	0.08	<QL
RRT 1.05 (Impurity 1)	<QL	ND	ND	ND
RRT 1.07	0.19	0.15	0.14	0.14
RRT 1.23	0.06	0.06	0.05	0.06
RRT 1.32	ND	ND	ND	<QL
RRT 1.36 (Intermediate 9)	0.05	ND	<QL	ND
RRT 1.39	0.67	0.45	0.58	0.63
RRT 1.54	ND	<QL	<QL	<QL
Total Impurities (%)	2.0	1.3	1.6	1.5
XRPD	Crystalline	Crystalline	Crystalline	Crystalline

'about 3 months after date of manufacture

[0516] Summary: after 2 months at ail température stations, no increase in impurities nor change in solid properties has been observed. After 5 months from the date of manufacture, no increase in impurities or change in solid properties has been observed. A small increase in the water content has been observed.

Example 13. Description and Composition of the Compound A Tablet

[0517] Compound A tablets are intended for oral administration. Tablets containing 5 mg and 35 mg of the drug substance were manufactured with a press weight of 100 mg and 700 mg, respectively, from a common granulation. The tablet compositions are listed in 10 Table IL

[0518] Table 11. Composition of Compound A 5 Tablets (5 mg and 35 mg)

Component and Quality Standard	Function	Strength
5 mg	35 mg
mg per unit	% w/w	mg per unit	% w/w
Compound A	Active	5	5	35	5
Microcrystalline Cellulose NF, Ph. Eur, JP	Filler	45.5	45.5	318.5	45.5
Lactose Monohydrate NF/USP, Ph. Eur, JP	Filler	45.5	45.5	318.5	45.5
Croscarmellose Sodium NF, Ph. Eur, JP	Dîsintegrant	3	3	21	3
Silicon Dioxide NF/USP, Ph. Eur, JP	Glidant	0.5	0.5	3.5	0.5
Magnésium Stéarate NF, Ph. Eur, JP	Lubricant	0.5	0.5	3.5	0.5
Total Weight	100	100	700	100

NF/USP: National Formulary/United States Pharmacopoeia; Ph. Eur.: European Pharmacopoeia; JP; Japanese Pharmacopoeia

Example 14. Préparation of Spray-Dried Dispersion Intermediate.

10519] Multiple compositions were manufactured at the small scale and evaluated both in vitro (e.g., dissolution, stability, etc.) and in vivo (e.g., bioavailability, exposure levels, etc.). There was no advantage observed with dispersions that incorporated polymers and/or surfactants compared to pure spray-dried Compound A. In order to maintain simplicity and maximize drug load, the pure API spray dried was employed.

[0520] One engineering and two clinical batches of spray-dried intermediate hâve been manufactured. The information shown below is taken from the GMP Manufacturîng Batch Record (MBR) ofthe first clinical batch. Because this originates from an MBR, reference is made to spécifie pièces of equipment. There is no reason to expect that équivalent manufacturîng equipment would not be equally effective.

[0521] The process for the préparation of a spray-dried intermediate;

1. Starting from crystalline solid Compound A, préparé a 2.5% (w/w) solution of Compound A in 90%/10% (w/w) dichloromethane/methanol;

116

2. Spray dry solution în PSD-1 spray dryer using SK80-16 nozzle using the following conditions:

Parameter	Target	Target Range
Dryer Inlet Temperature	95°C	65-125°C
Dryer Outlet Temperature	37.5	32.5-42.5°C
System Gas Flow	1850 g/min	1550-2150 g/min
Liquid Feed Rate	180 g/min	145-205 g/min
Liquid Feed Pressure	450 psig	300-600 psig

3. Collect solid in cyclones and transfer to tray dryer to remove residuai dichloromethane and methanol to below ICH guideline levels using a defined temperature/humidity ramp.

[0522] Updated Préparation of Spray-Dried Dispersion

[0523] The process above was further refmed. The updated process is as follows:

1. Starting from crystalline solid Compound A, préparé a 6% (w/w) solution of

Compound A in 93%/7% (w'/w) dichloromethane/methanol;

2. Spray dry solution in PSD-1 spray dryer using Schlick Model 121 nozzle using the following conditions:

Parameter	Target	Target Range
Dryer Inlet Temperature	95°C	65-125°C
Dryer Outlet Temperature	37.5	32.5-42.5°C
System Gas Flow	1850 g/min	1550-2150 g/min
Condenser Temperature	-5 °C	-10-0 °C
Liquid Feed Rate	180 g/min	145-205 g/min
Liquid Feed Pressure	450 psig	300-600 psig

3. Collect solid in cyclones and transfer to filter dryer to remove residuai dichloromethane and methanol to below ICH guideline levels under vacuum at between 40 and 60 °C.

[0524] Granulation B tends and Tablets of Pure Spray-dried Compound A

[0525] Table 12 below shows the composition for the first clinical batch of 5 mg and 35 mg tablets as taken from the GMP MBR. The actual quantities used in the batch matched

117 the target levels to the décimal indicated. On a percent basis, the composition of the precursor engineering batch and second clinical batch was the same, though the absolute quantities of material employed were different. Again, because it originates from an MBR, the information below references spécifie pièces of equipment. There is no reason to 5 expect that équivalent manufacturing equipment would not be equally effective.

[0526] Table 12. Composition of First Clinical Batches of Tablets of Pure Spray-dried Compound A.

Component ID	Item	Unit Composition (w/w%)	Target batch Quantity (g)	Purpose
100% Compound A Spray-Dried Intermediate	l	5.00	750.0	Active Ingrédient
Microcrystalline Cellulose (Avicel PH102)	2	45.50	6825.0	Filler
Lactose Monohydrate (Fast Flo 316)	3	45.50	6825.0	Filler
Croscarmellose Sodium (Ac-Di-Sol)	4	3.00	450.0	Disintegrant
Colloïdal Silicon Dioxide (Syloid 244FP)	5	0.50	75.0	Glidant
Magnésium Stéarate	6	0.25	37.5	Lubricant (intragranular)
P regranulation Blend Totals		99.75	14962.5

118

Magnésium Stearate	7	0.25	37.5	Lubricant (extragranular)
Final Blend Totals		100.00	15000.0

[0527] The process for preparing Tablets of Pure Spray-dried Compound A;

I. Charge Bin blender with Items 1 -5

2, At 12 RPM, rotate blender 180 times

3. De-lump blend by passing through Ul 0 Comil with an 032R screen into Bin blender

4. At 12 RPM rotate blender 180 times

5. Screen Item 6 through 20 mesh screen and add to blender

6. At 12 RPM. Rotate blender 48 times

7. Granulate blend through Gerteis Roller Compacter with knurled rolls and 1.25 mm square wire granulator screen

8. Collect granulated material in Bin blender and charge with Item 7 passed through 20 mesh screen

9. At 12 RPM rotate blender 48 times to produce final blend

10. Partition final blend into one vessel for 5 mg tablets and another for 35 mg tablets

11. With 5-station Korsch XL100 and 0.3403”*0.6807” oval tooling press 35 mg tablets with suitable compression force (-14 kN)

12. With 10-statîon Korsch XL100 and 0.25” SRC tooling, press 5 mg tablets with suitable compression force (-4 kN) |0528] Particle size of granulation used in préparation of clinical supplies was not measured. However, the size distribution, as detennined by a sieve analysis, was measured of the engineering batch using the same percent composition and équivalent equipment and is shown FIG. 10.

Example 15. Compound A Drug Product.

[0529] Compound A 5 mg and 35 mg tablets were manufactured from a common granulation of spray-dried amorphous Compound A with the following compendial excipients:

• Microcrystalline Cellulose • Lactose Monohydrate • Croscarmellose Sodium • Silicon Dioxide

119 • Magnésium Stéarate

[0530| The tablets were packaged and shipped to the clinical pharmacies in heat-induction sealed high-density polyethylene bottles, that are capped with a lined, polypropylene closure. A silica desiccant canister is included to maintaîn a low-moisture environment.

[0531] Drug Substance Considérations

[0532| Compound A is designated as BCS IV (low solubility, low permeability). The désignation is supported by the low in vitro permeability in MDCK cells, and the crystalline solid’s low solubility of 1.2 pg/mL in pH 6.5 simulated intestinal fluid (SIF). This results in the modest oral bioavailability observed in the face of low hepatic clearance when 10 colloid-forming, précipitation-résistant solutions are administered. The cotnpound’s amorphous solubility in SIF is 30 pg/mL. A membrane flux experiment was conducted in which a fixed amount of compound was introduced into the donor compartment at various concentrations of the SIF bile salts, and appearance of drug was monitored on the receiver side. The rate of compound perméation was strongly dépendent on the concentration of 15 micellar species present in the donor solution (Table 13), indicating that absorption is limited not only by low aqueous solubility, but also by diffusion of solubilized drug across the unstirred water layer adjacent to the intestinal wall. If absorption is limited entîrely by solubility, the flux would not change with concentration of such species. Thus, colloidforming excipients are not only likely to improve bioavailability through the inhibition of 20 précipitation, but also by providing carriers that rapidly resupply the luminal surface with free drug as absorption occurs.

|0533[ Table 13. Flux Measurements as Function of SIF Concentration

SIF (mg/mL)	Flux (pg-min'Lcm'²)
0	0.02
5	0.09
10	0.14
20	0.20

SIF = simulated intestinal fluid

120

[0534] The mechanism-based understanding of absorption limitations described above suggested the use of amorphous dispersions as a means of leveraging the higher solubility characteristic of non-crystalline solids. Compound A possesses thermal characteristics compatible with this solubilization strategy. The melting point of neat crystalline material is 290°C, consistent with a high propensity to remain in the crystalline State, and a high glass transition température (Tg) of 146°C. Thus, while crystals of Compound A are quite stable, there is a significant barrier to transforming to a crystalline State from an amorphous form. Indeed, a ramped température increase of a partially-crystalline sample does eventually lead to a recrystallization event, but not until a température of 200-220°C is achieved. Hence, a very large amount of energy is required to induce the mobility and potential crystallization of amorphous Compound A even in the pure State. As discussed below, this robust résistance to crystallization is preserved even in the presence of water. [0535] A 90-minute non-sink dissolution experiment was conducted in which a Compound A suspension was introduced into pH 2 HCl at a final concentration of 1 mg/mL, which was then periodically sampled and prepared for analysis via centrifugation. A shift to pH 6.5 SIF was carried out 30 minutes into the experiment. The improved solubility of amorphous solid over the crystalline form is clearly demonstrated in FIG. 11. Higher concentrations are achieved in the gastric phase of the experiment and sustained in the intestinal phase with spray-dried amorphous Compound A.

[0536] Early Formulation Development

[0537] Due to the limited solubility of Compound A, early rat PK studies were conducted with solutions of Compound A in a variety of vehicles. Dose-linear exposure escalation in rats using solutions containing solubilizers and précipitation inhibitors demonstrated that compound can be delivered into systemic circulation if sufficient concentrations of absorbable drug can be sustained in the upper gastrointestinal (GI) tract.

[0538] Rat Studies with Spray-Dried Dispersions

[0539] Male rats were orally adminîstered Compound A as spray-dried dispersions (SDDs) in aqueous suspension containing 0.5% Methocel A4M at 10 mL/kg. Drug loads of 10, 25, and 50% in polyvinylpyrrolidone/vinyl acetate copolymer (PVPVA) were dosed along with loads of 25% with either hydroxypropyl methyIcellulose (IIPMC) or L-grade hydroxypropyl methylcellulose acetate succinate (HPMCAS-L). This allowed comparison

I2l across drug loads for the lead polymer as well as with other polymers at a common drug load.

[0540] Data from the pharmacokinetic studies described in Table 14 show that use of

PVPVA led to better exposures compared to the other polymers, but only at 10% drug 5 loading, which in turn compared favorably to the solution at a similar dose. This data led to the sélection ofthe 10:90 Compound A:PVPVA dispersion as the formulation employed in the rat good laboratory practice (GLP)-toxicology study.

[0541] While a 10% drug loaded SDD enabled the rat 28-day GLP toxicology study because ofthe high dosing volume permitted in preclinical species, such a value is too low 10 to be employed in a human solid dosage form. Performance of pure spray-dried amorphous

Compound A achieved the second-highest exposures of ail the amorphous solids adminîstered and would maximize strengths ofthe clinical solid dosage form.

[0542] Table 14. Formulations Tested in Rat Pharmacokinetic Studies

Dose (mg/kg)	Composition	Dosage Form	AUC (ngxh/mL)
125	Cosolvent + Précipitation Inhibitor	Solution	31,700
150	10:90 Compound A:PVPVA	Suspension	34,537
150	25:75 Compound A:PVPVA	Suspension	10,286
150	50:50 Compound A:PVPVA	Suspension	14,337
150	25:75 Compound A:HPMCAS-L	Suspension	11,293
150	25:75 Compound A:HPMC E3	Suspension	10,649
150	100% Spray-Dried Amorphous Compound A	Suspension	19,362

DMSO = dimethylsulfoxide; HPMC = hydroxypropyl methylcellulose; HPMCAS-L = L-grade hydroxypropyl methylcellulose acetate succinate; PEG400 = polyethylene glycol 400; PVPVA = polyvinyipyrrolidone/vinyl acetate copolymer

[0543] Dog Studies with Spray-Dried Dispersions

[0544] Data from the pharmacokinetic studies described in Table 15 show the formulations administering Compound A as 0.5% Methocel suspensions of four different polymer

122 dispersions ofthe drug (10 mg/kg of active) to fasted, pentagastrin pre-treated male dogs. Suspensions in dog yielded lower exposure compared to the solution. As a conséquence, the solution formulation was used in the 28-day GLP toxicology study. With respect to development of a clinical solid dosage form, however, within the variability of the area 5 under the curve (AUC) values, there is no indication of improved exposure with low drug loaded SDDs. This data, when combined with the experimental results from the rat, suggests that 100% spray-dried amorphous Compound A will be as effective in achieving exposure as a Compound A/polymer combination. Hence, this form of the drug was chosen for incorporation into a solid oral dosage form.

[0545] Table 15. Formulations Tested in Dog Pharmacokinetic Studies.

Dog Formulation ____
Composition	Dosage Form	AUC (ngxh/mL)
Avg	SD
Cosolvent + Précipitation Inhibitor	Solution	5,705	2,256
90:10:0 Compound A:PVPVA:TPGS	Suspension	1,635	309
10:80:10 Compound A:PVPVA:TPGS	Suspension	866	190
25:65:10 Compound A:PVPVA:TPGS	Suspension	2,486	1,549
80:10:10 Compound A:PVPVA:TPGS	Suspension	1,201	540

DMSO = dimethylsulfoxide; HPMC = hydroxypropyl methyIceIlulose; HPMCAS-L = L-grade hydroxypropyl methyIcellulose acetate succinate; PEG400 — polyethylene glycol 400; PVPVA= polyvinylpyrrolîdone/vinyl acetate copolymer

[0546] A flux experiment similar to that performed to obtain the data in Table 13 for several amorphous suspensions was conducted with results presented în Table 16. Flux remains constant regardless of polymer inclusion or drug load, thus demonstrating the 15 ability of pure spray-dried amorphous Compound A without polymer to source free, absorbable drug in solution.

|0547] Table 16. Flux Measurements of Spray-Dried Amorphous and Crystalline Compound A

123

Table 0-1 Flux Measurements of Spray-Dried Amorphous and Crystalline Compound A
Donor Compartment Contents	Flux (pg-min’-cm·²)
Spray-Dried Amorphous Compound A	0.15
10:90 Compound A:PVPVA	0.15
90:10 Compound A:PVPVA	0.11

PVPVA = polyvinylpyrrolidone/vinyl acetate copolymer

[0548] The amorphous form of pure Compound A is robust with a high Tg and even higher recrystallization température. The glass transition température does decrease under the plasticizing conditions of high humidity. However, the value is still well above the 5 commonly applied 40-50°C différence between Tg and any température the clinical présentation will encounter. Pure, spray-dried amorphous Compound A is predîcted to be more stable under high humidity conditions than is a polymer dispersion as shown in Table 17.

[0549] Table 17. Glass Transition Températures of Spray-Dried Amorphous 10 Compound A-Containing Solids as Function of Température and Relative Humidity.

Powder	Temperature/RH (°C/%)
25/0	40/75
100% Spray Dried Amorphous Compound A	146°C	103°C
10% API in PVPVA	114°C	25°C

API = active pharmaceutical ingrédient; PVPVA = polyvinylpyrrolidone/vinyl acetate copolymer; RH = relative humidity

[0550] In conclusion, in vitro and in vivo data support the use of pure, spray-dried amorphous Compound A API within the clinical formulation.

Example 16. Solvent Screen

[0551] A screen was conducted to détermine the optimum solvent for use purifying Compound A and for dissolution of crystalline Compound A prior to spray drying. The results of the screen are shown in Table 18.

124

[0552] Table 18. Solvent screening preliminary data.

Solvent system	Solids (wt%.)	Température	Dissolution
DCM:Acetone, 53:47%wt.	0.82	RT	Not dissolved
DCM:Ethanol, 92:8%wt.	2.26	RT	Dissolved__
DCM	0.6	RT	Not dissolved
DCM:Methanol, 95:5 wt.%.	4.2	RT	Dissolved
DCM:Methanol, 90:10%wt.	5 4.75	RT	Dissolved
6.6	30	Dissolved
8.1	35	Dissolved
DCM: Methanol, 80:20% wt.	3.4	RT	Dissolved
DCM:Methanol, 70:30% wt.	3.2	RT	Turbid solution
Methanol	2.8	RT	Not dissolved
THF	0.7	RT	Not dissolved

Example 17. Manufacturé g Process Development Spray-Dried Amorphous Compound A Intermediate

[0553] Amorphous Compound A produced at small (laboratory) and -0.5 kg (démonstration) scales was employed to optimize processing conditions for recovery, and study Chemical stability, non-sink dissolution performance, particle size, thermal characteristics, and residual solvent levels. Crystalline Compound A was dissolved in 90:10 dichloromethane:methanol (DCM:MeOH) to afford a concentration of 2.5 wt% and 10 was then introduced into a spray dryer to create the amorphous state. A two-stage traydrying procedure was used to remove residual solvents.

[0554] Particle size of the dried powder was measured via laser diffraction and is shown in Table 19. As expected, the particle size obtained with a smaller scale dryer are slightly smaller than those resulting from spray drying with a larger dryer. Dv(50) values of 10 pm 15 were reproducibly obtained using the latter equipment. This same, larger dryer supplied material for ail tablet development and in vivo testing carried out using spray-dried amorphous Compound A and will also do so for the clinical formulations.

[0555] Table 19. Laser Diffraction Particle Sizes of Spray-dried Intermediates.

125


Dryer	Sample	Volume-Average Diameter (pm)
Dv(10)	Dv(50)	Dv(90)
BLD35	Small Scale	1	5	11
PSD-1	Scale-Up#l	3	9	18
Scale-Up #2	4	10	20
Démonstration	4	10	20

Dv(10) = size below which 10% ofthe material volume is present

Dv(50) = size below which 50% of the material volume is present Dv(90) = size below which 90% of the material volume is present |0556] Suitable Chemical stability of the spray solution and the solvent-damp spray-dried intermediate (SDI) over a period of one week, hâve been confïrmed as shown in Table 20. [0557| Table 20. Chemical Stability of Solvent-damp Spray-dried Amorphous Compound 5 A and DCM/MeOH Spray Solution at 25°C.

Sample	Weeks @ 25°C	Total Impurities (%)	Weight Percent of Compound A
Damp Spray-Dried Amorphous Compound A	0	1.17	99.1
1	1.20	97.3
2	1.45	96.3
Spray Solution	0	1.18	N/A
1	1.10
2	1.40

DCM = dichloromethane; MeOH = methanol

[0558] Finally, from a performance perspective, non-sink dissolution of several amorphous Compound A samples from different manufacturîng scales, shown in Figure 12 reconfirms the pH-shift non-sink dissolution profile observed in the initial formulation 10 design phase.

Example 18: Compound A Tablet Development.

126

[0559] Several different compositions of 35 mg strength Compound A tablets (Table 21) were made as laboratory scale prototypes using conventional fillers, glidants, disintegrants, and lubricants for évaluation of Chemical stability (Table 22) and dissolution (FIG. 13) both immediately after manufacture and after stress storage conditions (2-weeks at

50°C/75%RH open).

[0560] Table21. Compositions of 35 mg Compound A Tabiet Prototypes.

Formulation Reference	Al	A2	A3
Tabiet Strength/ Press Weight (mg/mg)	35/700	35/700	35/700
Function	Ingrédient	% of Blend
Intra Granular
Active	Spray-dried amorphous Compound A	5.00	5.00	5.00
Filler	Microcrystalline cellulose	44.50	44.50	45.50
Filler	Lactose monohydrate	44.50	44.50	45.50
Di s intégrant	Crospovidone	3.00	—	—
Disintegrant	Croscarmellose sodium	—	3.00	3.00
Glidant	Silicon dioxide	0.50	0.50	0.50
Lubricant	Magnésium stéarate	0.25	0.25	0.25
Extra Granular
Disintegrant	Crospovidone	2.00	—	—
Disintegrant	Croscarmellose sodium	—	2.00	—
Lubricant	Magnésium stéarate	0.25	0.25	0.25
Totals:		100.00	100.00	100.00

[0561] Table 22. Chemical Stability of Prototype Tablets After 2 Weeks at 50°C/75%RH Open

Sample	t= (week)	Total Impurities (wt %)	Percent of Label
Formulation A1	0	LIO	98.7
2	1.67	98.3
Formulation A2	0	1.06	98.2
2	1.92	96.8
Formulation A3	0	1.15	99.0

127

I I 2 I 1-74 I 97.3 I

[0562] Based on the acceptable chemical stability of ail compositions and the improved dissolution profde observed with formulation A3, A3 was selected for clinical development.

Example 19: Compound A Manufacturing Process Development of a Spray-Dried Amorphous Compound A Intermediate Product: Characterization and Process Assessment

[0563] As demonstrated above, the maintenance of Compound A in the amorphous state 10 is intégral to achieving in vivo performance. Hence, effort was applied to assure a thorough understanding of the génération and subséquent use of the Compound A intermediate product.

[0564] The batch analysis for the spray-dried amorphous Compound A intermediate product is provided in Table 23. This data demonstrates that conversion of Compound A 15 from a crystalline to an amorphous fonn via spray drying does not materially affect either the potency or impurity profile. It also confirms the amorphous nature of the spray dried intermediate.

