Methods of making a-1 antitrypsin modulators

Abstract

The present disclosure provides methods of large-scale preparation of alpha-1 antitrypsin (AAT) activity modulators useful for treating alpha-1 antitrypsin deficiency (AATD), such as 4-(5-(4-fluorophenyl)-6-(tetrahydro-2H-pyran-4-yl)-1,5-dihydropyrrolo[2,3-f]indazol-7-yl)benzoic acid (Compound 1), 3-[5-(4-fluorophenyl)-6-isopropyl-1H-pyrrolo[2,3-f]indazol-7-yl]propanoic acid (Compound 2), or any pharmaceutically acceptable salt of any of the foregoing.

Description

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 056,958, filed July 27, 2020, U.S. Provisional Application No. 63 / 079,735, filed September 17, 2020, U.S. Provisional Application No. 63 / 080,877, filed September 21, 2020, and U.S. Provisional Application No. 63 / 114,739, filed November 17, 2020, the contents of each of which are incorporated herein by reference in their entirety.

[0002] The present disclosure provides methods for preparing modulators of alpha-1-antitrypsin (AAT) activity useful in the treatment of alpha-1 antitrypsin deficiency (AATD), including 4-(5-(4-fluorophenyl)-6-(tetrahydro-2H-pyran-4-yl)-1,5-dihydropyrrolo[2,3- f]indazol-7-yl)benzoic acid (Compound 1) in solid form, e.g., Compound 1 in solid form, 3-[5-(4-fluorophenyl)-6-isopropyl-1H-pyrrolo[2,3-f]indazol-7-yl]propanoic acid (Compound 2) in solid form, e.g., Compound 2 in solid form, and any pharmaceutically acceptable salt of any of the foregoing.

[0003] AATD is a genetic disorder characterized by low circulating levels of AAT. While there are treatments for AATD, there is currently no cure. AAT is produced primarily in hepatocytes and secreted into the blood, but it is also produced by other cell types, including lung epithelial cells and certain leukocytes. AAT inhibits several serine proteases (most notably neutrophil elastase [NE], proteinase 3, and cathepsin G) secreted by inflammatory cells, thereby protecting organs such as the lung from protease-induced damage, particularly during inflammation.

[0004] The most common mutation associated with AATD includes a substitution of glutamic acid with lysine (E342K) in the SERPINA1 gene, which encodes the AAT protein. This mutation is referred to as the Z mutation or Z allele, resulting in a translated protein that misfolds and thus is not secreted into the blood and can polymerize within the cell of production. As a result, circulating AAT levels are significantly reduced in individuals homozygous for the Z allele (PiZZ); only about 15% of mutant Z-AAT protein is correctly folded and secreted by the cell. Another consequence of the Z mutation is that secreted Z-AAT has reduced activity compared to wild-type protein, exhibiting 40% to 80% of normal antiprotease activity (American Thoracic Society / European Respiratory Society, Am J Respir Crit Care Med. 2003; 168(7):818-900; and Ogushi et al. J Clin Invest. 1987; 80(5): 1366-74).

[0005] Accumulation of polymerized Z-AAT protein within hepatocytes leads to gain-of-function cytotoxicity, which can result in cirrhosis or hepatocarcinoma in 12% of patients later in life, and neonatal liver disease. This accumulation can resolve spontaneously, but is fatal for a small number of children. Deficiency of circulating AAT leads to unregulated protease activity, which over time degrades lung tissue, leading to a form of chronic obstructive pulmonary disease (COPD), emphysema. This effect is severe in PiZZ individuals and typically manifests in middle age, leading to reduced quality of life and shortened lifespan (mean: 68 years) (Tanash et al. Int J Chron Obstruct Pulm Dis. 2016; 11: 1663-9). The effect is more pronounced in smoking PiZZ individuals, leading to further shortened lifespan (58 years) (Piitulainen and Tanash, COPD 2015; 12(1): 36-41). PiZZ individuals make up the majority of patients with clinically relevant AATD lung disease. Thus, there is a need for additional effective treatments for AATD.

[0006] A milder form of AATD is associated with the SZ genotype, in which a Z allele is combined with an S allele. The S allele is associated with reduced levels of circulating AAT, but does not cause cytotoxicity in hepatocytes. The result is clinically significant lung disease, but not liver disease (Fregonese and Stolk, Orphanet J Rare Dis. 2008; 33: 16). As with the ZZ genotype, circulating AAT deficiency in SZ genotype subjects leads to unregulated protease activity, which over time degrades lung tissue, and can lead to emphysema, particularly in smokers.

[0007] For AAT-deficient individuals who have or show signs of developing significant lung or liver disease, the current standard of care is either augmentation therapy or protein replacement therapy. Augmentation therapy involves administration of a human AAT protein concentrate purified from pooled donor plasma to augment the missing AAT. While infusion of plasma proteins has been shown to improve survival or slow the rate of emphysema progression, augmentation therapy is often inadequate in challenging situations, such as during active lung infections. Similarly, while protein replacement therapy shows promise in slowing disease progression, augmentation therapy does not restore normal physiological regulation of AAT in patients, and its efficacy is difficult to prove. Furthermore, augmentation therapy requires weekly visits for treatment, and does not address liver disease driven by the toxic gain-of-function of the Z allele. Thus, there is a continuing need for new and more effective treatments for AATD.

[0008] 4-(5-(4-fluorophenyl)-6-(tetrahydro-2H-pyran-4-yl)-l,5-dihydropyrrolo[2,3- f]indazol-7-yl)benzoic acid or Compound 1 is disclosed in International Patent Application No. PCT / US2020 / 032832, published as International Patent Application Publication No. WO 2020 / 247160, which is incorporated by reference herein in its entirety, as an effective modulator of AAT activity for the treatment of AATD:

[0009]

[0010] WO 2020 / 247160 also describes methods of synthesis of Compound 1 and pharmaceutically acceptable salts thereof.

[0011] Additionally, 3-[5-(4-fluorophenyl)-6-isopropyl-lH-pyrrolo[2,3-f]indazol-7-yl]propanoic acid or Compound 2 is disclosed in International Patent Application No. PCT / US2019 / 054681, published as International Patent Application Publication No. WO 2020 / 081257, which is incorporated by reference herein in its entirety, as an effective modulator of AAT activity for the treatment of AATD:

[0012]

[0013] WO 2020 / 081257 also describes methods of synthesis of Compound 2 and pharmaceutically acceptable salts thereof.

[0014] As further research is conducted on the medical uses of Compound 1 and Compound 2, there is a need for alternative methods of synthesis of each compound that can produce large quantities of the compound or pharmaceutically acceptable salts thereof, in order to support clinical research conducted at multiple sites, each with a large number of subjects. Such large-scale methods of synthesis would also be useful if either compound is approved for the treatment of AATD and becomes publicly available.

[0015] It is a consensus in the pharmaceutical industry that large-scale production, scaling up drug production from milligram levels to kilogram levels, is not a simple linear process. Common problems encountered when scaling up drug production include the formation of new impurities, different impurity profiles, and changes in polymorphic forms. It appears that if a drug’s production cannot be successfully scaled up, then even if it has received a safe regulatory approval, the drug can never make it to market.

[0016] The present disclosure addresses unmet needs by providing a synthesis method that is capable of producing large quantities of Compound 1, or a pharmaceutically acceptable salt thereof (e.g., 100 kg and above), and that complies with current GMP (Good Manufacturing Practices) guidelines. The present disclosure also provides alternative syntheses of Compound 1, or a pharmaceutically acceptable salt thereof, in solid form, as well as alternative methods for preparing intermediates used in the synthesis of Compound 1.

[0017] Additionally, the present disclosure addresses unmet needs by providing a synthesis method that is capable of producing large quantities of Compound 2, or a pharmaceutically acceptable salt thereof (e.g., 100 kg and above), and that complies with current GMP (Good Manufacturing Practices) guidelines. The present disclosure also provides alternative syntheses of Compound 2, or a pharmaceutically acceptable salt thereof, in solid form. DETAILED DESCRIPTION

[0018] DEFINITIONS

[0019] As used herein, the term“solid form” includes any solid form of a compound, e.g., Compound 1 or Compound 2, including substantially crystalline forms, amorphous forms, solid dispersions, solvates, co-crystals, or salts of the solid form of the compound. A crystalline form is a crystal structure (or polymorph) having a specific molecular packing arrangement in the crystal lattice. Crystalline forms can be identified and distinguished from one another by one or more characterization techniques, including, for example, X-ray powder diffraction (XRPD), single crystal X-ray diffraction, solid state nuclear magnetic resonance (SSNMR), differential scanning calorimetry (DSC), dynamic vapor sorption (DVS), and / or thermogravimetric analysis (TGA). In some embodiments, a crystalline form is characterized by an X-ray powder diffraction pattern having a signal at one or more specified theta values (°2Q). An amorphous form, on the other hand, is a solid material that has no long-range order in its molecular positions. An amorphous solid is typically a supercooled liquid in which the molecules are arranged in a random fashion such that there is no definite arrangement (e.g., molecular packing) and no long-range order. For example, an amorphous material is a solid material that has no sharp feature signals in its X-ray power diffraction pattern (i.e., is not crystalline as determined by XRPD).

[0020] “Compound 1” as used throughout the present disclosure refers to 4-(5-(4- fluorophenyl)-6-(tetrahydro-2H-pyran-4-yl)-1,5-dihydropyrrolo[2,3-f]indazol-7-yl)benzoic acid, which can be depicted as having the following structure:

[0021]

[0022] Compound 1 can be in the form of a mixture of isomers or an enantiomerically enriched (e.g., >90% ee, >95% ee, >98% ee) isomer. Compound 1 can be in the form of a pharmaceutically acceptable salt.

[0023] As used throughout the present disclosure, “Compound 2” refers to 3-(5-(4- fluorophenyl)-6-isopropyl-l,5-dihydropyrrolo[2,3-f]indazol-7-yl)propanoic acid, which can be depicted as having the following structure:

[0024]

[0025] Compound 2 can be in the form of a mixture of isomers or an enantiomerically enriched (e.g., >90% ee, >95% ee, >98% ee) isomer. Compound 2 can be in the form of a pharmaceutically acceptable salt.

[0026] “Pharmaceutically acceptable salt” means any non-toxic salt that, upon

[0027] Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, and related inorganic and organic acids. Such pharmaceutically acceptable salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caprates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, tatarates, fumarates, maleates, butyne-l,4-dioates, hexyne-l,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, terephthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, beta-hydroxybutyrates, glycolates, maleates, tartrates, methanesulfonates, propanesulfonates, naphthalene- 1 -sulfonates, naphthalene-2-sulfonates, mandelates, and other salts. In some embodiments, pharmaceutically acceptable acid addition salts include salts formed with mineral acids such as hydrochloric and hydrobromic acids, and with organic acids such as maleic, benzenesulfonic, fumaric, furoic, gluconic, glucuronic, xinafoic, formic, glutamic, methanesulfonic, ethanesulfonic, benzenesulfonic, lactic, oxalic, p-bromophenylsulfonic, carbonic, succinic, citric, benzoic, and acetic acids.

[0028] Pharmaceutically acceptable salts derived from appropriate bases include, but are not limited to, alkali metal salts, alkaline earth metal salts, ammonium salts, and salts with + (C 1-4 alkyl)4 salts. The present disclosure also contemplates quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Suitable non-limiting examples of alkali and alkaline earth salts include sodium, lithium, potassium, calcium, and magnesium. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. Other suitable non-limiting examples of pharmaceutically acceptable salts include benzenesulfonic acid salts and glucuronic acid salts.

[0029] Examples of suitable solvents that can be used in the present disclosure include, but are not limited to, water, methanol (MeOH), ethanol (EtOH), 1-propanol, 2-propanol, dichloromethane (DCM) or “methylene dichloride” (CH2Cl2), dimethylacetamide (DMAc), toluene, xylene, methylcyclohexane, acetonitrile (MeCN; ACN), dimethylformamide (DMF), dimethylsulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (EtOAc), heptane, isopropyl acetate (IPAc), tert-butyl acetate (t-BuOAc), isopropyl alcohol (IPA), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-Me THF), methyl ethyl ketone (MEK), tert-butyl alcohol, diethyl ether (Et20), methyl-tert-butyl ether (MTBE), 1,4-dioxane, trifluoromethylbenzene, cyclopentyl methyl ether (CPME), prop-2-one / cyclopentane mixture, ethyl acetate / ethanol mixture, N-methylpyrrolidone (NMP) piperidine, N-formylpiperidine, 2,2,6,6-tetramethylpiperidine, pyridine, and the like. Suitable solvents for specific reaction steps in the methods provided herein are described in more detail in the non-limiting exemplary embodiments and the appended examples.

[0030] Examples of suitable bases that can be used in the present disclosure include, but are not limited to, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), potassium tert-butoxide (KOtBu), sodium tert-butoxide (NaOtBu), sodium tert-amylate (NaOt-Am), sodium carbonate (Na2CO3), potassium carbonate (K2CO3), cesium carbonate (Cs2CO3), N-methylmorpholine (NMM), triethylamine (Et3N; TEA), diisopropylethylamine (i-Pr2EtN; DIPEA), pyridine, potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), and sodium methoxide (NaOMe; NaOCH3). Suitable bases for specific reaction steps in the methods provided herein are described in more detail in the non-limiting exemplary embodiments and the appended examples.

[0031] As used herein, the term “palladium-phosphine complex-based catalyst” refers to a catalyst having one or more palladium ions coordinated by a polyphosphine (PR A 3) ligand, wherein R Ahydrogen, an organoaliphatic group, or an aryl group. The positive charge of the palladium-phosphine complex is typically neutralized by pairing the complex with an anion such as chloride, fluoride, and the like. Non-limiting examples of palladium-phosphine complex-based catalysts include 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl palladium or XPhos Pd (Gl-G4), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl palladium or tBuXPhos Pd (Gl-G4), dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[l,l'-biphenyl]-2-yl)phosphine or BrettPhos Pd (Gl-G4), 2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-l,l'- biphenyl, tBuBrettPhos Pd (Gl-G4), bis(tri-tert-butylphosphine)Pd, bis(triphenylphosphine) palladium dichloride or Pd(PPh3)2Cl2, and palladium (II) dichloride optionally complexed with Pd(dppf)Cl2or Pd(dppf)Cl2.CH2Cl2. Suitable catalysts from the above list for specific reaction steps in the processes provided herein are described in more detail in non-limiting exemplary embodiments and the appended examples.

[0032] The term "silicon-based reducing agent" as used herein refers to a species containing at least one Si-X group (e.g., X = Cl or OR B , R B is an organoaliphatic or aryl group) bond that can be reduced to Si-H and in turn is capable of providing an electron to an electron acceptor (oxidizing agent) in a redox chemical reaction, such as a silane (where the central silicon is bonded to four atoms (not all four are hydrogen) or functional groups) or a siloxane (where the -Si-O-Si- bond). Non-limiting examples of silicon-based reducing agents or silane reducing agents include triethylsilane, trichlorosilane, methyldichlorosilane, dimethylchlorosilane, triphenylsilane, tris(trimethylsilyl)silane, and dimethylsilyloxy(dimethyl)silane. Suitable silicon-based reducing agents for specific reaction steps in the processes provided herein are described in more detail in non-limiting exemplary embodiments and the appended examples.

[0033] The term "phospholane oxide catalyst" as used herein refers to a catalyst having the general formula wherein each open valence of the carbon atoms or phosphorus atom on the four-membered ring can be substituted with, for example, an organoaliphatic or aryl group or a halogen atom.

[0034] The terms“about” and“approximately,” when used in connection with a dose, amount, or weight percent of a composition or a component of a dosage form, include values or ranges of values of the specified dose, amount, or weight percent that a person of ordinary skill in the art would consider to provide an equivalent pharmacological effect as that obtained from the specified dose, amount, or weight percent. Generally, the term“about” refers to a variation of up to 10%, up to 5%, or up to 2% of a given value.

[0035] Synthetic methods for Compound 1 previously disclosed

[0036] As described above, synthetic methods for Compound 1 and pharmaceutically acceptable salts thereof are provided in International Patent Application PCT / US2020 / 032832, published as International Patent Application Publication No. WO 2020 / 247160. These methods described in WO 2020 / 247160 are described in Schemes 1A-1C below. Optional reaction steps are indicated with dashed arrows.

[0037] Scheme 1A - Part A: Synthesis of Intermediate C13

[0038]

[0039] Scheme 1B - Part B: Synthesis of Intermediate S6 or S4

[0040]

[0041] Scheme 1C - Part C: Synthesis of Compound 1

[0042]

[0043] Referring to the above Scheme 1A-1C, the synthetic process described in WO 2020 / 247160 can be divided into three parts: Part A, which starts with the starting material C1 (5-bromo-6-iodo-1H-indazole) and ends up with the intermediate C13: 5-(4-fluorophenyl)-6-(tetrahydro-2H-pyran-4-yl)-1,5-dihydropyrrolo[2,3- f]indazole; Part B, which ends up with the key intermediate with a protecting group that prevents the 1 -nitrogen atom of the tricyclic 1,5-dihydropyrrolo[2,3- f]indazole core from reacting with: S6 (5-(4-fluorophenyl)-7-iodo-1-(phenylsulfonyl)-6- (tetrahydro-2H-pyran-4-yl)-1,5-dihydropyrrolo[2,3-f]indazole) with a phenylsulfonyl protecting group or S4 (1-(5-(4-fluorophenyl)-7-iodo-6-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,3- f]indazol-1(5H)-yl)-2,2-dimethylpropan-1-one) with a pivaloyl protecting group; and Part C, which ends up with the synthesis of Compound 1 from the intermediate S6 or S4 derived from Part B, via the formation of any one of the following esters: C57 (ethyl 4-(5-(4-fluorophenyl)-1-(phenylsulfonyl)-6-(tetrahydro-2H-pyran-4-yl)-1,5- dihydropyrrolo[2,3-f]indazol-7-yl)benzoate), C58A (ethyl 4-(5-(4-fluorophenyl)-1-pivaloyl-6- (tetrahydro-2H-pyran-4-yl)-1,5-dihydropyrrolo[2,3-f]indazol-7-yl)benzoate) or C58B (methyl 4-(5-(4-fluorophenyl)-1-pivaloyl-6-(tetrahydro-2H-4-yl)-1,5-dihydropyrrolo[2,3- f]indazol-7-yl)benzoate).

