WO2023230236A1 - Process for preparing jak inhibitors and intermediates thereof - Google Patents

Abstract

The present disclosure relates generally to compounds which are useful as intermediates for the preparation of Janus kinase (JAK) inhibitors, and to processes for preparing the JAK inhibitors and intermediate compounds.

Description

PROCESS FOR PREPARING JAK INHIBITORSAND INTERMEDIATES THEREOF

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. §119(e) of United States Provisional Application No. 63/346,108, filed May 26, 2022, which is hereby incorporated by reference in its entirety.

FIELD

[0002] The disclosure is directed to compounds which are useful as intermediates for the preparation of Janus kinase (JAK) inhibitors, and to processes for preparing the JAK inhibitors and intermediate compounds.

BACKGROUND

[0003] The JAK family comprises four members, JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). Binding of cytokine to a JAK-dependent cytokine receptor induces receptor dimerization which results in phosphorylation of tyrosine residues on the JAK kinase, effecting JAK activation. Phosphorylated JAKs, in turn, bind and phosphorylate various STAT proteins, which dimerize, internalize in the cell nucleus, and directly modulate gene transcription, leading, among other effects, to the downstream effects associated with inflammatory disease. The JAKs usually associate with cytokine receptors in pairs as homodimers or heterodimers. Each of the four members of the JAK family is implicated in the signaling of at least one of the cytokines associated with inflammation. Consequently, a chemical inhibitor with pan-activity against all members of the JAK family could modulate a broad range of pro-inflammatory pathways that contribute to inflammatory diseases, such as severe asthma, COPD, Chronic Lung Allograft Dysfunction (CLAD), and/or Irritable Bowel Disease (IBD). It would, therefore, be desirable to have an efficient process for preparing specific JAK inhibitors.

SUMMARY

[0004] The present disclosure, in one embodiment, provides processes for preparing Compound I, or a pharmaceutically acceptable salt or solvate thereof, and intermediates for the preparation of Compound I (used interchangeably with Compound of Formula I or Formula I), or a pharmaceutically acceptable salt or solvate thereof. Compound I has the following chemical structure:

[0005] In some embodiments, provided is a process for preparing a compound of Formula X-1:

or a salt thereof, wherein Bn is benzyl (-CH₂-C₆H₅); as described herein. [0006] In some embodiments, provided is a crystalline form of compound X-1 dihydrochloride salt of formula:

wherein Bn is -CH₂-C₆H₅. [0007] In some embodiments, provided is a compound of Formula X-2:

or a salt thereof, wherein Bn is -CH₂-C₆H₅. [0008] In some embodiments, provided is a compound of Formula X-5: or a salt thereof, wherein Bn is -CH

[0009] In some embodiments, provided is a compound of Formula X-6: or a salt thereof, wherein Bn is -CH₂-C₆

[0010] In some embodiments, provided is a compound of Formula X-8:

or a salt thereof, wherein Bn is -CH2-C6H5. [0011] In some embodiments, provided is a crystalline form of compound X-11 .

- or a salt thereof, wherein Bn is -CH₂-C₆H₅. [0012] FIG.1A shows an X-ray powder diffractogram of crystalline compound X-12HCl salt. [0013] FIG.1B shows a thermogravimetric analysis for crystalline compound X-12HCl salt. [0014] FIG.2A shows an X-ray powder diffractogram of crystalline compound X-2. [0015] FIG.2B shows a thermogravimetric analysis for crystalline compound X-2. [0016] FIG.3A shows an X-ray powder diffractogram of crystalline compound X-5. [0017] FIG.3B shows a thermogravimetric analysis for crystalline compound X-5. [0018] FIG.4A shows an X-ray powder diffractogram of crystalline compound X-6. [0019] FIG.4B shows a thermogravimetric analysis for crystalline compound X-6. [0020] FIG.5A shows an X-ray powder diffractogram of crystalline compound X-8, 2.5X pTSA salt. [0021] FIG.5B shows a thermogravimetric analysis for crystalline compound X-8, 2.5X pTSA salt. [0022] FIG.6A shows an X-ray powder diffractogram of crystalline compound X-11. [0023] FIG.6B shows a thermogravimetric analysis for crystalline compound X-11. DETAILED DESCRIPTION [0024] The synthetic methods described herein allow for synthesis of Compound I in fewer steps and with improved purity. Previous protocols for the synthesis of Compound I led to telescoping of unwanted regioisomers such as compounds Z-1, Z-2, Z-5, and/or Z-8. The methods described herein comprise the use of a single regioisomer of benzyl histidine, compound X-10, thereby reducing or eliminating unwanted regioisomers in subsequent steps, and improving atom economy and yield. Further, the methods described herein minimize the use of column chromatography, which renders the methods more amenable to manufacturing scale up. The present methods provide improved yields and purity while also reducing the overall cost of the process of synthesis of Compound I. In some embodiments, the methods described herein reduce the occurrence of impurities such as Z-3, Z-4, Z-6, Z-7, Z-9, Z-10, Z-11, and/or Z-12. [0025] The following description sets forth exemplary embodiments of the present technology. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments. [0026] As used in the present specification, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise. [0027] A dash (“-”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -C(O)NH₂ is attached through the carbon atom. A dash at the front or end