[0565] Table 23. Batch Analysis Results for Spray-Dried Amorphous Compound A Intermediate Product Démonstration Batch (SDI) Contrasted to Input API

Test	In Process Spécification	API	SDI
Appearance	FIO	—	Light yellow powder
DCM (ppm)	<600	16	200
MeOH (ppm)	<1,000	<1.5 (LOD)	<100 (LOQ)
Assay (% label)	—	98.1	99.1
Impurities > 0.05%		—	—
RRT = 0.50		Area % = 0.06	Area % = 0.05
0.89		0.07	0.08
0.92		0.07	0.07
0.96		0.16	0.16
1.02 '		0.39	0.37

128

1.04		0.12	<0.05 (LOQ)
1.07		0.19	0.18
1.23		0.06	0.05
1.36		0.05	<0.05 (LOQ)
1.39		0.67	0.22 ____
Total Impurities	—	1.84	1.18
D50 (gm)	FIO	—	10
PXRD	FIO	Crystalline	Amorphous
SEM Morphology	FIO	—	No crystallization or fusing

DCM = dichloromethane; FIO = for information only; MeOH = methanol; LOD = limit of détection; LOQ = limit of quantitation; PXRD = powder x-ray diffraction; RRT = relative rétention time; SEM = scanning électron microscopy (0566] The différence in the low impurity levels is considered to be caused by method variability.

Example 20: Stability of the Amorphous form of Compound A (“the Spray-Dried 5 Intermediate”)

[0567] The stability of amorphous Compound A was assessed at three stability conditions: 2-8°C; 25°C/60%RH; and 40°C/75%RH for a period of 12 months.

[0568] During stability testing, amorphous Compound A was stored in wire-tied lowdensity polyethylene bags placed in heat-induction sealed, high-density polyethylene 10 (HDPE) bottles containing a desiccant canister, and capped with polypropylene-lined closures.

[0569] After 6 months of storage at 2-8°C, the purity of the amorphous form of Compound

A was >95% (95.7%), with water being the major impurity (0.9%).

[0570] After 12 months of storing at 25°C/60%RH, the purity of the amorphous form of

Compound A was >97% (97.7%), with water being the major impurity ( 1.62%).

[05711 After 12 months of storing at 4Û°C/75%RH, the purity of the amorphous fonn of Compound A was 98%, with water being the major impurity (2.16%, as measured by Karl Fischer titration).

[0572] It is noteworthy that under ali three storage conditions, there was no évidence of 20 recrystallization of the amorphous form Compound A at any time during these studies.

129

Example 21. Batch Manufacture of Compound A Tablets

[0573] Compound A tablets, 5 and 35 mg, were prepared from a single, common blend.

Prior to blending, Compound A drug substance (DS) is dissolved, then spray-dried to fonn an amorphous drug product intermediate (amorphous Compound A). Formulas for each strength ofthe démonstration batches (5 mg and 35 mg tablets) are provided in Table 24 and Table 25, respectively.

[0574] Table 24. Démonstration Batch Formula for Compound A Tablets, 5 mg

Component	Function	Quantity Per Batch (g)
Compound A Intermediate Product	Active Agent	250.05
Microcrystalline Cellulose Avicel® PH102 (NF, Ph. Eur, JP)	Filler	2275.04
Lactose Monohydrate Foremost™ 316 (NF/USP, Ph. Eur, JP)	Filler	2275.07
Croscarmellose Sodium Ac-Di-Sol® (NF, Ph. Eur, JP)	Disintegrant	150.04
Silicon Dioxide Syloid® 244FP (NF/USP, Ph. Eur, JP)	Glidant	25.06
Magnésium Stéarate (NF, Ph. Eur, JP)	Intragranular Lubricant	12.52
Magnésium Stéarate (NF, Ph. Eur, JP)	Extragranular Lubricant	I0.34^a
Total Blend Weight	4998.12^b
Tablet Press Weight	100 mg
Total Number of 5 mg Tablets	6930

^a Extragranular magnésium stéarate amount adjusted based on granule yield.

^b Total weight of common blend, which was appropriately divided to make both 5 mg and 35 mg tablets.

[0575] Table 25. Démonstration Batch Formula for Compound A Tablets, 35 mg

Component	Function	Quantity Per Batch (g)
Compound A Intermediate Product	Active Agent	250.05

130

Microcrystalline Cellulose Avicel® PH 102 (NF, Ph. Eur, JP)	Filler	2275.04
Lactose Monohydrate Foremost™ 316 (NF/USP, Ph. Eur, JP)	Filler	2275.07
Croscarmellose Sodium Ac-Di-Sol® (NF, Ph. Eur, JP)	Disintegrant	150.04
Silicon Dioxide Syloid® 244FP (NF/USP, Ph. Eur, JP)	Glidant	25.06
Magnésium Stéarate (NF, Ph. Eur, JP)	Intragranular Lubricant	12.52
Magnésium Stéarate (NF, Ph. Eur, JP)	Extragranular Lubricant	10.34^a
Total Blend Weight	4998.12^b
Tablet Press Weight	700 mg
Total Number of 35 mg Tablets_________________________	3500

^a Extragranular magnésium stéarate amount adjusted based on granule yield.

[0576] Container Closure System for Compound A Tablets

[0577] Compound A Tablets, 5 mg and 35 mg, were packaged in heat-induction sealed, high-density polyethylene bottles, 100 cc and 500 cc in size, respectively, containing a desiccant, and closed with a child-resistant cap. The primary container closure components 5 are in compliance with relevant United States (US) and European Union (EU) guidelines pertaining to materials that corne in contact with food.

Example 22. Batch Formula for Compound A Tablets.

[05781 Compound A tablets, 5 and 35 mg, were prepared from a single, common blend. 10 Prior to blending, Compound A DS was dissolved, then spray-dried to form an amorphous drug product intermediate (amorphous Compound A). Représentative formulas for each strength are provided in Table 26 and Table 27.

[0579] Table 26. Batch Formula for Clinical Compound A Tablets, 5 mg

Component	Function	Batch Target Quantity (g)
Compound A Intermediate Product	Active Agent	750

131

Microcrystalline Cellulose Avicel® PH 102 (NF, Ph. Eur, JP)	Filler	6,825
Lactose Monohydrate Foremost™ 316 (NF/USP, Ph. Eur, JP)	Filler	6,825
Croscarmellose Sodium Ac-Di-Sol® (NF, Ph. Eur, JP)	Disintegrant	450
Silicon Dioxide Syloîd® 244FP (NF/USP, Ph. Eur, JP)	Glidant	75
Magnésium Stéarate (NF, Ph. Eur, JP)	Intragranular Lubricant	37.5
Magnésium Stéarate (NF, Ph. Eur, JP)	Extragranular Lubricant	37.5
Total Blend Weight	15,000*
Tablet Press Weight	100 mg
TotalNumberof5mgTablets____	21,400

JP = Japanese Formulaiy; NF = National Formulary; Ph. Eur. = European

Pharmacopoeia; USP = United States Pharmacopeia *Total weight of common blend, which is appropriately divided to make two batches of tablets.

[0580] Table 27. Batch Formula for Clinical Compound A Tablets, 35 mg

Component	Function	Batch Target Quantity (g)
Compound A Intermediate Product	Active Agent	750
Microcrystalline Cellulose Avicel® PH102 (NF, Ph. Eur, JP)	Filler	6,825
Lactose Monohydrate Foremost™ 316 (NF/USP, Ph. Eur, JP)	Filler	6,825
Croscarmellose Sodium Ac-Di-Sol® (NF, Ph. Eur, JP)	Disintegrant	450
Silicon Dioxide Syloid®244FP (NF/USP, Ph. Eur, JP)	Glidant	76
Magnésium Stéarate (NF, Ph. Eur, JP)	Intragranular Lubricant	37.5
Magnésium Stéarate (NF, Ph. Eur, JP)	Extragranular Lubricant	37.5
Total Blend Weight	15,000*
Tablet Press Weight	700 mg

132

Total Number of 35 mg Tablets 12,400

JP = Japanese Formulary; NF = National Formulary; Ph. Eur. European

Pharmacopoeia; U SP = United States Pharmacopeia *Total weight of common blend, which is appropriately divided to make two batches of tablets.

Example 23. Manufacturing and Process Description for the Compound A Tablets.

[0581] Compound A Intermediate Product: Compound A was dissolved in a 90/10 (w/w) mixture of dichloromethane (DCM) and methanol (MeOH), both of which are National Formulary (NF) grade, and stirred until a clear, yellow solution of 25 mg/mL was obtained. This solution was introduced to a spray dryer. The damp solid output was tray-dried to produce an amorphous solid (amorphous Compound A). This solid was checked for residual DCM and MeOH as an in-process test. A flow diagram of the manufacturing process of Compound A intermediate product is presented in FIG.14.

[0582] Tableting: a common dry granulation was used to produce Compound A tablets. Amorphous Compound A was blended with microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, and Silicon dioxide in a suitabie blender. The resulting powder was delumped and magnésium stéarate added and blended. The blend was granulated using a suitabie roller compacter and passed through a screen. Extragranular magnésium stéarate was added and the bulk powder was blended in a suitabie blender. The blend was compressed into tablets using a rotary press and the resulting tablets packaged in bulk containers. The flow diagram of the manufacturing process of Compound A tablets is presented in FIG. 15.

[0583] Controls of Critical Steps and Intermediates in the Manufacturing Process for Compound A Tablets.

[0584] A summary of Controls performed at the critical steps of the manufacturing process for Compound A intermediate product and for Compound A tablets are provided in Table 28 and Table 29, respectively.

[0585] The residual solvents level in the Compound A intermediate product is a quality attribute that is carefully monitored to assure safety. Acceptance criteria are those specified in the International Council for Harmonisation (ICH) harmonized guidelines for residual solvents Q3C(R6). Tablet properties are monitored to assure consistent size and

performance. Additional Controls may be added or refîned as drug development progresses.

[0586] Table 28. In-process Controls for the Manufacture of Compound A Intermediate Product.

Critical Step	Test	Method	Acceptance Criteria
Spray drying of Compound A	Residual dîchloromethane	TEST-099	<600 ppm
Spray drying of Compound A	Residual methanol	TEST-099	<3000 ppm

[0587] Table 29. In-process Controls for the Manufacture of Compound A Tablets, 5 mg and 35 mg.

Critical Step	Test	Method Type	Alert Limit (5 mg)	Alert Limit (35 mg)
Tableting	Individual press weight	Weîghing	100 mg ± 5%	700 mg ± 5%
Average hardness	Sotax Hardness Tester	6.5 kp ± 2 kp	27 kp ± 2 kp

[0588] Control of Excipients (Compound A, Tablet)

[0589] Spécifications: The excipients used in the manufacture of 5 mg and 35 mg tablets meet multi-compendial requirements: microcrystalline cellulose (National Formulary (NF), European Pharmacopoeia (Ph. Eur.), Japanese Pharmacopoeia (JP)), lactose monohydrate (NF/USP, Ph. Eur., JP), croscarmellose sodium (NF, Ph. Eur., JP), Silicon dioxide (NF/USP, Ph. Eur., JP), and magnésium stéarate (NF, Ph. Eur., JP). There are no non-compendial excipients used in the manufacturing process or present in the drug product.

[0590] Control of Drug Product (Compound A, Tablet)

[0591] Spécifications for Compound A tablets, 5 mg and 35 mg, are outlined in Table 30 and Table 31, respectively.

[0592] Table 30. Spécifications for Compound A Tablets, 5 mg

134

Test	Analytical Procedure	Acceptance Criteria
Appearance	TEST-009	Yellow to light-yellow, round tabiet
Identity by HPLC	TEST-513	The différence between HPLC rétention time of the sample and that of the main peak in the closest working standard injection is NMT 5%.
Assay (5 mg, % label)	TEST-513	90-110% of label claim ____
Related Substances (%)	TEST-513	Report ail impurities > 0.05% ____
DP Related Substances (%)	TEST-513*	Report ail impurities related to drug product manufacture or dégradation > 0.05%. Total of impurities related to drug product manufacture or dégradation < 2.5%. No single unspecified impurity > 1%.
Content Unifonnity	TEST-513	Meets USP <905>
Dissolution	TEST-514	Q>75%@T = 45 min

DP = drug product; HPLC = high performance liquid chromatography; NMT = not more than; USP = United States Pharmacopoeia; Q = amount of dissolved active ingrédient as percentage of labeled content *Value obtained by comparing chromatographie impurity peak areas of drug product with those of corresponding peaks reported in the drug substance Certificate of Analysis and taking the différence.

[0593] Table 31. Drug Product Spécifications for Compound A Tablets, 35 mg

Test	Analytical Procedure	Acceptance Criteria
Appearance	TEST-009	Yellow to light-yellow, oval tabiet
Identity by HPLC	TEST-513	The différence between HPLC rétention time of the sample and that of the main peak in the closest working standard injection is NMT 5%.
Assay (35 mg, % label)	TEST-513	90-110% of label claim
Related Substances (%)	TEST-513	Report ail impurities > 0.05%

Test	Analytical Procedure	Acceptance Criteria
DP Related Substances (%)	TEST-513*	Report ail impurities related to drug product manufacture or dégradation > 0.05%. Total of impurities related to drug product manufacture or dégradation < 2.5%. No single unspecified impurity > 1%.
Content Uniformity	TEST-513	Meets USP <905>
Dissolution	TEST-514	Q > 75% @ T = 45 min

[0594] Analytical Procedures for Compound A Tablets; analytical methods for identity, assay, related substances, content uniformity, and dissolution that ensure quality of Compound A tablets, 5 mg and 35 mg, hâve been developed. The method summaries are described in the section below.

[0595] Table 32. Analytical Procedures for Compound A Tablets

Assay	Method Number
Appearance	TEST-009
Identity by HPLC	TEST-513
Assay	TEST-513
Related Substances	TEST-513
Content Uniformity	TEST-513
Dissolution	TEST-514

HPLC = high performance liquid chromatography

[0596] Appearance (Method TEST-009)

[0597] Using a light box for uniform illumination, material is examined for color and shape confirmation is referenced to standard color wheels and figures, respectively.

136

[0598] Compound A Identity, Assay, Related Substances, and Content Uniformity by High

Performance Liquid Chromatography (HPLC) (TEST-513)

[0599] Samples are weighed out, dissolved in 80:20 (v/v) methanol:0.1% trifluoroacetic acid (TFA) in water, passed through a filter, and injected onto a HPLC with the conditions shown in Table 33.

[0600] Table 33. Chromatographie Conditions For TEST-513
Parameter	Value ___
Column	Waters Atlantis T3, 4.6 χ 150 mm, 3 pm__
Column Température	45°C
Détection	260 nm ___
Mobile Phase A	0.1% Trifluoroacetic acid in Water
Mobile Phase B	0.05% Trifluoroacetic acid in 75/25 acetonitrile/methanol
Flow Rate	1.0 mL/minute ___
Injection Volume	10.0 pL
Run Time	36 minutes

[0601] Identity is reported as the percent différence between HPLC rétention time of the sample and that of the main peak in the closes! working standard injection. Potency is 10 determined by comparison of peak area to that of the working standard and reported as percent of label claim. Ail impurities with peak area > 0.05% that are not Compound A are reported. Impurities spécifie to drug product manufacture or dégradation are obtained by comparing chromatographie impurity peak areas of drug product with those of corresponding peaks reported in the drug substance Certificate of Analysis and taking the 15 différence. A sample of 10 tablets is analyzed to perform a content uniformity assessment, with the results reported per United States Pharmacopeia (USP) <905>.

[0602] Dissolution (Method TEST-514)

[0603] Tablets are introduced into a U SP II apparatus with 1-liter vessels containing 900 mL (35 mg tablet) or 500 mL (5 mg tablet) of 50 mM Na^UPCU, pH 6.5 with 0.5 w/v% 20 sodium lauryl sulfate at 37°C using a paddle speed of 75 RPM. Samples are removed at , 15, 20, 30, 45, and 60 min, filtered through a 10 pm full-flow filter, diluted with acetonitrile, injected onto a HPLC with the conditions shown in Table 34.

[0604] Table 34. Chromatographie Conditions For TEST-514

Parameter	Value ___________
Column:	Agilent Zorbax SB-C18 4.6 x 150 mm, 3.5 pm_______
Column Température	30°C
Détection Wavelength	260 nm
Mobile Phase	60:40 Water:Acetonitrile, 0.1%TFA (v/v), 0.00025% SLS (w/v) __
Flow Rate	1.0 mL/minute
Injection Volume	2 pL ___
Run Time	4.0 minutes_________________________

TFA = trifluoroacetic acid; SLS = sodium iauryl sulfate

[0605] Six replicates of each tablet are tested, and results are reported as percent dose dissolved of label claim.

[0606] Batch Analyses (Compound A, Tablet)

[0607] The clinical batches intended for use in the proposed Phase 1 clinical trial are produced using the same formula and process as the 5 mg and 35 mg tablet démonstration batches characterized in Table 37 and Table 38, respectively.

[0608] Batch Analyses of Compound A Tablets, 5 mg and 35 mg

[0609] A description of the démonstration batches of Compound A 5 mg and 35 mg tablets 10 are provided in Table 35, Table 36, and Table 37.

[0610] Table 35. Description of Batches of Compound A Tablets, 5 and 35 mg

Strength and Batch Number	Batch Size (number of tablets)	Date of Manufacture	Use
5 mg	6930	Aug-2018	Démonstration, stability
35 mg	3500	Aug-2018	Démonstration, stability

[0611] Table 36. Batch Analysis Results for Compound A 5 mg Tablets

Test	Acceptance Criteria	Resuit
Appearance	Light yellow/yellow round tablet	Conforms

138

Identity by HPLC	ART <5%	Conforms
Assay (% label)	90-110%	98.3
Related Substances (%)	Report ail impurities > 0.05%	RRT	Area %
0.49 0.89 0.92 0.95 1.02 1.07 1.23 1.38	0.06 0.08 0.07 0.17 0.32 0.17 0.06 0.52
Related Substances (%)	Report ail impurities related to drug product manufacture or dégradation > 0.05%	NR
Total of impurities related to drug product manufacture or dégradation < 2.5%. No single unspecified impurity > 1%.	0.00
Content Uniformity	Meets USP <905>	Conforms
Dissolution	Q > 75% @ T = 45 min	Conforms

HPLC = high performance liquid chromatography; NR = none reported; RT = rétention tiine; RRT = relative rétention time; USP = United States Pharmacopeia; Q = amount of dissolved active ingrédient as percentage of labeled content

[0612] Table 37. Batch Analysis Results for Compound A 35 mg Tablets

Test	Spécification	Resuit
Appearance	Light yellow/yellow oval tablet	Conforms
Identity by HPLC	ART <5%	Conforms
Assay (% label)	90-110%	98.8
Related Substances (%)	Report ait impurities > 0.05%	RRT	Area %
0.49	0.05

139

		0.89	0.08
0.92	0.07
0.95	0.17
1.02	0.31
1.07	0.18
1.23	0.05
1.38	0.56
Related Substances (%)	Report ail impurities related to drug product manufacture or dégradation > 0.05%	NR
Total of impurities related to drug product manufacture or dégradation <2.5%. No single unspecified impurity > 1%.	0.00
Content Uniformity	Meets USP <905>	Con forms
Dissolution	Q > 75% @ T = 45 min	Conforms

HPLC = high performance liquid chromatography; NR = none reported; RT = rétention time; RRT = relative rétention time; USP = United States Pharmacopeia; Q = amount of dissolved active ingrédient as percentage of labeied content

[0613] Characterization of Impurities (Compound A, Tablet)

[0614] No additional impurities/degradants were identified as a conséquence of drug product manufacture and dégradation beyond those already present in the active pharmaceutical ingrédient (API).

Example 24: Stability of the Compound A Tablets

[06151 The protocol used for the Compound A, 5 mg and 35 mg, is described in Table 38

During stability testing, the tablets were stored in heat-induction-sealed high-density 10 polyethylene (HDPE) bottles containing a desiccant canister, and capped with a polypropylene-lined closure.

[0616] Table 38. Stability Protocol for Démonstration Batches of Compound A Tablets (5 mg and 35 mg)

Condition	Initial	Months
1	3	6	9*	12*

140

*Optional time points; KF = Karl Fischer titration

[0617] Summary of Stability Results

Phase 1 clinical trial drug product has been prepared using the same formula, process, and equipment.

[0618] No change in key quality attributes of Compound A tablets, 5 mg and 35 mg, was observed after 1 month at 40°C/75% relative humidity (RH) with the exception of the relative rétention time (RRT) = 1.02 chromatographie peak observed in some samples. The presence and magnitude of this peak is independent of storage conditions and is seen in both tablet strengths. It is thus potentially due to analytical variation. Likewise, real-time data for 1 month at 25°C/60%RH show no change in impurity profile.

[0619] After 6 months, all samples 40°C/75% RH are still within spécification. This implies that the samples will hâve a shelf-life of at least 2 years.

[0620] After 24 months, all samples at 25 °C/60%RH are still within spécification.

[0621] Stability data to support the clinical use of 5 mg Compound A tablets, at 2-8°C, 25°C/60%RH, and 40°C/75% RH, 35 mg Compound A tablets, at 2-8°C, 25°C/60% RH, 15 and 40°C/75% RH are presented in Tables 39-44.

[

[0622] Table 39.	Stability Results at 2-8°C Compound A Tablets, 5 mg____________________
Batch Size: 6930 ta	jlets	Packaging; Closed in heat-induction sealed pol y propylene closure	HDPE bottle containing desiccant canister with
Test	Acceptance Criteria	Method	Initia]	1 Month	3 Month	6 Month
Appcarance	Light ydlow/yellow round tablet	TEST-009	Confcrms	Conforma	Confcrms	Confcrms
Assav (% label)	90-110%	TEST-513	98.3	98	.3	95.8	98	2____
			RRT	Area %	RRT	Area %	RRT	Area %	RRT	Area %
			0.49	0.06	0.49	0.05	0.49	0.06	0.46	006
			0.88	0.08	NR	NR	0.88	0.06	0.87	0.07
			0.92	0.07	0.92	0 08	0 91	0.08	0.91	0.09
Related Substances (%)	Report ail impuritîes > 0.05%	TEST-513	0.96 1.02	0.17 0.32	0.95 1 02	0.16 0.40	0 94 1 02	0.14 0.06	0,95 1.02	0.20 0.07
			1.07	0.17	1.07	0.19	1.07	0 18	1.07	0.18
			1 23	0.06	1.23	0.06	1.24	0.06	1.25	0.06
			1 38	0.52	1.38	0.27	1.36	NR	1.39	0.40___
Related Substances (%)	Report ail impuritîes related to drug product manufacture or dégradation > 0 05%	TEST-513	NR	NR	NR	NR
Total of impuritîes related to drug product manufacture cr dégradation <2.5% and no single unspecified impurity > 1%	TEST-513	NR	NR	NR	NR
Dissolution	Q > 75% @ T = 45 min	TEST-514	Confomis	Confcrms	Confcrms	Con forms
Water by KF (%)	None	TEST-0268	4.7	4	3	4.2	4.6

HDPE = high-density polyelhylene; NR = none reperted, LOQ = limit of quantitation; RRT - relative rétention time; ND = none detected; Q - amount of dissolved active ingredtent as percentage of labeled content, T=Time; KF = Karl Fischer titration.