[0044] Non-limiting differences and advantages between the new processes for preparing Compound 1

[0045] The present disclosure provides alternative methods of preparing Compound 1 or a pharmaceutically acceptable salt thereof in solid form, which can be distinguished from previously disclosed methods in several ways. For example, S6 or S4, each of which is 5-(4-fluorophenyl)-6-(tetrahydro-2H-pyran-4-yl)-1,5- dihydropyrrolo[2,3-f]indazole with a phenylsulfonyl or pivaloyl protecting group, is a key intermediate common to all previously disclosed methods. In contrast, the methods provided herein do not produce such intermediates with a tricyclic fused ring system with a tetrahydro-2H-pyranyl ring and a phenyl ring attached. Rather, new intermediates are formed, such as B1 described in Scheme 3 and described in the accompanying Example 1. B1 is a phenyl-indazole amine that differs from S6 and S4 not only in that it has a bicyclic indazole ring core, but also in that the fluorophenyl ring is not attached directly to the indazole core but rather through an amino group. In addition, B1 lacks a tetrahydro-2H-pyranyl ring attached to the indazole core.

[0046] Further, the methods provided herein introduce different starting materials, reagents, and catalysts than those used in the previously disclosed methods. For example, the following Example 1 uses a starting material (e.g., A1) with a pivaloyl (Piv) protecting group and with a nitro and a halogen as substituents. This is in contrast to the starting material (i.e., C1) in the previously disclosed methods, which has a halogen group as a substituent. Further, the starting material in the following Example 1 is reacted with phenylboronic acid in the presence of a siloxane (i.e., with -Si-O-Si- bonds) and a phospholane oxide catalyst (see Scheme 3B, step 1) to form B1, neither of which are used in the previously disclosed methods. B1 is then reacted with methyl 4-(2-oxo-2-(tetrahydro-2H-pyran-4-yl)ethyl)benzoate or another new type of reagent D1 to form C58B.

[0047] Importantly, the methods provided herein enable the synthesis of Compound 1 using a reduced number of steps. Specifically, while the aforementioned methods comprise up to 7 reaction steps (as shown in Schemes 1A-1C), the methods of the present disclosure, such as Example 1, comprise at most 4 reaction steps. Further, the methods of the present disclosure enable the production of about 100 kg and above of Compound 1 or a pharmaceutically acceptable salt thereof in solid form.

[0048] A key advantage of bypassing one or more reaction steps is that such a method, especially when preparing compounds on a large scale, will be significantly more cost-, time-, and energy-efficient. As noted above, medical uses of Compound 1 are being investigated. As Compound 1 progresses to higher phase clinical studies, with larger populations of subjects, and when the drug is approved and accessible to the public, the advantages of a cost-, time-, and energy-efficient method of synthesizing Compound 1 will be even more apparent.

[0049] Alternative methods for preparing Compound 1 or a pharmaceutically acceptable salt thereof in solid form are described in more detail below in the following non-limiting exemplary embodiments and also in Example 1, appended hereto.

[0050] Non-limiting exemplary embodiments (Compound 1 methods)

[0051] 1. A method for preparing Compound 1 in solid form

[0052]

[0053] or a pharmaceutically acceptable salt thereof, comprising:

[0054] (a) reacting or a pharmaceutically acceptable salt thereof, with to form or a pharmaceutically acceptable salt thereof; and

[0055] (b) de-esterifying C58B or a pharmaceutically acceptable salt thereof to obtain Compound 1 or a pharmaceutically acceptable salt thereof in solid form.

[0056] 2. The method of embodiment 1, wherein step (a) comprises reacting B1 or a pharmaceutically acceptable salt thereof with D1 in the presence of a palladium-phosphine complex-based catalyst, a base, and a solvent selected from tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, toluene, dimethylformamide, acetonitrile, propionitrile, and combinations thereof.

[0057] 3. The method of embodiment 1 or embodiment 2, wherein the solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, acetonitrile, and combinations thereof (e.g., selected from tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, and combinations thereof).

[0058] 4. The method of embodiment 2 or embodiment 3, wherein the palladium-phosphine complex-based catalyst is selected from XPhos Pd, tBuXPhos Pd, BrettPhos Pd, tBuBrettPhos Pd, bis(tri-tert-butylphosphine)Pd, diamantylalkylphosphine Pd, 2-(di-tert-butylphosphino)-1-(2-methoxyphenyl)-1H- pyrrole Pd, and bis(triphenylphosphine)palladium dichloride.

[0059] 5. The method of any one of embodiments 2-4, wherein the palladium-phosphine complex-based catalyst is selected from XPhos Pd, tBuXPhos Pd, BrettPhos Pd, tBuBrettPhos Pd, bis(tri-tert-butylphosphine)Pd, and bis(triphenylphosphine)palladium dichloride.

[0060] 6. The method of any one of embodiments 2-4, wherein the palladium-phosphine complex-based catalyst is selected from XPhos Pd, BrettPhos Pd, diamantylalkyl phosphine Pd, and 2-(di-tert-butylphosphino)-l-(2-methoxyphenyl)-lH-pyrrole Pd.

[0061] 7. The method of any one of embodiments 2-5, wherein the palladium-phosphine complex-based catalyst is bis(tri-tert-butylphosphine) Pd.

[0062] 8. The method of any one of embodiments 2-7, wherein the base is selected from potassium dihydrogen phosphate, tri-potassium phosphate (e.g., anhydrous tri-potassium phosphate and potassium phosphate monohydrate), di-potassium hydrogen phosphate, cesium carbonate, sodium carbonate, potassium carbonate, and combinations thereof.

[0063] 9. The method of any one of embodiments 2-8, wherein the base is selected from potassium dihydrogen phosphate, di-potassium hydrogen phosphate, cesium carbonate, potassium carbonate, and combinations thereof.

[0064] 10. The method of any one of embodiments 2-8, wherein the base is selected from sodium carbonate, potassium carbonate, and combinations thereof.

[0065] 11. The method of any one of embodiments 2-10, wherein the base is potassium carbonate.

[0066] 12. The method of any one of embodiments 2-11, wherein the solvent is 2-methyltetrahydrofuran.

[0067] 13. The method of any one of embodiments 2-11, wherein the solvent is tetrahydrofuran.

[0068] 14. The method of any one of embodiments 1-13, wherein step (a) comprises reacting B1, or a pharmaceutically acceptable salt thereof, with D1 at about 35-100 °C (e.g., about 50-80 °C).

[0069] 15. The method of any one of embodiments 1-14, wherein step (a) comprises reacting B1, or a pharmaceutically acceptable salt thereof, with D1 at about 70-80 °C (e.g., 75 °C).

[0070] 16. The method of any one of embodiments 1-14, wherein step (a) comprises reacting B1, or a pharmaceutically acceptable salt thereof, with D1 at about 50-55 °C.

[0071] 17. The method of any one of embodiments 1 to 16, wherein step (b) comprises de- esterifying C58B, or a pharmaceutically acceptable salt thereof, with a base selected from lithium hydroxide, potassium hydroxide, sodium hydroxide, and combinations thereof.

[0072] 18. The method of embodiment 17, wherein the base is sodium hydroxide.

[0073] 19. The method of any one of embodiments 1 to 18, wherein step (b) comprises de- esterifying C58B, or a pharmaceutically acceptable salt thereof, in the presence of a solvent selected from 2-methyltetrahydrofuran, methanol, ethanol, isopropanol, and combinations thereof.

[0074] 20. The method of embodiment 19, wherein the solvent is tetrahydrofuran.

[0075] 21. The method of embodiment 19 or embodiment 20, wherein step (b) comprises de- esterifying C58B, or a pharmaceutically acceptable salt thereof, at about 55-65 °C.

[0076] 22. The method of any one of embodiments 1 to 21, wherein the method further comprises at least one additional step selected from:

[0077] (a1) reacting A0, or a pharmaceutically acceptable salt thereof, with pivaloyl chloride to form or a pharmaceutically acceptable salt thereof; and

[0078] (a2) reacting A1, or a pharmaceutically acceptable salt thereof, with 4- fluorophenylboronic acid to form B1, or a pharmaceutically acceptable salt thereof.

[0079] 23. The method of embodiment 22, wherein step (a1) comprises reacting A0, or a pharmaceutically acceptable salt thereof, with pivaloyl chloride in the presence of a base and a solvent selected from tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, and combinations thereof.

[0080] 24. The method of embodiment 23, wherein the solvent is tetrahydrofuran.

[0081] 25. The method of embodiment 23 or embodiment 24, wherein the base is selected from sodium tert-butoxide, potassium tert-butoxide, sodium tert-amylate, and combinations thereof (e.g., sodium tert-amylate).

[0082] 26. The method of embodiment 25, wherein the base is potassium tert-butoxide.

[0083] 27. The method of any one of embodiments 22 to 26, wherein step (al) comprises reacting AO, or a pharmaceutically acceptable salt thereof, with pivaloyl chloride at about -10 °C to 20 °C (e.g., about 10 °C - 20 °C).

[0084] 28. The method of any one of embodiments 22 to 27, wherein step (a2) comprises reacting Al, or a pharmaceutically acceptable salt thereof, with 4-fluorophenylboronic acid in the presence of a catalyst, a reducing agent, and a solvent selected from toluene, isopropyl alcohol, xylene, methylcyclohexane, cyclopentyl methyl ether, methyl tert-butyl ether, isopropyl acetate, tetrahydrofuran, an aqueous solution comprising sodium carbonate and / or potassium carbonate (e.g., an aqueous sodium chloride solution comprising sodium carbonate and / or potassium carbonate), and combinations thereof (e.g., an isopropyl alcohol / toluene mixture).

[0085] 29. The method of embodiment 28, wherein the catalyst is selected from hexamethyloxophospholane, (Mo02Cl2)DMF2 with PPh3 or silane, 4-methyl-l-phenyl-2,3- dihydrophospholene 1 -oxide 4, (2R,5R)-l-{2-[(2R,5R)-2,5-diethylphospholanyl]phenyl}-2,5- diethyl-l-phospholane-l-one, and l-non(gadamant-l-yloxyphospho)adamantane.

[0086] 30. The method of embodiment 28 or 29, wherein the catalyst is a phospholane oxide catalyst.

[0087] 31. The method of any one of embodiments 28 to 30, wherein the solvent is selected from toluene, cyclopentyl methyl ether, isopropyl acetate, tetrahydrofuran, and combinations thereof.

[0088] 32. The method of any one of embodiments 22 to 27, wherein step (a2) comprises reacting Al, or a pharmaceutically acceptable salt thereof, with 4-fluorophenylboronic acid in the presence of a phospholane oxide catalyst, a reducing agent, and a solvent selected from toluene, xylene, methylcyclohexane, and combinations thereof.

[0089] 33. The method of embodiment 30 or embodiment 32, wherein the phospholane oxide catalyst is hexamethyloxophospholane.

[0090] 34. The method of embodiment 32 or embodiment 33, wherein the reducing agent is selected from triethylsilane, trichlorosilane, polymethylsilane, methyldichlorosilane, dimethylchlorosilane, phenylsilane, triphenylphosphine, triphenylphosphine oxide, tris(trimethylsilyl)silane, dimethylsilyloxy(dimethyl)silane, and combinations thereof.

[0091] 35. The process of any one of embodiments 32-34, wherein the reducing agent is selected from polymethylsilane, phenylsilane, triphenylphosphine, triphenylphosphine oxide, dimethylsiloxy(dimethyl)silane, and combinations thereof.

[0092] 36. The process of embodiment 32 or embodiment 33, wherein the reducing agent is a silicon-based reducing agent selected from triethylsilane, trichlorosilane, methyldichlorosilane, dimethylchlorosilane, triphenylsilane, tris(trimethylsilyl)silane, dimethylsiloxy(dimethyl)silane, and combinations thereof.

[0093] 37. The process of embodiment 36, wherein the reducing agent is dimethylsiloxy(dimethyl)silane.

[0094] 38. The process of any one of embodiments 32-37, wherein the solvent is toluene.

[0095] 39. The process of any one of embodiments 32-38, wherein step (a2) comprises reacting A1, or a pharmaceutically acceptable salt thereof, with 4-fluorophenylboronic acid at about 85-105 °C (e.g., about 90 °C, about 100 °C).

[0096] 40. The process of any one of embodiments 32-39, wherein step (a2) comprises reacting A1, or a pharmaceutically acceptable salt thereof, with 4-fluorophenylboronic acid at about 85-95 °C (e.g., about 90 °C).

[0097] 41. The process of any one of embodiments 1-40, further comprising:

[0098] (c) converting the solid form of Compound 1, or a pharmaceutically acceptable salt thereof, to Compound 1 Form A.

[0099] 42. The process of embodiment 41, wherein step (C) comprises aging a slurry comprising the solid form of Compound 1, or a pharmaceutically acceptable salt thereof, at about 20-25 °C.

[0100] 43. The process of embodiment 41 or 42, wherein the solid form of Compound 1, or a pharmaceutically acceptable salt thereof, is a THF solvate of Compound 1.

[0101] 44. The process of any one of embodiments 1-43, wherein the process further comprises at least one additional step selected from:

[0102] (b1) reacting with oxan-4-carbonyl chloride to form

[0103] (b2) reacting E1 with an aqueous solution to form D1.

[0104] 45. The method of embodiment 44, wherein the aqueous solution comprises a chloride (e.g., sodium chloride, lithium chloride).

[0105] 46. The method of embodiment 44 or embodiment 45, wherein the aqueous solution is an aqueous sodium chloride solution.

[0106] 47. The method of any one of embodiments 44-46, wherein step (b2) comprises reacting E1 with the aqueous solution at about 100-200 °C (e.g., about 200 °C).

[0107] 48. The method of embodiment 46 or embodiment 47, wherein step (b2) comprises reacting E1 with an aqueous sodium chloride solution at about 120-180 °C (e.g., about 150 °C).

[0108] 49. The method of any one of embodiments 44-47, wherein step (b2) comprises reacting E1 with an aqueous solution (e.g., water) in the presence of tetrahydrofuran.

[0109] 50. The method of any one of embodiments 44-49, wherein step (b2) comprises reacting E1 with a chloride-containing aqueous solution (e.g., an aqueous sodium chloride solution, an aqueous lithium chloride solution) in the presence of a solvent selected from dimethylsulfoxide, ethyl acetate / ethanol mixture, 2-methyltetrahydrofuran, dimethylacetamide, and combinations thereof.

[0110] 51. The method of embodiment 50, wherein step (b2) comprises reacting E1 with an aqueous sodium chloride solution in the presence of a solvent selected from dimethylsulfoxide, ethyl acetate / ethanol mixture, 2-methyltetrahydrofuran, and combinations thereof.

[0111] 52. The method of embodiment 50 or embodiment 51, wherein the solvent is dimethylsulfoxide.

[0112] 53. The method of any one of embodiments 44-52, wherein step (b1) comprises reacting F1 with oxan-4-carbonyl chloride in the presence of a base and a solvent selected from tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, and combinations thereof.

[0113] 54. The method of embodiment 53, wherein the solvent is tetrahydrofuran.

[0114] 55. The method of either embodiment 53 or embodiment 54, wherein the base is selected from sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, sodium tert- amylate, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, and combinations thereof.

[0115] 56. The method of any one of embodiments 53-55, wherein the base is selected from sodium tert-butoxide, potassium tert-butoxide, sodium tert-amylate, and combinations thereof.

[0116] 57. The method of any one of embodiments 53-56, wherein the base is potassium tert- butoxide.

[0117] 58. The method of any one of embodiments 53-55, wherein the base is lithium bis(trimethylsilyl)amide.

[0118] 59. The method of any one of embodiments 44-58, wherein step (bl) comprises reacting Fl with oxazane-4-carbonyl chloride at about -40 °C to 15 °C (e.g., about 0 °C).

[0119] 60. The method of any one of embodiments 44-59, wherein step (bl) comprises reacting Fl with oxazane-4-carbonyl chloride at about -40 °C to 0 °C.

[0120] 61. A method for preparing Compound 1 in solid form

[0121]

[0122] or a pharmaceutically acceptable salt thereof, comprising:

[0123] (a1) reacting or a pharmaceutically acceptable salt thereof, with pivaloyl chloride to form or a pharmaceutically acceptable salt thereof;

[0124] (a2) reacting A1 or a pharmaceutically acceptable salt thereof, with 4-fluorophenylboronic acid to form or a pharmaceutically acceptable salt thereof;

[0125] (a) reacting B1 or a pharmaceutically acceptable salt thereof, with to form or a pharmaceutically acceptable salt thereof; and

[0126] (b) de-esterifying C58B or a pharmaceutically acceptable salt thereof, to obtain Compound 1 in solid form or a pharmaceutically acceptable salt thereof.

[0127] 62. The method of embodiment 61, wherein the method is further defined with the additional reaction steps, reagents, and conditions of any one of embodiments 2 to 60.