of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line drawn through a line in a structure indicates a point of attachment of a group. Unless chemically or structurally required, no directionality is indicated or implied by the order in which a chemical group is written or named. [0028] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” includes the indicated amount ± 10%. In other embodiments, the term “about” includes the indicated amount ± 5%. In certain other embodiments, the term “about” includes the indicated amount ± 1%. Also, the term “about X” includes description of “X”. Also, the singular forms “a” and “the” include plural references unless the context clearly dictates otherwise. Thus, e.g., reference to "the compound" includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art. [0029] Some of the compounds exist as tautomers. Tautomers are in equilibrium with one another. For example, amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown, and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise all possible tautomers, e.g., amide containing compounds are understood to comprise both amide and imidic acid tautomers. Thus, the amide containing compounds are understood to include their imidic acid tautomers. Likewise, the imidic acid containing compounds are understood to include their amide tautomers. [0030] Any formula or structure given herein, is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to ²H (deuterium, D), ³H (tritium), ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸F, ³¹P, ³²P, ³⁵S, ³⁶Cl and ¹²⁵I. Various isotopically labeled compounds of the present disclosure include, for example, those into which radioactive isotopes, such as ³H and ¹⁴C, are incorporated. Such isotopically labelled compounds may be useful, for example, in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients. [0031] The disclosure also includes “deuterated analogs” of Compound I and intermediates thereof in which from 1 to n hydrogens attached to a carbon atom is/are replaced by deuterium, in which n is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of Compound I when administered to a mammal, particularly a human. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci.5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium. [0032] Deuterium labelled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, reduced dosage requirements and/or an improvement in therapeutic index. An ¹⁸F labeled compound may be useful for PET or SPECT studies. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in the compound of Formula I and intermediates thereof. [0033] The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen”, the position is understood to have hydrogen at specifically designated as a deuterium (D) is meant to represent deuterium. [0034] In many cases, the compounds of this disclosure are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. [0035] Provided are also pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein. “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use. [0036] “Salts” of compounds or intermediates include, for instance, salts with inorganic acids and salts with an organic acid. Similarly, base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines (i.e., NH2(alkyl)), dialkyl amines (i.e., HN(alkyl)2), trialkyl amines (i.e., N(alkyl)3), substituted alkyl amines (i.e., NH2(substituted alkyl)), di(substituted alkyl) amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl) amines (i.e., N(substituted alkyl)3), alkenyl amines (i.e., NH2(alkenyl)), dialkenyl amines (i.e., HN(alkenyl)2), trialkenyl amines (i.e., N(alkenyl)3), substituted alkenyl amines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl) amines (i.e., HN(substituted alkenyl)2), tri(substituted alkenyl) amines (i.e., N(substituted alkenyl)3, mono-, di- or tri- cycloalkyl amines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di- or tri- arylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixed amines, etc. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like. [0037] The term “pharmaceutically acceptable salt” of Compound I refers to salts that retain the biological effectiveness and properties of the given compound, and which are not biologically or for example, salts with inorganic acids and salts with an organic acid. In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like. Likewise, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines (i.e., NH2(alkyl)), dialkyl amines (i.e., HN(alkyl)2), trialkyl amines (i.e., N(alkyl)3), substituted alkyl amines (i.e., NH2(substituted alkyl)), di(substituted alkyl) amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl) amines (i.e., N(substituted alkyl)3), alkenyl amines (i.e., NH2(alkenyl)), dialkenyl amines (i.e., HN(alkenyl)2), trialkenyl amines (i.e., N(alkenyl)3), substituted alkenyl amines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl) amines (i.e., HN(substituted alkenyl)2), tri(substituted alkenyl) amines (i.e., N(substituted alkenyl)3, mono-, di- or tri- cycloalkyl amines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di- or tri- arylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixed amines, etc. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like. [0038] The prefix “Cu-v” indicates that the following group has from u to v carbon atoms. For example, “C1-6 alkyl” indicates that the alkyl group has from 1 to 6 carbon atoms. [0039] “Alkyl” refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C_1-20 alkyl), 1 to 8 carbon atoms (i.e., C_1-8 alkyl), 1 to 6 carbon atoms (i.e., C_1-6 alkyl), or 1 to 4 carbon atoms (i.e., C_1-4 alkyl). Examples of alkyl groups include methyl, ethyl, hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by chemical name or identified by molecular formula, all positional isomers having that number of carbons may be encompassed; thus, for example, “butyl” includes n-butyl (i.e. -(CH₂)₃CH₃), sec-butyl (i.e. -CH(CH₃)CH₂CH₃), isobutyl (i.e. -CH₂CH(CH₃)₂) and tert-butyl (i.e. -C(CH₃)₃); and “propyl” includes n-propyl (i.e. -(CH₂)₂CH₃) and isopropyl (i.e. -CH(CH₃)₂). [0040] “Alkenyl” refers to an alkyl group containing at least one carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., C_2-20 alkenyl), 2 to 8 carbon atoms (i.e., C_2-8 alkenyl), 2 to 6 carbon atoms (i.e., C_2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C_2-4 alkenyl). Examples of alkenyl groups include ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl). [0041] “Amino” refers to the group -NR^yR^z wherein R^y and R^z are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, or heteroaryl; each of which may be optionally substituted. [0042] “Aryl” refers to an aromatic carbocyclic group having a single ring (e.g. monocyclic) or multiple rings (e.g. bicyclic or tricyclic) including fused systems. As used herein, aryl has 6 to 20 ring carbon atoms (i.e., C6-20 aryl), 6 to 12 carbon ring atoms (i.e., C6-12 aryl), or 6 to 10 carbon ring atoms (i.e., C6-10 aryl). Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. Aryl, however, does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused with a heteroaryl, the resulting ring system is heteroaryl. If one or more aryl groups are fused with a heterocyclyl, the resulting ring system is heterocyclyl. [0043] “Cycloalkyl” refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings including fused, bridged, and spiro ring systems. The term “cycloalkyl” includes cycloalkenyl groups (i.e. the cyclic group having at least one double bond). As used herein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-6 cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. [0044] “Heteroaryl” refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl includes 1 to 20 ring carbon atoms (i.e., C1-20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C_3-12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C_3-8 heteroaryl); and 1 to 5 heteroatoms, 1 selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Examples of the fused-heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, where the heteroaryl can be bound via either ring of the fused system. Any aromatic ring, having a single or multiple fused rings, containing at least one heteroatom, is considered a heteroaryl regardless of the attachment to the remainder of the molecule (i.e., through any one of the fused rings). Heteroaryl does not encompass or overlap with aryl as defined above. [0045] A “solvate” is formed by the interaction of a solvent and a compound. Solvates of salts of the compounds described herein are also provided. Suitable solvates are pharmaceutically acceptable solvates, such as hydrates, including monohydrates and hemi-hydrates. Accordingly, hydrates of the compounds described herein are also provided. [0046] In some embodiments, when used to describe chemical reactions as described herein, the term “reacting ... to provide” refers to “under conditions sufficient to” or “under reaction conditions sufficient to.” The term “under conditions sufficient to” or “under reaction conditions sufficient to” is intended to refer to the reaction conditions under which the desired chemical reaction may proceed. Examples of reaction conditions include, but are not limited to, one or more of following: reaction temperature, solvent, pH, pressure, reaction time, mole ratio of reactants, mole ratio of reagents, the presence of a base or acid, catalyst, radiation, concentration, etc. Reaction conditions may be named after the particular chemical reaction in which the conditions are employed, such as, coupling conditions, hydrogenation conditions, acylation conditions, reduction conditions, halogenation conditions etc. Reaction conditions for most reactions are generally known to those skilled in the art or may be readily obtained from the literature. Exemplary reaction conditions sufficient for performing the chemical transformations provided herein may be found throughout the present disclosure, and in particular, the examples below. It is also contemplated that the reaction conditions may include reagents in addition to those listed in the specific reaction. [0047] The term “reaction conditions” is intended to refer to the physical and/or environmental conditions under which a chemical reaction proceeds. [0048] As used herein, a “catalyst” refers to an agent that increases the rate of a chemical reaction. Non-limiting examples of a catalyst are as described herein. in conjunction therewith. [0050] The term “reducing agent” refers to an element or compound that loses an electron to an a reactant in a redox reaction. Reducing agents increase the electron density on carbon centers, either by bond formation between the carbon and a less electronegative atom, or by bond breaking between the carbon and a more electronegative atom. Reducing agents usually accomplish this change in electron density by the addition of hydrogen, or the substitution of hydrogen for an electronegative atom on the carbon center. [0051] “Crystalline form”, “polymorph”, “Form”, and “form” may be used interchangeably herein, and are meant to include all crystalline forms of a compound, including, for example, polymorphs, pseudopolymorphs, salts, solvates, hydrates, unsolvated polymorphs (including anhydrates), and conformational polymorphs of the compounds, as well as mixtures thereof, unless a particular crystalline form is referred to. Compounds of the present disclosure include crystalline forms of those compounds, including, for example, polymorphs, pseudopolymorphs, salts, solvates, hydrates, unsolvated polymorphs (including anhydrates), and conformational polymorphs of the compounds, as well as mixtures thereof. [0052] The term “substantially” when referring, for example, to an X-ray diffraction pattern or a TGA trace includes a pattern or trace that is not necessarily identical to those depicted herein, but that falls within the limits of experimental error or deviations when considered by one of ordinary skill in the art. List of Abbreviations and Acronyms Abbreviation Meaning %a/a Percent area over area °C Degree Celsius ACN Acetonitrile aq. Aqueous BBA Bis Boric Acid Bn Benzyl CDI 1,1’-Carbonyldiimidazole DCM Dichloromethane DIPEA Diisopopylethyl acetate DMA N, N dimethylacetamide DMF N, N-dimethylformamide EtOH Ethanol fwd forward g Grams iPAc or IPAc or Isopropyl acetate iPrOAc IPA Isopropyl alcohol Hrs or h Hours M Molar MeOH methanol mg Milligram MHz Megahertz ml/mL Milliliter mM Millimolar mmol Millimole nL Nanoliter nm Nanometer Org. or org Organic Ph Phenyl pTSA or p-TSA Para toluene sulfonic acid Pd(AmPhos)₂Cl₂ Bis(Di-Tert-Butyl(4- Dimethylaminophenyl)Phosphine)Dichloropalladium STAB Sodium TriAcetoxy Borohydride TEA Triethyl amine TFA Trifluoroacetic acid THF Tetrahydrofuran μL/ μl Microliter μM Micromolar V Volume(s) Methods [0053] Compound I, named (S)-(3-(dimethylamino)azetidin-1-yl)(2-(6-(2-ethyl-4-hydroxyphenyl)-1H- indazol-3-yl)-5-isopropyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-6-yl)methanone, has the structure shown below. Compound I is described in commonly owned U.S. Patent No.10,947,229. Compound I crystal hydrate is described in commonly owned U.S. Publication No.2021/0269437. Compound I. [0054] Provided her

ein is a process for preparing a compound of Formula X-1:

or a salt thereof, wherein Bn is -CH₂-C₆H₅; comprising: (a) reacting a compound of Formula X-2: or a salt thereof, with a compound

wherein R¹ and R² are each ind lkyl, or R¹ and R², together with the atoms

to which they are attached, form a 5- or 6-membered ring optionally substituted with 1, 2, 3, or 4 C1-3 alkyl; to provide the compound of Formula X-1; and (b) optionally forming a salt of compound of Formula X-1. [0055] As used herein, a “compound of Formula” may also be referred to herein as a “compound” of that formula number. For example, “compound of Formula X-1” may also refer to “compound X-1,” “compound of Formula X-2” may also refer to “compound X-2,” etc. [0056] In some embodiments, a compound of Formula X-3 is compound X-3-a:

[0057] In some embodiments of the process, step (a) provides less than 3% of a compound of Formula Z-4:

. , epared having less than 1% of the compound of Formula Z-1 as an impurity: [0059] In some embodime ed having less than 1% of the

compound of Formula Z-2 as an impurity: [0060] In some embodiments o

s than 1% of a compound of Formula Z-3 and less than 1% of a compound of Formula Z-3 or Z-4:

[0061] In some embodiments, step (a) provides a composition comprising less than 1% of a compound of Formula Z-3, less than 3% of a compound of Formula Z-4, and less than 0.5% of a compound of Formula Z-5:

[0062] In some embodiments, step (a) provides a composition comprising compound X-1, wherein the composition is at least 95% pure. In some embodiments, step (a) provides a composition comprising compound X-1, wherein the composition is at least 96% pure. In some embodiments, step (a) provides a composition comprising compound X-1, wherein the composition is at least 97% pure. [0063] In some embodiments described herein, the amount of impurities present in a composition (i.e. the purity of a product) can be measured according to methods known in the art, such as identifying the impurity present by HPLC and calculating the amount of such impurity based on measured HPLC area. [0064] In some embodiments of the process, the salt of compound X-1 is a dihydrochloride salt. [0065] In some embodiments of the process, the dihydrochloride salt of compound X-1 is formed by extracting a free base form of compound X-1 into isopropyl acetate (iPAc), conducting a solvent swap to obtain the free base form of compound X-1 in isopropyl alcohol (IPA), and adding an excess of HCl in dioxane. In some embodiments, extracting the free base form and conducting a solvent swap may be carried out according to methods as described herein. [0066] In some embodiments, step (a) is conducted in the presence of a catalyst, wherein the catalyst in step (a) is Pd(AmPhos)₂Cl₂. In some embodiments, the catalyst is present in an amount of about 3 to 5 mole percent, based on moles of compound X-1. from K₂CO₃ or Cs₂CO₃. [0068] In some embodiments, the proces further comprises compound X-1, or a salt thereof, being debenzylated (i.e. removal of the Bn groups) to provide the compound of Formula X-4

or a salt thereof. [0069] In some embodiments, the debenzylation conditions (i.e. the reaction conditions for preparing compound X-4 by removing the Bn groups of compound X-1) comprise Pd/C, H₂, and HCl. In some embodiments, the salt of compound X-4 obtained is a dihydrochloride salt. In some embodiments, the salt of compound X-4 is a trihydrochloride salt. In some embodiments, the salt of compound of Formula X-4 is a dihydrochloride salt or trihydrochloride salt. [0070] In some embodiments, the compound of Formula X-2, or a salt thereof, is prepared by reacting a compound of Formula X-5: with hydrazine to provide the comp

[0071] In some embodiments, the hydrazine is hydrazine hydrate. In some embodiments, the hydrazine is a solution of hydrazine in THF. solvent, wherein the solvent is dioxane, and wherein the reaction is conducted in an inert atmosphere. Inert atmospheres may be achieved according to methods known in the art. [0073] In some embodiments of the process, the compound of Formula X-5 comprises less than 1% of the compound of Formula Z-5: [0074] In some embodiments of paring compound X-2) provides less

than 1% of the compound of Formula Z-6:

[0075] In some embodiments, the process (of preparing compound X-2) provides a composition comprising compound X-2, wherein the composition is at least 97% pure. In some embodiments, the process (of preparing compound X-2) provides a composition comprising compound X-2, wherein the composition is at least 98% pure. [0076] In some embodiments of the process, the compound of Formula X-5, or a salt thereof, is prepared by reacting a compound of Formula X-6: or a salt thereof, with a compound of Fo

u a - : to provide the compound of Formula X-5.

[0077] In some embodiments of the process, the reaction of compound X-6 with compound X-7 is quenched with water. [0078] In some embodiments of the process, the compound of Formula X-6, or a salt thereof, is prepared by reacting a compound of Formula X-8:

or a salt thereof, with acetone in the presence of an acid and a reducing agent to provide the compound of Formula X-6. [0079] In some embodiments of the process, the compound of Formula X-8 is a 2.5 p-toluene sulfonic acid (2.5xpTSA) salt of compound of Formula X-8. [0080] In some embodiments, the reaction of compound X-8 with acetone is conducted in the presence of trifluoroacetic acid (TFA) and sodium tricetoxyborohydride (STAB). In some embodiments, the reaction is stirred at room temperature. In some embodiments, the reaction is stirred at temperatures ranging from about 20 °C to about 40 °C. [0081] In some embodiments of the process, the reaction of compound X-8 with acetone gives rise to less than 5% of a compound of Formula Z-7 (i.e. in a composition comprising a compound X-6):

. than 1% of the compound of Formula Z-8 as an impurity: [0083] Provided herein is a process fo nd of Formula I,:

or a pharmaceutically acceptable salt or solvate thereof, comprising: (a) reacting a compound of Formula X-8:

or a salt thereof, wherein Bn is -CH₂-C₆H₅; with acetone in the presence of an acid and a reducing agent to provide a compound of Formula X-6: or a salt thereof;

(b) reacting compound X-6, or a salt thereof, with a compound of Formula X-7: to provide a compound of Formula X-5:

or a salt thereof;

(c) reacting compound X-5, or a salt thereof, with hydrazine to provide a compound of Formula X-2: or a salt thereof,

(d) reacting compound X-2, or a salt thereof, with a compound of Formula X-3: wherein R¹ and R² are each ind

yl, or R¹ and R², together with the atoms to which they are attached, form a 5- or 6-membered ring optionally substituted with 1, 2, 3, or 4 C1- 3 alkyl; to provide a compound of Formula X-1:

or a salt thereof; (e) debenzylating compound X-1, or a salt thereof, to provide a compound of Formula X-4:

or a salt thereof; (f) reacting compound X-4, or a salt thereof, with a compound of Formula X-9:

or a salt thereof, to provide the compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof. [0084] In some embodiments, a process for preparing Compound I further comprises recrystallizing compound I from methanol, and exposing compound I to ambient humidity, to provide compound I hydrate of formula:

.

[0085] Conversion of Compound I to Compound I hydrate may be achieved according to methods known in the art. [0086] Provided herein is a composition comprising Compound I: or a pharmaceutically acce

n 3% by weight of any of the following compounds: -4;

0 ;

[0087] In some embodiments, provided herein is a composition comprising Compound I, or a pharmaceutically acceptable salt or solvate thereof, having at least 96% purity (e.g. less than 4% of any of the following compounds: Z-3, Z-4, Z-6, Z-7, Z-9, Z-10, Z-11, or a combination thereof are present). In some embodiments, provided herein is a composition comprising Compound I, or a pharmaceutically acceptable salt or solvate thereof, having at least 97% purity (e.g. less than 3% of any of the following compounds: Z-3, Z-4, Z-6, Z-7, Z-9, Z-10, Z-11, or a combination thereof are present). In some embodiments, provided herein is a composition comprising Compound I, or a pharmaceutically acceptable salt or solvate thereof, having at least 98% purity (e.g. less than 2% of any of the following compounds: Z-3, Z-4, Z-6, Z-7, Z-9, Z-10, Z-11, or a combination thereof are present). [0088] Provided herein is Compound I prepared by any process described herein. [0089] Provided herein is Compound I hydrate prepared by any process described herein. [0090] Provided herein is a crystalline form of a dihydrochloride salt of compound X-1:

characterized by a powder X-ray diffraction pattern (XRPD) comprising diffraction peaks at 2θ values of 10.70 ±0.2, 11.03 ±0.2, 13.39 ±0.2, and 16.08 ±0.2, as determined on a diffractometer using Cu-Ka radiation at a wavelength of 1.5406 Å. [0091] In some embodiments, the XRPD of the dihydrochloride salt of compound X-1 further comprises diffraction peaks at 2θ values of 7.29 ±0.2, 9.64 ±0.2, 14.41 ±0.2, 17.20 ±0.2, and 18.18 ±0.2. [0092] In some embodiments, the crystalline form of the dihydrochloride salt of compound X-1 is characterized by a powder X-ray diffraction pattern substantially as shown in Figure 1A. [0093] In some embodiments, the crystalline form of the dihydrochloride salt of compound X-1 is characterized by a thermogravimetric analysis trace substantially as shown in Figure 1B. [0094] Table 1 shows observed XRPD 2θ peak positions and d-spacings for a crystalline form of a dihydrochloride salt of compound X-1 (crystalline compound X-1 • 2HCl). Table 1 2 θ d(Å) Height % Area Area %