142

06231 Table 40. Stabîlity Results at 25°C/60%RH Compound A Tablets, 5 mg

Batch Size: 6930 tablets	Packaging: Closed in heat-induction sealed HDPEbottle containing desiccant canister with polypropylene closute
Test	Acceptance Criteria	Method	Initial	1 Month	3 Month	6 Month
Appearance	Light yellow/yellow round tablet	TEST-009	Conforma	Conforms	Conforms	Conforms
Assay (% label)	90-110%	TEST-513	98.3	97.8	96 6	98.7
Related Substances (%)	Report ail impurities > 0 05%	TEST-513	RRT	Area %	RRT	Area %	RRT	Area %	RRT	Area %
0.49 0.88 0.92 0 96 1 02 1 07 1 23 1.38	0.06 0.08 0.07 0.17 0.32 0.17 0.06 0.52	0.49 NR 0.92 0.95 1.02 1.07 1.23 1.38	0.05 NR 0.07 0 16 0.38 0 18 007 0.58	0 49 088 0 91 0.94 1.02 1.07 1.24 1.36	0.06 0.06 0.08 0.14 0.06 0.18 0 06 005	0.46 0.87 091 095 1 02 1 07 1 25 1 39	0.06 0.07 0.09 0.20 0.07 0,18 0.06 0.40
Related Substances (%)	Report ail impurities related to drug product manufacture or dégradation > 0.05%	TEST-S 13	NR	NR	NR	NR
Total of impurities related to drug product manufacture or dégradation < 2.5% and no single un specified impurity > 1%	TEST-513	NR	NR	NR	NR
Dissolution	Q>75%@T = 45 min	TEST-514	Conforma	Conforms	Conforms	Conforms
Water by KF (%)	None	TEST-0268	4.7	4.2	4.6	5.2

HDPE = high-density polyethylene, MR = none reported; LOQ = limit of quantitation; RRT = relative rétention time; ND ” none detected; Q = amount of dissolved active ingrédient as percentage of labeled content; T=Time; KF = Karl Fischer titration.

143

0624\| Table 41._____Stability Results at 40°C/75%RH Compound A Tabl .. Packaging. Closed i BatçhSize. 6930 tablets polypropylene closut	ets, 5 mg
t heat-induction sealed HDPE bottle containing desiccant canister with
Test	Acceptance Criteria	Method	Initial	1 Month	3 Month	6 Month
Appearance	Light ydlow/yd low round tablet	TEST-Û09	Conforms	Conforms	Conforms	Conforms
Assay (% label)	90-110%	TEST-513	98.3	98.4	96 1	97.4
Related Substances (%)	Report ail impunties > 0.05%	TEST-513	RRT	Area %	RRT	Area %	RRT	Area %	RRT	Area %
0.49 0.88 NR NR 0.92 0.96 1 02 1.07 NR 1.23 1 38	0.06 0.08 NR NR 0.07 0 17 0.32 0.17 NR 0.06 0.52	0-49 NR NR NR 0.92 0.95 1.02 l 07 NR 1.23 1.38	0.06 NR NR NR 0 08 0.16 0.41 0.18 NR 0.06 0 65	0.49 NR 0.88 0.89 0.91 0.94 1.02 1.07 NR 1 24 1.36	0.06 NR 0.08 0 06 0.12 0 14 0 06 0.19 NR 0.06 0.09	0.46 0 85 0.87 NR 0 91 0 95 1.02 1.07 1 11 1 25 1 39	0.07 0.05 0.10 NR 0.21 0 19 0.08 0.17 0.09 0.06 0.37
Related Substances (%)	Report ail impurities related to drug product manufacture or dégradation > Û.05%	TEST-513	NR	NR	0.89 0 91	006 0.05	0.85 0 91 LU	0.05 0 14 0.09
Total of impurities related to drug product manufacture or dégradation <2.5% and no single unspecified impurity > 1%	TEST-513	NR	NR	0.11	0.28
Dissolution	Q > 75% @ T = 45 min	TEST-514	Conforms	Conforms	Conforms	Conforms
Water by KF (%)	None	TEST-0268	4.7	4.4	4.9	5.1

H DPE = high-density polyethylene; NR = none reported; LOQ = limit of quanti talion; R RT - relative rétention time; ND = none detected, Q = amount of dissolved active ingrédient as percentage of labeled content; T=Time; KF = Karl Fischer titration

144

[0625] Table 42. Stability Results at 2-8°C Compound A Tablets, 35 mg __
Packaging- Closed in heat-induction sealed HDPE bottle containing desiccant canister with BatchSize, 3500 tablets polypropylene closure ______
Test	Acceptance Cri ter ia	Method	Initial	i Mont]»	3 Manth	6 Month
Appearance	Light ydlow/yellow round tablet	TEST-009	Conforms	Conforma	Conforms	Conforms
Assav (% label)	90-110%	TEST-513	98 8	100.2	95.8	97.1
Related Substances (%)	Report ail impurities > 0.05%	TEST-513	RRT	Area %	RRT	Area %	RRT	Area %	RRT	Area %
0.49 0.8S 092 0.95 1.02 1.07 1.23 NR 137	0.05 0.08 0.07 0.17 0 31 0 18 0.05 NR 0.56	049 089 0 92 0.95 1.02 1.07 1.23 1.36 1.38	0 05 0.11 0.07 0.16 0.50 0.17 0 06 0.06 0 65	0.48 0.87 0.91 0.94 NR 1.06 1.23 NR 1 35	0.05 0.06 0.07 0 13 NR 0 19 0.06 NR 0.06	0.46 0.87 0 91 0.94 1.02 1.07 1.25 NR 1,39	0.06 0.07 0.08 0.21 0.08 0.18 0.07 NR 0.59
Related Substances (%)	Report ail impurities related to drug product manufacture or dégradation £0.05%	TEST-513	NR	1 02	0.11	NR	0.94	0.05
Total of impurities related to drug product manufacture or dégradation < 2.5% and no single unspecified impurity > 1%	TEST-513	NR	Û 11	NR	0.05
Dissolution	Q> 75% @T = 45 min	TEST-514	Conforms	Conforms	Conforma	Conforms
Water by KF (%)	None	ΤΕΞΤ-0268	4.2	4.1	4.2	4.3

HDPE = high-density polyethylene. NR = none reported, LOQ = limit of quantitation, RRT = relative rétention time; ND = none detected; Q = amount of dissolved active ingrédient as percentage of labeied content; T=Time; KF “ Karl Fischer titration.

145

0626] Table 43. Stability Results at 25°C/60%RH Compound A Tablets, 35 mg
Packaging' Closed m heat-induction sealed HDPE bottle containing desiccant canister with ^{BillchSla:: 3500 tabteK} polypropylene closure
Test	Acceptance Criteria	Method	initial	1 Month	3 Month	6 Month
Appearance	Light yellow/yellow round tablet	TEST-009	Conforms	Conforms	Conforms	Conforms
Assay (% label)	90-110%	TEST-513	98 5	100 9	92.4	92.4
Related Substances (%)	Report ail impurities > 0.05%	TEST-513	RRT	Area %	RRT	Area %	RRT	Area %	RRT	Area%
0.49 0.88 0.92 0.95 1.02 1.07 1.23 1.37	0.05 0.08 0.07 0 17 0 31 0.18 0.05 0.50	0.49 0 89 0.92 0.95 1.02 1.07 1.23 1.38	005 0.11 0.07 0.16 0.49 0 18 0.06 0.56	0.48 0.87 0,91 0.94 1.02 1.06 1.23 NR	0.05 0.06 0.07 0.13 0.05 0.18 0.06 NR	0.46 0.87 0.91 0.94 1.02 1.07 1.25 1.39	0.06 Û.07 0.12 0.20 0.08 0.18 0.07 0.48
Related Substances (%)	Report ail impurities related to drug product manufacture or dégradation > 0.05%	TEST-513	NR	1.02	0.10	NR	0.91	0.05
Total of impurities related to drug product manufacture or dégradation < 2.5% and no single unspecified impurity > 1%	TEST-513	NR	0.10	NR	0.11
Dissolution	Q > 75% @ T = 45 min	TEST-514	Conforms	Conforms	Conforms	Conforms
Water by KF (%)	None	TEST-0268	4.2	4.1	4.3	4.4

HDPE = high-density polyethylene; NR = none reported; LOQ = limit of quant itation, RRT = relative rétention time; ND = none detected; Q = amount of dissolved active ingrédient as percentage of labeled content; T=Ttme; KF “ Karl Fischer titration.

146

06271 Table 44.	Stabilité Results al 4(FC/75%RH Compound A Tablets, 35 mg
Batch Size: 3500 tablets Packaging Closed in heat-induction sealed HDPE bottle containing desiccant canister with polyprupylene closure
Test	Acceptance Criteria	Method	Initial	1 Month	3 Month	6 Month
Appearance	Light yellow/yellow round tabiet	TEST-009	Conforma	Conforms	Conforms	Conforms
Assay (% label)	90-110%	TEST-513	93 8	99.9	87.4	95.4
			RRT	Area %	RRT	Area %	RRT	Area %	RRT	Area %
			0.49	0.05	0.49	0.06	0.48	0.06	0.46	0.07
			NR	NR	NR	NR	NR	NR	0.85	0.10
			0.88	0.08	0 89	0 11	087	0.08	0.87	ÛJ6
			NR	NR	NR	NR	NR	NR	0,88	0.05
			0.92	0.07	0.92	0.09	0 91	0.15	0.91	0.21
Related Substances (%)	Report ail impurities > 0.05%	TEST-513	0.95 1 02	0.17 0.31	0.95 1.02	0 15 0.51	0 94 1 02	0 13 0.05	0.94 l 02	0,20 0.08
			1.07	0.18	1.07	0.17	1.06	0.16	1.07	0.17
			1 23	0 05	1.23	0.06	1.23	0.06	1.11	0.06
			NR	NR	NR	NR	NR	NR	1.25	0 07
			1.37	0.56	l 38	0.58	1.35	û4û	1.39	0.39
			NR	NR	1.48	0.05	NR	NR	1.50	0.05
									0.85	040
					L 02	0.12			0.87	0.09
Related Substances (%)	Report ail impurities related to drug product manufacture or dégradation >0 05%	TEST-513	NR	NR	1.48	005	0 91	0.08	0.88 091 ni 1.50	005 0.14 0.06 005
	Total of impurities related to drug product manufacture or dégradation < 2 5% and tio single unspecified impurity > 1%	TEST-513	NR	0.17	0.08	0.49
Dissolution	Q > 75% @ T = 45 min	TEST-514	Conforma	Conforms	Conforms	Conforms
Water by KF (%)	None	TEST-0268	4.2	4.3	4 8	5.2

H DPE = high-density polyethylene; NR = none reported; LOQ = limit o P quan titat ion; RRT = relative rétention time; ND = none detected; Q = amount of dissolved active ingrédient as percentage of labeled content; T=Trme, KF = Karl Fischer titration.

147

FOURTH GENERATION SYNTHESIS

Example 25: Fourth Génération Synthesis of Compound A

[0628] Step 1: N-((lr,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(45 (hydroxymethyl)piperidin-l-yl)pyridazine-3-carboxamide (Intermediate 2)

[0629] To a 260 L glass-lined carbon Steel jacketed reactor was charged Intermediate 10 (7.00 kg), Intermediate 7 (8.89 kg), 2-pyrîdinol 1-oxide (HOPO) (491.4 g), and dîmethylacetamide (26.32 g), under nitrogen. The reaction mixture was agitated at 110 rpm (allowed range: 70 to 150 rpm) and cooled to approximately 10 °C (allowed température range: 5 °C to 15 °C) over 39 minutes. To the reactor was charged N,NDîisopropylethylamine (DIPEA) (4193.0 g) and the reaction mixture was agitated and the température re-adjusted back to approximately 10 °C (allowed température range: 5 °C to 15 °C) over 47 minutes, and the mixture held for a further 32 minutes. Agitation was halted, and the reactor was charged with l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDAC) (5936.0 g) and the reactor was purged for 6 minutes. The réaction mixture was agitated at 110 rpm, and dîmethylacetamide (6580.0 g) was added and the température was adjusted to approximately 20 °C (allowed température range: 10 °C to 30 °C) over 1 hour and 8 minutes. Agitation was maintained and the reactor was held at approximately 20 °C for 16 hours. At the end of 16 hours, in-process control (IPC) showed 0.3% area (acceptance criterion: < 1.0% area) of Intermediate 10, indicating completion.

[0630] To the reactorwas charged tap water (35.0 kg), producinga thîck slurry. The reactor was agitated at approximately 140 rpm (allowed range: 100 to 180 rpm) and heated to approximately 60 °C (allowed température range: between 55 °C to 65 °C) over the course of 1 hour and 15 minutes. To the reactor was charged additional tap water (35.0 kg) and isopropyl acetate (73.08 kg). The reactor température was adjusted to approximately 78 °C (allowed température range: 73 °C to 83 °C) and held for 40 minutes, during which time the slurry dissolved, and two layers formed. The contents of the reactor were allowed to settle for 3 hours at approximately 78 °C. The reactor was purged with nitrogen and the bottom aqueous layer was removed.

[0631] To an 800 L glass-lined carbon Steel jacketed reactor was charged isopropyl acetate (11.90 kg), followed by the organic layer from the 260 L reactor. A sodium chloride

148 solution (77.0 kg, 9.1% w/w) was charged, followed by isopropyl acetate (60.90 kg). A biphasic solution was formed, and the mixture was heated to approximately 78 °C (allowed température range: 73 °C to 83 °C) over 47 minutes under agitation. The mixture was agitated for 4 hours and 5 minutes at approximately 78 °C. The hot mixture was filtered 5 through Celite 545 into the 260 L reactor. The 800 L reactor was rinsed with isopropyl acetate (23.80 g), which was filtered and added to the 260 L reactor. The 260 L reactor was heated to approximately 78 °C (between 73 °C to 83 °C) over 3 hours and 6 minutes and the contents were allowed to settle for 4 hours and 1 minute. The reactor was purged with nitrogen and the bottom aqueous layer was removed.

[0632] The reactor was agitated at approximately 110 rpm (between 90 and 110 rpm). To the reactor was charged sodium chloride solution (76.3 kg, 9.1% w/w), and a biphasic solution was formed. The reactor was heated to approximately 78 °C (allowed température range: 73 °C to 83 °C) over 1 hour and 54 minutes and the température was held for 3 I minutes. Agitation was stopped and the contents were allowed to settle for 3 hours and 11 minutes. The reactor was purged with nitrogen and the bottom aqueous layer was removed.

|0633] The contents of the reactor were concentrated under vacuum distillation at 75 °C (allowed température range: 70 °C to 80 °C) to approximately 42 L. Isopropyl acetate (6.09 kg) was added and the reactor was heated to approximately 80 °C (allowed température range: 70 °C to 85 °C) under agitation. The reactor was held for 1 hour and 2 minutes at 20 approximately 80 °C and then cooled to approximately 20 °C (allowed température range:

°C to 25 °C) over 6 hours and 28 minutes. The reactor was held at approximately 20 °C for 4 hours and 31 minutes. The résultant slurry was quickly transferred to an electrically agitated Hastelloy filter dryer with an 8 μπι polypropylene filter cloth. The slurry was filtered under vacuum, and the mother liquor was used to rinse the reactor. The contents of 25 the reactor were added to the filter dryer and filtered under vacuum. The solid cake was washed twice with isopropyl acetate (9.17 kg x 2) and filtered under vacuum. The resulting cake was dried under vacuum with a jacket température of 60 °C (allowed température range: 55 °C to 65 °C) until total volatiles (by moisture analyzer) not more than 1.0% w/w (6 hours and 1 minute). The dryer was subsequently cooled, and the cake was collected to 30 afford Intermediate 2 (10.90 kg, 79%). Release results are shown below m Table 45:

Table 45: Release results for Intermedîate 2:

•	149
	Test Name	Spécification	Rcsult
Description	White to brown solid	Conforms
Identification (by IR)	Conforms to ref. spectrum	Conforms
Purity (by UPLC)	Not less than 96.0% (area)	99 7% (area)
Related Substances (by HPLC) Intermediate I0	Not more than 0.5% (area) Alert level: More than 0.15 %(area)	Not detected
Related Substances (by HPLC) Intermediate 7	Not more than 0.5% (area) Alert level: More than 0 15 %(area)	Not detected
Related Substances (by HPLC) Any individual impurity	Report resuit by RRT in % (area) Alert level: More than 0 15 %(area)	RRT 0.907: 0.07%(area) RRT 1.204: 0 20%(area) RRT 1.218 Less than 0 05 % (area)
Related Substances (by HPLC) Total impurities	Not more Uian 2.0% (area)	0 .2% (area)

[0634] Step 2: N-((lr,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-formylpiperidinl-yl)pyridazine-3-carboxamide (Intermediate 3)

[0635] To an 800 L glass-lined carbon Steel jacketed reactor, under nitrogen, Intermediate

2 (10.80 kg), sodium bromide (4.75 kg), sodium bicarbonate (3.89 kg) were added. The reactor was purged with nitrogen (*3), and deionized water (I29.6 kg), and dichloromethane (l 86.73 kg) were subsequently added. The reactor was then allowed to agitate at 50 rpm (allowed range: 30 to 70 rpm) for l hour and 39 minutes.

[0636] Agitation was halted and (2,2,6,6-tetramethylpiperidin-l-yl)oxyl (TEMPO) (35.64

g) was added over 40 mins. The reactor was purged with nitrogen (x 3), and the reaction subsequently charged with dichloromethane (7.18 kg). The reactor was then allowed to agitate at 50 rpm (allowed range: 30 to 70 rpm). The reactor was further charged with isopropyl alcohol (2.81 kg) and dichloromethane (7.18 kg). Agitation was increased to 110 rpm (allowed range: 105 to 115 rpm) and the reaction mixture was allowed to adjust to 20 °C (allowed température range: 15 °C to 25 °C), over 33 minutes. Once adjusted, ensuring ail solids were dissolved, the reaction mixture, at this température and agitation speed, was held for 2 hours and 5 minutes.

[0637] The reaction mixture was then cooled to -2 °C (allowed température range: -3 °C to 0 °C) over 2 hours and l minute, and a sodium hypochlorite solution (34.85 kg) was

150 then added over 40 minutes, ensuring the température was maintained between -3 °C and 0 °C (allowed température range: -3 °C and 3 °C), with agitation maintained at approximately 110 rpm (allowed range: 105 to 115 rpm). The addition rate and batch température are critical due to the exothermic nature of the reaction. Deionized water (5.40 5 kg) was then added through the transfer line used in the sodium hypochlorite transfer, ensuring the température was maintained between -3 °C and 0 °C. The mixture was then subsequently held at -2 °C (allowed température range: -3 °C and 3 °C) for 1 hour and 2 minutes. After 1 hour, the in-process control (IPC) showed 0.3% area (acceptance criterion: < 1.0% area) of Intermediate 2, indicating reaction completion.

[0638] The reaction mixture was allowed to warm to 20 °C (allowed température range:

°C and 25 °C), and agitation held at 90 rpm (allowed range: 80 to 100 rpm), and the reaction mixture was charged with acetic acid (4.104 kg), and the mixture held for 2 hours and 37 minutes, upon which a biphasic solution formed. An electrically agitated Hastelloy filter dryer with a 3-5 pm poly propylene filter cloth, was charged with Celite 545, and 15 dichloromethane (24. 6 kg) subsequently filtered through. A portion ofthe reaction mixture was filtered into a 260 L reactor, and the remaining mixture subsequently transferred into a 100 L reactor, and the 800 L reactor rinsed with dichloromethane (28.73 kg), which was filtered and added into the 100 L reactor. The 800 L reactor was rinsed with dichloromethane and filtered. The mixture was transferred from both the 260 L, and the 20 100 L reactor, back into the 800 L reactor, subsequently rinsing both with dichloromethane (5.40 kg x 2).

[0639J Agitation was halted and the mixture allowed to settle into two phases for 3 hours and 25 minutes. The organic phase that separated was transferred into a 260 L reactor. The organic layer was transferred back into the 800 L, and the 260 L vessel subsequently rinsed 25 with dichloromethane and the contents transferred into the 800 L reactor. Deionized water (108.0 kg) was added and the reactor allowed to agitate and the température increased to 20 °C and the content held at this agitation and température for 49 minutes. Agitation was halted and the mixture allowed to settle over 2 hours and 14 minutes, and two layers formed. The organic layer was transferred into the 260 L reactor, and the aqueous layer 30 dîscarded appropriately.

I5l

[0640] The mixture was then concentrated by distillation, under normal atmosphère at 40 °C (allowed température range: 35 °C to 45 °C) maintaining the volume approximately between 38-49 L by repienishing as required with tetrahydrofuran allowing the température to increase to 60 °C (allowed température range: 55 °C to 65 °C) and the final volume approximately 46 L. The contents of the reactor were then concentrated under vacuum distillation, repienishing with tetrahydrofuran as required, at 60 °C (allowed température range: 55 °C to 65 °C) until < l.0% v/v of dichloromethane remained.

[0641] Recrystallization was undertaken by the addition of n-heptane (29.38 kg) (65 °C), and held for 1 hour and 10 minutes, maintaining a température of approximately 65 °C, until a thick slurry was obtained. The slurry was subsequently cooled down slowly to 20 °C (allowed température range: 15 °C to 25 °C) by 4 hours and 34 minutes (température should not reach below 20 °C before 4 hours), and held at 20 °C for an additional 6 hours and 53 minutes. The résultant slurry was quickly transferred to an electrically agitated Hastelloy filter dryer with an 8 pm polypropylene filter cloth and the slurry was filtered under vacuum. The cake was washed twice with a tetrahydrofuran (4.86 kg) and w-heptane (3.67 kg) solution (x 3) and filtered under vacuum. The resulting cake was dried under vacuum with a jacket température of 50 °C (allowed température range: 45 °C and 55 °C) for 8 hours and 2 minutes, and then increasing the jacket température of 75 °C (allowed température range; 70 °C and 80 °C) for 7 hours and 42 minutes, until total volatiles (by moisture analyzer) not more than 1.0% w/w. The dryer was subsequently cooled, and the cake was collected to afford Intermediate 3 (10.20 kg, 95%). Release results are shown below in Table 46.