[0128] 63. The method of embodiment 61 or embodiment 62, further comprising:

[0129] (c) converting the solid form of Compound 1, or a pharmaceutically acceptable salt thereof, to Compound 1 Form A.

[0130] 64. The method of embodiment 63, wherein step (C) comprises aging a slurry comprising the solid form of Compound 1, or a pharmaceutically acceptable salt thereof, at about 20-25 °C.

[0131] 65. The method of embodiment 63 or embodiment 64, wherein the solid form of Compound 1, or a pharmaceutically acceptable salt thereof, is a THF solvate of Compound 1.

[0132] 66. A compound or a pharmaceutically acceptable salt thereof.

[0133] 67. A compound or a pharmaceutically acceptable salt thereof.

[0134] 68. A compound or a pharmaceutically acceptable salt thereof.

[0135] 69. A compound or a pharmaceutically acceptable salt thereof.

[0136] 70. A method for preparing a solid form of Compound 1

[0137]

[0138] or a pharmaceutically acceptable salt thereof, comprising:

[0139] (i) reacting or a pharmaceutically acceptable salt thereof, with trimethyl((tetrahydro-2H-pyran-4- yl)ethynyl)silane to form or a pharmaceutically acceptable salt thereof;

[0140] (ii) reacting C13 or a pharmaceutically acceptable salt thereof, with benzenesulfonyl chloride to form or a pharmaceutically acceptable salt thereof;

[0141] (iii) halogenating C15 or a pharmaceutically acceptable salt thereof, to form or a pharmaceutically acceptable salt thereof;

[0142] (iv) reacting S6, or a pharmaceutically acceptable salt thereof, with (4- (ethoxycarbonyl)phenyl)boronic acid to form or a pharmaceutically acceptable salt thereof; and

[0143] (v) de-esterifying C57, or a pharmaceutically acceptable salt thereof, to yield the solid form of Compound 1, or a pharmaceutically acceptable salt thereof.

[0144] 71. The method of embodiment 70, further comprising:

[0145] (vi) converting the solid form of Compound 1, or a pharmaceutically acceptable salt thereof, to Compound 1 Form A.

[0146] 72. The method of embodiment 71, wherein step (vi) comprises aging a slurry comprising the solid form of Compound 1, or a pharmaceutically acceptable salt thereof, at about 20-25 °C.

[0147] 73. The method of embodiment 71 or embodiment 72, wherein the solid form of Compound 1, or a pharmaceutically acceptable salt thereof, is a THF solvate of Compound 1.

[0148] 74. A method for preparing a solid form of Compound 1

[0149]

[0150] or a pharmaceutically acceptable salt thereof, comprising:

[0151] (i) reacting or a pharmaceutically acceptable salt thereof, with trimethyl((tetrahydro-2H-pyran-4- yl)ethynyl)silane to form or a pharmaceutically acceptable salt thereof;

[0152] (ii) reacting C13, or a pharmaceutically acceptable salt thereof, with pivaloyl chloride to form a pharmaceutically acceptable salt thereof;

[0153] (iii) halogenating C14, or a pharmaceutically acceptable salt thereof, to form or a pharmaceutically acceptable salt thereof;

[0154] (iv) reacting S4, or a pharmaceutically acceptable salt thereof, with (4- (ethoxycarbonyl)phenyl)boronic acid to form or a pharmaceutically acceptable salt thereof; or alternatively reacting S6, or a pharmaceutically acceptable salt thereof, with (4-(methoxycarbonyl)phenyl)boronic acid to form or a pharmaceutically acceptable salt thereof; and

[0155] (v) de-esterifying C58A or a pharmaceutically acceptable salt thereof or C58B or a pharmaceutically acceptable salt thereof to obtain the solid form of Compound 1 or a pharmaceutically acceptable salt thereof.

[0156] 75. The method of embodiment 74, further comprising:

[0157] (vi) converting the solid form of Compound 1 or a pharmaceutically acceptable salt thereof to Compound 1 Form A.

[0158] 76. The method of embodiment 75, wherein step (vi) comprises aging a slurry comprising the solid form of Compound 1 or a pharmaceutically acceptable salt thereof at about 20-25 °C.

[0159] 77. The method of embodiment 75 or embodiment 76, wherein the solid form of Compound 1 or a pharmaceutically acceptable salt thereof is a THF solvate of Compound 1.

[0160] 78. A method for preparing C13:

[0161]

[0162] or a pharmaceutically acceptable salt thereof, comprising:

[0163] (i) reacting or a pharmaceutically acceptable salt thereof with trimethyl((tetrahydro-2H-pyran-4- yl)ethynyl)silane to produce C13 or a pharmaceutically acceptable salt thereof;

[0164] 79. The method of any one of embodiments 70-78, wherein step (i) comprises reacting B1 or a pharmaceutically acceptable salt thereof with trimethyl((tetrahydro-2H-pyran-4- yl)ethynyl)silane in the presence of a base selected from lithium hydroxide, potassium hydroxide, sodium hydroxide, and combinations thereof.

[0165] 80. The method of embodiment 79, wherein the base is potassium hydroxide.

[0166] 81. The method of any one of embodiments 70-80, wherein step (i) comprises reacting B1 or a pharmaceutically acceptable salt thereof with trimethyl((tetrahydro-2H-pyran-4- yl)ethynyl)silane in the presence of copper iodide.

[0167] 82. The method of any one of embodiments 70-81, wherein step (i) comprises reacting B1 or a pharmaceutically acceptable salt thereof with trimethyl((tetrahydro-2H-pyran-4- yl)ethynyl)silane in the presence of copper iodide.

[0168] 83. The method of embodiment 82, wherein the palladium-phosphine complex-based catalyst is selected from XPhos Pd, tBuXPhos Pd, BrettPhos Pd, tBuBrettPhos Pd, bis(tri-tert- butylphosphine)Pd, and dichlorobis(triphenylphosphine)palladium.

[0169] 84. The method of embodiment 83, wherein the palladium-phosphine complex-based catalyst is dichlorobis(triphenylphosphine)palladium.

[0170] 85. The method of any one of embodiments 70-84, wherein step (i) comprises reacting B1, or a pharmaceutically acceptable salt thereof, with trimethyl((tetrahydro-2H-pyran-4- yl)ethynyl)silane in the presence of an alcohol selected from 2-propanol, 1-butanol, and ethanol.

[0171] 86. The method of embodiment 85, wherein the alcohol is 2-propanol.

[0172] 87. The method of any one of embodiments 70-86, wherein step (i) comprises reacting B1, or a pharmaceutically acceptable salt thereof, with trimethyl((tetrahydro-2H-pyran-4- yl)ethynyl)silane in the presence of acetic acid, a combination of acetic anhydride and acetic acid, or potassium bisulfite (e.g., in the presence of acetic acid).

[0173] 88. The method of embodiment 87, wherein step (i) comprises reacting B1, or a pharmaceutically acceptable salt thereof, with trimethyl((tetrahydro-2H-pyran-4-yl)ethynyl)silane in the presence of acetic acid.

[0174] 89. The method of any one of embodiments 70, 74, and 79-88, wherein step (ii) comprises reacting C13, or a pharmaceutically acceptable salt thereof, with benzenesulfonyl chloride or pivaloyl chloride in the presence of a base selected from sodium tert-butoxide, potassium tert-butoxide, sodium tert-pentoxide, and combinations thereof.

[0175] 90. The method of embodiment 89, wherein the base is potassium tert-butoxide.

[0176] 91. The method of any one of embodiments 70, 74, and 79-90, wherein step (ii) comprises reacting C13, or a pharmaceutically acceptable salt thereof, with benzenesulfonyl chloride or pivaloyl chloride in the presence of a solvent selected from tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, and combinations thereof.

[0177] 92. The method of embodiment 91, wherein the solvent is tetrahydrofuran.

[0178] 93. The method of any one of embodiments 70, 74, and 79-92, wherein step (iii) comprises reacting C15, or a pharmaceutically acceptable salt thereof, or C14, or a pharmaceutically acceptable salt thereof, with l-iodopyrrolidine-2,5-dione.

[0179] 94. The method of any one of embodiments 70, 74, and 79-93, wherein step (iii) comprises reacting C15, or a pharmaceutically acceptable salt thereof, or C14, or a pharmaceutically acceptable salt thereof, in the presence of a solvent selected from dichloromethane, prop-2-one / cyclopentane mixture, ethyl acetate / ethanol mixture, and combinations thereof (e.g., C15, or a pharmaceutically acceptable salt thereof, in the presence of a solvent selected from dichloromethane, prop-2-one / cyclopentane mixture, ethyl acetate / ethanol mixture, and combinations thereof; C14, or a pharmaceutically acceptable salt thereof, in the presence of dichloromethane).

[0180] 95. The method of embodiment 94, wherein the solvent is dichloromethane.

[0181] 96. The method of any one of embodiments 70, 74, and 79-95, wherein step (iv) comprises reacting S6, or a pharmaceutically acceptable salt thereof, or S4, or a pharmaceutically acceptable salt thereof, with (4-(ethoxycarbonyl)phenyl)boronic acid or (4- (methoxycarbonyl)phenyl)boronic acid in the presence of a palladium-phosphine complex-based catalyst.

[0182] 97. The method of embodiment 96, wherein the palladium-phosphine complex-based catalyst is selected from XPhos Pd, tBuXPhos Pd, BrettPhos Pd, tBuBrettPhos Pd, bis(tri-tert- butylphosphine)Pd, bis(triphenylphosphine)palladium dichloride, [l,l’-bis(diphenylphosphino) ferrocene]palladium(II) dichloride, and [l,l’-bis(diphenylphosphino)ferrocene]palladium(II) dichloride complexed with dichloromethane.

[0183] 98. The method of embodiment 97, wherein the palladium-phosphine complex-based catalyst is [l,l’-bis(diphenylphosphino)ferrocene]palladium(II) dichloride or [l,l’-bis(diphenylphosphino) ferrocene]palladium(II) dichloride complexed with dichloromethane (i.e., [l,l’-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, optionally complexed with dichloromethane).

[0184] 99. The method of any one of embodiments 70, 74, and 79-98, wherein step (iv) comprises reacting S6, or a pharmaceutically acceptable salt thereof, or S4, or a pharmaceutically acceptable salt thereof, with (4-(ethoxycarbonyl)phenyl)boronic acid or (4-(methoxycarbonyl)phenyl)boronic acid in the presence of a base selected from triethylamine, sodium carbonate, potassium carbonate, and combinations thereof.

[0185] 100. The method of any one of embodiments 70, 74, and 79-99, wherein step (v) comprises reacting C58A, or a pharmaceutically acceptable salt thereof, or C58B, or a pharmaceutically acceptable salt thereof, with a base selected from lithium hydroxide, potassium hydroxide, sodium hydroxide, and combinations thereof.

[0186] 101. The method of embodiment 100, wherein the base is sodium hydroxide.

[0187] 102. The method of any one of embodiments 70, 74, and 79-101, wherein step (v) comprises reacting C58A, or a pharmaceutically acceptable salt thereof, or C58B, or a pharmaceutically acceptable salt thereof, with a base in the presence of a solvent selected from piperidine, N- formylpiperidine, 2,2,6,6-tetramethylpiperidine, pyridine, and combinations thereof.

[0188] 103. The method of embodiment 102, wherein the solvent is piperidine.

[0189] 104. The method of any one of embodiments 70-103, wherein the method can be further defined with the additional reaction steps, reagents, and conditions of any one of embodiments 22-65.

[0190] 105. A method for preparing A1:

[0191]

[0192] or a pharmaceutically acceptable salt thereof, comprising:

[0193] (a1) reacting or a pharmaceutically acceptable salt thereof, with pivaloyl chloride to form A1 or a pharmaceutically acceptable salt thereof.

[0194] 106. A method for preparing B1:

[0195]

[0196] or a pharmaceutically acceptable salt thereof, comprising:

[0197] (a1) reacting or a pharmaceutically acceptable salt thereof, with pivaloyl chloride to form or a pharmaceutically acceptable salt thereof; and

[0198] (a2) reacting A1, or a pharmaceutically acceptable salt thereof, with 4-fluorophenylboronic acid to form B1, or a pharmaceutically acceptable salt thereof.

[0199] 107. The method of either embodiment 69 or embodiment 70, wherein the method can be further defined with the additional reaction steps, reagents, and conditions of any one of embodiments 23-43.

[0200] 108. A method for making E1:

[0201]

[0202] comprising:

[0203] (b1) reacting with oxan-4-carbonyl chloride to form E1.

[0204] 109. A method for making D1:

[0205]

[0206] comprising:

[0207] (b1) reacting with oxan-4-carbonyl chloride to form

[0208] (b2) reacting E1 with an aqueous solution (e.g., an aqueous solution comprising a chloride (e.g., sodium chloride, lithium chloride)) to form D1.

[0209] 110. The method of either embodiment 72 or embodiment 73, wherein the method can be further defined with the additional reaction steps, reagents, and conditions of any one of embodiments 47-60.

[0210] 111. A method for making C13:

[0211]

[0212] or a pharmaceutically acceptable salt thereof, comprising:

[0213] (a1) reacting or a pharmaceutically acceptable salt thereof, with trimethyl((tetrahydro-2H-pyran-4- yl)ethynyl)silane to form or a pharmaceutically acceptable salt thereof;

[0214] (a2) reacting C12, or a pharmaceutically acceptable salt thereof, with an acid to give C13, or a pharmaceutically acceptable salt thereof.

[0215] 112. The method of embodiment 111, wherein step (al) comprises reacting H184, or a pharmaceutically acceptable salt thereof, with trimethyl((tetrahydro-2H-pyran-4- yl)ethynyl)silane in the presence of copper iodide.

[0216] 113. The method of embodiment 111 or embodiment 112, wherein step (al) comprises reacting H184, or a pharmaceutically acceptable salt thereof, with trimethyl((tetrahydro-2H- pyran-4-yl)ethynyl)silane in the presence of a palladium-phosphine complex-based catalyst, an alcohol, and a base.

[0217] 114. The method of embodiment 113, wherein the palladium-phosphine complex-based catalyst is bis(triphenylphosphine)palladium(II) dichloride.

[0218] 115. The method of embodiment 113 or embodiment 114, wherein the alcohol is selected from the group consisting of 1-butanol, ethanol, 2-propanol, and combinations thereof.

[0219] 116. The method of any one of embodiments 113-115, wherein the alcohol is 2-propanol.

[0220] 117. The method of any one of embodiments 113-116, wherein the base is selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, and combinations thereof.

[0221] 118. The method of any one of embodiments 113-117, wherein the base is potassium hydroxide.

[0222] 119. The method of any one of embodiments 111-118, wherein step (al) comprises reacting H184, or a pharmaceutically acceptable salt thereof, with trimethyl((tetrahydro-2H- pyran-4-yl)ethynyl)silane at about 70-85 °C.

[0223] 120. The method of any one of embodiments 111-119, wherein step (a2) comprises reacting C12, or a pharmaceutically acceptable salt thereof, with an acid at about 70-85 °C.

[0224] 121. The method of any one of embodiments 111-120, wherein step (a2) comprises reacting C12, or a pharmaceutically acceptable salt thereof, with acetic acid.

[0225] 122. A method for preparing C58B:

[0226]

[0227] or a pharmaceutically acceptable salt thereof, comprising:

[0228] (a) reacting or a pharmaceutically acceptable salt thereof, with to form or a pharmaceutically acceptable salt thereof; and

[0229] (b) reacting G1or a pharmaceutically acceptable salt thereof, with a base in the presence of a solvent to form C58B.

[0230] 123. The method of embodiment 122, wherein step (b) comprises reacting G1or a pharmaceutically acceptable salt thereof, with a base at about -40 °C to about 20 °C (e.g., 35 °C).

[0231] 124. The method of embodiment 122 or embodiment 123, wherein the base is selected from lithium hexamethyldisilazane, potassium tert-butoxide, lithium diisopropylamide, and combinations thereof.

[0232] 125. The method of any one of embodiments 122-124, wherein the base is lithium hexamethyldisilazane.

[0233] 126. The method of any one of embodiments 122-125, wherein the solvent is selected from tetrahydrofuran, tetrahydropyran, 1,3-dioxolane, and combinations thereof (e.g., tetrahydrofuran).

[0234] 127. The method of any one of embodiments 122-126, wherein step (a) comprises reacting B1or a pharmaceutically acceptable salt thereof, with D1in the presence of a palladium-phosphine complex-based catalyst, a base selected from tri-potassium phosphate, potassium carbonate, and cesium carbonate, and a solvent selected from tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, toluene, dimethylformamide, acetonitrile, propionitrile, and combinations thereof.

[0235] 128. The method of embodiment 127, wherein the palladium-phosphine complex-based catalyst is selected from XPhos Pd, tBuXPhos Pd, BrettPhos Pd, tBuBrettPhos Pd, bis(tri-tert-butylphosphine)Pd, bis(adamantylalkylphosphine)Pd, 2-(di-tert-butylphosphino)-1-(2-methoxyphenyl)-1H-pyrrole Pd, and bis(triphenylphosphine)palladium dichloride.

[0236] 129. The method of either embodiment 127 or embodiment 128, wherein the palladium- phosphine complex-based catalyst is selected from XPhos Pd, tBuXPhos Pd, BrettPhos Pd, tBuBrettPhos Pd, bis(tri-tert-butylphosphine)Pd, and bis(triphenylphosphine)palladium dichloride.

[0237] 130. The method of either embodiment 127 or embodiment 128, wherein the palladium- phosphine complex-based catalyst is selected from XPhos Pd, BrettPhos Pd, diamantylalkyl phosphine Pd, and 2-(di-tert-butylphosphino)-l-(2-methoxyphenyl)-lH-pyrrole Pd.