[0095] Provided herein is compound of Formula X-2: or a salt thereof, wherein Bn is -C

[0096] Provided herein is a crystalline form of a free base of compound X-2, characterized by a powder X-ray diffraction pattern comprising diffraction peaks at 2θ values of 5.57 ±0.2, 12.68 ±0.2, 13.37 ±0.2, and 14.14 ±0.2, as determined on a diffractometer using Cu-Ka radiation at a wavelength of 1.5406 Å. [0097] In some embodiments, the XRPD of the crystalline form of the free base of compound X-2 further comprises diffraction peaks at 2θ values of 7.38 ±0.2, 8.07 ±0.2, 9.81 ±0.2, 10.15 ±0.2, and 12.31 ±0.2. [0098] In some embodiments, the crystalline form of the free base of compound X-2 is characterized by a powder X-ray diffraction pattern substantially as shown in Figure 2A. [0099] In some embodiments, the crystalline form of the free base of compound X-2 is characterized by a thermogravimetric analysis trace substantially as shown in Figure 2B. [0100] Table 2 shows observed XRPD 2θ peak positions and d-spacings for a crystalline form of a free base of compound X-2. Table 2 2 θ d(Å) Height % Area Area %

9.38 9.01 1.0 0.2 1.3

[0101] Provided herein is a compound of Formula X-5: or a salt thereof, wherein Bn is -CH

[0102] Provided herein is a crystalline form of a free base of the compound X-5, characterized by a powder X-ray diffraction pattern comprising diffraction peaks at 2θ values of 10.95 ±0.2, 18.92 ±0.2, and 20.20 ±0.2, as determined on a diffractometer using Cu-Ka radiation at a wavelength of 1.5406 Å. [0103] In some embodiments, the XRPD of the crystalline form of the free base of the compound X-5 further comprises diffraction peaks at 2θ values of 9.29 ±0.2, and 16.45 ±0.2. [0104] In some embodiments, the crystalline form of the free base of the compound X-5 is characterized by a powder X-ray diffraction pattern substantially as shown in Figure 3A. [0105] In some embodiments, the crystalline form of the free base of the compound X-5 is characterized by a thermogravimetric analysis trace substantially as shown in Figure 3B. free base of the compound X-5. Table 3 2 θ d(Å) Height % Area Area % 548 1541 122 24 105

[0107] Provided herein is a compound of Formula X-6

[0108] In some embodimetns, the crystalline form of a free base of compound X-6 is characterized by a powder X-ray diffraction pattern comprising diffraction peaks at 2θ values of 7.50 ±0.2, 13.45 ±0.2, and 15.00 ±0.2, as determined on a diffractometer using Cu-Ka radiation at a wavelength of 1.5406 Å. [0109] In some embodimetns, the XRPD of the crystalline form of the free base of compound X-6 further comprises diffraction peaks at 2θ values of 6.73 ±0.2, 10.44 ±0.2, and 20.01 ±0.2. [0110] In some embodimetns, the crystalline form of the free base of compound X-6 is characterized by a powder X-ray diffraction pattern substantially as shown in Figure 4A. [0111] In some embodimetns, the crystalline form of the free base of compound X-6 is characterized by a thermogravimetric analysis trace substantially as shown in Figure 4B. [0112] Table 4 shows observed XRPD 2θ peak positions and d-spacings for a crystalline form of the free base of compound X-6. Table 4 2 θ d(Å) Height % Area Area %

20.01 4.24 11.2 11.1 10.9

[0113] Provided herein is a compound of Formula X-8:

or a salt thereof, wherein Bn is -CH2-C6H5. [0114] In some embodiments, the salt of compound X-8 is a di-para toluene sulfonic acid salt. [0115] In some embodiments, the crystalline form of the di-para toluene sulfonic acid salt of compound X-8 is characterized by a powder X-ray diffraction pattern comprising diffraction peaks at 2θ values of 5.30 ±0.2, 10.58 ±0.2, and 15.02 ±088, as determined on a diffractometer using Cu-Ka radiation at a wavelength of 1.5406 Å. In some embodiments, the XRPD of the crystalline form of the di-para toluene sulfonic acid salt of compound X-8 further comprises diffraction peaks at 2θ values of 18.55 ±0.2, and 21.22 ±0.2. [0116] In some embodiments, the crystalline form of the di-para toluene sulfonic acid salt of compound X-8 is characterized by a powder X-ray diffraction pattern substantially as shown in Figure 5A. In some embodiments, the crystalline form of the di-para toluene sulfonic acid salt of compound X-8 is characterized by a thermogravimetric analysis trace substantially as shown in Figure 5B. [0117] Table 5 shows observed XRPD 2θ peak positions and d-spacings for a crystalline form of a di- para toluene sulfonic acid salt of compound X-8 (compound X-8 • 2.5 pTSA). 2 θ d(Å) Height % Area Area % 2.67 31.61 0.2 1.7 0.2

[0118] Provided herein is a crystalline form of compound X-11: .

- or a salt thereof, wherein Bn is -CH₂-C₆H₅; ±0.2, 9.52 ±0.2, 14.53 ±0.2, and 16.33 ±0.2, as determined on a diffractometer using Cu-Ka radiation at a wavelength of 1.5406 Å. [0119] In some embodiments, the XRPD of the crystalline form of compound X-11 further comprises diffraction peaks at 2θ values of 17.92 ±0.2, and 18.37 ±0.2. [0120] In some embodiments, the crystalline form of compound X-11 is characterized by a powder X- ray diffraction pattern substantially as shown in Figure 6A. [0121] In some embodiments, the crystalline form of compound X-11 is characterized by a thermogravimetric analysis trace substantially as shown in Figure 6B. Synthesis of the Compounds [0122] The compounds may be prepared using the methods disclosed herein and routine modifications. Typical embodiments of the processes described herein are shown in the general reaction schemes described below. It will be apparent given the description herein that the general schemes may be altered by substitution of the starting materials and/or other reagents known to one of skill in the art. Starting materials are typically obtained from commercial sources or synthesized using published methods. In general, compounds described herein are typically stable and isolatable at room temperature and pressure. If available, reagents may be purchased commercially, e.g., from Sigma Aldrich or other chemical suppliers. Scheme 1

[0123] Referring to Scheme 1, compound X-10 (wherein, in Scheme 1, R is H) is prepared using published literature procedures as described in, e.g., Tetrahedron, Vol.52, No.15, pp.5363-5370, 1996.

[0124] Referring to Scheme 2, compound X-10 is prepared using published protocols. Cyclization of compound X-10 to compound X-11 is achieved in the presence of a base (e.g., DIPEA). Other suitable of crystalline X-11, as described in Example 1. In some embodiments, the reaction is conducted in methanol. Other suitable solvents and anti-solvents are contemplated within the scope of this disclosure. The reaction is conducted at temperatures ranging from about room temperature to about reflux temperature of the solvent. In some embodiments, the reaction is conducted at temperatures ranging from about 60 °C to about 80 °C. In some embodiments, the pH of the reaction mixture is adjusted to about 10 by use of, e.g., ammonium hydroxide, and a mixture of water and acetone is used as an anti-solvent during the work up of the reaction, thereby inducing crystal formation and/or purification of the product X-11. [0125] Esterification of compound X-11 is achieved in the presence of an acid and a solvent such as dichloromethane, chloroform or other suitable solvents. It was found that the use of pTSA allows for superior yields and addition of iPrOAc as an antisolvent allows for filtration of the product X-8 as shown in Example 2. The reaction is conducted in the presence of an excess of pTSA and at a temperature ranging from about room temperature to about the reflux temperature of the solvent. [0126] The reductive amination step where Compound X-8 is converted to compound X-6 is conducted in the presence of a hydride source (e.g., a borohydride such as STAB) and an acid (e.g., trifluoroacetic acid) as shown in Example 3. Other suitable hydride sources may be used such as sodium hydride, sodium borohydride, or lithium aluminum hydride. It is believed that the acid such as TFA acts as an acid to facilitate imine formation, and also as a cosolvent to help all reactants stay in solution. The reaction is conducted at a temperature ranging from about room temperature to about 40 °C. In some embodiments, the reaction is conducted at about 20 °C or at about room temperature. The reaction is stirred for a period ranging from about 2 hours to about 24 hours. It was found that the stirring the reaction for a longer duration reduces the occurrence of compound Z-7: -7.