[0642] Table 46: Release results for Intermediate 3:

Test Name	Spécification	Resuit
Description	White to light brown solid	Conforms
Loss on Drying	Not more than 1.5% w/w (2 gram at 120 ®C)	0.7% (w/w)
Identification (by HPLC)	Rétention time of the main peak in the sample solution is consistent with reference standard (Not more than 5%)	Conforms
Purity (by HPLC)	Not less than 95.0% (area)	99.0% (area)

152

Related Substances (by HPLC) Intermediate 2	Noi more than l.5% (area)	0.3 % (area)
Related Substances (by HPLC) Impurity' 1	Not more than 3.0% (area)	0.7% (area)
Related Substances (by HPLC) Major unspecified impurity	Not more than 0.50% (areal	Less than 0.05%(area)
Related Substances (by HPLC) at RRT 1.24	Report results Alert limit: More than 0.35% (area)	0 06% (area)
Related Substances (by HPLC) Any other unspecified individual Impurity	Report results Alert limit: More than 0 15% (area)	RRT 1.24: Less than 0.05% (area) RRT 1.42 Less than . 0.05% (area)
Identification (by IR)	Report resuit	Report test

[0643] Step 3: N-((Ir,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(2-(2,6dioxopiperidm-3-yl)-6-fluorQ-l,3-dioxoisoindolin-5-yl)piperazin-I-yl)methyl)pipetndin-l·· yl)pyndazine-3-carboxamide (Compound A)

[0644| To a 260 L glass-lined carbon steel jacketed reactor, under nitrogen, Intermediate (8.48 kg), Intermediate 5 (7.62 kg), and dimethylacetamide (38.45 kg) were added. The reaction mixture was agitated at 110 rpm (allowed range: 80 to 130 rpm) and allowed to cool to 0 °C (allowed range: -5 °C to 5 °C) over l hour and 26 minutes. To this was added Arinethylmorpholine (4.50 kg), and dimethylacetamide (0.751 kg), and the reaction heled 10 at 0 °C and 110 rpm agitation for 3 h and 7 mins.

[0645] In a 100 L reactor, under nitrogen, a solution of sodium triacetoxyborohydride (STAB) (5.66 kg), in dimethylacetamide (21.60 kg) was prepared, and the solution allowed to agitate at 110 rpm (allowed range: 90 to 120 rpm), at 20 °C (allowed température range: 15 °C and 25 °C for 6 hours and 24 minutes. The STAB/dimethylacetamide solution was 15 slowly added to the reaction mixture contained in the 260 L reactor over 2 hours, maintaining the température at 0 °C (allowed température range: -5 °C to 5 °C) and agitation at 110 rpm (allowed range: 80 to 130 rpm). Upon addition completion, the reactor was washed with dimethylacetamide (5.00 kg), subsequently cooled to 0 °C, and its contents added to the reaction mixture in the 260 L reactor over 20 minutes, ensuring the 20 température and agitation of 0 °C and 110 rpm, respectively, were maintained. The reaction

153 mixture was held at 0 °C (allowed température range: -5 °C to 5 °C), 110 rpm for 6 h and 43 min. At the end of the 6 h and 43 mins, the in-process control (IPC) showed 0.7% area (acceptance criterion; < 2.0% area) of Intermediate 3, indicating reaction completion.

[0646] Recrystallization was undertaken by charging the reactor vessel with absolute éthanol (40.78 kg), and deionized water (51.71 kg), under nitrogen, and allowing it to heat at 50 °C (allowed température range: 45 °C to 55 °C) over 1 hour and 14 minutes, and then further held at this température for 1 hour and 24 minutes. The mixture was then allowed to cool to 20 °C (allowed température range: 15 to 25) and held at this température for 4 hours and 3 minutes. The mixture was transferred to an electrically agitated Hastelloy filter dryer with 3-5 pm polypropylene filter cloth. The mixture was filtered under vacuum and the mother liquor was used to rinse the reactor, and was subsequently refiltered.

[0647] An absolute ethanohwater (deionized) wash solution was prepared by mixing absolute éthanol (11.51 kg), and deionized water (14.60 kg). The wash was used to rinse the reactor, and the filter cake was washed using this solution. The ethanohwater wash was repeated. The filter cake was agitated (^x 3) forming a slurry that was subsequently allowed to settle. The filter cake was further washed with absolute éthanol (23.02 kg x 4), agitating the filter cake and sufftciently allowing the solid to deliquor.

[0648] The solid filter cake was dissolved in a solution of dichloromethane (155.12 kg) and methanol (9.26 kg), and the résultant solution subsequently transferred into an 800 L reactor through a 0.2 pm polytetrafluoroethylene capsule filter. The filter dryer was rinsed twice with dichloromethane/methanol, and the rinse solutions were filtered through a 0.2 pm polytetrafluoroethylene capsule filter into the 800 L reactor. The mixture was then subject to atmospheric distillation, under normal atmosphère at 45 °C (allowed température range: 35 °C to 50 °C) maintaining the volume by replenishing as required with absolute éthanol to the final volume of approximately 292 L, and a slurry was obtained. The température was then allowed to increase to 55 °C, maintaining the volume by replenishing as required with absolute éthanol to the final volume of approximately 292 L, The contents of the reactor were then subject to vacuum distillation, replenishing with absolute éthanol as required, at 55 °C (allowed température range: 45 °C to 65 °C), to the final volume of approximately 300 L. The vacuum distillation step was repeated until < 1.0% v/v of dichloromethane remained.

154

[0649] The température of the mixture was then adjusted to 55 °C (allowed température range: 50 °C and 60 °C), and agitation maintained at approximately 100 rpm (allowed range: 90 to HO rpm) over 30 minutes, and then subsequently held at 55 °C for34 minutes. The mixture was then allowed to slowly cool to 20 °C (allowed température range: 15 °C 5 and 25 °C), over 3 hours and 59 minutes (température should not reach below 20 °C before hours), and then held at 20 °C for an additional 4 hours and 16 minutes. The résultant slurry' was qutckly transferred to an electrically agitated Hastelloy filter dryer with 3-5 pm polypropylene filter cloth and the slurry was filtered under vacuum.

[0650] The cake was washed with absolute éthanol (23.02 kg, x 3) and IPC criterion required to be met. The wet cake was subsequently dried under vacuum with a jacket température of 65 °C (allowed température range: 60 °C to 70 °C) for 29 hours and 59 minutes, until total volatiles (by moisture analyzer) are not more than 1.0% w/w. The dryer was subsequently cooled, and the cake was collected to afford Compound A (13.08 kg, 89%). Release results are shown below in Table 47.

[06511 Table 47: Release results for Compound A:

Test Name	Spécification	Resuit
Description	Lighl yellow to greenish yellow crystals	Conforms
Identification (by IR)	Conforms to ref spectrum	Conforms
Identification (by HPLC)	Rétention time of the main peak in the sample solution is consistent with reference standard (Not more than 5%)	Conforms
Purity (by HPLC)	Not less than 98.0% (area)	99.6% (area)
Related Substances (by HPLC) Impurity 2	Not more dian 0 15% (area)	Not detected
Related Substances (by UPLC) Impurity 3	Not more than 0.13% (area)	Less than 0.05% (area)
Related Substances (by UPLC) Impurity 4	Not more than 0.15% (area)	Not detected
Related Substances (by UPLC) impurity at RRT -1.64	Not more than 0.35% (area)	0.12% (area)
Related Substances (by UPLC) Major unspectfied impurity	Not more than 0.13% (area)	0.11 % (area)

155

Test Naine	.Spécification	Resuit
Related Substances (by UPLC) Any individual unspecifted impurity	Report resuit by RRT in % (area)	RRT 0.39: 0.11% (area) RRT 0 41:0.05% (area) RRT 0.46: 0.06% (area) RRT 0.50:0.05% (area) RRT 0.56: 0.09% (area) RRT (0.06, 0.33, 0 48, 0 64, 0 65, 0.68, 1.12 and 1.17): Less than 0.05% (area)
Residual Solvents (by GC) Ethanol	Not more than 10000 ppm	5962 ppm
Residual Solvents (by GC) Acetonitrile	Not more man 410 ppm	Less than 123 ppm
Residual Solvents (by GC) Acetone	Not more man 5000 ppm	Not detected
Residual Solvents (by GC) Isopropyl Alcohol	Not more man 5000 ppm	Not detected
Residual Solvents (by OC) Tetrahydrofuran	Not more than 720 ppm	Not detected
Residual Solvents (by GC) Isopropyl Acetate	Not more than 5000 ppm	Less than 1500 ppm
Residual Solvents (by GC) n-Heptane	Not more than 5000 ppm	Not detected
Residual Solvents (by GC) 4 -Methy I morp ho Ιί n e	Not more than 1000 ppm	Not detected
Residual Solvents (by GC) Di isopropy lethy lamine	Not more than 1000 ppm	Not detected
Residual Solvents (by GC) N-N, Di methy l acetam ide	Not more than 1090 ppm	Less than 327 ppm
Residual Solvents (by GC) Methanol	Report resuit	Less than 900 ppm
Residual Solvents (by OC) Dichloromethane	Report resuit	Less than 180 ppm
Water content (by KF- Oven)	Report resuit	Less than 0.5 % (w/w)
Residue on ignition	Report resuit	0.0 % (w/w)
Particle size d(O.l)	Report resuit	3 pm
Particle size d(0 5)	Report resuit	12 pm
Particle size d(0.9)	Report resuit	33 pm
X-ray powder diffraction	Report resuit	Crystalline

156

Test Name	Spécification	Resuit
Content of (by HPLC) Acetic Acid	Report resull	Not detected
Differential scanning calorimetry (DSC)	Report resuit (Onset and endotlienn températures)	Onset température: 289.85°C Endotherm température: 293.68^0

FIFTH GENERATION SYNTHESIS

Example 26: Fifth Génération Synthesis of Compound A

[0652] The fifth génération sequence followed the same general scheme as the fourth génération sequence. The steps of the fifth génération sequence are shown below. Material quantities are normalized to a hypothetical 1 kg starting material for each step. The quantities of starting materials are adjusted for potency according to the foilowing formulae:

[0653] Step 1:

[0654] Reaction is performed under N2.

[0655] Potency Calculations to Détermine input (per Kg) of Intermediate 10 and Intermediate 7

Intermediate 7 potency = (100% - Loss on Drying%) x Purity = a wt.%

Intermediate 7 corrected target calculation = Intermediate 7: 1.00 kg x [1.0/(Intermediate 7(% w/w)/100)]

Intermediate 10 potency = (100% - (Loss on Drying% + Residue on Ignition%)) x Purity = b wt.%

Intermediate 10 corrected target calculation = 1.00 kg x [O.S43/(Intermediate 10 Potency(%w/w)/100)|

1. To Reactor A, add Intermediate 7 (1.000 Kg ± 1.0%, corrected for potency as described above), Intermediate 10 (0.843 Kg± 1.0%), HOPO (0.0580 Kg± 1.0%, corrected for potency as described above).

2. To Reactor A add DMAc (2.82 Kg; or 3.0 L ± 5.0%) by spray bail.

3. Purge with N₂.

4. Cool to 10 ± 5 °C.

157

5. To Reactor A add DIPEA (0.495 Kg, or 0.669 L ± 1.0%) at 10 ± 5 °C. Note: slightly exothermic, control addition to maintain température range.

6. Rinse line with DMAc (0.09 Kg or 0.10 L ± 5.0%).

7. Adjust to 10 ± 5 °C.

8. Stir at 10 ± 5 °C forNLT 0.5 h.

9. To Reactor A add EDAC (0.701 Kg± 1,0%).

10. Chase with additional DMAc (0.66 Kg or 0,70 L ± 5.0%) via spray bail if necessary

11. Adjust to 20 ± 10 °C.

12. Stir at 20 ± 5 °C.

13. After NLT 20 hrs, sample for IPC-1.

Note: IPC < 1.0 AP residual Intermediate 7 ;

14. To Reactor B add NaCI (1.00 Kg ± 5.0 %).

15. To Reactor B add tap water (6.6 Kg, or 6.6 L ± 5.0 %).

16. Stir at 25 ± 5 °C until a solution is formed.

17. Transfer contents of Reactor B to Reactor A

18. To Reactor A add tetrahydrofuran (5.34 Kg or 6.0 L ± 5.0%).

19. Adjust the internai température to 50 ± 5 °C.

20. Stir at 50 ± 5 °C for NLT 0.5 h.

21. Transfer the mixture from Reactor A through a Celite bed to Reactor B.

22. Wash Reactor A and the Celite bed with Tetrahydrofuran (1.34 Kg or 1.5 L± 5%) and transfer to Reactor B.

23. Adjust contents of Reactor B to 50 ± 5 °C

24. Stop agitation and hold for NLT 1 hr.

25. Separate out the bottom aqueous layer.

26. To Reactor A add Sodium Chloride (L25 Kg ± 5.0%).

27. To Reactor A add tap Water (6.60 Kg or 6.6 L/Kg ± 5.0%).

28. Agitate Reactor A for NLT 0.5 h. at 25 °C until a solution is formed.

29. Transfer contents of Reactor A to Reactor B.

30. Adjust contents of Reactor B to 50 ± 5 °C

31. Stop agitation and hold forNLT I h.

158

32. Separate out the bottom aqueous layer from Reactor B.

33. To Reactor A add sodium chloride (1.50 Kg ± 5.0%).

34. To Reactor A add tap water (6.60 Kg or 6.6 L/Kg ± 5.0%).

35. Agitate Reactor A for NLT 0.5 h. at 25 °C until a solution is formed

36. Transfer contents of Reactor A to Reactor B.

37. Adjust contents of Reactor B to 50 ±5 °C

38. Stop agitation and hold for NLT l h.

39. Separate out the bottom aqueous layer from Reactor B.

40. To Reactor B add tetrahydrofuran (7.57 Kg or 8.5 L ± 5.0%).

41. Heat contents of Reactor B to 65 ±5 °C

42. Distill contents of Reactor B under atmospheric pressure at 65 ± 5 °C with slight vacuum bleed (scrubber) until the volume is 3.30 L/Kg (± 0.5 L).

43. To Reactor B add tetrahydrofuran (7.57 Kg or 8.5 L ± 5.0%).

44. Heat contents of Reactor B to 65 ± 5 °C

45. Distill contents of Reactor B under atmospheric pressure at 65 ± 5 °C with slight vacuum bleed (scrubber) until the volume is 3.30 L/Kg (± 0.5 L).

46. Clean Reactor A with water and Tetrahydrofuran.

47. To Reactor A add Tetrahydrofuran (4.45 Kg or 5.0 L ± 5.0%).

48. Heat contents of Reactor A to 65 ± 5 ’C.

49. Transfer contents of Reactor A to Reactor B via spray bail

50. Transfer contents of Reactor B to Reactor A via an in-line filter.

.Rinse contents of Reactor B with Tetrahydrofuran (l .34 Kg or 1.5 L ± 5.0%) via spray bail and transfer to Reactor A via in-line filter.

52. Adjust contents of Reactor A to 65 ± 5 °C.

53. Clean Reactor B with water and THF.

54. Distill contents of Reactor A under atmospheric pressure at 65 ± 5 °C with slight vacuum bleed (scrubber) until the volume is 6.0 L/Kg (± 0.5 L).

55. To Reactor B charge THF (l.34 Kg, 1.5L±5.0%).

56. Heat contents of Reactor B to 65 ±5 °C.

57. Transfer contents of Reactor B to Reactor A via spray bail.

58. Take sample for Water content (KF couiometric).

159

59. If resuit is 50.50 wt.% then continue to Step 62, if not continue to Step 60.

60, To Reactor A charge THF via spray bail (4.45 Kg or 5,0 L i 5.0%).

61. Continue to Step 54.

62. Verify solution is present, increase agitation to help dissolve any solids on walis of reactor that are above solution.

63. To Reactor A charge n-Heptane (0.68 Kg, or l .0 L ± 5%) at 65 ± 5 °C.

64. Charge a slurry of Intermediate 2 seed or Intermediate 2 (0.002 Kg) in n-Heptane (0.034 Kg or 0.05 L).

65. Stir at 65 ±5 °C for l hr (± 30 minutes).

66. To Reactor A charge n-Heptane (2.72 Kg, or 4.0 L ± 5%) at 65 ± 5 °C over 3 hrs (±30 minutes),

67. Stir at 65 ± 5 °C for I hr (± 30 minutes).

68. Cool down to 20 ± 5 °C over 3 hrs (± 60 minutes).

69. Stir at 20 ± 5 °C for 6 hrs (± 60 minutes).

70. Filter the slurry under vacuum at 20 ± 5 °C and de-liquor the cake.

71. Verify solids from Reactor A hâve been transferred to filter dryer.

72. Clean Reactor B with Water and Tetrahydrofuran.

73. To a Reactor B add Tetrahydrofuran (l .34 Kg or 1.5 L/Kg).

74. To a Reactor B add n-Heptane (0.68 Kg or l ,0 L/Kg).

75. Stir contents of Reactor B for 5 minutes at 20 ± 5 °C.

76. Transfer contents of Reactor B via spray bail to Reactor A.

77. Transfer contents of Reactor A to filter dryer and then re-slurry the cake for NLT minutes.

78. De-liquor the cake under vacuum and nitrogen.

79. Dry the wet cake at 580 °C (filter dryer jacket temperature) under vacuum until LOD passes (NLT 6 hrs).

LOD spec. = < l.0%/l20 °C

80. The expected yield of Intermediate 2 = l .44 Kg (88 mol% yield).

[0656] Step 2:

[0657] Reaction îs performed under N₂.

160

l. To Reactor A add Intermediate 2 (l.00 Kg ± 1.0%), NaBr (0,219 Kg ± 1.0%), and NaHCOj (0.3575 Kg ± 1.0%) and NaCl (1.80 kg ± 1.0%).

2. To Reactor A add TEMPO (3.325 g ± 1.0%).

3. To Reactor A add DCM (19.0 L ± 5.0%).

4. Chase TEMPO addition with DCM (0.50 L ± 5.0%) and add the solution to Reactor A.

5. Stir at 20 °C for 0.5 h.

6. To Reactor A add deionized H2O (7.0 L ± 5.0%).

7. To Reactor A add IPA (0.127 Kg ± 1.0%).

8. Chase IPA addition with DCM (0.50 L ± 5.0%) and add the solution to Reactor A

9. Stir at 20 °C for NLT 2.0 h.

10. Cool the mixture to -12 to -10 °C, preferably to -11 °C.

Note: maximum cooling control of the batch température is critical for this step;

11. To Reactor A add aq. NaCIO (1.15 eq ± 1.0%) by Spray Bail inNLT 15 min but NMT 45 min, preferably in < 0.5 h, while controlling the internai température between -12 to -3 °C, preferably -12 to -8 °C.

Note: Mass of aq. NaCIO (Kg) = (1.15x 74.44)/(469.97 x Conc of aq. NaCIO (wt%))

Note: the bleach solution is pre-cooled to 0 ± 5 °C.

12. Chase the line with additional deionized H2O (0.50 L ± 5.0%) by Spray Bail in NLT 5 min but NMT 0.5 h.

13. Stir at-12 to-3 °C for NLT 1.0 h.

14. Sample the organic layer for IPC-I analysis.

15. If IPC-l fails, kicker charge of aq NaCIO (pre-cooled to 0 ± 5 °C) by Spray Bail in NLT 15 min but NMT 45 min, preferably in < 0.5 h, while controlling the internai température between -12 to -3 °C, preferably - 12 to -8 °C.

16. Chase the line with additional deionized H2O (0.50 L ± 5.0%) by Spray bail in NLT 5 min but NMT 0.5 h.

17. Stir at -12 to -3 °C for NLT 1.0 h

18. Sample for IPC-1.

I6l

19. If IPC-I passes, adjust to 20 ± 5 C.

21. Separate the bottom DCM layer in Reactor A to Reactor B.

Approximate volume of organic DCM phase (20 L/Kg) and solution is colorless to brown soin.

Approximate volume of aqueous phase is (10 L/Kg) and solution is colorless to light brown.

22. Remove aqueous phase from Reactor A and send to waste.

23. Clean Reactor A with Water, THF.

24. To Reactor B charge H2O (7.0 L/Kg ± 5.0%).

25. Stir Reactor B for NLT 0.5 h at 20 ± 5 °C.

26. Filter the mixture through a Celite bag to Reactor A.

27. Chase wash Reactor B with DCM (2.0 L/Kg) to Reactor A.

28. Wash Reactor B with H2O and THF.

29. Stop agitation of Reactor A for NLT 2.0 h.

30. Separate the bottom organic layer to Reactor B.

Note; Sample the DCM layer for UPLC analysis;

31. Distill the organic solution in Reactor B to volume = 5.0 L/Kg (+/- 0.5 vol) under normal atmosphère and batch température = 40 ± 5 °C

32. To Reactor B charge THF (1.0 L/Kg ± 5.0%) by spray bail.

33. Adjust the batch température to 38 ± 2 °C.

34. Add 5.0 L/Kg of n-Heptane over 0.5 h maintaining the batch température of 38 ± °C.

35. Add Intermediate 3 seeds (5.0 g/Kg) in n-Heptane (0.10 L/Kg).

36. Stir at 38 ± 2 °C for NLT 4.0 h.

37. Add additional 5.0 L/Kg of n-Heptane over 1.0 h.

38. Stir at 38 ± 2 °C for NLT 2.0 h.

39. Cool down to 20 ± 5 °C over NLT 4 h.

40. Stir at 20 ± 5 °C for additional NLT 6 h.

4L Filter the slurry under vacuum at 20 °C and nitrogen.

42. If solids remain in the reactor, recirculate mother liquors back into reactor through spray bail and Filter mixture again.

162

43. Wash Reactor B with l.5 L/Kg of n-Heptane by spray bail.

44. Slurry wash the cake and remove liquors under vacuum until most of liquors are removed.

45. Remove liquors under vacuum and pull until most of liquors are removed.

46. Dry the cake at NMT 50 °C ± 5 °C for NLT 8 h under vacuum and nitrogen.

47. Continue drying the cake at 75 ± 5 °C under vacuum and nitrogen flow until LOD < 1.0%/120 °C.

48. Expected Intermediate 3 amount = 0.95 Kg (95 mol%).

[0658] Step 3:

[0659] Potency Calculations to Determine input (per Kg) of Intermediate 3 and

Intermediate 5

Intermediate 3 potency calculation = ( 100% - Loss on Drying%) x Purity = a wt.%

Intermediate 3 corrected target calculation:

Intermediate 5: l .00 Kg x (l .0/(Intermediate 3 Potency(% w/w)/l00))

Intermediate 5 potency calculation = (100% - (Water Content% + Residual Solvents%)) x Purity = b wt.%

Note: Water Content, Residual Solvents, and Purity data obtained from

Intermediate 5 CofA

Intermediate 5 corrected target calculation:

Intermediate 5: 1.00 Kg x (0.848/(overall potency /100))

1. To Reactor A, charge NaBH(OAc)j (0.679 Kg ± 1.0%).

2. To Reactor A, charge DMAc-1 (2.75 vol ± 5%).

3. Once dissolved, hold Reactor A at 20 ± 5 °C for NLT 1.0 h

4. To Reactor B, charge Intermediate 5 [0.848 / (b wt.%/100)] Kg) ± 1.0%),

Intermediate 3 (1.000 / (a wt.%/100) Kg ± 1.0%) and DMAc-2 (4.90 vol ± 5%).