[0238] 131. The method of any one of embodiments 127-129, wherein the palladium-phosphine complex-based catalyst is bis(tri-tert-butylphosphine)Pd.

[0239] 132. The method of any one of embodiments 122-131, wherein step (a) comprises reacting B1, or a pharmaceutically acceptable salt thereof, with D1 at about 45 °C-100 °C.

[0240] 133. A compound or a pharmaceutically acceptable salt thereof.

[0241] 134. The method of any one of embodiments 70-77, wherein C13, or a pharmaceutically acceptable salt thereof, is alternatively prepared by a method comprising:

[0242] (c1) reacting 5-bromo-6-iodo-lH-indazole with trimethyl((tetrahydro-2H-pyran-4- yl)ethynyl)silane to form 5-bromo-6-((tetrahydro-2H-pyran-4-yl)ethynyl)-lH- indazole;

[0243] (c2) reacting 5-bromo-6-((tetrahydro-2H-pyran-4-yl)ethynyl)-lH-indazole with 4- fluorobenzenamine to form N-(4-fluorophenyl)-6-((tetrahydro-2H-pyran-4- yl)ethynyl)-lH-indazol-5-amine; and

[0244] (c3) reacting N-(4-fluorophenyl)-6-((tetrahydro-2H-pyran-4-yl)ethynyl)-lH-indazol-5- amine with an acid (e.g., AcOH) to form C13, or a pharmaceutically acceptable salt thereof.

[0245] 135. The method of embodiment 134, wherein step (cl) is performed at about 70 °C-80 °C (e.g., about 75 °C).

[0246] 136. The method of either embodiment 134 or embodiment 135, wherein step (cl) comprises reacting 5-bromo-6-iodo-lH-indazole with trimethyl((tetrahydro-2H-pyran-4- yl)ethynyl)silane in the presence of an organic solvent selected from DMF, EtOH, MeOH, 1-butanol, t-butanol, isopropyl alcohol (IPA), tAmOH, THF / alcohol mixtures, and 2-MeTHF alcohol mixtures (e.g., EtOH), a base selected from NaOH, KOH, K2CO3, Na2CO3, Cs2CO3 NaOtBu, KOtBu, and DBU (1,8-diazabicyclo(5.4.0)undec-7-ene) (e.g., KOH), and a catalyst selected from Pd(PPh3)4, CuI, CuI / PPh3, and water (e.g., Pd(PPh3)4).

[0247] 137. The method of any one of embodiments 134 to 136, wherein step (c2) is performed at about 60-70 °C (e.g., about 65 °C).

[0248] 138. The method of any one of embodiments 134 to 137, wherein step (c2) comprises reacting 5-bromo-6-((tetrahydro-2H-pyran-4-yl)ethynyl)-lH-indazole with 4-fluoroaniline in the presence of a catalyst selected from PdtBuXPhos Gl-4; (PdOAc)2, Pd(cinnamyl)Cl2 with ligand, BrettPhos, SPHos, XPhos, XantPhos, Pd(dppf)Cl2-CH2Cl2, JosiPhos, and A (e.g., PdtBuXPhos), an organic solvent selected from EtOH, MeOH, 1-butanol, t-butanol, isopropyl alcohol (IPA), tAmOH, THF, 2-MeTHF, CPMe, toluene, DMF, ACN, DMA, and diglyme (e.g., EtOH), and a base selected from NaOH, K3PO4, K2CO3, NaOtBu, KOtBu, and NaOEt (e.g., NaOtBu).

[0249] Previously disclosed method of synthesis of compound 2

[0250] As described above, methods of synthesis of compound 2 and pharmaceutically acceptable salts thereof are provided in International Patent Application Publication No. WO 2020 / 081257. These methods described in WO 2020 / 081257 are described in Scheme 2 below. Optional reaction steps are indicated with dashed arrows.

[0251] Scheme 2 - Part A: synthesis of intermediate T4

[0252]

[0253] Scheme 2 - Part B: synthesis of compound 2 from intermediate T4

[0254]

[0255] Referring to Scheme 2 above, the synthetic process described in WO 2020 / 081257 can be divided into two parts: Part A, which ultimately forms the key intermediate T4 (benzyl 5-(4-fluorophenyl)-6-isopropylpyrrolo[2,3- f]indazole-1(5H)-carboxylate); and Part B, which ultimately synthesizes compound 2 from intermediate T4 derived from Part A. In summary, in Part A, there are two options for the starting material, either 5-bromo-6-iodo-1H-indazole (H7) or 6-bromo-5-chloro-1H-indazole (H1). H7 or H1 is reacted with 3-methylbut-1-yn in the presence of copper iodide (Cul), Pd(PPh3)2Cl2 as catalyst and di- or tri-ethylamine. This step gives 5-halo-6-(3-methylbut-1-yn-1-yl)-1H-indazole (H8 or H2), which is further reacted with 4-fluoroaniline in the presence of sodium tert-butoxide (NaOtBu) (1.3 g, 13.0 mmol) and a palladium-phosphine complex-based catalyst (i.e. tBuXPhos Pd G1 or BrettPhos Pd G4) to give a solution of product N-(4-fluorophenyl)-6-(3-methylbut-1-yn-1-yl)-1H-indazol-5-amine (H4) (determined by HPLC analysis). At this point, the two alternative paths of Part A have converged and the H4 solution is diluted and washed with different solvents, then concentrated in vacuo. The solid is filtered and dried to give T3 (5-(4-fluorophenyl)-6-isopropyl-1H-pyrrolo[2,3- f]indazole) as a solid. T3 is then reacted with benzyl chloroformate (Cbz-Cl) in the presence of potassium tert-butoxide (KOtBu) and the resulting slurry is diluted with methyl tert-butyl ether (MTBE) and water. The organic layer is slurried in methanol (MeOH), cooled overnight, collected and dried to give the key intermediate T4 as a light yellow solid. The main purpose of converting T3 to T4 is to introduce the carboxybenzyl (CBz) protecting group, which prevents the 3,3-dimethoxypropionic acid methyl ester, a reagent in the next reaction step in Part B as described below, from reacting at the wrong position of the intermediate.

[0256] In Part B, T4 is reacted with methyl 3,3-dimethoxypropanoate and trifluoroacetic acid to give 5-(4-fluorophenyl)-6-isopropyl-7-[(E)-3-methoxy-3-oxo-prop-1-enyl]pyrrolo[2,3- f]indazole-1-carboxylate benzyl ester (H35). A 10% palladium on carbon (Pd / C) catalyst is added to H35 and the mixture is placed under a hydrogen atmosphere or triethylsilane (Et3SiH) is added to the mixture to give product H36 (methyl 3-[5-(4-fluorophenyl)-6-isopropyl-1H-pyrrolo[2,3- f]indazol-7-yl]propanoate). Finally, an aqueous solution of lithium hydroxide (LiOH) or potassium hydroxide (KOH) is added to a solution of H36 to convert the -C(=O)OMe ester group to -C(=O)OH. After 1 hour, the reaction mixture is concentrated in vacuo, washed, acidified to ~pH 3-4, and extracted with ethyl acetate (EtOAc). The resulting precipitate is filtered and dried in vacuo to give the product as a solid of Compound 2.

[0257] Non-limiting advantages of the new method of making Compound 2

[0258] The present disclosure provides additional alternative methods of making Compound 2 or a pharmaceutically acceptable salt thereof in solid form, which can be distinguished from the previously disclosed methods in several respects. For example, T4, which has a carboxybenzyl (CBz) protecting group, is a key intermediate common to all of the previously disclosed methods. The step of introducing the CBz protecting group is the same as in the previously disclosed methods, specifically the step of reacting T3 with CBz-Cl in the presence of KOtBu as shown in Scheme 2. In contrast, the methods provided herein bypass the reaction step of introducing the CBz protecting group to the intermediate, and T4 and other downstream compounds (e.g., H35 and H36) are no longer formed as intermediates. Instead, a new intermediate (e.g., II in the non-limiting exemplary embodiments and Scheme 7B) is formed in the methods described herein. From a chemical standpoint, it is important that even in this new method, methyl 3,3-dimethoxypropanoate is still used to introduce the -C(=O)OMe ester group to intermediate II without the need to use a protecting group to prevent methyl 3,3-dimethoxypropanoate from reacting at the wrong position on T3.

[0259] From an economic standpoint, a key advantage of bypassing one or more reaction steps is that this approach, especially when preparing compounds on a large scale, will be significantly more cost-, time- and energy-efficient. In addition, in some embodiments, at least one other intermediate does not need to be isolated and purified, and the process can proceed directly to the next reaction step (see, e.g., Example 5, where H184 does not need to be isolated). As noted above, Compound 2 is being investigated for medical use. As the drug progresses through higher phase clinical studies, with larger populations of subjects, and when the drug is approved and available to the public, the advantages of a cost-, time- and energy-efficient synthesis of Compound 2 will even more clearly emerge.

[0260] Second, some embodiments of the processes described herein introduce different starting materials and reagents than those in previously disclosed processes. For example, Example 5 below uses a starting material with a pivaloyl (Piv) protecting group and with a nitro and a halogen as substituents (J1, also referred to herein as A1). This is in contrast to the starting materials in previously disclosed processes (H2 or H7), which have a halogen group as a substituent. In addition, the starting material in Example 5 below is reacted with phenylboronic acid in the presence of a siloxane (i.e., with -Si-O-Si- linkages) and an oxaphosphorane catalyst (see Step 1A of Scheme 7) to form a phenyl-indazolamine intermediate K1 (also referred to herein as B1) and H184. These initial reaction steps in the process described in Example 5 use reagents and catalysts not previously described and provide a phenyl-indazolamine intermediate that is also not present in previously described processes. The final phenyl-indazolamine intermediate H184 in Example 5 is then reacted with a silane in a subsequent reaction step, which is another class of reagent not described in the corresponding reaction step(s) of previously disclosed processes.

[0261] Alternative processes for preparing Compound 2 or a pharmaceutically acceptable salt thereof in solid form are described in more detail in the following non-limiting exemplary embodiments, and also in the appended Examples 5 and 6. Non-limiting exemplary embodiments (Compound 2 processes)

[0262] 1. A process for preparing Compound 2 in solid form

[0263]

[0264] or a pharmaceutically acceptable salt thereof, comprising:

[0265] (a) reacting or a pharmaceutically acceptable salt thereof, with methyl 3,3-dimethoxypropanoate to form or a pharmaceutically acceptable salt thereof;

[0266] (b) reducing II or a pharmaceutically acceptable salt thereof to or a pharmaceutically acceptable salt thereof; and

[0267] (c) de-esterifying H36 or a pharmaceutically acceptable salt thereof to obtain Compound 2 or a pharmaceutically acceptable salt thereof in solid form.

[0268] 2. The method according to embodiment 1, wherein step (a) comprises reacting T3 or a pharmaceutically acceptable salt thereof with methyl 3,3-dimethoxypropanoate in the presence of a sulfonic acid and a solvent or solvent system selected from dichloromethane, trifluoromethylbenzene, 2-methyltetrahydrofuran, propan-2-one / cyclopentane mixture, ethyl acetate / ethanol mixture, and combinations thereof.

[0269] 3. The method according to embodiment 2, wherein the solvent is dichloromethane.

[0270] 4. The method according to embodiment 2 or embodiment 3, wherein the sulfonic acid is selected from p-toluenesulfonic acid, p-toluenesulfonic acid monohydrate, camphorsulfonic acid, trifluoromethanesulfonic acid, and combinations thereof (e.g., selected from p-toluenesulfonic acid, camphorsulfonic acid, trifluoromethanesulfonic acid, and combinations thereof; p-toluenesulfonic acid).

[0271] 5. The method according to embodiment 4, wherein the sulfonic acid is p- toluenesulfonic acid monohydrate.

[0272] 6. The method according to any one of embodiments 1 to 5, wherein step (a) comprises reacting T3 or a pharmaceutically acceptable salt thereof with methyl 3,3-dimethoxypropanoate at about 40-50 °C and under stirring.

[0273] 7. The method according to any one of embodiments 1 to 6, wherein step (b) comprises reducing II or a pharmaceutically acceptable salt thereof with a reducing agent selected from hydrogen gas and a silicon-based reducing agent and in the presence of a palladium catalyst.

[0274] 8. The method according to embodiment 7, wherein the palladium catalyst is a catalyst comprising palladium supported on activated carbon.

[0275] 9. The method according to embodiment 7 or embodiment 8, wherein the reducing agent is hydrogen gas.

[0276] 10. The method according to embodiment 7 or embodiment 8, wherein the reducing agent is a silicon-based reducing agent and the silicon-based reducing agent is selected from triethylsilane, trichlorosilane, methyldichlorosilane, dimethylchlorosilane, triphenylsilane, tris(trimethylsilyl)silane, dimethylsilyloxy(dimethyl)silane, and combinations thereof.

[0277] 11. The method of embodiment 9, wherein step (b) comprises reducing II or a pharmaceutically acceptable salt thereof with hydrogen gas in the presence of tetramethylethylenediamine and a solvent selected from tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, and combinations thereof.

[0278] 12. The method of embodiment 11, wherein the solvent is tetrahydrofuran.

[0279] 13. The method of embodiment 11 or embodiment 12, wherein step (b) comprises reducing II or a pharmaceutically acceptable salt thereof with hydrogen gas at a pressure level of about 1-10 bar.

[0280] 14. The method of embodiment 10, wherein step (b) comprises reducing II or a pharmaceutically acceptable salt thereof with a silicon-based reducing agent in the presence of an alcohol selected from methanol, ethanol, isopropanol, tert-butanol, and combinations thereof.

[0281] 15. The method of any one of embodiments 1-14, wherein step (b) comprises reducing II or a pharmaceutically acceptable salt thereof at about 25-35 °C.

[0282] 16. The method of any one of embodiments 1-15, wherein step (c) comprises de-esterifying H36 or a pharmaceutically acceptable salt thereof with a base selected from lithium hydroxide, potassium hydroxide, sodium hydroxide, and combinations thereof.

[0283] 17. The method of embodiment 16, wherein the base is potassium hydroxide.

[0284] 18. The method of embodiment 16 or embodiment 17, wherein step (c) comprises de- esterifying H36 or a pharmaceutically acceptable salt thereof with a base (e.g., potassium hydroxide) in the presence of an alcohol selected from methanol, ethanol, isopropanol, tert-butanol, and combinations thereof.

[0285] 19. The method of embodiment 18, wherein the alcohol is ethanol.

[0286] 20. The method of any one of embodiments 1-19, wherein step (C) comprises de- esterifying H36 or a pharmaceutically acceptable salt thereof at 20-30 °C.

[0287] 21. The method of any one of embodiments 1-20, wherein the method further comprises at least one additional step selected from:

[0288] (a0) reacting or a pharmaceutically acceptable salt thereof, with pivaloyl chloride to form or a pharmaceutically acceptable salt thereof; and

[0289] (a1) reacting J1, or a pharmaceutically acceptable salt thereof, with 4-fluorophenylboronic acid to form or a pharmaceutically acceptable salt thereof; and

[0290] (a2) deprotecting K1, or a pharmaceutically acceptable salt thereof, and adding trimethyl(3-methylbut-1-yn-1-yl)silane to form T3, or a pharmaceutically acceptable salt thereof.

[0291] 22. The method of embodiment 21, wherein step (a0) comprises reacting J0, or a pharmaceutically acceptable salt thereof, with pivaloyl chloride in the presence of a base and a solvent selected from tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, and combinations thereof.

[0292] 23. The method of embodiment 22, wherein the solvent is tetrahydrofuran.

[0293] 24. The method of embodiment 22 or embodiment 23, wherein the base is selected from sodium tert-butoxide, potassium tert-butoxide, sodium tert-amylate, and combinations thereof (e.g., sodium tert-amylate).

[0294] 25. The method of embodiment 24, wherein the base is potassium tert-butoxide.

[0295] 26. The method of any one of embodiments 21 to 25, wherein step (a0) comprises reacting J0, or a pharmaceutically acceptable salt thereof, with pivaloyl chloride at about 10-20 °C.

[0296] 27. The method of any one of embodiments 21 to 26, wherein step (a1) comprises reacting J1, or a pharmaceutically acceptable salt thereof, with 4-fluorophenylboronic acid in the presence of a phospholane oxide catalyst and a reducing agent.

[0297] 28. The method of embodiment 27, wherein the phospholane oxide catalyst is hexamethyloxophospholane.

[0298] 29. The method of embodiment 27 or embodiment 28, wherein the reducing agent is a silicon-based reducing agent selected from triethylsilane, trichlorosilane, methyldichlorosilane, dimethylchlorosilane, triphenylsilane, tris(trimethylsilyl)silane, dimethylsilyloxy(dimethyl)silane, and combinations thereof.

[0299] 30. The method of embodiment 29, wherein the reducing agent is dimethylsilyloxy(dimethyl)silane.

[0300] 31. The method of any one of embodiments 27 to 30, wherein step (a2) comprises deprotecting K1, or a pharmaceutically acceptable salt thereof, with a base selected from lithium hydroxide, potassium hydroxide, sodium hydroxide, and combinations thereof.

[0301] 32. The method of embodiment 31, wherein the base is potassium hydroxide.

[0302] 33. The method of any one of embodiments 27 to 32, wherein step (al) comprises reacting J1, or a pharmaceutically acceptable salt thereof, with 4-fluorophenylboronic acid at about 85 °C to 95 °C.