[0127] The conversion of compound X-6 to compound X-5 by reaction with compound X-7 is achieved in the presence of a base such as triethylamine. Other suitable bases such as methylamine, ethylene diamine, or diisorpropyl ethyl amine may be used. Any solvent including and not limited to DCM, ACN, or THF may be used. It was found that when a solution of X-5 was added to solution of X-7, as shown in is stirred at a temperature ranging from about room temperature to about 40 °C. In some embodiments, the reaction is conducted at about 20 °C or at about room temperature. A water quench converts X-7 to its corresponding acid which can be extracted using aqueous base. A water quench also reduced occurrence of compound Z-10 when ethylene diamine was used as the base. It was found that a solvent swap to IPA allowed for crystallization of the product X-5. -10 [0128]

Cyc zat on o compoun -5 to - can e con ucte n t e presence o y raz ne, or hydrazine hydrate, and a suitable solvent such as dioxane, THF, acetonitrile, and the like. It was found that an inert atmosphere reduced the occurrence of compounds Z-6 and Z-11. The reaction is stirred at a temperature ranging from about room temperature to about the reflux temperature of the solvent. In some embodiments, the reaction is stirred at a temperature ranging from about 50 °C to about 80 °C, or from about 60 °C to about 70 °C. Use of water as an antisolvent allowed for crystallization of compound X-2 as shown in Example 5. -11

[0129] Compound X-2 is converted to compound X-1 via a metal-mediated coupling reaction with compound X-3-a. Suitable palladium catalysts include bis(di-tert-butyl(4- dimethylaminophenyl)phosphine)dichloropalladium(II), tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3), palladium (II) acetate (Pd(OAc)2), dichloro(1,1’-bis(diphenylphosphino)- ferrocene)dipalladium(II) (Pd(dppf)Cl2), dichloro bis(triphenylphosphine)-palladium(II) (Pd(PPh3)2Cl2), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (PdAm(Phos)2Cl2), and the like, where the common abbreviations are given in parentheses. Phosphine ligands useful in the reaction bis(diphenylphosphino)-ferrocene (dppf), 1,1'-bis(di-tert-butylphosphino)ferrocene, tri(2-furyl)phosphine, 1,3-bis(diphenylphosphino)propane (dppp), 1,5-bis(diphenylphosphino)pentane (dpppe), tri-tert- butylphosphine (P(t-Bu)₃), Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine (AmPhos), and 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (Xantphos). An additional catalyst may be used. The additional catalyst may be a diboron reagent. The additional catalyst may be tetrahydroxydiboron (Bis Boric Acid (BBA)), a diboronic ester or the product of the reaction of bis(pinacolato)diboron with potassium fluoride hydrofluoride. [0130] Typical bases for the coupling reaction include potassium fluoride, cesium carbonate, and cesium fluoride. Alternatively, sodium carbonate, potassium carbonate, sodium phosphate, potassium phosphate, sodium acetate, potassium tert-butoxide, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or 1,4- diazabicyclo[2.2.2]octane (DABCO) can be used for the base. The reaction is typically conducted in an inert diluent, such as tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, or N- methylpyrrolidone. Suitable mixed solvent systems include tetrahydrofuran and water, tetrahydrofuran and N,N-dimethylformamide, tetrahydrofuran and N-methylpyrrolidone, acetone and water, ethanol and water, and isopropanol and water. The reaction is conducted at reflux temperatures or lower. The reaction is conducted at temperatures ranging from about 50 °C to about 100 °C. It was found that reaction temperatures of about 85 °C to about 95 °C, or about 88 °C to about 90 °C, reduced the occurrence of compounds Z-3 and Z-4. A solvent swap allowed for crystallization of compound X-1, as shown in Example 6. -4;

[0131] The hydrogenolysis of the benzyl ester in compound X-1 to obtain compound X-4 is achieved via a debenzylation reaction, as described in U.S. Publication No.2021/0269437. Other ester hydrolysis protocols such as acid-mediated or base-mediated hydrolysis may be used. and any suitable solvent (e.g., DMF, DMA), may be used for the amide coupling, including the use of HATU as described in U.S. Publication No.2021/0269437. Suitable amide coupling reagents include and are not limited to dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), ethyl-(N’,N’- dimethylamino)propylcarbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBt), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1- yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), (7aAzabenzotriazol-1- yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), Bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl), O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HBTU), O-(benzotriazol-1- yl)- N,N,N’,N’-tetramethyluronium tetrafluoroborate (TBTU), N,N,N’,N’-tetramethyluronium tetrafluoroborate (TATU), and O-(6-chlorobenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HCTU). [0133] Compound I is converted to Compound I hydrate according to the procedure described in U.S. Publication No.2021/0269437. EXAMPLES [0134] The X-ray powder diffraction data was obtained with a Bruker D8-Advance X-ray diffractometer using Cu-Kα radiation (λ = 1.5406 Å) with output voltage of 45 kV and current of 40 mA. The instrument was operated in Bragg-Brentano geometry with incident, divergence, and scattering slits set to maximize the intensity at the sample. For measurement, a small amount of powder (5-25 mg) was gently pressed onto a sample holder to form a smooth surface and subjected to X-ray exposure. The samples were scanned in 2θ-2θ mode from 2° to 35° in 2θ with a step size of 0.02° and a scan speed of 0.30°seconds per step. The data acquisition was controlled by Bruker DiffracSuite measurement software and analyzed by Jade software (version 7.7). The instrument was calibrated with a corundum standard, within ±0.02° two-theta angle. [0135] Thermogravimetric analysis (TGA) measurements were performed using a TA Instruments Model Q-50 module equipped with high resolution capability. Data were collected using TA Instruments Thermal Analyst controller and analyzed using TA Instruments Universal Analysis software. A weighed temperature to 360 °C. The balance and furnace chambers were purged with nitrogen flow during use. [0136] The following examples are included to demonstrate specific embodiments of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques to function well in the practice of the disclosure, and thus can be considered to constitute specific modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure. [0137] Reagents and solvents were purchased from commercial suppliers (Aldrich, Strem Chemicals, Inc., etc.), and used without further purification. Progress of reaction mixtures was monitored by analytical high performance liquid chromatography and mass spectrometry. Reaction mixtures were worked up as described specifically in each reaction, for instance, purified by extraction and other purification methods, such as temperature- and solvent-dependent crystallization, and precipitation. Characterization of reaction products was routinely carried out by mass and ¹H-NMR spectrometry. EXAMPLE 1 Preparation of (S)-3-benzyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-6- carboxylic acid (X-11)

[0138] Compound X-10 was prepared using an adaptation of a literature procedure described in Tetrahedron, Vol.52, No.15, pp.5363-5370, 1996. [0139] Compound X-10 (165 g, 673 mmol), paraformaldehyde (42.4 g, 1413 mmol), and MeOH (825 mL, 5V) were charged to a nitrogen-inert glass jacketed reactor (R1) equipped with overhead mixing and a condenser. DIPEA (357 mL, 0.22 V) was added to the agitated slurry. The slurry was warmed to 66 °C (internal), and stirred for 1.5 h at 66 °C, at which time all remaining solids had fully dissolved and HPLC solution was cooled to 20 °C. [0140] In a separate reactor (R2) was added acetone (3920 mL, 23.76 V), H₂O (40 mL, 0.24 V), and NH₄OH (175 mL, 1.06 V). The temperature of the reactor was adjusted to 20 °C and seeds of X-11 were added. The seed crystals of X-11 were prepared by crystallizing X-11, which may be made according to methods described herein without seeding, from a mixture of 1.0 % v/v water and acetone containing 4 equivalents of ammonium hydroxide at 5 °C. The solution from the first reactor R1 was added to the second reactor R2 while maintaining a temperature of 20 °C in the second reactor. The first reactor R1 was rinsed with minimal MeOH (248 mL, 1.5V), and the contents transferred to the second reactor R2. The slurry in the second reactor R2 was cooled to 5 °C over 2 h and held for no less than 12 h. The slurry was filtered and rinsed with cold (5-10 °C) acetone (990 mL, 6V). The cake was blown dry under nitrogen for 3 h, then dried in vacuum (>27 in Hg) at 50 °C to afford 167.442 g of compound X-11 (97 % yield, 99.66% HPLC purity). EXAMPLE 2 Preparation of benzyl (S)-3-benzyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-6-carboxylate (X-8); pTSA salt