5. Cool Reactor B to 0 ± 5 °C.

6. To Reactor B, charge Λ-Methylmorpholine (0.540 Kg ± 1.0%) in NLT

0.5 h while keeping the batch température at 0 ± 5 °C.

7. Agitate Reactor B at 0 ± 5 °C for NLT 2.0 h but NMT 4.0 h.

163

S. Transfer the contents in Reactor A to Reactor B over NLT 1.0 h, while maintaining internai température at 0 ± 5 °C.

9. Rinse Reactor A with DMAc-4 (0.64 vol ± 5%) and transfer to Reactor B in NLT 15 min.

10. Agîtate Reactor B at 0 ± 5 °C for NLT 6.0 h.

11. Sample for IPC-I.

IPC-1 criteria: Intermediate 3 < 2.0%;

12. If IPC-1 fails, continue agitation at 0 4 5 °C for an additional 6 h.

13. Sample again for IPC-1.

14. If IPC-1 fails again, check for technical advice.

15. To Reactor B, charge EtOH (6.2 vol ± 5%) over NLT 0.5 h while maintaining température at 0 ± 5 °C.

16. To Reactor B, charge H₂O (6.2 vol ± 5%) over NLT 0.5 h while maintaining température at 0 ± 5 °C.

17. Adjust the content in Reactor B to 50 ± 5 °C in NMT 2.0 h.

18. Hold the content in Reactor B at 50 ± 5 °C for NLT 1.0 h but NMT 2.0 h.

19. Cool the content in Reactor B to 20 ± 5 °C in 3.0 h ± 0.5 h,

20. Hold the content in Reactor B at 20 ± 5 °C for NLT 4.0 ± 0.5 h.

21. Transfer the slurry in Reactor B to Filter C (filter cloth = 3-5 pm) under

N₂ blanket and filter.

22. Wash Reactor B by spray bail with EtOH (1.75 vol ± 5%) and H₂O (1.75 vol ± 5%) at 20 ± 5 °C.

23. Filter the content in Reactor B (re-slurry) under N₂ blanket.

24. Wash the wet cake (re-slurry) with EtOH/H₂O (1:1; 3.5 vol ± 5%) at 20 ± 5 °C.

25. After de-liquoring washes, continue to de-liquor the wet cake for NLT 2 hrs and until no major solvent is removed from the filter drier.

26. Perform four slurry washes of the wet cake in Filter C with EtOH (4 x 3.5 vol ± 5%).

-27. De-liquor the wet cake in Filter C for NLT 1 h after each of the four

164 slurry washes.

28. Sample the wet cake in Filter C for 1PC-2 (LOD (2 g, 120 °C)) and perform the calculation:

Correction for EtOH in Compound A crude cake (97 mol% Compound

A):

Intermediate 3 (Kg) input x 1.684 = Calculated Compound A crude product (Kg)

EtOH in wet Compound A crude product (Kg) = LOD% x Calculated

Compound A crude product (Kg) / (1-LOD%) (EtOH in wet Compound A crude product (Kg) / 0.789) / (Intermediate 3 (Kg) input) = EtOH content (vol) to be corrected

EtOH content (vol) to be corrected -> Subtract from EtOH to be added in

Step 38 (7 vol EtOH) *Charges based on initial Intermediate 3 input*

29. Charge DCM (28.0 vol ± 5% of Intermediate 3) to Reactor A.

30. Charge MeOH (2.8 vol ± 5% of Intermediate 3) to Reactor A and agitate for NLT 0.5 h.

31. Transfer half of DCM/MeOH (10:1, 15.4 vol ± 20%) from Reactor A to

Filter C.

32. Agitate Filter C at 20 ± 5 °C for NLT 0.5 h to dissolve most ofthe wet crude solids.

33. Polish filter the solution in Filter C to Reactor B via an in-line capsule filter.

34. Transfer part of the remaining DCM/MeOH (10:1, 14.4 vol ± 5%) from Reactor A to Filter C.

35. Agitate Filter C at 20 ± 5 °C for NLT 0.5 h to dissolve all ofthe remaining crude solids.

36. Polish filter the solution in Filter C to Reactor B via an in-line capsule filter.

165

37. Rinse Filter C with remaining DCM/MeOH (10:1; 1.0 vol ± 5%) and filter to Reactor B via an in-line capsule filter.

38. Distill the solution in Reactor B while maintaining a constant volume (vmax -32 vol) under atmospheric conditions with continuous addition of EtOH (7.0 vol ± 5% ; vol EtOH from Step 28 calculation) at an internai température between 35-45 °C.

39. Sample for IPC-3, GC analysis for DCM content.

IPC-3 criteria: DCM < 67 vol % (relative to total volume of DCM+MeOH+EtOH peaks);

Report EtOH vol % and MeOH vol %.

40. If DCM content is passing, go directly to Step 43. If it îs failing, go to Step 41

41. If IPC-3 fails, continue distillation with additional EtOH (1.0 vol ± 5%) and re-sample for GC analysis

IPC-3 criteria: DCM < 67% (relative to total volume of DCM+MeOH+EtOH peaks);

Report EtOH vol % and MeOH vol %.

42. If IPC-3 fails again, repeat Step 41.

43. Cool Reactor B to 35 ± 2 °C and charge Compound A seeds (0.50 wt% ± 5%) in EtOH (0.075 vol ± 5%).

44. Agitate Reactor B at 35 ± 2 °C for NLT 0.5 h

45. Heat Reactor B back up to reflux conditions (41 ± 2 °C) and continue constant volume distillation (vmax -32 vol) under atmospheric conditions with the continuous addition of EtOH (7.0 vol ± 5%) while maintaining batch température between 40-50 °C.

46. Continue distillation in Reactor B under constant volume (vmax -32 vol) under atmospheric conditions until the internai température reaches at least 50 °C.

47. Perform remainder of distillation in Reactor B under vacuum maintaining a constant volume (vmax -32 vol) with addition of EtOH (28.0 vol ± 5%) and maintaining internai température at 55 ± 10 °C.

166

48. Sample Reactor B for IPC-4 by GC.

IPC-4 criteria: DCM/EtOH < 1.0%.

49. If IPC-4 fails, repeat the vacuum distillation with additional EtOH (4.0 vol ± 5%) and continue to step 50.

50. Sample Reactor B for IPC-4 by GC.

IPC-4 criteria: DCM/EtOH < 1.0%.

51. If IPC-4 passes, adjust the batch temperature to 55 ± 5 °C.

52. Agitate the slurry in Reactor B at 55 ± 5 °C for NLT 0.5 h.

53. Cool the slurry in Reactor B down to 20 ± 5 °C in NLT 3.0 h.

54. Agitate the slurry in Reactor B at 20 ± 5 °C for NLT 4.0 h.

55. Filter the slurry in Reactor B to Filter C (filter cloth = 8 pm).

56. Rinse Reactor B with EtOH (3.5 vol ± 5%).

Note: EtOH should be polish filtered.

57. Filter the rinse in Reactor B and transfer to Filter C as a slurry wash.

58. Perform two slurry washes of the wet cake in Filter C with EtOH (2x3.5 vol ± 5%).

Note: EtOH should be polish filtered.

59. De-liquor the cake in Filter C for NLT 1 h

60. Sample Filter C for IPC-5 for the impurity profile of the wet cake.

IPC-5	Specified Impurities	Unspecified Individual Impurity	Compound A
Impurity	Impurity 2	Impurity 3	Impurity 4	RRT 1.64	Any
Criteria (%)	<0.15	<0.13	<0.15	£0.35	<0.13	NLT 98.0%

61. If IPC-5 fails, go back to step 28 (Sample wet cake for LOD, perform

EtOH Calculation and start the distillation).

62. If IPC-5 passes, dry the cake under vacuum with agitation at 80 ± 5 °C. Note: sample the wet cake for PDXR, DSC and KF (FIO).

63. Sample contents in Filter C for IPC-6, LOD (2 g, 120 °C)

1PC-6 criteria: LOD (2 g, 120 °C) < 1.0% after NLT 8 h.

64. If IPC-6 fails, continue drying until LOD criteria is met,

65. If 1PC-6 passes, sample for IPC-7 (GC analysis).

66. IPC-7 criteria: GC residual solvents

Solvent	ACN	Acetone	1PA	EtOH	THF	iPAc	Heptane	N MM	DIPEA	DMA
NMT	NMT	NMT	NMT	NMT	NMT	NMT	NMT	NMT	NMT
ppm	410	5000	5000	10000	720	5000	5000	1000	1000	1090

67. If IPC-7 faits, continue drying until GC criteria is met.

68. Once IPC-7 passes, discharge the material from Filter C.

[0660J The fifth génération process described above was conducted on a 1.7 kg scale (relative to Intermediate 3), to afford Compound A (2.420 kg). Purity was calculated to be

99.9% by UPLC (see FIG. 26 and Table 48).

Table 48: Peak Results for Chromatogram of Purified Compound A

	Name	RT	RRT	Area	% Area	USE Résolution	USP Tailing
l	Intermediate 5	1.361
2	Intermediate 7	5.252
3	Impurity 1	6.374
4	Impurity at RT -7.78	7.782
5	Impurity at RT -7.95	7.949
6	Intermediate 3Acetal	8.379
7	Diacid Impurity	8.594
8	Impurity at RT -8 78	8.784
9	Impurity at RT -9.72	9 715
10	Intermediate 2	10.169
11	intermediate 3Methyl Hemiacetal	11.219
12	Intermediate 3	13.057
13	Ring 2 Methanolysis Ad duct-1	16.232
14	Ring 2 Medianolysis Adducl-2	18.381
15	Impurity 2	19097
16	Impurily 3	20.529
17	Impurity at RT -21.77	21.770
18	Impurity 4	22176
19	Compound A	23 871	1 00	3784159	99.854		0 9
20	Impurity at RT ~24.18	24.181
21	Impurity at RT ~24 90	24.897
22	Carbamate Impurity	26 735
23	Impurity at RRT -1 64	39 101	1 64	5527	0 146	138.8	2.3
S uni				3789585

168

[0661] Example 27: Development of High-Strength Compound A Tablet

[0662] Due to a demand for a higher strength tablet for Phase 1 dose escalation trials, a higher strength tablet was developed.

[0663] The higher strength tablet formulation was accomplished in two phases. The first phase screened the loading of the 100% amorphous spray dried API (SDI) in the tablet formulation using miniaturized laboratory techniques, and the second phase optimized the selected formulation composition.

[0664] The formulation compositions during the screening phase encompassed a range of 10 SDI loads equal to 10% to 40%, and tablet strengths equal to 70 mg, 140 mg, and 280 mg (for 700 mg Tablet Press Weight), as outlined in Table 49

Table 49: Formulation compositions of higher strength SDI loads - 10%, 20% and 40% (700 mg Tablet Press Weight)

Formulation Reference	Cl	C2	C3
Tablet Strength/ Tablet Press Weight (tng/nig)	70/700	140/700	280/700
Function	Ingrédient	% of Blend
lutta Granular
Active	Spray-dried amorphous Compound A	10.00	20.00	40.00
Filler	Microcrystailine cellulose	57.33	50.67	37.33
Filler	Lactose mono hydrate	28.67	25.33	18.67
Disintegrant	Croscarmellose sodium	3.00	3.00	3.00
Glidant	Silicon dioxide	0.50	0.50	0.50
Lubricant	Magnésium stéarate	0.25	0.25	0.25
Extra Granular
Lubricant	Magnésium stéarate	0.25	0.25	0.25
Totals:		100.00	100.00	100.00

[0665] Tablets were made using a miniaturized laboratory technique to simulate dry granulation and compression. The pregranulatîon blend was slugged on an F-press. The slugs were size reduced using a mortar/pestle, and passed through a 20-mesh sieve for proper sizing. The granules were mixed with magnésium stéarate and compressed on an F-press.

[0666] After selecting a tablet tensile strength to achieve a sufficiently hard tablet with disintegration time of less than 5 minutes, the tablet in vitro performance of each tablet

169 composition (Cl, C2 and C3) was evaluated using a USP sink dissolution test. As a benchmark, the 10-40% SDI loaded tablets were compared against the original 5% SD1 loaded tablets (Tablet reference A3, above).

[0667] Dissolution method TEST-I973: To maintain équivalent sink conditions that enabled a valid comparison between formulations, the dissolution media consisted of 0.01 N HCl with 0.1 wt% Tween 80. Using USP compatible vessels, the volume of the media was adjusted for each tablet strength to maintain a constant sink condition (approximately 4 x). The dissolution parameters are USP 11 paddles, 37.0 ± 0.5°C media température, 75 RPM and sampling times equal to 10, 15, 20, 30, 45 and 60 minutes. The dissolution results are shown in FIG. 27. The data for each composition was normalized to the 90 minute time point to compensate for variability in the potency and permit a more valid comparison. The dissolution extent for ail compositions was équivalent at 60 minutes. The 20% load tablet provided sufficient tablet strength for intended use.

[0668] Since the goal was to maximize the SDI loadîng, the 20% formulation composition was systematically modified with the aim of increasing the dissolution rate. Refer to Table 50 for a listing of the 20% SDI loaded compositions. These formulations were prepared using the miniaturized laboratory techniques described above for the 10, 20 and 40% compositions. The rationale of the modifications is a more rapid de-aggregation phase of the disintegration/dissolution mechanism. The changes are summarized below:

• Dl- smaller microcrystalline cellulose to enhance the association with the micron sized SDI particles and therefore enhance disintegration • D2 - addition of extra-granular disintegrant to reduce the time for the primary SDI particles to be exposed to the dissolution medium • D3 - addition of smaller size glidant to aid în the more intimate association with the SDI particles and therefore favor the physical séparation of the SDI particles in the formulation • D4 — similar to D2, increased the total level of the disintegrant to favor a faster disintegration time

Table 50: Formulation compositions of 20% SDI loaded higher strength tablet compositions (700 mg Tablet Press Weight)

170

Formulation Reference	Dl	D2	D3	D4
Tablet Strength/ Tablet Press Weight (mg/mg)	140/700	140/700	140/700	140/700
Function	Ingrédient	% of Blend
Intra Granular
Active	Spray-dried amorphous Compound A	20.00	20.00	20.00	20.00
Filler	Microcrystalline cellulose (Avicei PH 102)	-	49.33	50.33	46.00
Filler	Microcrystalline cellulose (Avicel PH 101)	76.00	-	-	-
Filler	Lactose monohydrate	-	24.67	25.17	23.00
Disintegrant	Croscarmellose sodium	3.00	3.00	3.00	6.00
Glidant	Silicon dioxide (Syloid 244 FP)	0.50	0.50	-	0.50
Glîdanl	Silicon dioxide (Cab-O-Sil M5P)	-	-	1.00	-
Lubricant	Magnésium stéarate	0.25	0.25	0.25	0.25
Extra Granular
Disintegrant	Croscarmellose sodium	-	2.00	-	4.00
Lubricant	Magnésium stéarate	0.25	0.25	0.25	0.25
Totals:		100.00	100.00	100.00	100.00

[ 0669] Overall, the formulations processed similarly except for flowability of DI and ail of them exhibited disintegration times in 0.01 N HCl of less than 1 minute; therefore, a major sélection criterion for further évaluation was the dissolution characteristics.

Dissolution profiles using the 0.01 N HCl media method (TEST-1973) for Dl, D2, D3, D4 and 35 mg (5%) are illustrated in FIG. 28.

|0670| The scale up and process évaluation of the D2 formulation was conducted to identify the processing conditions to be used for the planned clinical manufacture. The batch size was approximately 3 kg and consisted of the foîlowing major steps:

· Pre-granulation blend using the 100% spray-dried intermediate of Compound A • Roller compaction (Gerteis Minipactor machine) • Final blend (addition of extra-granular disintegrant and lubrication) • Compression (Korsch XM12)

[0671] The flow properties of the pre-granulation blend and final blend were determined 15 using laboratory techniques (Carr Index, shear cell flow function/cohesion coefficient and

FloDex measurements), roller compaction parameters determined and a compression évaluation (compressibility, tabletabilty and compactability) was conducted.

171

[0672] During the compression of the final blend on the Korsch XM-12 equipped with 2 tool stations to accommodate the batch size, the granulation exhibîted insuffle ient flow. The materiai rat-holed and bridged in the feed hopper, starving the feed frame, and thus, resulted in poor weight control.

[0673] Due to the flow challenges, it was determined that the D2 formulation and process were not suitable and therefore, not transferrable for clinical manufacture. As a result, another round of formulations was evaluated in the laboratory to improve flowability characteristics.

[0674] The modification strategy for the D2 formulation hinged on évaluation of the 10 glidant system being used and optimized its functionality. Two new formulations, F7 and Fl 1 are shown in Table 51.

Table 51: D2, F7 and Fil Formulation compositions of 20% SDI loaded tablet (525 mg Tablet Press Weight)

Formulation Reference	D2	F7	Fl!
Tablet Strength/ Tablet Press Weight (mg/mg)	/05/525	105/525	105/525
Function	Ingrédient	% of Blend
Intra Granular
Active	Spray-dried amorphous Compound A	20.00	20.00	20.00
Filler	Microcrystalline cellulose (Avicel PH 102)	49.33	48.17	49.00
Filler	Lactose monohydrate	24.67	24.33	24.50
Disintegrant	Croscarmellose sodium	3.00	3.00	3.00
Glidant	Silicon dioxide (Syloid 244 FP)	0.50	-	-
Glidant	Silicon dioxide (Cab-O-Sil M5P)	-	1.00	0.50
Lubricant	Magnésium stéarate	0.25	0.25	0.25
Extra Granular
Glidant	Silicon dioxide (Cab-O-Sîl M5P)	-	1.00	0.25
Disintegrant	Croscarmellose sodium	2.00	2.00	2.00
Lubricant	Magnésium stéarate	0.25	0.25	0.50
Totals:		100.00	100.00	100.00

[0675| The F7 and Fl 1 compositions were manufactured at bench scale (50g per blend) at a Tablet Press Weight of 105 mg using the miniaturization techniques described above for formulations CI-C3. The lower Tablet Press Weight was chosen to represent the midpoint of a range of Tablet Press Weights that may be needed for further dose escalation. Both formulations implemented an initial SDl/glidant blend-mill-blend process as part of the

172 pre-granulation blend manufacture in an attempt to adhéré to the SDl particles and reduce their cohesivity. Formulation F7 încreased the overall glidant levels (intra- and extragranular) and formulation Fil added glidant extra-granular and also încreased extragranular lubricant to assess if încreased extra-granular glidant and lubricant had a 5 synergistic effect on blend flow.

|0676] The flowability of F7 and Fil was compared to D2. Table 52 shows a modest improvement in the flowability (FloDex, FFc and Cohésion Coefficient) for the final blend for both F7 and Fl l compositions however, Carr Index remained at an unacceptable value. [0677] Scanning électron microscopie analysis showed minimal adhérence of Cab-O-Sil 10 to SDI particles, and miniscule to no surface coverage of SDI particles with Cab-O-Sil.

Table 52: Compound A Formulation D2, F7 and FU Pre-granulation and Final Blend Flow Properties

Parameter	Formulation D2^A	Formulation F7	Formulation F11
Pregranulation Blend	Final Blend	Pregranulation Blend	Final Blend	Pregranulation Blend	Final Blend
Bulk Density (g/mL)	0.42	0.50	0.36^B	0.44^B	0.39^e	0.48^B
Tapped Density (g/mL)	0.63	0.70	0.59^B	0.63^e	0.63^B	0.69^B
Carr index (%)	34	28	39	30	38	31
FloDex (mm)	24	30	26	20	24	22
FFc^c	4.9	5.1	5.9	7.6	4.7	6.1
Cohésion Coefïicient^D	103	103	84	64	107	83

^A Values from scale up manufacture. Blend nol remanufactured at ben ch scale.

^B Generaled using lOmL cylinder due to limited material. Results less reliable than those generated using lOOmL cylinder.

^cFFc is the shear cell flow function °Cohesion coefficient was derived from the shear cell data

[0678] Tablet compression évaluation of F7 and Fl I showed similar results with D2 and 15 confirmed no significant adverse impact of changing the glidant system. The formulations formed acceptable tablets at relatively low range compression stress (75 to 100 MPa), and both formulations exhibited dis intégration times of less than l minute.

[0679] Dissolution characteristics of F7 and Fil were similar to D2 demonstrating no adverse effect of new glidant system on the dissolution properties.

173

[0680] In conclusion, the modest improvement in flowability of F7 and Fl 1 compared to D2 was not sufficient to nominate either one of them as the clinical formulation candidate, therefore, further formulation optimization was undertaken.

[0681] Since the additional step of pre-mixing glidant with SDI did not produce a désirable 5 outcome, this approach was abandoned. However, the unexpected resuit of almost no adhesion of the glidant to the SDI formed the basis of evaluating a chemicalîy modified formed of colloida! Silicon dioxide to increase its hydrophobicity and lower its surface free energy.

[0682] A direct comparison of Cab-O-Sil M5P and Aerosil R972 was carried out. As 10 mentioned above, Aerosil R972 is colloïdal Silicon dioxide chemicalîy modified to produce trimethylsilyl groups on the surface. It compiles with USP/NF monograph for colloïdal Silicon dioxide. In this comparison, each of these glidants was added to the D2 blend from the scale up batch to directly study their impact on flowability compared to D2. The formulation compositions are listed in Table 53.

Table 53: Compound A - Gl* and G2* formulation compositions

Formulation Reference	Gl*	G2*
Dose/Tablet Press Weight (mg/mg)	105/530.3
Function	Ingrédient	% of Blend
Active	200mg/g Compound A Formulation D2 Final Blend	99.00%	99.00%
Glidant	Silicon Dioxide (Cab-O-Sil M5P)	1.00%	-
Glidant	Silicon Dioxide (Aerosil R972)	-	1.00%
Total	100.00%	100.00%

[0683] The flow metrics are listed in Table 55. G2* exhibited the best flow properties compared to D2 and Gl*.

174

Table 54: Compound A Formulations D2, Gl* and G2* Final Blend Flow Properties

Parameter	Formulation D2^A	Formulation Gl*	Formulation G2*
Pregranulation Blend	Final Blend	Final Blend	Final Blend
Bulk Density (g/mL)	0.42	0.50	0.49	0.54
Tapped Density (g/mL)	0.63	0.70	0.65	0.69
Carr Index (%)	34	28	25	22
FloDex (mm)	24^B	30^B	26	14
FFc^c	4.9	5.1	6.2	8.0
Cohésion Coefficient⁰	103	103	81	64

^A Values from scale up manufacture, Blend not remanufactured at bench scale.