[0303] 34. The method of any one of embodiments 27 to 33, wherein step (a2) comprises deprotecting K1, or a pharmaceutically acceptable salt thereof, to form or a pharmaceutically acceptable salt thereof, and reacting H184, or a pharmaceutically acceptable salt thereof, with trimethyl(3-methylbut-l-yn-l-yl)silane.

[0304] 35. The method of embodiment 34, wherein step (a2) comprises reacting H184, or a pharmaceutically acceptable salt thereof, with trimethyl(3-methylbut-l-yn-l-yl)silane in the presence of a palladium-phosphine complex-based catalyst, copper iodide, a base, and an alcohol.

[0305] 36. The method of embodiment 35, wherein the base is selected from lithium hydroxide, potassium hydroxide, sodium hydroxide, and combinations thereof.

[0306] 37. The method of embodiment 36, wherein the base is potassium hydroxide.

[0307] 38. The method of embodiment 35, wherein the alcohol is selected from methanol, ethanol, isopropanol, tert-butanol, and combinations thereof.

[0308] 39. The method of embodiment 38, wherein the alcohol is isopropanol.

[0309] 40. The method of embodiment 35, wherein the palladium-phosphine complex-based catalyst is selected from XPhos Pd, tBuXPhos Pd, BrettPhos Pd, tBuBrettPhos Pd, and bis(triphenylphosphine)palladium dichloride.

[0310] 41. The method of embodiment 40, wherein the palladium-phosphine complex-based catalyst is bis(triphenylphosphine)palladium dichloride.

[0311] 42. The method of any one of embodiments 34 to 41, wherein step (a2) comprises deprotection of K1, or a pharmaceutically acceptable salt thereof, and reacting H184, or a pharmaceutically acceptable salt thereof, with trimethyl(3-methylbut-1-yn-1-yl)silane at about 75-85 °C.

[0312] 43. The method of any one of embodiments 1 to 20, wherein the method further comprises at least one additional step selected from:

[0313] (a0) reacting or a pharmaceutically acceptable salt thereof, with 4-fluorophenylboronic acid to form or a pharmaceutically acceptable salt thereof; and

[0314] (a1) reacting H184, or a pharmaceutically acceptable salt thereof, with trimethyl(3- methylbut-1-yn-1-yl)silane to form or a pharmaceutically acceptable salt thereof.

[0315] 44. The method of embodiment 43, wherein step (a0) comprises reacting J0, or a pharmaceutically acceptable salt thereof, with 4-fluorophenylboronic acid in the presence of a catalyst, a reducing agent, and a solvent selected from toluene, isopropyl alcohol, xylene, methylcyclohexane, cyclopentyl methyl ether, methyl tert-butyl ether, isopropyl acetate, tetrahydrofuran, an aqueous solution comprising sodium carbonate and / or potassium carbonate (e.g., an aqueous sodium chloride solution comprising sodium carbonate and / or potassium carbonate), and combinations thereof (e.g., an isopropyl alcohol / toluene mixture).

[0316] 45. The method of embodiment 44, wherein the catalyst is selected from hexamethylphos- phorin oxide, (Mo02Cl2)DMF2with PPh3or silane, 4-methyl-1-phenyl-2,3-dihydrophospho- lene 1-oxide 4, (2R,5R)-1-{2-[(2R,5R)-2,5-diethylphospholane-1-yl]phenyl}-2,5-diethyl-1- phospholane-1-one, and 1-non(gadamant-1-yloxophospho)adamantane.

[0317] 46. The method of embodiments 44 or 45, wherein the catalyst is a phospholane oxide catalyst.

[0318] 47. The method of embodiment 46, wherein the phospholane oxide catalyst is hexamethyl- phosphorin oxide.

[0319] 48. The method of any one of embodiments 44 to 47, wherein the solvent is selected from toluene, cyclopentyl methyl ether, isopropyl acetate, tetrahydrofuran, and combinations thereof.

[0320] 49. The method of any one of embodiments 44-48, wherein the solvent is toluene.

[0321] 50. The method of any one of embodiments 44-49, wherein the reducing agent is selected from the group consisting of triethylsilane, trichlorosilane, polymethylsilane, methyldichlorosilane, dimethylchlorosilane, phenylsilane, triphenylphosphine, triphenylphosphine oxide, tris(trimethylsilyl)silane, dimethylsilyloxy(dimethyl)silane, and combinations thereof.

[0322] 51. The method of any one of embodiments 44-50, wherein the reducing agent is selected from the group consisting of polymethylsilane, phenylsilane, triphenylphosphine, triphenylphosphine oxide, dimethylsilyloxy(dimethyl)silane, and combinations thereof.

[0323] 52. The method of any one of embodiments 44-49, wherein the reducing agent is a silicon-based reducing agent selected from the group consisting of triethylsilane, trichlorosilane, methyldichlorosilane, dimethylchlorosilane, phenylsilane, tris(trimethylsilyl)silane, dimethylsilyloxy(dimethyl)silane, and combinations thereof.

[0324] 53. The method of embodiment 52, wherein the reducing agent is dimethylsilyloxy(dimethyl)silane.

[0325] 54. The method of any one of embodiments 43-53, wherein step (a0) comprises reacting J0, or a pharmaceutically acceptable salt thereof, with 4-fluorophenylboronic acid at about 85-105 °C (e.g., about 90-100 °C).

[0326] 55. The method of any one of embodiments 43-54, wherein step (a0) further comprises cooling the reaction mixture and adding an aqueous mixture comprising a base.

[0327] 56. The method of embodiment 55, wherein the base is sodium hydroxide, potassium hydroxide, or potassium carbonate aqueous solution.

[0328] 57. The method of any one of embodiments 43-56, wherein step (al) comprises reacting H184, or a pharmaceutically acceptable salt thereof, with trimethyl(3-methylbut-l-yn-l-yl)silane in the presence of a palladium-phosphine complex-based catalyst, copper iodide, a base, and an alcohol.

[0329] 58. The method of embodiment 57, wherein the base is selected from the group consisting of lithium hydroxide, potassium hydroxide, sodium hydroxide, and combinations thereof.

[0330] 59. The method of embodiment 58, wherein the base is potassium hydroxide.

[0331] 60. The method of any one of embodiments 43-59, wherein the alcohol is selected from the group consisting of methanol, ethanol, isopropanol, tert-butanol, and combinations thereof.

[0332] 61. The method of embodiment 60, wherein the alcohol is isopropanol.

[0333] 62. The method of any one of embodiments 43-61, wherein the palladium-phosphine complex-based catalyst is selected from the group consisting of XPhos Pd, tBuXPhos Pd, BrettPhos Pd, tBuBrettPhos Pd, and dichlorobis(triphenylphosphine)palladium.

[0334] 63. The method of embodiment 62, wherein the palladium-phosphine complex-based catalyst is dichlorobis(triphenylphosphine)palladium.

[0335] 64. The method of any one of embodiments 43-63, wherein step (al) reacts H184, or a pharmaceutically acceptable salt thereof, with trimethyl(3-methylbut-l-yn-l-yl)silane at about 70-85 °C (e.g., 75-80 °C).

[0336] 65. The method of any one of embodiments 1-20, wherein the method further comprises at least one additional step selected from the group consisting of:

[0337] (a1’) reacting or a pharmaceutically acceptable salt thereof

[0338] with trimethyl(3-methylbut-l-yn-l-yl)silane to form or a pharmaceutically acceptable salt thereof; and

[0339] (a2’) reacting H8, or a pharmaceutically acceptable salt thereof, with 4-fluoroaniline to form T3, or a pharmaceutically acceptable salt thereof.

[0340] 66. The method of embodiment 65, wherein step (al) comprises reacting H7, or a pharmaceutically acceptable salt thereof, with trimethyl(3-methylbut-l-yn-l-yl)silane in the presence of a palladium-phosphine complex-based catalyst, copper iodide, a base, and an alcohol.

[0341] 67. The method of embodiment 66, wherein the base is selected from the group consisting of lithium hydroxide, potassium hydroxide, sodium hydroxide, and combinations thereof.

[0342] 68. The method of embodiment 67, wherein the base is potassium hydroxide.

[0343] 69. The method of embodiment 66, wherein the alcohol is selected from the group consisting of methanol, ethanol, isopropanol, tert-butanol, and combinations thereof.

[0344] 70. The method of embodiment 69, wherein the alcohol is ethanol.

[0345] 71. The method of embodiment 66, wherein the palladium-phosphine complex-based catalyst is selected from the group consisting of XPhos Pd, tBuXPhos Pd, BrettPhos Pd, tBuBrettPhos Pd, and bis(triphenylphosphine)palladium dichloride.

[0346] 72. The method of embodiment 71, wherein the palladium-phosphine complex-based catalyst is bis(triphenylphosphine)palladium dichloride.

[0347] 73. The method of any one of embodiments 66-72, wherein step (al’) comprises reacting H7, or a pharmaceutically acceptable salt thereof, with trimethyl(3-methylbut-l-yn-l-yl)silane at about 70-80 °C.

[0348] 74. The method of any one of embodiments 66-73, wherein step (a2’) comprises reacting H8, or a pharmaceutically acceptable salt thereof, with 4-fluoroaniline in the presence of a palladium-phosphine complex-based catalyst, copper iodide, a base, and an alcohol.

[0349] 75. The method of embodiment 74, wherein the base is selected from the group consisting of sodium tert-butoxide, potassium tert-butoxide, sodium tert-pentoxide, and combinations thereof.

[0350] 76. The method of embodiment 75, wherein the base is sodium tert-butoxide.

[0351] 77. The method of embodiment 74, wherein the alcohol is selected from the group consisting of methanol, ethanol, isopropanol, tert-butanol, and combinations thereof.

[0352] 78. The method of embodiment 77, wherein the alcohol is ethanol.

[0353] 79. The method of embodiment 74, wherein the palladium-phosphine complex-based catalyst is selected from the group consisting of XPhos Pd, tBuXPhos Pd, BrettPhos Pd, tBuBrettPhos Pd, and bis(triphenylphosphine)palladium dichloride.

[0354] 80. The method of embodiment 79, wherein the palladium-phosphine complex-based catalyst is tBuXPhos Pd.

[0355] 81. A method for preparing compound 2 in solid form

[0356]

[0357] or a pharmaceutically acceptable salt thereof, comprising:

[0358] (a0) reacting or a pharmaceutically acceptable salt thereof, with 4-fluorophenylboronic acid to form or a pharmaceutically acceptable salt thereof; and

[0359] (a1) reacting H184 or a pharmaceutically acceptable salt thereof with trimethyl(3- methylbut-1 -yn-1 -yl)silane to form or a pharmaceutically acceptable salt thereof;

[0360] (a) reacting T3 or a pharmaceutically acceptable salt thereof with methyl 3,3- dimethoxypropanoate to form or a pharmaceutically acceptable salt thereof;

[0361] (b) reducing II1 or a pharmaceutically acceptable salt thereof to or a pharmaceutically acceptable salt thereof; and

[0362] (c) de-esterifying H36 or a pharmaceutically acceptable salt thereof to obtain Compound 2 in solid form or a pharmaceutically acceptable salt thereof.

[0363] 82. The method according to Embodiment 81, wherein the method can be further defined with the reagents and conditions described in any one of Embodiments 2 to 80.

[0364] 83. A method for preparing Compound 2 in solid form

[0365]

[0366] or a pharmaceutically acceptable salt thereof, comprising:

[0367] (a0) reacting or a pharmaceutically acceptable salt thereof, with pivaloyl chloride to form or a pharmaceutically acceptable salt thereof; and

[0368] (a1) reacting J1 or a pharmaceutically acceptable salt thereof with 4-fluorophenylboronic acid to form or a pharmaceutically acceptable salt thereof;

[0369] (a2) de-protecting K1 or a pharmaceutically acceptable salt thereof and adding trimethyl(3-methylbut-1-yn-1-yl)silane to form or a pharmaceutically acceptable salt thereof;

[0370] (a) reacting T3, or a pharmaceutically acceptable salt thereof, with methyl 3,3- dimethoxypropanoate to form or a pharmaceutically acceptable salt thereof;

[0371] (b) reducing II, or a pharmaceutically acceptable salt thereof, to or a pharmaceutically acceptable salt thereof; and

[0372] (c) de-esterifying H36, or a pharmaceutically acceptable salt thereof, to obtain Compound 2, or a pharmaceutically acceptable salt thereof, in solid form.

[0373] 84. The method according to Embodiment 83, wherein the method can be further defined with the reagents and conditions described in any one of Embodiments 2 to 80.

[0374] 85. A method for preparing Compound 2 in solid form

[0375]

[0376] or a pharmaceutically acceptable salt thereof, comprising:

[0377] (a1’) reacting or a pharmaceutically acceptable salt thereof

[0378] with trimethyl(3-methylbut-1-yn-1-yl)silane to form or a pharmaceutically acceptable salt thereof;

[0379] (a2’) reacting H8, or a pharmaceutically acceptable salt thereof, with 4-fluoroaniline to form or a pharmaceutically acceptable salt thereof;

[0380] (a) reacting T3, or a pharmaceutically acceptable salt thereof, with methyl 3,3- dimethoxypropanoate to form or a pharmaceutically acceptable salt thereof;

[0381] (b) reducing II, or a pharmaceutically acceptable salt thereof, to or a pharmaceutically acceptable salt thereof; and

[0382] (c) de-esterifying H36, or a pharmaceutically acceptable salt thereof, to obtain Compound 2, or a pharmaceutically acceptable salt thereof, in solid form.

[0383] 86. The method according to Embodiment 85, wherein the method can be further defined with the reagents and conditions described in any one of Embodiments 2 to 80.

[0384] 87. A compound or a pharmaceutically acceptable salt thereof.

[0385] 88. A method of preparing (E)-3-(5-(4-fluorophenyl)-6-isopropyl-1,5- dihydropyrrolo[2,3-f]indazol-7-yl)acrylic acid methyl ester (II) or a pharmaceutically acceptable salt thereof, comprising:

[0386]

[0387] or a pharmaceutically acceptable salt thereof, comprising:

[0388] reacting or a pharmaceutically acceptable salt thereof, with methyl 33-dimethoxypropanoate to form or a pharmaceutically acceptable salt thereof.

[0389] 89. The method according to Embodiment 88, comprising reacting T3 or a pharmaceutically acceptable salt thereof with methyl 3,3-dimethoxypropanoate in the presence of a sulfonic acid and a solvent or solvent system selected from dichloromethane, trifluoromethylbenzene, 2-methyltetrahydrofuran, propan-2-one / cyclopentane mixture, ethyl acetate / ethanol mixture, and combinations thereof.

[0390] 90. The method according to Embodiment 89, wherein the solvent is dichloromethane.

[0391] 91. The method according to Embodiment 89 or Embodiment 90, wherein the sulfonic acid is selected from p-toluenesulfonic acid, p-toluenesulfonic acid monohydrate, camphorsulfonic acid, triflic acid, and combinations thereof (e.g., selected from p- toluenesulfonic acid, camphorsulfonic acid, triflic acid, and combinations thereof; p- toluenesulfonic acid).

[0392] 92. The method according to Embodiment 91, wherein the sulfonic acid is p- toluenesulfonic acid monohydrate.

[0393] 93. The method according to any one of Embodiments 88 to 92, comprising reacting T3 or a pharmaceutically acceptable salt thereof with methyl 3,3-dimethoxypropanoate at about 40-50 °C and under stirring.

[0394] Example 1: Large-scale synthesis of Compound 1

[0395] Scheme 3C depicts a large-scale synthesis of Compound 1 that utilizes 1-(6-bromo-5- nitro-1H-indazol-1-yl)-2,2-dimethylpropan-1-one (A1) as a starting material. This method is expected to produce Compound 1 or a pharmaceutically acceptable salt thereof in at least about 100 kg quantities in solid form. Scheme 3A describes the preparation of starting material A1. Scheme 3B describes the preparation of D1, which reacts with B1 in step 2 of Scheme 3C to form C58B. Scheme 3B’ describes an alternative method of preparation of D1.

[0396] Preparation 1 -(6-bromo-5-nitro- 1 H-indazol- 1 -yl)-2,2-dimethylpropan- 1 -one (A1)

[0397] Scheme 3A

[0398]

[0399] To commercial A0 (3.1 kg, 11.9 mol) in THF (35 L) at -26 °C was added sodium tert- pentoxide (33.4 wt% in THF, 4.55 kg, 13.8 mol) over 15 minutes and the mixture was rinsed with THF (300 mL). The mixture was re-cooled to -26 °C over 15 minutes and then pivaloyl chloride (Piv-Cl) (1.75 kg, 14.5 mol) was added over 4 minutes. The mixture was rinsed with THF (300 mL). The mixture was warmed to 15 °C over 55 minutes and held for 30 minutes. A solution of sodium bicarbonate (150 g) in water (2 L) was added, followed by additional water (9 L). The resulting two-phase slurry was concentrated under vacuum to ~25 L volume and then diluted with methanol (11.2 L). The slurry was heated to 40 °C for 30 minutes, diluted with water (11.3 L) for 30 minutes, and then cooled to room temperature. A second run was similarly performed from 3.1 kg of A0. The two slurries were combined, filtered, and washed with 1 : 1 methanol:water (20 L). The solid was dried with heated nitrogen to give A1 (7.69 kg, 23.6 mol, 99%) as a tan solid.