[0141] X-11 (160 g, 553 mmol), pTSA•H₂O (337 g, 1771 mmol), and benzyl alcohol (573 mL, 5535 mmol) and CHCl3 (183 mL, 7.4V) were charged to a nitrogen-inert glass jacketed reactor equipped with overhead mixing and a dean-stark apparatus. The slurry was warmed to reflux (68-78 °C internal). Water was collected in the Dean-stark trap over the course of the reflux. Reflux was continued for 20 h, at which time HPLC %a/a indicated >99% conversion. The solution was cooled to about 45 °C to 50 °C and iPrOAc (2848 mL, 17.8V) was added over no less than about 1.5 h – 2 h at this temperature. The hazy solution was then cooled to 5 °C and held for no less than 3 h. The hazy solution became a slurry over the course of the cooling. The mixture was filtered and the reactor was rinsed with iPrOAc (854 mL, 5.34V). The filter cake was blown dry under nitrogen for 3 h, then dried under vacuum (>27 inHg) at 50 °C to afford X-8•2.5XpTSA (394 g, 92% yield, 96.94% HPLC purity). Preparation of benzyl (S)-3-benzyl-5-isopropyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-6- carboxylate (X-6)

[0142] X-8 •2.5XpTSA (100 g, 129 mmol), 3A Mol Sieves (75 g, 0.75X), and acetone (1500 mL, 15V) were charged to a nitrogen-inert glass jacketed reactor (R1) equipped with overhead mixing. To the slurry was added TFA (29.4 g, 257 mmol) and the mixture was stirred at 20 °C for 1.5 h. STAB (54.5 g, 257 mmol) was added in two portions over 15 minutes. Mild exotherm of +5 °C after the addition of each portion of STAB was observed. The internal temperature in the reactor was <25 °C. The reaction mixture was stirred at 20 °C for no less than 1 h, at which time HPLC indicated >99.5% conversion. The mixture was further stirred at 20 °C for no less than 23 h. [0143] 5% NaHCO3 aq soln (1250 mL, 12.5V) was added to the reactor. Some off-gassing, and mild exotherm was observed (+6 °C). The mixture was stirred for no less than 2 h at 20 °C. [0144] The reaction mixture was filtered to remove sieves, and the filtrate was collected in a separate glass vessel. A coarse prefilter followed by a fine filter was used to ensure a sufficient filtration rate. The reactor and the filter cake were rinsed with acetone (250 mL, 2.5V) [0145] The reactor was cleaned, and the clear yellow filtrate was returned to the vessel. Toluene was charged to the reactor (800 mL, 8V) and the mixture was stirred for 10 minutes and settled for 10 minutes, resulting in a clean phase biphasic split (clear yellow top organic, bottom clear aqueous). The aqueous phase was drained and collected in a second reactor (R2) equipped with a mechanical agitator. iPAc (600 mL, 6V) was added, and the mixture was stirred for 10 minutes and settled for 10 minutes, resulting in a clean phase split (clear yellow top organic, bottom clear aqueous). The bottom aqueous phase was drained and discarded. The top organic phase was combined with the top organic phase in the first reactor (R1). R2 was cleaned and used in the following step. biphasic mixture was stirred for no less than 30 min and settled for no less than 1 h. The bottom aqueous phase was drained. The organic layer was concentrated to 300 mL/3V by vacuum distillation and transferred to a clean reactor (R2) through a filter to remove precipitated inorganic solids. The first reactor was charged with toluene (100 mL, 1V), followed by heptane (100 mL, 1V). This solution was used to rinse forward through the filter into the clean reactor (R2). [0147] The temperature of the reactor (R2) was adjusted to 20 °C and heptane (2500 mL, 25V) was added over no less than 1.5 h. The clear solution became hazy after ~400 mL/4V heptane added, and seeds (1 g, 0.01X) were charged to R2. The seed crystals of X-6 were prepared by crystallizing X-6, which may be made according to methods described herein without seeding, from a mixture of toluene and heptane at 20 °C. Heptane addition was continued after seed charge, generating a free-flowing white slurry. After heptane addition, the slurry was cooled to -5 °C internal temperature and held for no less than 12 h. The slurry was filtered and rinsed forward from R2 with heptane (600 mL, 6V). The filter cake was blown dry under nitrogen for 3 h before drying under vacuum (>27 inHg) at 50 °C to afford X-6 (44 g, 88% yield, 98.41% HPLC purity). EXAMPLE 4 Preparation of benzyl (S)-3-benzyl-2-(4-bromo-2-fluorobenzoyl)-5-isopropyl-4,5,6,7-tetrahydro- 3H-imidazo[4,5-c]pyridine-6-carboxylate (X-5) O O O N Bn

[0148] X-6 (100 g, 257 mmol) and DCM (400 mL, 4V) were charged to a nitrogen-inert glass jacketed reactor (R1) equipped with overhead mixing and the temperature was adjusted to 20 °C. TEA (143 mL, 1.43V) was charged to R1. X-7 (91 g, 385 mmol) and DCM (500 mL, 5V) were charged to a nitrogen- flushed glass jacketed reactor (R2) equipped with overhead mixing and the temperature was adjusted to 20 °C. of R2 at 20-25 °C (mild exotherm). R2 was rinsed forward to R1 with DCM (100 mL, 1V) through the same transfer line. The contents of R2 were stirred at 20 °C for no less than 1.5 h, whereupon HPLC indicated >99.5% conversion to product. Water (700 mL, 7.0V) was charged to R1, controlling the internal temperature at 20-25 °C. The biphasic mixture was stirred rapidly for no less than 3h, till HPLC %a/a indicated conversion of X-7 to the corresponding carboxylic acid. [0150] Agitation of the mixture was halted and phases were allowed to separate out and settle for no less than 15 minutes. The bottom organic phase was collected in a separate vessel (V1). DCM (300 mL, 3V) was charged to V1. The mixture was agitated for no less than 15 min and settled for no less than 30 min to allow phases to separate. The bottom organic phase was collected and combined with the original organic phase. The aqueous phase was drained, and the combined organics returned to V1. [0151] The contents of V1 were distilled under vacuum (-21 inHg, 45 °C jacket) to a target volume of 3V (300 mL). After the target volume was achieved, V1 was backfilled with nitrogen and IPA (1700 mL, 17V) was charged to V1. The contents of V1 were distilled under vacuum (-27.5 inHg, 55 °C jacket) to a target volume of 12.5 V (1250 mL). After the target volume was achieved, V1 was backfilled with nitrogen and the temperature of the contents was adjusted to 45 °C. [0152] Seeds (0.005X, 0.5 g) were charged and the mixture agitated at 45 °C for no less than 1 h, by which time a thick slurry had formed. The seed crystals of X-5 were prepared by crystallizing X-5 (made according to methods described herein) from a mixture of isopropyl alcohol and water at 5 °C. The slurry was cooled to 20 °C over no less than 45 min. Water (550 mL, 5.5V) was added to the slurry over no less than 2 h while maintaining the internal temperature at 20-25 °C. The slurry was cooled to 5 °C over no less than 1 h, and then held at 5 °C for no less than 12 h. The slurry was transferred to a filter, and the wet cake collected. R1 was washed forward to rinse the cake with a premixed solution of IPA (700 mL, 7V) and H2O (300 mL, 3V), which was precooled to 5 °C. The light yellow/tan colored cake was blown dry under nitrogen for 3 h before drying under vacuum (<27 inHg) at 50 °C to afford X-5 (138.3 g, 91% yield, 98.85% HPLC purity).