^B Scale-up blend samples retested using the same fill levels as used for formulation Gl* and G2* blends. ^cFFc is the shear cell flow function ^DCohesion coefficient was derived from the shear cell data

[0684] The compressibiiity (solid vs compression stress), tabletability (tablet tensile strength vs compression stress) and compactability (tablet tensile strength vs tablet solid fraction) i.e. CTC profiles, for G1 and G2 were compared. Formulation Gl had similar CTC properties to formulation D2 suggesting Cab-O-Sil had minimal impact on the final blend material properties. Formulation G2 showed an improvement in compressibiiity but a réduction in both tabletability and compactability properties compared to both formulations G1 and D2. The significance of this finding was eventually assessed at larger scale and rotary press. The compressive stress régime for both G formulations was well within the typical range observed for optimal tooling wear performance and tablet porosity (100 to 300 MPa).

[0685] A dissolution comparison of the bench-scale tablets of Gl and G2 demonstrated comparable dissolution profile, as shown in FIG. 29.

[0686] Given G2 exhibited the best flowability, acceptable compression/tablet properties, and similar dissolution profile to D2, it was selected for further évaluation for a predemonstration processability assessment.

[0687] A processability pre-demonstration assessment was conducted on a Gerteis Mini pacte r using bench scale batch size equal to 100 gram to détermine target Gerteis settings for the démonstration batch. The Gerteis was set up with a feed funnel system designed to feed material quantifies that are too small to use the auger feed and tampîng

175

Systems. Ribbons were collected and then manually fed through the oscillating granulator to size them.

[0688] The main purpose was to evaluatethe effect ofribbon solid fraction on granule size.

[0689] The G2 formulation composition is listed in Table 55. The composition differs 5 slightly from the composition of G2* but was not expected to significantly impact granule or tablet properties. The tablet press weight was adjusted to 525 mg (vs 530 mg for G2*) and the Aerosil R972 quantity is exactly 1% of the composition.

Table 55: G2 formulation composition (20% SDI loaded tablet - 525 mg Tablet

Press Weight)

Formulation Reference	G2
Tablet Strength/ Tablet Press Weight (mg/mg)	105/525
Function	Ingrédient	%of Blend
infra Granular
Active	Spray-dried amorphous Compound A	20.00
Filler	Microcrystalline cellulose (Avicel PFI 102)	48.67
Filler	Lactose monohydratc	24.33
Dis intégrant	Croscarmellose sodium	3.00
Glidant	Silicon dioxide (Syloid 244 FP)	0.50
Fabricant	Magnésium stéarate	0.25
Extra Granular
Glidant	Silicon dioxide (Aerosil R972)	1.00
Disintegrant	Croscarmellose sodium	2.00
Lubricant	Magnésium stéarate	0.25
Totale:		100.00

[0690] The effect of adjusting the ribbon tensile strength on the granule size distribution and the effect of final blending on the granule size distribution is shown in FIGs. 30A and 30B. Granule size decreased as the ribbon tensile strength increased.

[0691] The effect of ribbon tensile strength (granulator screen constant = 1.00 mm) on flow 15 properties was also assessed and shown in Table 57. The flow metrics are better compared to the bench-scale trials, Carr Index = 21-23; FloDex = 16, and FFc = 7.1 - 8.5 are indicative of a free-flowing granulation.

176

Table 56: Pre-demo G2 composition final blend flow characteristics

Parameter	1	2	3
Rîbbon Tensile Strength (MPa)	1.10	0,60	0.77
Flow Characteristics
Bulk Density (g/mL)	0.60	0.55	0.51
Tapped Density (g/mL)	0.76	0.71	0.66
Carr Index (%)	21	23	22
FloDex (mm)	16	16	16
Flow Function, FFc	7.1	8,1	8.5
Cohésion Coefficient (Pa)	73	65	58

[0692] CTC scans of tablets made on the F-press using G2 pre-demo batches are consistent with wbat was observed for the tablets manufactured using bench-scale equipment. The granulation is highly compressible and compact i b le and produces a tablet with acceptable tensile strength at compressive stresses in the range of 100 MPa. Noteworthy is a steep tensile strength vs. solid fraction, as noted previously. Higher solid fraction means lower tablet porosity. Tablet porosity is a known factor that can affect dissolution, therefore, the effect of tensile strength of tablets on dissolution rate and extent was also evaluated.

[0693] The dissolution profiles of G2 pre-demo tablets compressed at 2.0 and 2.5 MPa are compared to the D2 tablets compressed at 2.5 MPa, as shown in FIG. 31. The dissolution profiles are similar, showing no discernable différence in dissolution profile as function of tablet porosity.

[0694] In conclusion, based on improved flow behavior, acceptable tablet properties and acceptable tablet dissolution, the G2 tablet composition using Gerteis settings determined during the pre-demo Laboratory-sized batches was selected for manufacture of a démonstration batch.

[0695] Biopharmaceutical performance of 5% (A3) and 20% (G2) drug loaded tablets was assessed by orally dosing the corresponding tablets and comparing the plasma levels thereby obtained. 24 dogs were divided into two groups. Each group was fasted overnight and then fed regular chow 30 minutes before tablet administration followed by 30 mL of water. Otherwise, water was withheld from l hour before to l hour after dosing. 50 minutes before tablet dosing ail subjected were pretreated with a 6 pg/mL intramuscular pentagastrin solution. Blood samples were collected at 0, 0.5, l, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 36, 48, 72, 96, 120, 144, and 168 hours post-dose. One group was administered 2

177 of the 35 mg tablets containing a 5% load of Compound A and the other group was given 1 of the 70 mg tablets containing a 20% of Compound A.

[06961 As shown in Table 57, similar exposure in pentagastrin pretreated, fed state dogs was observed when orally administered two of the 35 mg (5%) or one of the 70 mg 5 (20%) tablets.

Table 57. Comparison of Oral Exposure Derived From Dosing Two 35 mg (5% Drug

Load) orOne 70 mg (20% Drug Load) Tablet to Dogs

Tablets Administered	AUCO-last (ngxh/mL)
Avg	SD
2*35 mg	5,489	3,511
1*70 mg	5,481	4,404

[0697] Example 28. Late Phase 1 Tablet Démonstration Batch Formulas

[0698] A common granulation/bracketing strategy was applied for manufacturing the démonstration batch for the 20% SDI drug load formulation composition. The manufacture of tablets with a tablet press weight bracketed between 35 mg and 140 mg tablet strength (i.e. 175 mg to 700 mg tablet press weight) was implemented in the following manner. A portion of a démonstration common granulation final blend was aliquoted to com press 35 mg, 70 mg and 140 mg tablets using a single-station compression machine. The remainder of the common granulation was used to compress a batch at 105 mg strength (525 mg tablet press weight) on a rotary tablet press, représentative of the clinical manufacturing tablet machine. The 35 mg, 70 mg, 105 mg and 140 mg démonstration batches were used in the stability studies described in Example 29 below.

[0699] The formulation compositions, granulation batch quantities and number of tablets are listed in Table 58.

178

Table 58: Démonstration Batch Formulae for Compound A Tablets, 35 mg, 70 mg,

105 mg and 140 mg Strengths Using 20% SDI Load.

Ingrédient	Theoretical Quantity per Batch (g)
Common Granulation	35 mg Strength/ 175 mg Tablet Press Weight	70 mg strength/ 350 mg Tablet Press Weight	105 mg strength/ 525 mg Tablet Press Weight	140 mg strength/ 700 mg Tablet Press Weight
Inlra-granular
100% Compound A SDI	398.61	10.50	9.80	278.62	41.40
Microcrystalline cellulose (Avicel pH102)	970.06	25.55	23.85	678.06	100.74
Lactose monohydrate (FastFlo 316}	485.01	12.77	11.92	339.02	50.37
Croscannellose sodium (Ac-Di-Sol)	59.78	1.57	1.47	41.79	6.21
Silicon Dioxide (Syloid-244)	10.03	0.26	0.25	7.01	1.04
Magnésium stéarate	5.01	0.13	0.12	3.50	0.52
Total Intra-granular	1928.5	50.79	47.4]	1348.00	200.27
Extra-gran ular
Croscarmellose sodium (Ac-Di-Sol)	39.87	1.05	0.98	27.87	4.14
Silicon Dioxide (AeiOsil R972)	19.93	0.53	0.49	13.93	2.07
Magnésium stéarate	4.98	0.13	0.12	3.48	0.52
Total granulation	1993.28	53	49	1393.28	207
Total number of tablets	-	300	140	2654	296
Theoretical quantity per batch for the 105 mg tablet was calculated after samples taken for testing and manufacture of the 35 mg, 70 mg, and 140 mg tablet strengths Common granulation was divided to manufacture the 35 mg, 70 mg, 105 mg and 140 mg tablet strengths

|0700] Prior to blending, Compound A drug substance is dissolved, then spray-dried to 5 fonn an amorphous drug product intermediate as described above.

[0701] The common granulation ribbons were manufactured to achieve an actual ribbon solid fraction = 0.60 that equates to an estimated tensile strength of 0.8 MPa.

[0702] The final blend granule size distribution was reproducible, comparing favorably to the pre-demo batch, as depicted in FIG. 32.

[0703] The final blend flow metrics were also reproducible, comparing favorably to the pre-demo batch, shown in Table 59.

179

Table 59: Comparison of flow metrics between the pre-dcmonstration and démonstration final blend batches of G2 composition, granulated to a ribbon tensile strength of 0.8 MPa.

Parameter	Final Blend-Pre-demo Batch	Final Blend - Demo Batch
Bulk Density (g/mL)	0.51	0.55
Tapped Density (g/mL)	0.66	0.69
Carr Index (%)	22	20
FloDex (mm)	16	14
Flow Function, FFc	8.5	13.8
Cohésion Coefficient (Pa)	58	34

[0704] The final blend was divided into 4 portions, Three portions of 100 gram each were used to manufacture the 35 mg, 70 mg and 140 mg tablets on the single-station machine, and the remainder (approximately 2 kg) was used to manufacture the 105 mg batch on a rotary tablet machine,

[0705] The 35 mg, 70 mg and 140 mg tablet strengths were compressed to 2.0 MPa tensile strength round tablets. The tablet disintegration times were 2.3 to -3.0 minutes for the 140 mg, 1.5 to 2.0 minutes for the 70 mg and ~1 to 1.3 minutes for the 35 mg tablet.

[0706] The 105 mg démonstration batch exhibited good flow as evidenced by the excellent weight and hardness control and excellent uniformity of dosage units. Tablet press weights were easily maintained at the in-process limit for individual tablets of ± 5 %. Uniformity of dosage units UPS <905> AV = 3.5, mean = 97.2 % label claim.

[0707] Comparison of the dissolution for 35 mg, 105 mg and 140 mg are shown în FIG. 33. The dissolution was performed for the tablet strengths that were used in stability studies, which bracketed the highest, lowest and mid-range strengths. The dissolution profiles are comparable, demonstrating no tablet strength effect on the dissolution rate and extent.

[0708] In conclusion, based on acceptable processability and final product performance, the G2 composition was nominated for manufacture of clinical tablets that can be bracketed between 35 mg and 140 mg strengths

Example 29: Stability of Formulation G2 Tablets

180

[0709] Tablets of formulation G2 with strengths of35 mg, 105 mg, and 140 mg Compound A were subjected to a stability study (Table 61).

[0710] Protocol (Tablet Packaging)

[0711] Packaging Supplies;

· White 500cc HDPE Pharma Round Bottles with HIS lids • 1g Sorb-It desiccant canisters

[0712] Tablet Packaging Protocol:

1. Add (22) tablets to a 500cc HDPE bottle.

2. Add (1) Ig Sorb-it desiccant canister to the HDPE bottle.

3. Place a HIS lid on the HDPE bottle and seal the bottle using an Enercon Super Seal

Jr. cap sealer at 60% sealing power for one second.

4. Remove the bottle lid to ensure the foil seal is properly adhered to the bottle. Screw the cap back on the bottle before placing the bottle in the appropriate stability chamber.

Table 60: Tablet Stability Conditions, Time Points and Testing

Condition	1 Month (1)	3 Month (2)	6 Month (3)	12 Month (4)
(a) 5°C. closed with desiccant	A	A	A	A, B, C
(b) 25°C/60%RH, closed with desiccant	A, B, C	A, B, C	Λ, B, C	A, B, C
(c) 40°C/75%RH, closed with desiccant	A, B, C	A, B, C	A, B, C
A - 105mg Formulation G2 B - 140mg Formulation G2 C - 35mg Formulation G2

[0713] The tablets were analyzed for appearance, assay and related substances by UPLC, dissolution by USPII, and water content by volumétrie KF. Based upon the characterization below, ail of the tablet doses were as expected for appearance, assay, dissolution 20 performance, and water content. The purity was slightly increased when compared with the SDI used for manufacture and should be monitored closely in subséquent stability pulls. [0714] The tablets were visually evaluated for appearance. Ail of the tablets were yellow, smooth surfaced tablets.

[0715] Tablet assay values were consistent for each dose and met the current spécification 25 of 90% - 110% LC (Table 62).

Table 61: Tabulated Composite Assay Data for Compound A Stability Tablets | Sample | %LC | Range (n=2, 5 tablet composite) |

I8l

140 mg Tabiet	95	0.2
105 mg Tabiet	97	0.2
3 5mg Tabiet	95	0.3

[0716] Protocol (Blister Packaging)

[0717] Tablets were Blister Packaged by Fisher • 5 tablets per strip (1 X 5), with 1 tab/ cavity · ALU/ALU - blisters (Cold form foil)

10718] At each time point below, 5 strips (25 total tablets) were pulled at each time point for each stability condition for analysis.

Table 62; Blister Stability Conditions, Time Points and Testing

Condition	1 Month (1)	3 Month (2)	6 Month (3)	12 Month (4)
(a) 5 °C, closed with desiccant	A	A	A	A
(b) 25°C/60% RH, closed with desiccant	A	A	A	A
(c) 40°C/75% RH, closed with desiccant	A	A	A

[0719] Stability study results are shown below in Tables 63-66.

Table 63: Summary of the 140 mg Dose Compound Tabiet Bottle Stability Results

140mg, Formulation G2	Condition	Initia]	1 Month	3 Month	6 Month
Appea rance	25 °C/60% RH	Light Yellow	Light Yellow	Light Yellow	Light Yellow
40 °C/75% RH	Light Yellow	Light Yellow	Light Yellow
Assay	25 °C/60% RH	95	96	96	96
40 °Cn5% RH	95	95	95
Total Related Substances	25 °C/60% RH	0.28	0.35	0 24	0.36
40 °C/75% RH	0.33	0.27	0.55*
Water Content	25 ”C/60% RH	4.06	3.64	3.71	3.90
40 °C/75% RH	3.70	4.57	5.06
% LC at 45 minutes	25 °C/60% RH	95	92	94	95
40 °C/75% RH	93	93	92
lablet Hardness	25 °C/60% RH	21.8	212	21.3	21.8
40 °C/75% RH	21.8	21.0	19.4

Hncrease appears to be related to an increase in peak at RRT 0 43

182

Table 64: Summary of the 105 mg Dose Compound Tablet Bottle Stability Results

140mg, Formulation G2	Condition	Initial	1 Month	3 Month	6 Month
Appearance	5 °C	Light Yellow	Light Yellow	Light Yellow	Light Yellow
25 °C/60% RH	Light Yellow	Light Yellow	Light Yellow
40 °C/75% RH	Light Yellow	Light Yellow	Light Yellow
Assay	5 °C	97	96	95	97
25 °C/60% RH	99	98	100
40 °C/75% RH	97	98	97
Total Related Substances	5 °C	0.25	031	0.24	.044
25 °C/60% RH	0.34	0.25	0.47
40 °C/75% RH	0.32	0.27	0.52*
Water Content	5 °C	3.40	3.04	2.78	3.11
25 %760% RH	3.23	3.46	3.55
40 “075% RH	3.32	4 31	5.12
% LC ai 45 minutes	5 °C	97	92	95	95
25 °C/60% RH	91	95	97
40 ^eC/75% RH	93	93	96
Tablet Hardness	5°C	20.4	19.9	20.4	18.2
25 °C/60% RH	18.9	21.5	19.9
40 °Ε.Π5% RH	20.2	18.0	18.2

*]ncrease appears to be related to an increase in peak at RRT 0.43

Table 65: Summary of the 105 mg Dose Compound Tablet Blister Stability Results

140mg, Formulation G2	Condition	Initial	1 Month	3 Month
Appea rance	5 °C	Light Yellow	Light Yellow	Light Yellow
25 °C/60% RH	Light Yellow	Light Yellow
40 °C/75% RH	Light Yellow	Light Yellow
Assay	5 C	97	99	98
25 °C/60% RH	99	99
40 C/75% RH	99	97
Total Related Substances	5 ‘C	0.25	046	0.44
25 °C/60% RH	0.46	0.45
40 °C/75% RH	0.41	0 39
Water Content	5 C	34	3.55	3 56
25 °C/60% RH	3.56	3 61
40 °C/75% RH	3.55	3.58
% LC at 45 minutes	5 °C	97	97	95
25 °C/60% RH	97	95
40 °C/75% RH	95	94
Tablet Hardness	5 °C	20.4	20.4	18 1
25 °C/60% RH	19.6	18 9
40 °C/75% RH	19.6	19.5

Table 66: Summary of the 35 mg Dose Compound Tablet Bottle Stability Results

14Ûmg, Formulation G2	Condition	Initial	1 Month	3 Month	6 Month
Appearance	25°C/60%RH	Light Yellow	Light Yellow	Light Yellow	Light Yellow
40 °C/75% RI I	Light Yellow	Light Yellow	Light Yellow
Assay	25 °C/60% RH	95	93	97	96
40 °C/75% RH	95	95	94
Total Related	25 C/60% RH	0 26	0 35	0.19	0.47
Substances	40 °C/75% RH	0.32	0.27	0.50*
Water Content	25 °C/60% RH	5.05	3.65	3.38	4.16
40 °C/75% RH	3.72	4.95	5.97
% LC at 45 minutes	25 °C/60% RH	94	91	94	94

183

‘Increase appears to be related to an increase tn peak al RRT0.43

Embodiments:

[0720] The aspects of the present disclosure are further described with reference to the following numbered embodiments:

l. A crystalline form of Compound A

having a powder x-ray diffraction pattern comprising peaks at 7.6° ± 0.2° 2θ, 11.5° ± 0.2° 20, and 17.6° ± 0.2° 20, wherein said powder x-ray diffraction pattern is obtained using Cu Ka radiation at an x-ray wavelength of 1.5406 À.

2. The crystalline form of Compound A of Embodiment 1, further comprising a peak at 18.5° ±0.2° 20.

3. The crystalline form of Compound A of Embodiment 1 or 2, further comprising a peak at 21.4° ± 0.2° 20.

4. The crystalline form of Compound A of any one of Embodiments 1-3, further comprising a peak at 3.1° ± 0.2° 20.

5. A crystalline form of Compound A having a powder x-ray diffraction pattern as shown in FIG. 3A.

6. A crystalline form of Compound A having a powder x-ray diffraction pattern comprising peaks at 11.0° ± 0.2° 20, 16.1° ± 0.2° 20, and 17.9° ± 0.2° 20, wherein said powder x-ray diffraction pattern is obtained using Cu Ka radiation at an x-ray wavelength of 1.5406 À.

7. The crystalline form of Compound A of Embodiment 6, further comprising a peak at 11.3° ±0.2° 20.

184

8. The crystalline form of Compound A of Embodiment 6 or 7, further comprising a peak at 17.2° ±0.2° 26.

9. The crystalline form of Compound A of any one of Embodiments 6-8, further comprising a peak at 7.9° ± 0.2° 26.

10. A crystalline form of Compound A having a powder x-ray diffraction pattern as shown in FIG. 3C.

11. A process for manufacturing Compound A, wherein the process comprises the reductive amination ofN-((lr,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4formylpiperidin-l-yl)pyridazine-3-carboxamide (Intermediate 3) with 2-(2,6- dioxopiperidin-3-yl)-5-fluoro-6-(piperazin-l-yl)isoÎndoline-l,3-dione hydrochloride (Intermediate 5) and a reducing agent to provide Compound A:

Intermediate 3

Compound A

12, The process of Embodiment 11, wherein the reductive amination is conducted in a polar solvent.

13. The process of Embodiment 12, wherein the polar solvent for the reductive amination is dimethylacetamide (DMA).

185

14. The process of any one of Embodiments 11-13, wherein the reducing agent for the reductive amination is sodium triacetoxyborohydride.

15. The process of any one of Embodiments 11-14, wherein the reductive amination is conducted at a température range of about -15 to about 30°C, about -10 to about 25°C, about -5 to about 20°C, about 0 to about 15°C, or about 5 to about 10°C.

16. The process of any one of Embodiments 11-15, wherein once the reductive amination reaction is complété, a mixture of éthanol and water is added to the crude reaction mixture to precipitate Compound A.

17. The process of Embodiment 16, wherein the mixture of éthanol to water has an ethanohwater ratio of about 1:1 (v/v).

18. The process of any one of Embodiments 11-17, wherein the reductive amination is conducted in the presence of a base

19. The process of Embodiment 18, wherein the base for the reductive amination is triethylamine or N-methyl morpholine.

20. The process of Embodiment 19, wherein the ratio of Intermediate 5 to base is about 1:0.7 (w/v).

21. The process of Embodiment 19, wherein the ratio of Intermediate 5 to base is about l .7:1 (w/w).

22. The process of Embodiment 19, wherein the ratio of Intermediate 5 to base is about 1.9:1 (w/w).

23. The process of any one of Embodiments 11-22, wherein the molar ratio of Intermediate 3 to Intermediate 5 is about 1,1:1.

24. The process of any one of Embodiments 11-22, wherein the molar ratio of Intermediate 3 to Intermediate 5 is about 1.05:1.

25. The process of any one of Embodiments 11-22, wherein the molar ratio of Intermediate 3 to Intermediate 5 is between about 1:1 and about 1.1:1.

186

26. The process of any one of Embodiments 11-22, wherein the molar ratio of Intermediate 3 to Intermediate 5 is about 1.0:1,0.

27. The process of any one of Embodiments 11-26, further comprising a step for the purification of Compound A.

28. The process of Embodiment 27, wherein the purification of Compound A comprises:

(Al) dissolving Compound A in about a mixture of dichloromethane and methanol;

(A2) filtering the solution comprising Compound A;

(A3) dîstillatîvely exchanging the solvent of the solution comprising Compound A with éthanol;

(A4) crystallizing Compound A from the éthanol solution; and (A5) drying the purified crystalline solid form of Compound A.

29. The process of Embodiment 28, wherein the ratio of dichloromethane to methanol in (Al) is about 9:1 (w/w).

30, The process of Embodiment 28, wherein the ratio of dichloromethane to methanol in (Al) is about 10:1 (v/v).

31. The process of Embodiment 28, wherein the volume of éthanol in step (A3) is approximately 7 volumes relative to the amount of Intermediate 3 provided in the reductive amination step.