[0400] Alternatively, to commercial A0 (43.0 kg, 1.0 eq) in THF (382.7 kg) at -5 °C to 5 °C was added potassium tert-butoxide (23.9 kg) over 2 hours. Then pivaloyl chloride (piv-Cl) (25.7 kg) was added at -5 °C to 5 °C over 2 hours. The mixture was stirred at -5 °C to 5 °C for 1 hour, water (215 kg) was added at 0-10 °C over one hour, and the mixture was stirred for an additional hour. The solids were filtered, and the filter cake was washed with THF (38.3 kg). The wet product was slurried in THF (76.5 kg) and water (301.0 kg) at 50 °C to 60 °C and stirred for 1-2 hours. The mixture was cooled to 10 °C to 20 °C and stirred for an additional 2-4 hours. The solids were filtered, and the wet filter cake was rinsed with THF (38.3 kg). The wet filter cake was dried with heated nitrogen to give tan solid A1 (46 kg, 79.45% yield).

[0401] 1 H NMR (400 MHz, DMSO) δ 8.63 (d, J = 0.4 Hz, 1H), 8.36 (d, J = 1.0 Hz, 1H), 8.07 (dd, J = 1.1, 0.4 Hz, 1H).

[0402] Preparation of methyl 4-(2-oxo-2-(tetrahydro-2H-pyran-4-yl)ethyl)benzoate (D1)

[0403] Scheme 3B

[0404]

[0405] To the reactor was added commercially available methyl 4-(2-methoxy-2- oxoethyl)benzoate (F1) (500 mg, 2.401 mmol, 1 equiv) and tetrahydrofuran (4.0 mL, 8 vol) at ambient temperature, followed by the addition of potassium tert-butoxide (2.8 mL, 1.0 M, 1.2 equiv). The resulting slurry was transferred to a solution of oxalyl chloride (0.59 mL, 2 equiv) and tetrahydrofuran (1.0 mL, 1 vol). The reaction was quenched with saturated aqueous ammonium chloride (5.0 mL, 10 vol) and extracted with ethyl acetate (5.0 mL, 10 vol) three times. The combined organics were washed with 50% saturated aqueous sodium chloride (10.0 mL, 20 vol), then dried over sodium sulfate, filtered, and concentrated in vacuo to yield methyl 4-(1-methoxy-1,3-dioxo-3-(tetrahydro-2H-pyran-4-yl)propan-2-yl)benzoate (E1).

[0406] 1 H NMR (400 MHz, CDC13) δ 8.03 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 4.95 (s, 1H), 3.92 (s, 3H), 3.75 (s, 3H), 3.40 - 3.27 (m, 2H), 3.14 (td, J = 12.1, 2.0 Hz, 2H), 2.69 (tt, J = 11.1, 4.1 Hz, 1H), 2.02 - 1.90 (m, 2H), 1.48 - 1.39 (m, 2H).

[0407] Next, to the reactor was added methyl 4-(1-methoxy-1,3-dioxo-3-(tetrahydro- 2H-pyran-4-yl)propan-2-yl)benzoate (E1) (489 mg, 1.528 mmol, 1 equiv), dimethyl sulfoxide (4.9 mL, 10 vol), and aqueous sodium chloride (0.68 mL, 4.5 M, 2.0 equiv). The reaction mixture was heated to 150 °C for 3 hours, then cooled to room temperature. The reaction mixture was diluted with H20 (4.9 mL, 10 vol) and extracted with ethyl acetate (4.9 mL, 10 vol) three times. The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo to yield methyl 4-(2-oxo-2-(tetrahydro-2H-pyran-4-yl)ethyl)benzoate (D1).

[0408] 1 H NMR (400 MHz, CDC13) δ 8.00 (d, J = 8.3 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 3.99 (dt, J = 11.5, 3.5 Hz, 2H), 3.91 (s, 3H), 3.81 (s, 2H), 3.45 - 3.35 (m, 2H), 2.73 - 2.61 (m, 1H), 1.79 - 1.68 (m, 4H).

[0409] Alternative preparation of methyl 4-(2-oxo-2-(tetrahydro-2H-pyran-4- yl)ethyl)benzoate (D1)

[0410] Scheme 3B’

[0411]

[0412] To a solution of methyl 4-(2-methoxy-2-oxoethyl)benzoate (Fl) (5.0 g, 24.01 mmol) in THF (10.0 mL) at 0 °C was added LiHMDS (48.0 mL, 1.0 M, 48.03 mmol). In a separate vessel, a solution of oxan-4-carbonyl chloride (5.9 mL, 48.03 mmol) in THF (30.0 mL) was prepared. At 0 °C, after both reagent solutions were completely added, the two solutions were simultaneously added to the empty reactor over 2 h, the mixture was diluted to pH 4 with water (50 mL) and HC1 (2.0 M) at 0 °C, then extracted with MTBE (50 mL) three times. The combined organic phase was washed with HC1 (1.0 M, 50 mL) twice, then with water (50 mL) twice, dried over Na2S04, filtered, and concentrated in vacuo to give methyl 4-(l-methoxy-l,3-dioxo-3-(tetrahydro-2H-pyran-4-yl)propan-2-yl)benzoate (El).

[0413] 1 H NMR (400 MHz, CDC13) δ 8.00 (d, J = 8.3 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 3.99 (dt, J = 11.5, 3.5 Hz, 2H), 3.91 (s, 3H), 3.81 (s, 2H), 3.45 - 3.35 (m, 2H), 2.73 - 2.61 (m, 1H), 1.79 - 1.68 (m, 4H).

[0414] A solution of methyl 4-(l-methoxy-l,3-dioxo-3-(tetrahydro-2H-pyran-4- yl)propan-2-yl)benzoate (400 mg, 1.25 mmol) in THF (2.8 mL) and water (1.75 mL) was sealed and heated to 200 °C in a microwave reactor for 10 minutes. The mixture was then cooled to room temperature, diluted with water (4.0 mL), extracted with EtOAc (4.0 mL) three times. The combined organics were dried over Na2S04, filtered, and concentrated in vacuo to give methyl 4-(2-oxo-2-(tetrahydro-2H-pyran-4-yl)ethyl)benzoate (D1).

[0415] 1 H NMR (400 MHz, CDC13) δ 8.00 (d, J = 8.3 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 3.99 (dt, J = 11.5, 3.5 Hz, 2H), 3.91 (s, 3H), 3.81 (s, 2H), 3.45 - 3.35 (m, 2H), 2.73 - 2.61 (m, 1H), 1.79 - 1.68 (m, 4H).

[0416] Alternative telescoped preparation of methyl 4-(2-oxo-2-(tetrahydro-2H-pyran-4- yl)ethyl)benzoate (D1)

[0417] A solution of oxan-4-carbonyl chloride (1249.3 g, 8.4 mol) in THF (4690.0 mL) was slowly added to a solution of methyl 4-(2-methoxy-2-oxoethyl)benzoate (Fl) (1167.0 g, 5.6 mol) in THF (5600.0 mL) at 5 °C. The reaction mixture and LiHMDS (11.2 L, 1.0 M in THF) were injected using two syringe pumps, mixed in a T-mixer, and then flowed into a spiral reactor cooled to 10 °C. The effluent was flowed into HCl (5250.0 mL, 4.5 M) cooled to 15 °C and the organic phase was separated. The mixture was then flowed into a spiral reactor heated to 180 °C. The effluent was cooled to 20 °C and then concentrated in vacuo. The concentrate was diluted with water (1750.0 mL) and then concentrated. The resulting concentrate was diluted with MeOH (1750.0 mL) and stirred at 20 °C for 1 h. The mixture was filtered and the filter cake was resuspended in MeOH (3500.0 mL) and stirred at 20 °C for 1 h. The mixture was filtered. The wet filter cake was washed with MeOH (2335.0 mL) and then dried at 45 °C to give methyl 4-(2-oxo-2-(tetrahydro-2H-pyran-4-yl)ethyl)benzoate (D1) (1167.0 g, 86%).

[0418] 1H NMR (400 MHz, CDC13) δ 8.00 (d, J = 8.3 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 3.99 (dt, J = 11.5, 3.5 Hz, 2H), 3.91 (s, 3H), 3.81 (s, 2H), 3.45 - 3.35 (m, 2H), 2.73 - 2.61 (m, 1H), 1.79 - 1.68 (m, 4H).

[0419] Example 2: Alternative preparation of Compound 1 and intermediate C13

[0420] Intermediate 1 -(6-bromo-5-((4-fluorophenyl)amino)-1 H-indazol-1 -yl)-2,2- dimethylpropan-1 -one (B1) described in Example 1 can be used as a starting material for the preparation of C13. As described in Schemes 1 B-1 C, C13 is a key intermediate in the synthesis of Compound 1. Accordingly, the present disclosure provides an alternative preparation of Compound 1 and C13, wherein H184 is used as a starting material, as shown in Scheme 4 below and described below:

[0421] Scheme 4

[0422]

[0423] Add 6-bromo-N-(4-fluorophenyl)-1H-indazole-5-amine (6.3 g, 20.579 mmol, 1 equivalent), 99.9% copper iodide (0.274 g, 1.441 mmol, 0.07 equivalent), and bis(triphenylphosphine)palladium(II) dichloride (0.144 g, 0.206 mmol, 0.01 equivalent) to the reactor. Add 2-propanol (50.4 mL, 0.408 M, 8 volumes) to the reaction mixture and start stirring. Evacuate the system and purge three times with nitrogen. Add potassium hydroxide (2.887 g, 7.216 mL, 40 w / v%, 51.448 mmol, 2.5 equivalent), followed by trimethyl((tetrahydro-2H-pyran-4-yl)ethynyl)silane (4.878 g, 26.753 mmol, 1.3 equivalent). Evacuate the system and purge three times with nitrogen. Upon completion of the reaction, the mixture was heated to 75-80°C. Acetic acid (5.87 g, 5.596 mL, 1.049 g / mL, 97.752 mmol, 4.75 equivalents) was added to the mixture, and stirring was continued at 75-80°C upon completion of the reaction, as assessed by HPLC. The mixture was then cooled to 50°C, and water (50.4 mL, 0.408 M, 8 volumes) was slowly added. The reaction was cooled to 23°C, and the solid was collected by filtration. The wet filter cake was washed with water. The substance was dried under vacuum at 55°C. 5-(4-fluorophenyl)-6-(tetrahydro-2H-pyran-4-yl)-1,5-dihydropyrrolo[2,3-f]indazole was isolated in 94% yield.

[0424] Non-limiting examples of alternative reagents and solvents that can be used to convert B1 to C13 include:

[0425] Solvents: Other alcohol solvents, such as 1-butanol, ethanol, etc.;

[0426] Alkali: NaOH.

[0427] The subsequent reaction steps for preparing compound 1 are described in schemes 1B and 1C, and also in international patent application number PCT / US2020 / 032832, which is published under international patent application publication number WO 2020 / 247160.

[0428] Example 3: Alternative preparation of compound 1

[0429] Scheme 5 describes an alternative large-scale synthesis of compound 1, using 1-(6-bromo-5-nitro-1H-indazol-1-yl)-2,2-dimethylprop-1-one (A1) as the starting material.

[0430] Option 5

[0431]

[0432] Step 1: Synthesis of 1-(6-bromo-5-((4-fluorophenyl)amino)-1H-indazol-1-yl)-2,2- dimethylpropan-1-one (B1)

[0433] To the reactor was added 1,2,2,3,4,4-hexamethylphosphorinan 1 -oxide (0.026 kg, 0.151 mol, 0.125 eq) followed by toluene (4000 L, 10 vol). The reaction mixture was stirred. To the reactor was added 1,1,3,3-tetramethyldisiloxane (0.324 kg, 0.426 L, 2.411 mol, 2.0 eq) and the reaction mixture was heated to 100 °C, the reactor was cooled to 25 °C, IPA (7 vol, 2.8 L) was added. The solution was filtered through a pad of Celite (0.110 kg), the reactor was rinsed with IPA (3 vol, 1.2 L) and the rinse was dropped on the Celite pad. The filtrate was heated to 35 °C and then to the reactor was added potassium carbonate aqueous solution (1.0 M, 2.4 L, 6 vol). The mixture was stirred for 30 minutes. The stirring was then stopped and the phases were allowed to settle for 30 minutes. The bottom aqueous phase was drained. The top organic phase was distilled under vacuum to 8 vol. To the reactor was added IPA (4 L, 10 vol) and distilled again to 8 vol. To the reactor was added IPA (1.6 L, 4 vol) (total 12 vol). The reactor was heated to 78 °C internal temperature and stirred at 78 °C for no less than 1 hour. The reaction mixture was cooled to 0 °C over 6 hours and then the reaction mixture was stirred at 0 °C for 1 hour and then filtered. The wet cake was rinsed with IPA (0.8 L, 2 vol) and dried in a vacuum oven at 45 °C with nitrogen purge. The product 1-(6-bromo-5-((4-fluorophenyl)amino)-1H-indazol-1-yl)-2,2-dimethylpropan-1-one (B1) was off-white to beige solid (about 75% yield). 1 H NMR (400 MHz, Chloroform-d) δ 8.76 (d, J = 0.9 Hz, 1H), 7.87 (d, J = 0.9 Hz, 1H), 7.24 (d, J = 5.9 Hz, 2H), 7.18 - 6.97 (m, 4H), 5.97 (s, 1H), 1.54 (s, 9H), 1.43 (d, J = 0.8 Hz, 1H).

[0434] Non-limiting examples of alternative reagents and solvents that can be used to convert A1 to B1 are:

[0435] Solvents: CPME, IPAc, THF;

[0436] Reductants: phenylsilane, polymethylsilane, PPh3; PPh3O;

[0437] Catalysts: (Mo02CI2)DMF2with PPh3or silanes; 4-methyl-1-phenyl-2,3- dihydrophosphol-1-oxide 4, (2R,5R)-1-{2-[(2R,5R)-2,5-diethylphospholane-1- yl]phenyl}-2,5-diethyl-1-phospholane-1-one and 1-(adamantan-1-yloxyphosphoryl)adamantane.

[0438] Step 2: Synthesis of methyl 4-(5-(4-fluorophenyl)-1-oxopentan-2-yl-6- (tetrahydro-2H-pyran-4-yl)-1,5-dihydropyrrolo[2,3-f]indazol-7-yl)benzoate (C58A)

[0439] A solution of 2-MeTHF (100 mL, 10 vol) and ACN (10 mL, 1 vol) was degassed and sparged with nitrogen 3 times. 1-(6-bromo-5-((4-fluorophenyl)amino)-1H-indazol-1-yl)-2,2- dimethylpropan-1-one (B1) (10 g, 25.63 mmol, 1 equiv, limiting reagent) was added to the reactor. Methyl 4-(2-oxo-2-(tetrahydro-2H-pyran-4-yl)ethyl)benzoate (7.4 g, 28.19 mmol, 1.1 equiv) was added to the reactor followed by anhydrous K3PO4 (6.53 g, 30.750 mmol, 1.2 equiv). 2-MeTHF / ACN solvent was added to the reactor and the reaction mixture was stirred. The solution was degassed and sparged with nitrogen 3 times. Bis(tri-tert-butyl-phosphine)palladium(0) (9.82 g, 19.22 mmol, 0.075 equiv) was added to the reactor at 20-25 °C, the solution was degassed and sparged with nitrogen 3 times. The reaction mixture was heated to 50-55 °C, once the reaction reached completion as assessed by HPLC, the reactor was cooled to 20 °C and acetic acid (4.63 g, 4.4 mL, 77.1 mmol, 3 equiv) was added to the reactor at 20-25 °C, water (500 mL, 5 vol) was added followed by 2-MeTHF (150 mL, 15 vol). The mixture was stirred for 30 minutes, then the phases were allowed to separate. The bottom aqueous layer was removed and water (500 mL, 5 vol) was added. The mixture was stirred for 15 minutes, the phases were allowed to separate. The bottom aqueous layer was removed and set aside. The organic solution was distilled under reduced pressure, 2-MeTHF was added to a volume of 25. SEM 26 (20 wt%, 2 g) was added to the reactor, the reactor was heated to an internal temperature of 40-45 °C, the reaction mixture was stirred for 12 hours and then filtered. The reactor was washed with 2-MeTHF (20 mL, 2 vol), the rinse was added dropwise to the filter. The filtrate was distilled and the solvent was exchanged to THF. THF was added to the reactor to a volume of 8-9. The contents of the reactor were heated to 60-65 °C to obtain a solution. The reactor was cooled to 50 °C over 1 hour, and the contents were stirred at 50 °C for 30 minutes. EtOH (180 mL, 18 vol) was added over 3 hours. The reactor was cooled to an internal temperature of 10 °C over 8 hours. The slurry was stirred at 10 °C for no less than 1 hour, the mixture was filtered. The reactor was rinsed twice with EtOH (20 mL, 2 vol), and the rinse was added dropwise to the wet cake. The wet cake was dried in a vacuum oven set to 65 °C and dried for 16 hours. The product, methyl 4-(5-(4-fluorophenyl)-1-neopentanoyl-6-(tetrahydro-2H-pyran-4-yl)-1,5- dihydropyrrolo[2,3-f]indazol-7-yl)benzoate (C58B), was isolated as an off-white solid (about 68% yield).

[0440] Non-limiting examples of alternative reagents and solvents that can be used to convert B1 to C58B are:

[0441] Solvents: MeTHF, THF, toluene, CPME, DMF, ACN, propionitrile, THF / ACN; MeTHF / ACN, THF / propionitrile; MeTHF / propionitrile;

[0442] Bases: K2HPO4, K2H2PO4, K2CO3, Cs2CO3;

[0443] Pd ligands: XPhos, Brett Phos; 2-(di-tert-butylphosphino)-1-(2-methoxyphenyl)-1H- pyrrole; catacXium.