Preparation of benzyl (S)-3-benzyl-2-(6-bromo-1H-indazol-3-yl)-5-isopropyl-4,5,6,7-tetrahydro- 3H-imidazo[4,5-c]pyridine-6-carboxylate (X-2) [0153] X-

( g, mmo) an oxane ( m , ) were c arge to a n trogen- nert glass jacketed reactor (R1) equipped with overhead mixing and the temperature was adjusted to 20 °C. The contents of R1 were degassed 6X by vacuum/nitrogen backfill. Hydrazine•H₂O (55.5 mL, 0.41V) was added to R1, the internal temperature was adjusted to 65 °C, and the reaction was held at this temperature for 8.5 h at which time HPLC %a/a indicated >99.5% consumption of the starting material. [0154] The reaction mixture was cooled to 35-45 °C, and dioxane (8V, 1080 mL) was charged to R1. The solvent was distilled under vacuum (-29 inHg, internal temp <40 °C) until the target volume of ~5.5V was achieved (8V distillate removed). The temperature of the reaction mixture was adjusted to 45 °C, and EtOH (1080 mL, 8V) was added to R1. The temperature of the mixture was adjusted to 70 °C [0155] H₂O (945 mL, 7V) was charged over no less than 30 min. Then seeds (0.675 g, 0.005X) were added and the solution was stirred for no less than 30 minutes while a thin seed bed formed. The seed crystals of X-2 were prepared by crystallizing X-2 (made according to methods described herein) from ethanol at 5 °C. The slurry was cooled to 5 °C over no less than 6 h, and held at 5 °C for no less than 2.5 h. The slurry was filtered and rinsed forward from R1 with a premixed solution of EtOH (486 mL, 3.6V) and H₂O (324 mL, 2.4V), precooled to 5 °C. The filter cake was blown dry under nitrogen for 3 h before drying under vacuum (<27 inHg) at 60 °C to afford X-2 (124.752 g, 93% yield, 98.7% HPLC purity).

Preparation of benzyl (S)-3-benzyl-2-(6-(4-(benzyloxy)-2-ethylphenyl)-1H-indazol-3-yl)-5- isopropyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-6-carboxylate (X-1); dihydrochloride salt [015

6] X-2 (50.0 g, 86 mmol), X-3-a (43.4 g, 128 mmol), Bis-boric acid (BBA) (11.5 g, 128 mmol), and Pd(AmPhos)₂Cl₂ (3.03 g, 4.28 mmol) were added to a nitrogen-flushed glass reactor equipped with overhead mixing (R1). Dioxane (300 mL, 6V) was charged to a separate nitrogen-flushed glass reactor equipped with overhead mixing (R2) equipped with overhead mixing. The dioxane was degassed by vacuum (<50 torr) and nitrogen backfill cycles (3X). The degassed dioxane was transferred from R2 into R1 by nitrogen pressure transfer. [0157] K₂CO₃ (23.64g, 171 mmol) and H₂O (165 mL, 3.3V) were charged to R2 and mixed until homogenous. The homogenous solution was degassed by vacuum (<50 torr) and nitrogen backfill cycles (3X). The degassed base solution was transferred from R2 into R1 by nitrogen pressure transfer, forming a yellow biphasic slurry in R1. [0158] R1 was degassed by vacuum (<50 torr) and nitrogen backfill cycles (3X). The internal temperature of R1 was adjusted to 88 °C, forming a red-orange biphasic slurry, and the mixture was held at 88 °C (reflux) for no less than 20 h, at which time HPLC %a/a indicated >99% conversion of the starting material to product. [0159] The reaction mixture was cooled to 45 °C and R1 was charged with iPAc (150 mL, 3V), followed by H2O (200 mL, 4V), forming a biphasic mixture (red/orange top organic phase, bottom clear aq phase). The mixture was stirred for 10 minutes and settled for 20 minutes. The bottom aqueous phase was drained and transferred to R2. minutes. The bottom aqueous phase was drained and discarded. The top organic phase was transferred from R2 to R1. H₂O (200 mL, 4V) was charged to R1 forming a biphasic mixture (red/orange top organic phase, bottom clear aq phase). The mixture was stirred for 10 minutes and settled for 20 minutes. The bottom aqueous phase was drained and discarded. The combined organics in R1 were concentrated to 150 mL, 3V by vacuum distillation (jacket 50 °C, -27 to -30 mmHg). [0161] IPAc (Isopropyl Acetate) (500 mL, 10 V) was charged to R1. The mixture was concentrated to 150 mL, 3V by vacuum distillation (jacket 50 °C, -27 to -30 mmHg). Solvent swap was conducted, i.e., IPA (250 mL, 5V) was charged to obtain a solution, and the solution temperature warmed to 80 °C. HCl/dioxane (66.3 mL, 1.33V) was then added to R1 over 10 minutes. The homogenous solution turned from dark orange to yellow throughout the addition. IPAc (900 mL, 18V) was added to R1 dropwise over 2 h while maintaining an internal temperature of 80 C. After ~400 mL/4V of the IPAc was added, seeds (0.5 g, 0.01X) were added and a slurry began to form. The seed crystals of X-1 were prepared by crystallizing X-1 (made according to methods described herein) from a mixture of isopropyl alcohol, HCl/dioxane and isopropyl acetate at 10 °C. The slurry was held at 80 °C for 4 h after the complete addition of iPAc, then cooled to 20 °C internal temperature over 5 h and held at this temperature for no less than 20 h. [0162] The slurry was filtered and rinsed forward from R1 with a premixed solution of IPA (125 mL, 2.5V) and iPAc (375 mL, 7.5V). The filter cake was blown dry under nitrogen for 3 h before drying under vacuum (<27 inHg) at 45 °C to afford X-1 •2HCl (62.58 g, 93% yield, 97.22% HPLC purity). EXAMPLE 7 Preparation of (S)-2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl)-5-isopropyl-4,5,6,7- tetrahydro-3H-imidazo[4,5-c]pyridine-6-carboxylic acid (X-4); dihydrochloride salt

according to the procedure described in U.S. Publication No.2021/0269437. EXAMPLE 8 Preparation of (S)-(3-(dimethylamino)azetidin-1-yl)(2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol- 3-yl)-5-isopropyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-6-yl)methanone (Compound I) [01

] ompoun - y roc or e sa was conver e o ompoun accor ng o e proce ure described in U.S. Publication No.2021/0269437. EXAMPLE 9 Preparation of (S)-(3-(dimethylamino)azetidin-1-yl)(2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol- 3-yl)-5-isopropyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-6-yl)methanone (Compound I); hydrate

[0165] Compound I was converted to a hydrate according to the procedure described in U.S. Publication No.2021/0269437. * * * [0166] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising”, “including,” “containing”, etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. [0168] Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification, improvement and variation of the inventions embodied therein herein disclosed may be resorted to by those skilled in the art, and that such modifications, improvements and variations are considered to be within the scope of this invention. The materials, methods, and examples provided here are representative of preferred embodiments, are exemplary, and are not intended as limitations on the scope of the invention. [0169] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety, to the same extent as if each were incorporated by reference individually. In case of conflict, the present specification, including definitions, will control. [0170] It is to be understood that while the disclosure has been described in conjunction with the above embodiments, that the foregoing description and examples are intended to illustrate and not limit the scope of the disclosure. Other aspects, advantages and modifications within the scope of the disclosure will be apparent to those skilled in the art to which the disclosure pertains.