32. The process of Embodiment 31, wherein the amount of éthanol in step (A3) is corrected for the éthanol content in the crude Compound A.

33. The process of one of Embodiments 28-32, wherein the drying in step (A5) of the purified crystalline form of Compound A is conducted in vacuo.

34. The process of Embodiment 33, wherein the in vacuo drying occurs at about 15 to about 30 °C, about 20 to about 30 °C, about 30 to about 40 °C, or about 35 to about 45 °C.

187

35, The process of Embodiment 33, wherein the in vacuo drying occurs at greater than about 50 °C, greater than about 60 °C, greater than about 70 °C, or greater than about 80 °C.

36. The process of Embodiment 33, wherein the in vacuo drying occurs at between 5 about 60 °C and about 70 °C.

37. The process of Embodiment 33, wherein the in vacuo drying occurs at about 65 °C.

38. The process of Embodiment 33, wherein the in vacuo drying occurs at between about 75 °C and about 85 °C.

I0 39. The process of Embodiment 33, wherein the in vacuo drying occurs at about 80

40. The process of any one of Embodiments 1.1 -39, further comprising the oxidation of N-((lr,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(hydroxymethyl)piperidin-l yl)pyridazine-3-carboxamîde (Intermediate 2) to form N-((lr,4r)-4-(3-chloro-4- cyanophenoxy)cyclohexyl)-6-(4-formylpiperidin-1 -yl)pyridazine-3-carboxamide (Intermediate 3):

Intermediate 2

Intermediate 3

41. The process of Embodiment 40, wherein the oxidation is performed using about 0.01 équivalents of (2,2,6,6-tetramethylpiperidin-l-yl)oxyl (TEMPO) and about 1 équivalents of sodium hypochlorite.

42. The process of Embodiment 40, wherein the oxidation is performed using about 0.01 équivalents of TEMPO and about 1.15 équivalent of sodium hypochlorite.

43. The process of any one of Embodiments 41 or 42, wherein the oxidation is performed in a solvent comprising dichloromethane.

188

44. The process of any one of Embodiments 41-43, wherein the oxidation occurs in the presence of a secondary alcohol.

45. The process of Embodiment 44, where in the secondary alcohol is isopropanol.

46. The process of any one of Embodiments 43-45, wherein the solvent for the oxidation further comprises aqueous sodium chloride.

47. The process of any one of Embodiments 40-46, wherein the oxidation is performed at a température less than about 25°C, less than about 20°C, less than about 15°C, less than about 10°C, less than about 5°C, less than about 0°C, less than about -5 °C, or less than about -l l °C.

48. The process of any one of Embodiments 40-46, wherein the oxidation is performed at a température of about -11 °C.

49. The process of any one of Embodiments 41-46, wherein the sodium hypochlorite is added over the course of less than 60 minutes, less than 45 minutes less than 30 minutes, or less than 20 minutes.

50. The process of any one of Embodiments 41-46, wherein the sodium hypochlorite is added over the course of between about 15 and about 45 minutes.

51, The process of any one of Embodiments 41-46, wherein the sodium hypochlorite is added over the course of about 30 minutes.

52. The process of any one of Embodiments 41-51, further comprising the step of 20 exchanging the solvent comprising dichloromethane for a second solvent.

53. The process of Embodiment 52 wherein the second solvent comprises acetonitrile.

54. The process of Embodiment 52 wherein the second solvent comprises tetrahydrofuran.

55. The process of Embodiment 52, wherein the exchange of solvents is accomplished by distillation.

56. The process of any one of Embodiments 40-55 further comprising the step of purifying Intermediate 3 by recrystallization.

189

57. The process of Embodiment 56, wherein the purification of Intermediate 3 by recrystallization occurs in the presence of a solvent and an anti-solvent.

58. The process of Embodiment 56, wherein the recrystallization comprises the following steps:

Bi) combining crude Intermediate 3 with a mixture of solvent and anti-solvent;

Bii) stirring the mixture of crude Intermediate 3, solvent, and anti-solvent; and

Biii) filtering the mixture of crude Intermediate 3, solvent, and anti-solvent to obtain Intermediate 3.

59. The process of Embodiment 58, wherein the recrystallization solvent is a polar aprotic organic solvent and the anti-solvent is an aqueous solvent.

60. The process of Embodiment 59, wherein the recrystallization solvent for Intermediate 3 comprises acetonitrile.

61. The process of Embodiment 59, wherein the recrystallization solvent for Intermediate 3 comprises dichloromethane.

62. The process of Embodiment 59, wherein the recrystallization solvent for Intermediate 3 comprises tetrahydrofuran.

63. The process of Embodiment 59, wherein the recrystallization solvent for Intermediate 3 comprises dichloromethane and tetrahydrofuran.

64. The process of any one of Embodiments 59-63, wherein the recrystallization antisolvent is water.

65. The process of any one of Embodiments 59-63, wherein the recrystallization antisolvent comprises n-heptane.

66. The process of any one of Embodiments 59-65, wherein the ratio of recrystallization solvent to anti-solvent is about l : I (v/v).

67. The process of any one of Embodiments 59-65, wherein the ratio of recrystallization solvent to anti-solvent is about 1.04:1 (v/v).

190

68. The process of any one of Embodiments 59-65, wherein the ratio of recrystallization solvent to anti-solvent is about 0.6:1 (v/v),

69. The process of any one of Embodiments 59-68, wherein step Bii) is performed at a température between 15 °C and 25 °C.

70. The process of Embodiment 69, wherein step Bii) is performed at a température of about 18 °C.

71. The process of Embodiment 69, wherein step Bii) is performed at a température of about 20 °C.

72. The process of any one of Embodiments 59-71, wherein the stirring of step Bii) is performed forât least 5 hours, at least 12 hours, at least 14 hours, at least 16 hours, or at least 18 hours.

73. The process of Embodiment 72, wherein the stirring of step Bii) is performed for ai least 16 hours.

74. The process of Embodiment 72, wherein the stirring of step Bii) is performed for about 18 hours.

75. The process of any one of Embodiments 11 -74, further comprising a nucleophilic aromatic substitution reaction of 6-chloro-N-((lr,4r)-4-(3-chloro-4- cyanophenoxy)cyclohexyl)pyridazine-3-carboxamide (Intermediate 4) and piperidin-4yl methanol in the presence of a base to provide N-((lr,4r)-4-(3-chloro-4cyanophenoxy)cyclohexyl)-6-(4-(hydroxymethyl)piperidin-l-yl)pyridazine-3carboxamide (Intermediate 2):

Intermediate 4

Intermediate 2

76. The process of Embodiment 75, wherein the nucleophilic aromatic substitution reaction is conducted in a polar solvent.

191

77. The process of Embodiment 76, wherein the polar solvent for the nucleophilic aromatic substitution is dimethylacetamide (DMA).

78. The process of any one of Embodiments 75-77, wherein the base for the nucleophilic aromatic substitution is N,N-diisopropylethylamine.

79. The process of any one of Embodiments 75-78, wherein the nucleophilic aromatic substitution reaction is conducted at a température of about 60°C to about 130°C, about 75°C to about 115°C, or about 90°C to about 100°C.

80. The process of any one of Embodiments 75-79, further comprising the step of purifying Intermedîate 2 by recrystallization in an organic solvent.

81. The process of any one of Embodiments 75-80, wherein the recrystallization of

Intermediate 2 further comprises the following steps:

Ci) combining crude Intermediate 2 in an organic solvent with an agent that promûtes crystallization;

Cii) reducing the volume of organic solvent;

Ciii) adding additional amounts of the organic solvent;

Civ) stirring the mixture from part iii) at a température above 30 °C;

Cv) cooling the mixture from part iii) to a température below 25 °C;

Cvi) reducing the volume of organic solvent;

Cvii) stirring the mixture from part vi) at a température below 25 °C; and

Cvii) fîltering the mixture to obtain Intermediate 2.

82. The process of Embodiment 81, wherein the organic solvent in step Cii) is isopropyl acetate.

83. The process of Embodiment 81 or 82, wherein the agent that promûtes crystallization in Ci) is a seed crystal of Intermediate 2.

84. The process ofany one of Embodiments 81-83, wherein the reducing ofthe volume of organic solvent in step Ciii) is performed by vacuum distillation.

192

85. The process of any one of Embodiments 81-84, wherein the reducing of the volume of organic solvent in step Cvi) is performed by vacuum distillation.

86. The process of any one of Embodiments 81-85, wherein the temperature of step Civ) is about 50 °C.

87. The process of any one of Embodiments 81-86, wherein the temperature of step

Cv) is about 20 °C.

88. The process of any one of Embodiments 81-87, wherein the temperature of step Cvii) is about 10 °C.

89. The process of any one of Embodiments 11-88, further comprising an amide coupling of 4-(((Ir,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzonitrile hydrochloride (Intermediate 7) and 6-(4-(hy droxymethyl)piperid in-1-y l)pyridazine-3-carboxy lie acid (Intermediate 10), facilitated by a coupling agent, to providebl-((!r,4r)-4-(3-chloro-4cyanophenoxy)cyclohexyl)-6-(4-(hydroxymethyl)piperidin-l-yl)pyridazine-3carboxamide (Intermediate 2):

Intermediate 2

90. The process of Embodiment 89, wherein the amide coupling is conducted in a polar solvent,

91. The process of Embodiment 90, wherein the polar solvent for the amide coupling is dimethylacetamide (DMA).

193

92. The process of any one of Embodiments 89-91, wherein the coupling agent for the amide coupling is a carbodiimide.

93. The process of Embodiment 92, wherein the carbodiimide is l-ethyl-3-(3dimethylaminopropyl)carbodiimide.

94. The process of Embodiments 89-93, wherein the amide coupling reaction is conducted at a température of about 5 °C to about 15 °C, about 10 °C to about 20 °C, about 20 °C to about 40 °C, about 30 °C to about 50 °C, or about 35 °C to about 45 °C.

95. The process of any one of Embodiments 89-94, wherein the ratio of molar ratio of Intermediate 7 to Intermediate 10 is about 1.05:1.

96. The process of any one of Embodiments 89-94, wherein the ratio of molar ratio of

Intermediate 7 to Intermediate 10 is about 1.02:1.

97. The process of any one of Embodiments 89-96, further comprising the step of purifying Intermediate 2 by recrystallization in an organic solvent.

98. The process of Embodiment 97, wherein the organic solvent for the recrystallization of Intermediate 2 is isopropyl acetate.

99. The process of Embodiment 97, wherein the organic solvent for the recrystallization of Intermediate 2 comprises tetrahydrofuran and n-heptane.

100. The process of any one of Embodiments 97-99, wherein the organic solvent for the recrystallization of Intermediate 2 is seeded with crystals of pure Intermediate 2.

101. The process of any one of Embodiments 97-100, wherein the recrystallization of

Intermediate 2 is performed by réduction of the volume of the organic solvent for the recrystallization of Intermediate 2.

102. The process of Embodiment 101, wherein the réduction of the volume of the organic solvent for the recrystallization of Intermediate 2 is performed by vacuum 25 distillation.

103. The process of any one of Embodiments 97-102 wherein the recrystallization of

Intermediate 2 is performed by cooling the organic solvent for the recrystallization of

Intermediate 2.

194

104. The process of Embodiment 103, wherein organic solvent for the recrystallization of Intermediate 2 is cooled to a température between about 15 °C and about 25 °C.

105. The process of Embodiment 103, wherein organic solvent for the recrystallization of intermediate 2 is cooled to a température of about 20 °C.

106. The process of any one of Embodiments 11-105, wherein the purified form of

Compound A has a crystalline form with a powder x-ray diffraction pattern comprising peaks at 7.6° ± 0.2° 20, 11.5° ± 0.2° 20, and 17.6° ± 0.2° 20, wherein said powder x-ray diffraction pattern is obtained using Cu Ka radiation at an x-ray waveiength of 1.5406 Â.

107. A compound which is:

6-chloro-N-(( 1 r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)pyridazine-3carboxamide,

Intermediate 4

108. An ultrapure form of Compound A having a purity greater than about 98%.

109. An ultrapure form of Compound A having a purity greater than about 98%, and comprising less than about 1% of impurity Intermediate 2:

110. The ultrapure form of Compound A of Embodiment 109, comprising less than about 0.5% of impurity Intermediate 2.

111. The ultrapure form of Compound A of Embodiment 109, comprising less than 20 about 0.2% of impurity intermediate 2.

195

112. An ultrapure form of Compound A having a purity greater than about 98%, and comprising less than about 1% of impurity Intermediate 3:

Intermediate 3

113. The ultrapure form of Compound A of Embodiment 112, comprising less than about 0.5% of impurity Intermediate 3.

114. The ultrapure form of Compound A of Embodiment 112, comprising less than about 0.1% of impurity Intermediate 3.

115. An ultrapure form of Compound A having a purity greater than about 98%, and comprising less than about 1% of impurity Intermediate 5:

116. The ultrapure form of Compound A of Embodiment 115, comprising less than about 0.5% of impurity Intermediate 5.

117. The ultrapure form of Compound A of Embodiment 115, comprising less than about 0.1 % of impurity Intermediate 5.

118. The ultrapure form of Compound A of Embodiment 115, comprising less than about 0.05% of impurity Intermediate 5.

119. An ultrapure form of Compound A having a purity greater than about 98%, and comprising less than about 1% of Impurity 1 :

Impurity 1

120. The ultrapure form of Compound A of Embodiment 119, comprising less than about 0.5% of Impurity 1.

121. The ultrapure fonn of Compound A of Embodiment 119, comprising less than about 0.1% of Impurity 1.

122. The ultrapure form of Compound A of Embodiment 119, comprising than about 0.05% of Impurity 1.

123. An ultrapure form of Compound A having a purity greater than about 95%, and comprising less than about 1% of Impurity 2:

Impurity 2.

124. The ultrapure form of Compound A of Embodiment 123, comprising less than about 0.5% of Impurity 2.

125. The ultrapure form of Compound A of Embodiment 123, comprising less than 15 about 0.2% of Impurity 2.

126. The ultrapure form of Compound A of Embodiment 123, comprising less than about 0,15% of Impurity 2.

127. An ultrapure form of Compound A having a purity greater than about 95%, and comprising less than about 1% of Impurity 3:

I97

Impurity 3.

128. The ultrapure form of Compound A of Embodiment 127, comprising less than about 0.5% of Impurity 3.

129. The ultrapure form of Compound A of Embodiment 128, comprising less than about 0.2% of Impurity 3.

130. The ultrapure form of Compound A of Embodiment 129, comprising less than about 0.15% of Impurity 3.

131. An ultrapure form of Compound A having a purity greater than about 95%, and 10 comprising less than about 1% of Impurity 4:

Impurity 4.

132. The ultrapure form of Compound A of Claim 131, comprising less than about 0.5% of Impurity 4.

133. The ultrapure form of Compound A of Embodiment 131, comprising less than about 0.2% of Impurity 4.

134. The ultrapure form of Compound A of Embodiment 131, comprising less than about 0.15% of Impurity 4.

135A. The ultrapure form of Compound A of any one of Embodiments 108-134, wherein the purity of Compound A is determined by HPLC.

19S

135B. The ultrapure form of Compound A ofany one of Embodiments 109-135A, wherein the amount of the Intermediate or Impurity is determined by HPLC.

136. The ultrapure form of Compound A ofany one of Embodiments 108-135A, wherein the purity of Compound A is greater than about 99%, about 99.5%, or about

99.9%.

137. The ultrapure fonn of Compound A ofany one of Embodiments 108-135, wherein the purity of Compound A is greater than about 99.5%.

138. An ultrapure form of Compound A having a purity greater than about 98%, and comprising less than about 1% of at least two of the following impurities: Intermediate 2, 10 Intermediate 3, Intermediate 5, Impurity 1, Impurity 2, Impurity 3, and Impurity 4.

139. The ultrapure form of Compound A of embodiment 138, wherein the purity ot Compound A is greater than about 99%.

140. The ultrapure form ofCompound A ofany one of Embodiments 108-135, comprising less than about 0.9%, about 0.8%, about 0.7%, about 0.6%, or about 0.5% of 15 at least two of the following impurities: Intermediate 2, Intermediate 3, Intermediate 5,

Impurity 1, Impurity 2, Impurity 3, and Impurity 4.

141. The ultrapure form of Compound A of any one of Embodiments 108-135, wherein the Compound A has a purity of about 99.9%.

142. The ultrapure form of Compound A of any one of Embodiments 108-141, 20 wherein Compound A is in amorphous form.

143. The ultrapure form of Compound A of any one of Embodiments 108-141, characterized by a glass transition température, Tg, of 146°C at 25°C and 0% relative humidity.

144. The ultrapure form of Compound A of any one of Embodiments 108-141, further 25 characterized by a glass transition température, Tg, of 103°C at 40°C and 75% relative humidity.

145. The ultrapure form of Compound A of any one of Embodiments 108-144, further characterized by a Dv(50) particle size of about 5 to about 20 μιη.

199

146. The ultrapure form of Compound A ofany one of Embodiments 108-145, further characterized by a Dv(50) particle size of about 5 to about 15 pm.

147. The ultrapure form of Compound A of any one of Embodiments 108-146, characterized by a Dv(50) particle size of about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 5 18, 19, or 20 pm.

148. The ultrapure form of Compound A of any one of Embodiments 145-147, wherein particle size is measured by laser diffraction.

149. The ultrapure form of Compound A according to any one of Embodiments 108-

148, characterized in that the amorphous form is stable for at least 1 month at 2-8°C; for at 10 least 1 monthat25°C and 60%relative humidity; and forât least 1 month at40°C and 75% relative humidity.

150. A process for manufacturing the amorphous form of Compound A of any one of Embodiments 108-149, wherein the process comprises the following steps:

(Dl) dissolving crystalline Compound A in solvent to afford a solution of 15 Compound A;

(D2) introducing the Compound A solution from step (1) into a spray dryer;

(D3) spraying the Compound A solution from the spray dryer to form the amorphous form of the Compound A;

and (D4) Removing the residual solvent from the amorphous form of Compound A.

151. The process of Embodiment 150, wherein, the solvent of step (Dl) is a mixture of dichloromethane and methanol.

152. The process of Embodiment 151, wherein the solvent of step (Dl) is a mixture of about 95:5 (w/w) to about 80:20 (w/w) dichloromethane:methanol.

153. The process of any one of Embodiments 150-152, wherein the solvent of step (Dl) is about a 90:10 (w/w) mixture of dichloromethane:methanol.

154. The process of any one of Embodiments 150-152, wherein the solvent of step (Dl) is about a 95:5 (w/w) mixture of dichloromethane:methanol.

200

155. The process of any one of Embodiments 150-152, wherein the solvent of step (DI) is about a 93:7 (w/w) mixture of dichloromethane:methanol.

156. The process of any one of Embodiments 150-152, wherein removal of residual solvent in step (D4) is accomplished by tray-drying.

157. The process of any one of Embodiments 150-156, wherein removal of residual solvent in step (D4) is accomplished by filter-drying.

158. The process of any one of Embodiments 150-156, wherein the removal of residual solvent in step (D4) is accomplished by tumbie drying.

159. The process of any one of Embodiments 150-156, wherein the removal of residual solvent in step (D4) is accomplished by agitated conical drying.

160. The process of any one of Embodiments 150-156, wherein the removal of residual solvent in step (D4) is accomplished by fluid bed drying.

161. An oral dosage form comprising one or more pharmaceutically acceptable excipients and Compound A of any one of Embodiments 108-160, wherein the oral dosage form is selected from the group consisting of a tablet, a sachet, or a capsule.

162. The oral dosage form of Embodiment 161, wherein the Compound A is the ultrapure form of Compound Aofany one of Embodiments 108-149.

163. The oral dosage form of Embodiment 161 or 162, wherein the oral dosage form is a tablet.

164. The oral dosage fonn of Embodiment 161 or 162, wherein the oral dosage form is a sachet.

165. The oral dosage form of Embodiment 161 or 162, wherein the oral dosage form is a capsule.

166. The tablet of Embodiment 163, wherein the amount of Compound A in the tablet is between about 5 mg and 1000 mg.

167. The tablet of Embodiment 166, wherein the amount of Compound A in the tablet is about 35 mg to about 280 mg.

201

168. The tablet of Embodiment 167, wherein the amount of Compound A in the tablet is about 35 mg.

169. The tablet of Embodiment 167, wherein the amount of Compound A in the tablet is about 70 mg .

170. The tablet of Embodiment 167, wherein the amount of Compound A in the tablet is about 105 mg.

171. The tablet of Embodiment 167, wherein the amount of Compound A in the tablet is about 140 mg.

] 72. The tablet of Embodiment 167, wherein the amount of Compound A in the tablet 10 is about 175 mg.

173. The tablet of Embodiment 167, wherein the amount of Compound A in the tablet is about 210 mg.

174. The tablet of Embodiment 167, wherein the amount of Compound A in the tablet is about 245 mg.

175. The tablet of Embodiment 167, wherein the amount of Compound A in the tablet is about 280 mg.

176. The tablet of any one of Embodiments 163 or 166-175, wherein the pharmaceutically acceptable excipients are selected from the group consisting of flllers, disintegrants, glidants, and lubricants.

177. The tablet of Embodiment 176, wherein the filler is microcrystalline cellulose, silicified microcrystalline cellulose, lactose monohydrate, mannitol, sorbitol, xylitol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, pullulan, fast-dissolving carbohydrates such as Pharmaburst™, or any mixture thereof.

178. The tablet of Embodiment 176, wherein the disintegrant is sodium starch glycolate, 25 sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, chitosan, agar, alginic acid, calcium alginate, methyl cellulose, microcrystalline cellulose, powdered cellulose, lower alkylsubstituted hydroxypropyl cellulose, hydroxylpropyl starch, low-substituted hydroxypropylcellulose, polacrilin

202 potassium, starch, pregelatinized starch, sodium alginate, magnésium aluminum silicate, polacriiin potassium, povidone, or any mixture thereof.

179. The tablet of Embodiment 176, wherein the glidant is Silicon dioxide, colloïdal Silicon dioxide, calcium silicate, magnésium silicate, magnésium trisilicate, talc, starch, or 5 any mixture thereof.

180. The tablet of Embodiment 176, wherein the lubricant îs magnésium stéarate, calcium stéarate, glyceryl monostearate, glyceryl behenate, glyceryl palmitostearate, hexagonal boron nitride, hydrogenated vegetable oil, light minerai oil, minerai oil, polyethylene glycol, poloxamer, sodium benzoate, sodium lauryl sulfate, sodium steary1 10 fumarate, stearic acid, talc, zinc stéarate, or any mixture thereof.

181. The tablet of any one of Embodiments 163 or 166-175, comprising:

About I to about 50% w/w of Compound A;

About 35 to about 60% w/w microcrystalline cellulose;

About 15 to about 50% w/w lactose monohydrate;

About 1 to about 5% w/w croscarmellose sodium;

to about 1 % w/w Silicon dioxide; and to about I % w/w' magnésium stéarate.