[0444] Step 3A: Synthesis of Compound 1 Form A

[0445] Methyl 4-(5-(4-fluorophenyl)-1-neopentanoyl-6-(tetrahydro-2H-pyran-4-yl)- 1,5-dihydropyrrolo[2,3-f]indazol-7-yl)benzoate (25.1 g, 45.337 mmol, 1 eq, limiting reagent) (C58B) and THF (326.3 mL, 13 vol) were added to the reactor. Sodium hydroxide [2N] (5.44 g, 68.0 mL, 136.01 mmol, 3 eq) was added to the reactor, which was heated to 58 °C after the reaction was assessed to be complete by HPLC, the reactor was cooled to 20 °C, water (75.3 mL, 3 vol), acetic acid (10.89 g, 10.38 mL, 181.35 mmol, 4 eq), and 2-MeTHF (251 mL, 10 vol) were added to the reactor and stirred for no less than 30 minutes. Stirring was stopped and the layers were allowed to separate. Water (75.3 mL, 3 vol) was added to the organic layer and extracted. The layers were allowed to separate, and a 6.5 wt% aqueous sodium chloride (NaCl, 8.2 g, 0.14 mmol, 3.1 eq) solution in water (0.120 L, 4.7 vol) was added to the organic layer. The reaction mixture was stirred for no less than 30 minutes, then stirring was stopped and the layers were allowed to separate. The organic layer was distilled to 2-3 vol. EtOH (0.176 mL, 7 vol) was added to the reactor and distillation was continued. EtOH (0.150 L, 6 vol) and water (25.1 mL, 1 vol) were added, and the slurry was distilled to 2-3 vol. EtOH (0.150 L, 6 vol) and water (25.1 mL, 1 vol) were added to the reactor, and distillation was continued to 3 vol. EtOH (0.150 L, 6 vol) and water (25.1 mL, 1 vol) were added to the reactor, and the reaction mixture was stirred at 40 °C for no less than 30 minutes, the reactor was cooled to 20-25 °C at a rate of 5 °C / h. The reactor contents were stirred at 20 °C for at least 30 minutes, the slurry was filtered, and the resulting wet cake was rinsed with an EtOH / H2O 1:1 mixture (50 mL, 2 vol). The wet cake was dried in a vacuum oven set to 66 °C for no less than 12 hours. The product, 4-(5-(4-fluorophenyl)-6-(tetrahydro-2H-pyran-4-yl)-1,5- dihydropyrrolo[2,3-f]indazol-7-yl)benzoic acid (Compound 1 Form A), was isolated in 90% yield.

[0446] Non-limiting examples of alternative reagents and solvents that can be used to convert C58B to Compound 1 described above are as follows:

[0447] Solvents: MeTHF, EtOH, MeOH, IPA;

[0448] Bases: LiOH, NaOH, KOH;

[0449] Workup: acetic acid, HC1.

[0450] Step 3B: Alternative synthesis of Compound 1 Form A

[0451] To obtain Compound 1 Form A, methyl 4-(5-(4-fluorophenyl)-l-neopentanoyl-6- (tetrahydro-2H-pyran-4-yl)-l,5-dihydropyrrolo[2,3-f]indazol-7-yl)benzoate (25.1 g, 45.337 mmol, 1 equiv, limiting reagent) and THF (326.3 mL, 13 volumes) were added to a reactor. Sodium hydroxide [2N] (5.44 g, 68.0 mL, 136.01 mmol, 3 equiv) was added to the reactor, the reactor was heated to 58 °C after the reaction was assessed to be complete by HPLC, the reactor was cooled to 20 °C, water (3.00 volumes, 75.3 mL) was added to the reactor at 20 °C and stirred for 15 minutes. Acetic acid (10.89 g, 10.38 mL, 181.35 mmol, 4 equiv) was added to the reactor at 20 °C-25 °C and the reaction mixture was stirred for 30 minutes. The phases were allowed to settle for 30 minutes and the bottom aqueous layer was drained. Water (20 volumes, 502 mL) was added to the reactor over 5 hours at 20 °C, the resulting slurry was aged for 2 hours, filtered, and washed with a mixture of water (2.5 volumes, 125.5 L) and tetrahydrofuran (1.5 volumes, 37.7 mL). The wet cake was dried at 65 °C for no less than 16 hours. Compound 1 was isolated as a THF solvate in off-white to yellow solid (about 88% yield).

[0452] A solution of water (1.5 volumes, 37.7 mL) and ethanol (8.5 volumes, 231.4 mL) was prepared. The THF solvate of Compound 1 was added to a reactor and the reaction mixture was stirred to suspend the solids. The resulting slurry was aged for 4 hours at 20 °C-25 °C and filtered. The wet cake was washed with a solution of water (0.6 volumes, 15.1 mL) and ethanol (3.4 volumes, 85.3 mL). The wet cake was dried at greater than 65 °C to obtain Compound 1 Form A (about 87% yield).

[0453] Example 4: Alternative preparation of intermediate C58B

[0454] An alternative method for preparing intermediate C58B is described in Scheme 6.

[0455] Scheme 6

[0456]

[0457] Step 1: Synthesis of methyl 4-((5-(N-(4-fluorophenyl)tetrahydro-2H-pyran-4- carboxamido)-1-neopentanoyl-1H-indazol-6-yl)methyl)benzoate (G1)

[0458] An acetonitrile (101 mL, 10 vol) solution was degassed and sparged with nitrogen gas 3 times. 1-(6-bromo-5-((4-fluorophenyl)amino)-1H-indazol-1-yl)-2,2- dimethylpropan-1-one (B1) (10.1 g, 25.86 mmol, 1 equiv, limiting reagent) was added to the vessel. Methyl 4-(2-oxo-2-(tetrahydro-2H-pyran-4-yl)ethyl)benzoate (D1) (7.46 g, 28.441 mmol, 1.1 equiv) was added to the reactor followed by anhydrous K3PO4 (7.14 g, 33.61 mmol, 1.3 equiv). Stirring was initiated. The solution was degassed and sparged with nitrogen gas 3 times. Bis(tri-tert-butyl-phosphine)palladium(0) (991 mg, 1.94 mmol, 0.075 equiv) was added to the reactor, the solution was degassed and sparged with nitrogen gas 3 times. Once the reaction reached completion as assessed by HPLC, the reaction mixture was heated to 80-85 °C, the reaction mixture was cooled to 20 °C and acetic acid was added to obtain a pH of 4 at 20-25 °C, water (40.4 mL, 4 vol) was added. MtBE (8.75 mL, 5 vol) was added, the reaction mixture was stirred for 30 minutes. Stirring was stopped, and the phases were allowed to separate. The bottom aqueous layer was removed and water (8.75 mL, 5 vol) was added. The reaction mixture was stirred for 15 minutes, then stirring was stopped, the phases were allowed to separate. The bottom aqueous layer was removed and set aside. The organic solution was distilled under reduced pressure. The isolated material was dissolved in THF, and 40 wt% SEM26 was added. The reaction mixture was stirred at 40 °C for 16 hours, the reactor contents were filtered. The reactor was washed with THF (20 mL, 2 vol) and the rinse was dropped onto the filter. The filtrate was distilled and THF was added. Heptane (20 mL, 2 vol) was added, the reaction mixture was stirred. The precipitated solids were filtered. The filtrate was distilled and ethanol (100 mL, 10 vol) was added. The reaction mixture was heated to 50 °C to obtain a solution, the solution was cooled to 20-25 °C and stirred. The solids were collected and washed with ethanol. The isolated cake was dried at >65 °C. The product, methyl 4-((5-(N-(4-fluorophenyl)tetrahydro-2H-pyran-4-carboxamido)-1- neopentanoyl-1H-indazol-6-yl)methyl)benzoate (G1), was isolated as an off-white solid (first batch yield 39.8%).

[0459] 1H NMR (400 MHz, DMSO d6) δ 8.54 (s, 1H), 8.19 (s, 1H), 8.32 (s, 1H), 7.9 (m, 3H), 7.25 (m, 2H), 7.16 (m, 3H), 4.04 (m, 2H), 3.85 (s, 2H), 3.65 (m, 2H), 3.03 (m, 4H), 2.15 (m, 1H), 1.68 (m, 4H), 1.47 (m. 9H)

[0460] 13 C NMR (400 MHz, DMSO d6) δ 177.84, 174.88, 166.54, 162.31, 145.11, 140.02, 139.79, 138.09, 137.47, 131.12, 130.29, 130.13, 131.12, 123.8, 125.13, 121.79, 118.90, 117.26, 66.3, 52.53, 41.86, 40.19, 37.46, 29.44, 27.80

[0461] MS (compound + H) 572.2533

[0462] Step 2: Synthesis of C58B

[0463] To a solution of methyl 4-{[l-(2,2-dimethylpropanoyl)-5-[N-(4- fluorophenyl)siloxan-4-ylamido]indazol-6-yl]methyl}benzoate (Gl) (286 mg, 0.50 mmol) in THF (2.9 mL) was added LiHMDS (1.0 mL, 1.0 M, 1.00 mmol) at -35 °C.

[0464] Example 5: Large scale synthesis of compound 2-l-(6-bromo-5-nitro-lH-indazol-l- yl)-2,2-dimethylpropan-l-one as starting material

[0465] Scheme 7 depicts a large scale synthesis of compound 2 utilizing l-(6-bromo-5- nitro-lH-indazol-l-yl)-2,2-dimethylpropan-l-one as starting material. This method is expected to produce at least about 100 kg of compound 2 or a pharmaceutically acceptable salt thereof in solid form.

[0466] Scheme 7

[0467]

[0468] Step 1A: Synthesis of l-(6-bromo-5-((4-fluorophenyl)amino)-lH-indazol-l-yl)-2,2- dimethylpropan-l-one (Kl, also referred to herein as Bl)

[0469] Starting material J1 (also referred to herein as A1; 1-(6-bromo-5-nitro-1H- indazol-1-yl)-2,2-dimethylpropan-1-one, 15.3 g, 46.911 mmol, 1 eq) was added to the reactor followed by 4-m-fluorophenylboronic acid (8.533 g, 60.984 mmol, 1.3 eq) and hexamethyloxyposphorane (1.127 g, 7.037 mmol, 0.15 eq) as catalyst and toluene (153 mL, 0.307 M, 10 vol). Dimethylsilyloxane (dimethyl)silane (TMDS) (18.904 g, 24.873 mL, 0.76 g / mL, 140.733 mmol, 3 eq) was added to the reactor at 18.5 °C. The reaction was heated to an internal temperature of 90 °C. Once full conversion was achieved (>97% conversion, ~7 h), the internal temperature was set to 20 °C, half-saturated sodium bicarbonate or NaHCO3 (76.5 mL, 0.613 M, 5 vol) was added to the reactor, THF (2 vol, 30 mL) was added to the reactor at 20-25 °C, and the mixture was stirred for 15 min. Stirring was then stopped to allow the phases to separate. After phase separation, the organic layer was washed with 5 vol of half-saturated aqueous sodium chloride solution. The organic layer was distilled to 2 vol. Tetrahydrofuran (THF) was added, the organic layer was further distilled to 1-2 vol (repeated 3 times), and this step of THF addition and distillation was repeated 3 times before THF was added to a total of 3 vol. Methanol (MeOH) (45.9 mL, 1.022 M, 3 vol) was added to the reactor. The resulting slurry was heated to an internal temperature of 55-60 °C and then cooled to 45-50 °C to obtain a seeding layer. MeOH (92 mL, 6 vol) was added to the seeding layer over 180 min. The reactor was cooled over 4 h to 20-25 °C, the resulting slurry was filtered, and the reactor was rinsed with MeOH. The rinse was then dropped onto the wet cake. The wet cake was transferred to a vacuum oven for drying at 50 °C, and Compound K1 / B1 was isolated as a beige solid in an expected yield of 70%.

[0470] Non-limiting examples of other reagents and solvents that can be used for the conversion of A1 / J1 to B1 / K1 are:

[0471] Solvents: CPME, IPAc, THF;

[0472] Reducing agents: phenylsilane, polymethylsilane, PPh3; PPh3O;

[0473] Catalysts: (Mo02CI2)DMF2with PPh3or silanes; 4-methyl-1-phenyl-2,3- dihydrophosphol-1-oxide 4, (2R,5R)-1-{2-[(2R,5R)-2,5-diethylphospholane-1- yl]phenyl}-2,5-diethyl-1-phospholane-1-one and 1-(adamantan-1-yloxyphosphoryl)adamantane.

[0474] Step 2A: Synthesis of 6-bromo-N-(4-fluorophenyl)-1H-indazol-5-amine (H184) and

[0475] 5-(4-Fluorophenyl)-6-isopropyl-1,5-dihydropyrrolo[2,3-f]indazole (T3)

[0476] Compound K1 / B1 (12.24 g, 39.983 mmol, 1 eq) from Step 1A was added to the reactor followed by copper iodide (Cul) (0.533 g, 2.799 mmol, 0.07 eq), bis(triphenylphosphine)palladium(II) dichloride or Pd(PPh 3)2Cl2(0.281g, 0.4mmol, 0.01 equiv) and isopropanol or IPA (97.92 mL, 0.408M, 8 vol), and stir the reaction mixture. At 18.3 °C, add potassium hydroxide (KOH) (5.608g, 14.02 mL, 40 w / v%, 99.957 mmol, 2.5 equiv) to the reactor, and purge the reaction mixture with nitrogen. Then at 15.9 °C, add trimethyl(3-methylbut-1-yn-1-yl)silane (7.292g, 8.103 mL, 0.9 g / mL, 51.977 mmol, 1.3 equiv) to the reactor via syringe, purge the resulting dark solution with nitrogen, and then heat the reaction to 78-80 °C internal temperature (Note: reaction, internal temperature at 78.5 °C, reflux). As part of in-process control (IPC) measurements, take a sample for analysis. Target >97% conversion at 230 nm (Note: dark solution, some white precipitate). Then, at 77 °C, add acetic acid (11.405g, 10.883 mL, 1.048 g / mL, 189.917 mmol, 4.75 equiv) to the reactor over 5 minutes. As another IPC measurement, take another sample for analysis for 97.0% conversion to T3 at 210 nm or 95.8% at 230 nm. Stop heating, and stir the mixture at ambient temperature overnight. 10.6 wt% (97.92 mL, 0.408M, 8 vol) aqueous sodium bisulfite (NaHSO3) solution. Then add isopropyl acetate (IPAc) (122.4 mL, 0.327M, 10 vol) to the reactor, then add water (24.48 mL, 1.633M, 2 vol) to dissolve the solids. Heat the mixture to 55 °C internal temperature for 2 hours, forming a separate layer, including a water layer with a pH of 4-5 and a light green color. Add 10.6 wt% (55 mL, 0.727M, 4.493 vol) aqueous sodium bisulfite (NaHSO3) solution, and stir the reaction at 55 °C internal temperature for 2 hours, forming a second water layer with a pH of 4-5 and a light green color. Add semi-saturated ammonium chloride (NH4Cl) (100 mL, 0.4M, 8.17 vol), resulting in a mixture with a pH of ~4. Then add aqueous ammonium hydroxide (NH4OH) (24 mL, 1.666M, 1.961 vol), and stir for 30 minutes. Again, a separate layer forms, including a water layer with a pH of 4-5 and a blue color. Add semi-saturated NH4Cl (100 mL, 0.4M, 8.17 vol) to the organic phase and stir for 30 minutes, then drain the bottom aqueous layer. Next, add aqueous acetic acid to the organic layer, extracting the organic layer. Take a sample of the organic layer. The pH of the aqueous layer should be ~5. Then perform a solvent exchange distillation with 5 vol toluene, and heat the mixture to 85 °C internal temperature. Some particulates are observed.One volume of toluene was added to the mixture to obtain a solution which was then cooled to 45°C and stirred for 1 hour to form a solid precipitate. The mixture was further cooled to ambient temperature over 2 hours, then stirred at 24°C for 30 minutes, the resulting slurry was filtered, and the reactor with toluene and wet cake was drop washed, then the material was dried in a vacuum oven at 50°C with nitrogen bleed to give the product T3 as a solid in 82% yield. The maximum volume of aqueous wash in this step was 26-30 volumes.