Claims

1. A process for preparing a compound of Formula X-1:

or a salt thereof, wherein Bn is -CH2-C6H5; comprising: (a) reacting a compound of Formula X-2: or a salt thereof, with a compound

wherein R¹ and R² are each ind

kyl, or R¹ and R², together with the atoms to which they are attached, form a 5- or 6-membered ring optionally substituted with 1, 2, 3, or 4 C₁-₃ alkyl; to provide the compound of Formula X-1; and (b) optionally forming a salt of compound of Formula X-1. 2. The process of claim 1, wherein the salt of compound of Formula X-1 is a dihydrochloride salt. of compound of Formula X-1 into isopropyl acetate (iPAc), conducting a solvent swap to obtain the free base form of compound of Formula X-1 in isopropyl alcohol (IPA), and adding an excess of HCl in dioxane. 4. The process of claim 1, wherein step (a) is conducted in the presence of a catalyst, wherein the catalyst in step (a) is Pd(AmPhos)₂Cl₂. 5. The process of claim 4, wherein the catalyst is present in an amount of about 3 to 5 mole percent, based on moles of compound of Formula X-1. 6. The process of claim 4 or 5, wherein step (a) is conducted in the presence of a base selected from K2CO3 or Cs2CO3. 7. The process of any one of claims 1 to 6, wherein compound of Formula X-1, or a salt thereof, is debenzylated to provide the compound of Formula X-4:

or a salt thereof. 8. The process of claim 7, wherein the debenzylation conditions comprise Pd/C, H2, and HCl. 9. The process of claim 7 or 8, wherein the salt of compound of Formula X-4 is a dihydrochloride salt or trihydrochloride salt. 10. The process of any one of claims 1 to 9, wherein the compound of Formula X-2, or a salt thereof, is prepared by reacting a compound of Formula X-5:

with hydrazine to provide the compound of Formula X-2. 11. The process of claim 10, wherein the hydrazine is hydrazine hydrate. 12. The process of claim 10 or 11, comprising a solvent, wherein the solvent is dioxane, and wherein the reaction is conducted in an inert atmosphere. 13. The process of any one of claims 10 to 12, wherein the compound of Formula X-5, or a salt thereof, is prepared by reacting a compound of Formula X-6:

or a salt thereof, with a compound of Formula X-7:

to provide the compound of Formula X-5. 14. The process of claim 13, wherein the reaction is quenched with water. 15. The process of any one of claims 13 to 14, wherein the compound of Formula X-6, or a salt thereof, is prepared by reacting a compound of Formula X-8: or a salt thereof, with acetone in the pres

ence of an acid and a reducing agent to provide the compound of Formula X-6. 16. The process of claim 15, wherein the compound of Formula X-8 is a 2.5 p-toluene sulfonic acid (2.5xpTSA) salt of compound of Formula X-8. 17. The process of claim 15, wherein the reaction is conducted in the presence of trifluoroacetic acid (TFA) and sodium tricetoxyborohydride (STAB). 18. The process of any one of claims 15-17, wherein the reaction is stirred at room temperature. 19. A process for preparing a compound of Formula I: or a pharmaceutically acce

(a) reacting a compound of Formula X-8:

or a salt thereof, wherein Bn is -CH2-C6H5; with acetone in the presence of an acid and a reducing agent to provide a compound of Formula X-6: or a salt thereof;

(b) reacting compound of Formula X-6, or a salt thereof, with a compound of Formula X-7:

to provide a compound of Formula X-5: or a salt thereof;

(c) reacting compound of Formula X-5, or a salt thereof, with hydrazine to provide a compound of Formula X-2: or a salt thereof,

(d) reacting compound of Formula X-2, or a salt thereof, with a compound of Formula X-3:

wherein R¹ and R² are each independently H or C1-5 alkyl, or R¹ and R², together with the atoms to which they are attached, form a 5- or 6-membered ring optionally substituted with 1, 2, 3, or 4 Ci -3 alkyl: to provide a compound of Formula X-l:

or a salt thereof;

(c) dcbcnzylating compound of Formula X-l, or a salt thereof, to provide a compound of Formula

X-4:

X-4 or a salt thereof;

(f) reacting compound of Formula X-4, or a salt thereof, with a compound of Formula X-9:

X-9 or a salt thereof, to provide the compound of Formula 1, or a pharmaceutically acceptable salt or solvate thereof:

20. The process of claim 19, further comprising recrystallizing compound of Formula I from methanol, and exposing compound of Formula I to ambient humidity, to provide compound I hydrate of formula:

.

21. A composition comprising Compound I: or a pharmaceutically acce

n 3% by weight of any of the following compounds: -4;

0 ;

22. Compound I prepared by a process according to any one of claims 19-20. 23. Compound I hydrate prepared by a process according to any one of claims 19-20. 24. A crystalline form of a dihydrochloride salt of compound X-1:

wherein Bn is -CH2-C6H5, characterized by a powder X-ray diffraction pattern comprising diffraction peaks at 2θ values of 10.70 ±0.2, 11.03 ±0.2, 13.39 ±0.2, and 16.08 ±0.2, as determined on a diffractometer using Cu-Ka radiation at a wavelength of 1.5406 Å. 25. The crystalline form of claim 24, further comprising diffraction peaks at 2θ values of 7.29 ±0.2, 9.64 ±0.2, 14.41 ±0.2, 17.20 ±0.2, and 18.18 ±0.2. substantially as shown in Figure 1A. 27. The crystalline form of claim 24, characterized by a thermogravimetric analysis trace substantially as shown in Figure 1B. 28. A compound of Formula X-2: or a salt thereof, wherein Bn is -C

29. A crystalline form of a free base of the compound of claim 28, characterized by a powder X-ray diffraction pattern comprising diffraction peaks at 2θ values of 5.57 ±0.2, 12.68 ±0.2, 13.37 ±0.2, and 14.14 ±0.2, as determined on a diffractometer using Cu-Ka radiation at a wavelength of 1.5406 Å. 30. The crystalline form of claim 29, further comprising diffraction peaks at 2θ values of 7.38 ±0.2, 8.07 ±0.2, 9.81 ±0.2, 10.15 ±0.2, and 12.31 ±0.2. 31. A crystalline form of a free base of the compound of claim 28, characterized by a powder X-ray diffraction pattern substantially as shown in Figure 2A. 32. A compound of Formula X-5: or a salt thereof, wherein Bn is -CH₂

_{6 5}. diffraction pattern comprising diffraction peaks at 2θ values of 10.95 ±0.2, 18.92 ±0.2, and 20.20 ±0.2, as determined on a diffractometer using Cu-Ka radiation at a wavelength of 1.5406 Å. 34. The crystalline form of claim 33, further comprising diffraction peaks at 2θ values of 9.29 ±0.2, and 16.45 ±0.2. 35. A crystalline form of a free base of the compound of claim 32, characterized by a powder X-ray diffraction pattern substantially as shown in Figure 3A. 36. A compound of Formula X-6: or a salt thereof, wherein Bn is -CH2-C6

37. A crystalline form of a free base of the compound of claim 36, characterized by a powder X-ray diffraction pattern comprising diffraction peaks at 2θ values of 7.50 ±0.2, 13.45 ±0.2, and 15.00 ±0.2, as determined on a diffractometer using Cu-Ka radiation at a wavelength of 1.5406 Å. 38. The crystalline form of claim 37, further comprising diffraction peaks at 2θ values of 6.73 ±0.2, 10.44 ±0.2, and 20.01 ±0.2. 39. A crystalline form of a free base of the compound of claim 36, characterized by a powder X-ray diffraction pattern substantially as shown in Figure 4A. 40. A compound of Formula X-8:

41. The compound of claim 40, wherein the salt is a di-para toluene sulfonic acid salt. 42. A crystalline form of the di-para toluene sulfonic acid salt of claim 41, characterized by a powder X-ray diffraction pattern comprising diffraction peaks at 2θ values of 5.30 ±0.2, 10.58 ±0.2, and 15.02 ±088, as determined on a diffractometer using Cu-Ka radiation at a wavelength of 1.5406 Å. 43. The crystalline form of claim 42, further comprising diffraction peaks at 2θ values of 18.55 ±0.2, and 21.22 ±0.2. 44. A crystalline form of the di-para toluene sulfonic acid salt of the compound of claim 41, characterized by a powder X-ray diffraction pattern substantially as shown in Figure 5A. 45. A crystalline form of compound X-11: .

or a salt thereof, wherein Bn is -CH₂-C₆H₅; characterized by a powder X-ray diffraction pattern comprising diffraction peaks at 2θ values of 6.06 ±0.2, 9.52 ±0.2, 14.53 ±0.2, and 16.33 ±0.2, as determined on a diffractometer using Cu-Ka radiation at a wavelength of 1.5406 Å. 46. The crystalline form of claim 45, further comprising diffraction peaks at 2θ values of 17.92 ±0.2, and 18.37 ±0.2. 47. The crystalline form of claim 45, characterized by a powder X-ray diffraction pattern substantially as shown in Figure 6A.