182. The tablet ofany one of Embodiments 163 or 166-175, comprising:

About 5 % w/w of Compound A;

About 45.5 % w/w microcrystailine cellulose;

About 45.5 % w/w lactose monohydrate;

About 3 % w/w croscarmellose sodium;

About 0.5 % w/w Silicon dioxide; and

About 0.5 % w/w magnésium stéarate.

183. The tablet of any one of Embodiments 163 or 166-175, comprising an intra-granular portion and an extra-granular portion, wherein the întra-granular portion comprises

About 10 to about 40% w/w of Compound A;

About 35 to about 60% w/w microcrystalline cellulose;

About 15 to about 30% w/w lactose monohydrate;

203

About I to about 10% w/w croscarmellose sodium;

to about 1 % w/w Silicon dioxide; and to about 0.5% w/w magnésium stéarate;

and wherein the extra-granular portion comprises

About 1 to about 5% w/w croscarmellose sodium;

to about 1 % w/w magnésium stéarate; and to about 2 % w/w Silicon dioxide.

184. The tabiet ofany one ofEmbodiments 163 or 166-175, comprising an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises:

About 20% w/w of Compound A;

About 48.7% w/w microcrystalline cellulose;

About 24.3% w/w lactose monohydrate;

About 3% w/w croscarmellose sodium;

About 0.5 % w/w Silicon dioxide; and

About 0.25% w/w magnésium stéarate;

and wherein the extra-granular portion comprises:

About 2% w/w croscarmellose sodium;

About 0.5% w/w magnésium stéarate; and

About 0.25 % w/w Silicon dioxide.

185. The tabiet of Embodiment 183 or 184, wherein the Silicon dioxide in the extragranular portion comprises fumed silica.

186. The tabiet of any one of Embodiments 183-185, wherein the Silicon dioxide in the extra-granular portion comprises fumed silica after treated with dimethyldichlorosilane.

187. The tabiet of any one of Embodiments 183-186, wherein the Silicon dioxide in the extra-granular portion comprises fumed silica chemicalîy modified with trimethylsilyl groups on the surface of the silica.

188. The tabiet of any one of Embodiments 163 or 166-187, wherein the Compound A is an ultrapure form of Compound A.

204

189. The tablet of any one of Embodiments 163 or 166-187, wherein the Compound A is prepared according to the process of any one of Embodiments l50-160.

190. A method of manufacturing the tablet of any one of Embodiments 163 or 166-187 comprising the foilowing steps:

(El) blending a form of Compound A with at least one pharmaceutically acceptable excipient to create a powder;

(E2) delumping the powder from step (El), adding at least one pharmaceutically acceptable excipient, and blending to create a first blend;

(E3) granulating the blend from step (E2) and passing the résultant powder through 10 a screen to produce a plurality of granules;

(E4) adding at least one pharmaceutically acceptable excipient to plurality of granules from step (E3) and blending to produce a second blend; and (E5) compressing the second blend from step (E4) into one or more tablets.

191. The method of Embodiment 190, wherein the form of Compound A in step (El) is 15 the amorphous fonn of Compound A.

192. The method of Embodiment 190 or 191, wherein, in step (El), Compound A is blended with at least one filler, at least one disintegrant, and at least one glidant.

193. The method of Embodiment 192, wherein, in step (El), Compound A is blended with two fillers, one disintegrant, and one glidant.

194. The method of Embodiment 192, wherein, in step (El), Compound A is blended with two fillers, one disintegrant, one glidant, and one lubricant.

195. The method of Embodiment 193 or 194, wherein at least one filler is microcrystalline cellulose.

196. The method of Embodiments 193-195, wherein at least one filler is lactose 25 mono hydrate.

197. The method of any one of Embodiments 190-196, wherein at least one disintegrant is croscarmellose sodium.

205

198. The method of any one of Embodiments 190-197, wherein at least one glidant is Silicon dioxide.

199. The method of any one of Embodiments 190-198, wherein at least one lubricant is magnésium stéarate.

200. The method of any one of Embodiments 190-199, wherein at least one pharmaceutically acceptable excipient of step (E2) is a lubricant.

201. The method of Embodiment 200, wherein at least one lubricant is magnésium stéarate.

202. The method of any one of Embodiments 190-201, wherein the at least one 10 pharmaceutically acceptable excipient of step (E4) comprises at least one lubricant.

203. The method of Embodiment 202, wherein the at least one lubricant is extragranular magnésium stéarate.

204. The method of any one of Embodiments 190-203, wherein at least one glidant, at least one disintegrant, and at least one lubricant are added to the plurality of granules in 15 step (E4).

205. The method of Embodiment 204, wherein at least one glidant added in step (E4) is Silicon dioxide,

206. The method of any one of Embodiment 204 or 205, wherein at least one disintegrant added in step (E4) îs croscarmellose sodium.

207. The method of any one of Embodiments 204-206, wherein at least one lubricant added in step (4) is magnésium stéarate.

208. The method of any one of Embodiments 190-207, wherein the blend from step (E4) is compressed in step (E5) using a rotary press.

209. A method of treating cancer in a subject comprising administering to a subject in 25 need of said treatment one or oral dosage forms of any one of Embodiments 161-189.

210. The method of Embodiment 209, wherein the cancer is prostate cancer.

206

2Il. The method of Embodiment 210, wherein the prostate cancer is metastatic castration résistant prostate cancer.

212. The method of any one of Embodiments 209-211, wherein the one or more tablets are administered to the subject once a day, twice a day, three times a day, or four times a 5 day.

213. The method ofany one of Embodiments 209-212, wherein the one or more tablets are administered to the subject ail at once or subdivided in two, three, four, or more subportions.

214. The method of any one of Embodiments 209-213, wherein the subject is in a fed 10 state.

215. The method of any one of Embodiments 209-213, wherein the subject is in a fasted state.

216. The method of any one of Embodiments 209-215, wherein the subject is also taking or being administered an antacid médication.

217. The method of any one of Embodiments 209-216, further comprisingadministering an additional anti-cancer agent.

218. The method of Embodiment 217, wherein the additional anti-cancer agent is a PARP inhibitor.

= Appearance, Assay/Related Substances, Sink Dissolution, Water by KF

A crystalline form of Compound A (Compound A) having a powder x-ray diffraction pattern comprising peaks at 7.6° ± 0.2° 2Θ, 11.5° ± 0.2° 20, and 17.6° ± 0.2° 20, wherein said powder x-ray diffraction pattern is obtained usingCu Ka radiation at an x-ray wavelength of 1.5406 Â.
2. The crystalline fonn of Compound A of claim 1, further comprising a peak at 18.5° ± 0.2° 20.
3. The crystalline form of Compound A of claim 1 or 2, further comprising a peak at 21.4° ±0.2° 20.
4. The crystalline fonn of Compound A of any one of daims 1 -3, further comprising a peak at 3.1° ± 0.2° 20.
5 (E5) compressing the second blend from step (E4) into one or more tablets.

75. The method of claim 74, wherein the form of Compound A in step (El) is the amorphous fonn of Compound A.

76. The method of claim 74 or 75, wherein, in step (El), Compound A îs blended with at ieast one filler, at least one disintegrant, and at least one glidant.

10

77. The method of claim 76, wherein, in step (El), Compound A is blended with two

Allers, one disintegrant, and one glidant.

78. The method of claim 76, wherein, în step (El), Compound A is blended with two fillers, one disintegrant, one glidant, and one lubricant.

79. The method of any one of claims 74-78, wherein at least one pharmaceutically 15 acceptable excipient of step (E2) îs alubricant.

80. The method of any one of claims 74-79, wherein the at least one pharmaceutically acceptable excipient of step (E4) comprises at least onelubricant.

81. The method of any one of claims 74-80, wherein at least one glidant, at least one disintegrant, and at least one lubricant are added to the plurality of granules in step (E4).

20

82. Anorai dosage form of any one of claims 50-73 for use in a method of treating cancer in a subject.

83. Use of Compound A of any one of claims 22-46 in the préparation of an oral dosage fonn of any one of claims 50-73 for treating cancer în a subject.

84. The oral dosage form for use of claim 82 or the use of claim 83, wherein the 25 cancer is prostate cancer.

85. The oral dosage form for use or the useof claim 84, wherein the prostate cancer is metastatic castration résistant prostate cancer.

219

86. The oral dosage form for use or the useof any one of daims 82-85, wherein the one or more tablets areadministered to the subject once a day, twice a day, three times a day, or four times a day.

87. The oral dosage form for use or the useof any one of daims 82-86, wherein the 5 one or more tabletsare administered to the subject ail at once or subdîvtded in two, three, four, or more sub-portions.

88. The oral dosage fonn for use or the useof any one of daims 82-87, wherein the subject is in a fed state.

89. The oral dosage form for use or the useof any one of daims 82-88, wherein the 10 subject is in a l'asted state.

90. The oral dosage form for use or the useof any one of daims 82-89, wherein the subject is also taking or being administered an antacid médication.

91. The oral dosage form for use or the useof any one of daims 82-80, further comprising administering an additional anti-cancer agent.

5 comprising less than about 1% of Impurity 2:

Impurity 2.

32. The ultrapure fonn of Compound A of claim 31, comprising less than about 0,5% of Impurity 2.

10

33. An ultrapure fonn of Compound A having a purity greater than about 95%, and comprising less than about 1 % of Impurity 3:

Impurity 3.

34. The ultrapure fonn of Compound A of claim 33, comprising less than about 0.5%

15 of impurity 3.

213

35. An ultrapure form of Compound A having a purity greater than about 95%, and comprising less than about l % of Impurity 4:

Impurity 4.

36. The ultrapure form of Compound A of claim 35, comprising less than about 0.5% of Impurity 4.

37. The ultrapure form of Compound A of any one of claims 22-36, wherein the purity of Compound A is determined by HPLC.

38. The ultrapure form of Compound A of any one of claims 23-37, wherein the amount ofthe Intermediate or Impurity is determined by HPLC.

39. The ultrapure form of Compound A of any one of claims 22-38, wherein the purity of Compound A is greater than about 99%, about 99.5%, or about 99.9%.

40. The ultrapure form of Compound A of any one of claims 22-38, wherein the purity of Compound A is greater than about 99.5%.

41. An ultrapure form of Compound A having a purity greater than about 98%, and comprising less than about l% of at least two of the following impurities: Intermediate 2, Intermediate 3, Intermediate 5, Impurity l, Impurity 2, Impurity 3, and Impurity 4.

42. The ultrapure form of Compound A of claim 41, wherein the purity of Compound A is greater than about 99%.

43. The ultrapure form of Compound A of any one of claims22-38, comprising less than about 0.9%, about 0.8%, about 0.7%, about 0.6%, or about 0.5% of at least two of the following impurities: Intermediate 2, Intermediate 3, Intermediate 5, Impurity l, Impurity 2, Impurity 3, and Impurity 4.

44. The ultrapure form of Compound A of any one of claims 22-38, wherein the Compound A has a purity of about 99.9%.

214

45. The ultrapure form of Compound A of any one of claims 22-44, wherein Compound A is in amorphous fonn.

46. The ultrapurefonn of Compound A of any one of claims 22-45, further characterized by a Dv(50) particle size of about 5to about 20 μηι.

47. A process for manufacturing the amorphous form of Compound A of any one of claims 22-46, wherein the process comprises the foilowing steps:

(Dl) dissolving crystalline Compound A in solvent to afford a solution of Compound A;

(D2) introducing the Compound A solution from step (l) into a spray dryer;

(D3) spraying the Compound A solution from the spray dryer to form the amorphous form of the Compound A;and (D4) Removing the residual solvent from the amorphous form of Compound A.

48. The process of claim 47, wherein, the solvent of step (D l ) is a mixture of dichloromethane and methanol.

49. The process of claim 48, wherein the solvent of step (D 1 )is a mixture of about 95:5 (w/w) toabout 80:20 (w/w) dichloromethane:methanol.

50. An oral dosage form comprisingone or more pharmaceutically acceptable excipients and Compound A of any one of claims 22-46, wherein the oral dosage form is selected from the group consisting of a tablet, a sachet, or a capsule.

51. The oral dosage fonn of claim 50, wherein the Compound A is the ultrapure fonn of Compound A of any one of claims 22-46.

52. The oral dosage form of claim 50 or 5 ], wherein the oral dosage fonn is a tablet.

53. The tablet of claim 52, wherein the amount of Compound A in the tablet is betweenabout 5 mg and 1000 mg.

54. The tablet of claim 53, wherein the amount of Compound A in the tablet is about 35 mg to about 280 mg.

55. The tablet of claim 54, wherein the amount of Compound A in the tablet isabout

35 mg.

215

56. The tablet of claim 54, wherein the amount of Compound A in the tablet isabout

70 mg .

57. The tablet of claim 54, wherein the amount of Compound A in the tablet isabout 105 mg.

58. The tablet of claim 54, wherein the amount of Compound A in the tablet isabout 140 mg.

59. The tablet of claim 54, wherein the amount of Compound A in the tablet is about I75mg.

60. The tablet of claim 54, wherein the amount of Compound A in the tablet is about 2l0mg.

61. The tablet of claim 54, wherein the amount of Compound A in the tablet is about 245 mg.

62. The tablet of claim 54, wherein the amount of Compound A în the tablet is about 280 mg.

63. The tablet of any one of claims 52-62, wherein the pharmaceutically acceptable excipients are selected from the group consistîng of fîllers, disîntegrants, glidants, and lubricants.

64. The tablet of claim 63, wherein the fïller is microcrystalline cellulose, silicifted microcrystalline cellulose, lactose monohydrate,mannitol. sorbitol, xyiîtol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, pullulan, fast-dissolving carbohydrates such as Pharmaburst™, or any mixture thereof.

65. The tablet of claim 63, wherein the disintegrant is sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, chîtosan, agar, alginic acid, calcium alginate, methyl cellulose, microcrystalline cellulose, powdered cellulose, lower alkylsubstituted hydroxypropyl cellulose, hydroxylpropyl starch, low-substituted hydroxypropylcellulose, polacrilîn potassium, starch, pregelatinized starch, sodium alginate, magnésium aluminum silicate, polacrilîn potassium, povidone, or any mixture thereof.

216

66. The tablet of claim 63, wherein the glidant is Silicon dioxide, colloïdal Silicon dioxide, calcium silicate, magnésium silicate, magnésium trisilîcate, taie, starch, or any mixture thereof.

67. The tablet of claim 63, wherein the lubricant is magnésium stéarate, calcium 5 stéarate, glyceryl monostearate, glyceryl behenate, glyceryl palmitostearate, hexagonal boron nitride, hydrogenated vegetable oil, light minerai oil, minerai oil, polyethylene glycol, poloxamer, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, zinc stéarate, or any mixture thereof.

68. The tablet of any one of claims 52-62, comprising:

5 comprising less than about 1% of impuritylntermediate 3:

26. The ultrapure form of Compound A of claim 25, comprising less than about 0.5% of impurity Intermediate 3.

27. An ultrapure form of Compound A having a purity greater than about 98%, and

5 by recrystallization in an organic solvent.

20. The process of any one of claims 11-19, wherein the purified form of Compound

A has a crystalline form with a powder x-ray diffraction pattern comprising peaks at 7.6° ± 0.2° 20, 11.5° ± 0.2° 2Θ, and 17.6° ± 0.2° 20, wherein said powder x-ray diffraction pattern is obtained using Cu Ka radiation al an x-ray wavelength of 1.5406 Â.

10

21. A compound which is:

5 fomiylpiperidin-l-yi)pyridazine-3-carboxamide (Intermediate 3) with 2-(2,6dioxopiperidin-3-yI)-5-fluoro-6-(piperazin-l-yl)isoÎndoline-l,3-dione hydrochloride (Intermediate 5) and a reducing agent to provide Compound A:

Intermediate 5

Compound A

5. A crystalline form of Compound A having apowder x-ray diffraction pattern as shown in FIG. 3A.
6-chloro-N-((lr,4r)-4-(3-chioro-4-cyanophenoxy)cyclohexyl)pyridazine-3carboxamide,

Intermediate 4

22. An ultrapure form of Compound A having a purity greater than about 98%.

15

23. An ultrapure form of Compound A having a purity greater than about 98%, and comprising less than about 1% of impurity Intermediate 2:

24. The ultrapure form of Compound A of claim 23, comprising less than about 0.5% of impurity Intermediate 2.

25. An ultrapure form of Compound A having a purity greater than about 98%, and

6. A crystalline fonn of Compound A having a powder x-ray diffraction pattern comprising peaks at 11.0° ± 0.2° 20, 16.1° ± 0.2° 20, and 17.9° ± 0.2° 20, wherein said powder x-ray diffraction pattern îs obtained using Cu Ka radiation at an x-ray wavelength of 1,5406 Â.
7. The crystalline form of Compound A of daim 6, further comprising a peak at 11.3° ±0.2° 20.
8. The crystalline form of Compound A of daim 6 or 7, further comprising a peak at 17.2° ± 0.2° 20.
9. The crystalline fonn of Compound A of any one of daims 6-8, further comprising a peak at 7.9° ± 0.2° 20.

208
10 About 1 to about 50% w/w of Compound A;

About 35 to about 60% w/w microcrystalline cellulose;

About 15 to about 50% w/w lactose monohydrate;

About 1 to about 5% w/w croscarmellose sodium;

Oto about 1 % w/w Silicon dioxide; and

15 0 to about 1 % w/w magnésium stéarate.

69. The tablet of any one of claims 52-62, comprising:

About 5 % w/w of Compound A;

About 45.5 % w/w microcrystalline cellulose;

About 45.5 % w/w lactose monohydrate;

20 About 3 % w/w croscarmellose sodium;

About 0.5 % w/w Silicon dioxide; and

About 0.5 % w/w magnésium stéarate.

70. The tablet of any one of claims 52-62, comprising an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises

25 About 10 to about 40% w/w of Compound A;

About 35 to about 60% w/w microcrystalline cellulose;

About 15 to about 30% w/w lactose monohydrate;

About 1 to about 10% w/w croscarmellose sodium;

0 to about 1 % w/w Silicon dioxide; and

217

0 to about 0.5% w/w magnésium stéarate;

and wherein the extra-granular portion comprises

About 1 to about 5% w/w croscarmellose sodium;

0 to about 1 % w/w magnésium stéarate; and

0 to about 2 % w/w Silicon dioxide.

71. The tablet of any one of claims 52-62, comprising an intra-granular portion and an extra-granular portion, wherein the intra-granular portion comprises:

About 20% w/w of Compound A;

About 48.7% w/w microcrystalline cellulose;

About 24.3% w/w lactose monohydrate;

About 3% w/w croscarmellose sodium;

About 0.5 % w/w Silicon dioxide; and

About 0.25% w/w magnésium stéarate;

and wherein the extra-granular portion comprises:

About 2% w/w croscarmellose sodium;

About 0.5% w/w magnésium stéarate; and

About 0.25 % w/w Silicon dioxide.

72. The tablet of any one of claims 52-71, wherein the Compound A îs an ultrapure form of Compound A.

73. The tablet of any one of claims 52-71, wherein the Compound A is prepared according to the process of any one of claims 47-49.

74. A method of manufacturing the tablet of any one of claims 52-71 comprising the following steps:

(El) blending a fonn of Compound A with at least one pharmaceutically acceptable excipient to croate a powder;

(E2) delumpingthe powder from step (El), adding at least one phannaceutically acceptable excipient, and blending to croate a first blend;

218 (E3) granulating the blend from step (E2) and passing the résultant powder through a screen to produce a plurality of granules;

(E4) adding at least one pharmaceutically acceptable excipient to plurality of granules from step (E3) and blending to produce a second blend; and

10 comprising less than about 1% of impurity Intermediate 5:

O

Intermediate 5

28. The ultrapure fonn of Compound A of claim 27, comprising less than about 0.5% of impurity Intermediate 5.

29. An ultrapure form of Compound A having a purity greater than about 98%, and

15 comprising less than about 1 % of Impurity 1 :

Impurity 1

30. The ultrapure form of Compound A of claim 29, comprising less than about 0.5% of Impurity 1.

31. An ultrapure form of Compound A having a purity greater than about 95%, and

10 Compound A.

10. A crystalline form of Compound A having a powder x-ray diffraction pattern as shown in FIG. 3C.
11. A process for manufacturing Compound A, wherein the process comprises the reductive amination of N-(( 1 r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-
12. The process of claim 11, further comprising a step for the purification of
13. The process of claim 12, wherein the purification of Compound A comprises: (Al) dissolving Compound A in about a mixture of dichloromethane and methanol;

(A2) filtering the solution comprising Compound A;

15 (A3) distillatively exchanging the solvent of the solution comprising Compound

A with éthanol;

(A4) crystallizing Compound A from the éthanol solution; and

209 (A5) drying the purified crystalline solid form of Compound A.
14. The process of any one of claims 11-13, further comprising the oxîdation of N(( Ir,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyt)-6-(4-(hydroxymethyl)piperidin-lyl)pyridazine-3-carboxamide (Intermedîate 2) to form N-(( 1 r,4r)-4-(3-chloro-4cyanophenoxy)cyclohexyl)-6-(4-formylpiperidin-l-yl)pyridazine-3-carboxamide (Intermediate 3):

15. The process of claim 14further comprising the step of purifytng Intermediate 3 by recrystallization.

16. The process of any one of claims 11-15, further comprising a nucleophilic aromatic substitution reaction of 6-chloro-N-(( lr,4r)-4-(3-chloro-4- cyanophenoxy)cyclohexyl)pyridazine-3-carboxamide (Intermediate 4) and piperidin-4yl methanol in the presence of a base to provide N-((lr,4r)-4-(3-chloro-4cyanophenoxy)cyclohexyl)-6-(4-(hydroxymethyl)piperidin-l-yl)pyridazine-3carboxamtde (Intermediate 2):

17. The process of claim 16, further comprising the step of purifyîng Intermediate 2 by recrystallization in an organic solvent.

18. The process of any one of claims 11-17, further comprising an amide coupling of 4-((( lr,4r)-4-aminocyclohexyl)oxy)-2-chlorobenzomtrile hydrochloride (Intermediate 7) and 6-(4-(hydroxymethyl)piperidin-l-yl)pyridazine-3-carboxylic acid (Intermediate 10), facilîtated by a coupling agent, to provide N-((lr,4r)~4-(3-chloro-4-

210 cyanophenoxy)cyclohexyl)-6-(4-(hydiOxyniethyl)piperidin-l-yl)pyridazine-3carboxamide (Intermediate 2):

Intermediate 7

Intermediate 2

19. The process of claim 18, further comprising the step of purifying Intermediate 2
15 92. The oral dosage form for use or the useof claim 91, wherein the additional anticancer agent is a PARP inhibitor.