[0477] Step 3: Synthesis of (E)-3-(5-(4-fluorophenyl)-6-isopropyl-1,5-dihydropyrrolo[2,3- f]indazol-7-yl)acrylic acid methyl ester (11)

[0478] Step 3 is performed under current good manufacturing practice (GMP) guidelines. To the compound of Step 2A, T3 (1.00 equivalents), is added p-toluenesulfonic acid monohydrate (2.00 equivalents) and acetic acid (11 equivalents) or camphorsulfonic acid (3.00 equivalents, 2.21 w / w equivalents) and dichloromethane (15.0 volumes, 19.95 w / w equivalents). The mixture is stirred and heated to 40 ± 5 °C, then to the mixture is added ethyl 3,3-dimethoxypropanoate (1.50 equivalents, 0.705 w / w equivalents) and the mixture is stirred at 40 ± 5 °C for not less than 24 hours. A sample is taken to confirm completion of the reaction. The mixture is cooled to 25 ± 5 °C, a ~1 M aqueous potassium carbonate solution is prepared by stirring potassium carbonate (3.00 equivalents, 1.31 w / w equivalents) in water (9.5 volumes, 9.50 w / w equivalents) until it dissolves. The prepared 1 M aqueous potassium carbonate solution is added to the vessel and the mixture is stirred at a temperature maintained at 25 ± 5 °C for not less than 30 minutes, then the stirring is stopped to allow the phases to settle for not less than 30 minutes. The bottom organic layer is drained and samples are taken of both the organic and aqueous phases. The aqueous layer is discarded and the organic layer is returned to the reactor. To the organic layer is then added water (10.0 volumes, 10.0 w / w equivalents) and stirred at a temperature maintained at 25 ± 5 °C for not less than 1 hour, the stirring is again stopped to allow the phases to settle for not less than 30 minutes. The bottom aqueous layer is drained and samples are taken of both the organic and aqueous phases. Again, the aqueous layer is discarded and the organic layer is returned to the reactor. Stirring is again started, vacuum is applied, and the reaction mixture is distilled to a total of 3.0 volumes while maintaining the jacket temperature at equal to or below 50 °C (Distillation #1). To the distilled mixture is added THF (6.0 volumes, 5.33 w / w equivalents), vacuum is again applied, and the reaction mixture is distilled to a total of 3.0 volumes while maintaining the jacket temperature at equal to or below 50 °C (Distillation #2). To the distilled mixture is added THF (6.0 volumes, 5.33 w / w equivalents), a sample is taken to test for residual dichloromethane. Vacuum is again applied, and the reaction mixture is distilled to a total of 4.0 volumes while maintaining the jacket temperature at equal to or below 40 °C (Distillation #3). To the distilled mixture is added THF (6.0 volumes, 5.33 w / w equivalents), a sample is taken to test for residual dichloromethane. Vacuum is again applied, and the reaction mixture is distilled to a total of 3.0 volumes while maintaining the jacket temperature at equal to or below 50 °C (Distillation #4). A fine filtration is then performed. Stirring is again started, vacuum is applied, and the reaction mixture is distilled to a total of 6.0 volumes while maintaining the jacket temperature at equal to or below 50 °C (Distillation #5). The mixture is heated to 60 ± 5 °C, then cooled to 40 ± 5 °C, n-heptane (1.0 volume, 0.680 w / w equivalents) is added to the cooled mixture over not less than 30 minutes, then the mixture is stirred at 40 ± 5 °C for not less than two hours.At this point, if nucleation has not occurred, add an additional 0.5 volumes (0.340 w / w equivalents) of n-heptane over 30 minutes and allow the mixture to equilibrate at 40 ± 5 °C for not less than two hours. Add the remaining n-heptane (13.5-14.0 volumes) to the mixture over 12 hours. After this time, cool the mixture to 20 ± 5 °C over 4 hours by stirring the slurry at 20 ± 5 °C for not less than 4 hours. Then isolate the solids from the slurry by filtration and sample the mother liquor. Prepare a wash solution by mixing tetrahydrofuran (1.0 volume, 0.888 w / w equivalents) and n-heptane (3.0 volumes, 2.04 w / w equivalents). Add the prepared wash solution to the crystallizer and then apply to the wet cake. Sample the wash and the wet cake. Transfer the wet cake to a vacuum oven at not more than 45 °C until dry. Sample the dried solids II.

[0479] Step 4: Synthesis of 3-(5-(4-fluorophenyl)-6-isopropyl-l,5-dihydropyrrolo[2,3- f]indazol-7-yl)propionic acid methyl ester (H36)

[0480] Step 4 was performed under current GMP guidelines. Ii from Step 3 (1.82 kg, 1.0 eq) was added to the reactor and the reactor was purged with nitrogen 3 times. 5% Pd / C catalyst Johnson Matthey Type A405032-5 or A405028-5 (381 g, 10% wt, dry basis) was added to the reactor and the reactor was purged with nitrogen 3 times. THF (6.4 L, 3.5 volumes) was added to the reactor and the reactor was purged with nitrogen 3 times. The reactor was evacuated under vacuum and purged with nitrogen 3 times. Tetramethylethylenediamine or TMEDA (1.18 L, 2.1 eq) was added to the reactor and the reactor was purged with nitrogen 3 times. The reactor was heated to 25 °C and pressurized with hydrogen to 3 bar. The reaction was stirred until complete conversion as assessed by HPLC (~7-10 hours) and a sample was taken for IPC (expected conversion: >99.5%). The reaction was filtered with filter aid to remove the Pd / C. The reactor was rinsed twice with THF (2 L, 1.1 volumes) and the Celite cake was drip rinsed. The product in THF solution was transferred to the reactor and the line was rinsed with 2 x 1 L THF. The THF solution was stable in the dark for at least one week, although the product solution was photosensitive. The batch was vacuum distilled at 35 °C to 2-3 volumes, then ethyl acetate (7.3 L, 4 volumes) was added to the reactor and distilled to 2-3 volumes (repeated 3 times). When the reactor was charged with ethyl acetate (7.3 L, 4 volumes) for the fourth time, the reactor was heated to 70-75 °C to achieve complete dissolution. The reactor was cooled to 60 °C and then n-heptane (3.6 L, 2.0 volumes) was added to it at 60 °C over 30 minutes. The batch was stirred for 1 hour to obtain a seeding layer. Then, while maintaining the temperature at 60 °C, n-heptane (20 L, 11.1 volumes) was added to the reactor again over 4 hours and stirred for 4 hours. The reactor was then cooled to 20 °C over 5 hours and stirred at the same temperature for not less than 1 hour. The batch was filtered, the reactor was rinsed with n-heptane (2.7 L, 1.5 volumes) and ethyl acetate (0.9 L, 0.5 volumes), and the wet cake was drip rinsed. The wet cake was dried under vacuum at 50-55 °C to obtain H36 as an off-white solid (yield ~82%).

[0481] Step 5: Synthesis of compound 2

[0482] Step 5 was performed under current GMP guidelines. H36 from Step 4 (1.0 eq) was added to the reactor followed by ethanol (13 vol). Agitation was started. Then 40% w / v KOH (2.7 eq) was added to the reactor over 30 minutes at no more than 25 °C and the batch was agitated at 25 °C for no less than 3 hours. After agitation, a sample was taken for IPC (average 100.0% conversion; target > 99.6% conversion). The sample was polished through a 0.45 micron in-line filter and acetic acid (2.9 eq) was added to the batch through the polish filter while maintaining the temperature at no more than 25 °C (note: the expected pH range is 6-7). The reaction was then heated to 50 °C and purified water (12.4 vol) was added to the reactor over 2 hours through the polish filter. Next, the reactor was cooled to an internal temperature of 20 °C over 5 hours. The batch was filtered and a solution of EtOH (1.0 vol) and water (1.0 vol) was added to the reactor through the polish filter. The filter cake was washed with the ethanol-water solution and then washed with purified water (2.0 vol). The wet filter cake was dried under vacuum at 50 °C to give Compound 2 as an off-white solid. The maximum volume of the precipitate after the addition of water in this step was 28 vol.

[0483] Optional recrystallization of Compound 2 for form conversion

[0484] THF (5.0 vol, 4.45 w / w eq) was added to Compound 2 from Step 5. The mixture was heated to 55 ± 5 °C, then cooled to 42 °C, then spray milled Compound 2 seed material (0.05 w / w eq) was added and the mixture was held for no less than 3 hours. A sample was taken to confirm the desired form (Compound 2 Form C) by X-ray powder diffraction (XRPD). The sample was then filtered to isolate the solids from the supernatant. At 42 °C, n-heptane (2.5 vol, 1.71 w / w eq) was added to the solids at an approximate linear rate for no less than 20 hours, the sample was again taken for IPC purposes, and the sample was filtered to isolate the solids from the supernatant. At 42 °C, n-heptane (2.5 vol, 1.71 w / w eq) was again added to the solids at an approximate linear rate for no less than 16 hours, the sample was again taken for IPC purposes, and the sample was filtered to isolate the solids from the supernatant. The solids were cooled to 25 ± 3 °C for no less than 4 hours, then agitated at the same temperature for no less than 1 hour. The sample was again taken for IPC purposes, and the sample was filtered to isolate the solids from the supernatant. The solids were further purified by centrifugation or filtration. If possible, the mass of the mother liquor was obtained and sampled. A wash solution was prepared by mixing THF (1.8 vol, 1.60 w / w eq) and n-heptane (2.2 vol, 1.50 w / w eq). The reaction vessel was rinsed with the prepared wash solution and applied to the filter cake. If possible, the mass of the wash was obtained and sampled. The solids were dried under nitrogen at 60 °C and sampled.

[0485] Alternatively, 6-bromo-N-(4-fluorophenyl)-lH-indazol-5-amine (H184) and

[0486] 5-(4-Fluorophenyl)-6-isopropyl-l,5-dihydropyrrolo[2,3- f]indazole (T3)

[0487]

[0488] Step 1: Synthesis of 6-bromo-N-(4-fluorophenyl)-lH-indazol-5-amine (H184) and

[0489] 5-(4-Fluorophenyl)-6-isopropyl-l,5-dihydropyrrolo[2,3- f]indazole (T3)

[0490] A mixture of J0 (also referred to herein as A0, 3.0 kg, 11.5 mol), 4- fluorophenylboronic acid (2.64 kg, 18.9 mol), triphenylphosphine (7.16 kg, 27.3 mol), Mo02Cl2(dmf) (235 g, 0.63 mol), 2,2’-bipyridine (100 g, 0.64 mol), and toluene (30 L) was heated to 93-99 °C over 16 hours. The mixture was cooled to 23 °C, a mixture of 45% KOH (3.2 L, 37 mol) in water (15 L) was added. The mixture was stirred for 20 minutes, then allowed to settle. The layers were separated, and the upper organic layer was washed with a mixture of water (12 L) and saturated brine (4 L). The mixture was filtered through a pad of Celite, rinsing with toluene (7 L), then the layers were separated. The organic layer was diluted with MTBE (39 L), then stirred with silica (3 kg) and magnesium chloride (6 kg) at 22-28 °C for 16 hours, and the slurry was filtered through a 6 kg pad of silica, washing with 1 : 1 toluene:MTBE (70 L). The main filtrate was concentrated to dryness to give crude H184 (wet weight 4.6 kg) as a light brown solid. A solution of crude H184 (4.6 kg, 8.8 mol) and p-TSA (1.51 kg, 7.9 mol) in THF (20 L) was heated to 60-65 °C, and toluene (20 L) was added over 20 minutes by pump. The resulting slurry was stirred at 60-65 °C for 30 minutes, then cooled to 15-20 °C and stirred for 1 hour. The solids were collected by filtration to give the p-TSA salt (2.46 kg, 5.1 mol) as a yellow crystalline solid. The process was repeated with 6 kg of J0 / A0. The p-TSA salt (3.6 kg, 7.5 mol) was added to a reactor, then 2-MeTHF (35 L) was added and stirred until the solids dissolved. The organic phase was washed with water (2 x 20 L), 2N NaOH (2 x 20 L), and brine (10 L), and the organics were dried over sodium sulfate. The solids were filtered off, and the mixture was concentrated in vacuo to give H184 (2.1 kg) as a tan solid. In total, 9 kg of J0 / A0 (about 93% purity, 34.6 mol) was converted to 5.29 kg of H184 (17.3 mol, 50% yield).

[0491] 1 H NMR (400 MHz, DMSO-d6) δ 13.06 (s, 1H), 7.99 (d, J = 1.1 Hz, 1H), 7.89 (d, J = 1.0 Hz, 1H), 7.60 (s, 1H), 7.47 (s, 1H), 7.04 - 6.94 (m, 2H), 6.84 - 6.73 (m, 2H).

[0492] Step 2: Synthesis of 5-(4-fluorophenyl)-6-isopropyl-1,5-dihydropyrrolo[2,3- f]indazole (T3)

[0493] H184 (12.24 g, 39.983 mmol, 1 equiv), copper iodide (0.533 g, 2.799 mmol, 0.07 equiv) and Pd(PPh3)2Cl2(0.281 g, 0.4 mmol, 0.01 equiv) were suspended in degassed IPA (97.92 mL, 0.408 M, 8 vol). Potassium hydroxide (5.608 g, 14.02 mL, 40 w / v%, 99.957 mmol, 2.5 equiv) was added and the reaction was purged with nitrogen. Trimethyl(3-methylbut-1-yn-1-yl)silane (7.292 g, 8.103 mL, 0.9 g / mL, 51.977 mmol, 1.3 equiv) was added via syringe and the mixture was purged with nitrogen. The reaction was heated to an internal temperature of 75-80 °C. Once the reaction was complete, acetic acid (11.405 g, 10.883 mL, 1.048 g / mL, 189.917 mmol, 4.75 equiv) was added over 5 minutes at 77 °C and the reaction was stirred for at least 2 hours. The reaction was cooled to ambient temperature, NaHSO310.6 wt% (97.92 mL, 0.408 M, 8 vol) was added followed by IPAC (122.4 mL, 0.327 M, 10 vol). Water (24.48 mL, 1.633 M, 2 vol) was added, the mixture was heated to 55 °C for 2 hours. The mixture was cooled and the phases were separated. The organic layer was treated with NaHSO310.6 wt% (55 mL, 0.727 M, 4.493 vol) in water at 55 °C, the mixture was cooled to ambient temperature and the phases were separated. The organic layer was treated with a mixture of half-saturated aqueous NH4Cl (100 mL, 0.4 M, 8.17 vol) and aqueous NH4OH (24 mL, 1.666 M, 1.961 vol). The layers were separated and the organic layer was treated with half-saturated aqueous NH4Cl (100 mL, 0.4 M, 8.17 vol). The layers were separated and the organic layer was treated with acetic acid to give a pH of 5. The organic layer was separated and the solvent was exchanged for toluene. The product was isolated from 6 vol of toluene by heating the mixture to an internal temperature of 85 °C. The solution was then cooled to 45 °C and stirred for 1 hour to form a solid precipitate. The mixture was further cooled to ambient temperature over 2 hours and then stirred at 24 °C for 30 minutes. The resulting slurry was filtered and the reactor with toluene and wet cake was drop-washed and the material was dried in a vacuum oven at 50 °C with nitrogen bleed to give the product T3 as a solid in 63% yield.

[0494] Example 6: Large scale synthesis of compound 2-5-bromo-6-iodo-1H-indazole as starting material

[0495] Scheme 8 describes the large scale synthesis of compound 2 utilizing 5-bromo-6-iodo-1H-indazole (H7) as the starting material. This process is expected to produce at least about 300 kg of compound 2 or a pharmaceutically acceptable salt thereof in solid form.

[0496] Scheme 8

[0497]

[0498] Step 1B: Synthesis of 5-bromo-6-(3-methylbut-1-yn-1-yl)-1H-indazole (H8)

[0499] To the reactor was added the starting material 5-bromo-6-iodo-1H-indazole (H7) (1.00 equivalents, 1.00 w / w equivalents), followed by Cul (0.100 equivalents, 0.0590 w / w equivalents) and bis(triphenylphosphine)palladium dichloride (0.001 equivalents, 0.0043 w / w equivalents) catalyst. Ethanol (5.00 volumes, 3.95 w / w equivalents) was added to the reactor and stirring was initiated. The temperature was adjusted to 20 ± 5 °C and an aqueous potassium hydroxide solution was prepared by adding potassium hydroxide (2.10 equivalents) and 1.04 volumes of total water addition (1.04 w / w equivalents). The aqueous potassium hydroxide solution was added to the reactor and the temperature was maintained at 20 ± 5 °C to replace the potassium hydroxide as described in the previously published process using triethylamine or triethylamine as the base in Scheme 2. The reaction vessel was inertized with nitrogen while the mixture was stirred by performing 3 to 4 pressure-purge cycles or evacuation-purge cycles. Ammonium hydroxide solution (28-30 wt%, 0.500 equivalents, 0.194 wt equivalents) was added to the reactor and the temperature was maintained at 20 ± 5 °C, and trimethyl(3-methylbut-1-yn-1-yl)silane (1.20 equivalents, 0.521 w / w equivalents) was added to the reactor while the temperature was maintained at 20 ± 5 °C. Instead of trimethyl(3-methylbut-1-yn-1-yl)silane, H7 was reacted with 3-methylbut-1-yn in the previously published process as described in Scheme 2.

[0500] The reaction vessel was again inertized with nitrogen while the mixture was stirred by performing 1 to 2 pressure-purge cycles or evacuation-purge cycles. The mixture was heated to 75 ± 5 °C, stirred for not less than 24 hours, and an IPC sample was withdrawn to confirm reaction completion (IPC-1). While this IPC step was being performed, the reaction vessel was again made inert with nitrogen. If the IPC target was not met, the reaction was stirred for not less than 1 additional hour and resampled. After the IPC target was met, the reaction mixture was cooled to 25 ± 5 °C and then concentrated to ~ 3.0 volumes. To the concentrated mixture was added dichloromethane (5.0 volumes, 6.64 w / w equivalents). A 20 wt% aqueous ammonium chloride solution (9.0 volumes total) was added to the reaction while maintaining the temperature at 25 ± 5 °C, and the resulting two-phase mixture was stirred at 25 ± 5 °C for not less than 0.5 hours. Stirring was stopped to allow the phases to settle for not less than 0.5 hours. The bottom organic phase was first drained from the reactor, followed by the top aqueous phase, and samples were taken of both phases. The organic phase was returned to the reactor and stirring was commenced. The temperature of the organic phase was adjusted to 25 ± 5 °C, and the remaining 3.0 volumes of the aqueous ammonium chloride solution was added to the organic phase while maintaining the temperature at 25 ± 5 °C, and the steps of stirring the two-phase mixture, stopping the stirring to allow the phases to settle, draining and sampling the phases, and returning the organic phase to the reactor were repeated. A solution was prepared containing water (2.0 volumes, 2.00 w / w equivalents) and 8.5 wt% phosphoric acid (0.03 volumes, 0.0313 w / w equivalents), and the prepared phosphoric acid solution was added to the organic phase, followed by the addition of 1 M HCl (0.14 volumes, 0.143 w / w equivalents) while maintaining the temperature at 25 ± 5 °C, and the steps of stirring the two-phase mixture, stopping the stirring to allow the phases to settle, draining and sampling the phases, and returning the organic phase to the reactor were again repeated. Water (2.0 volumes, 2.00 w / w equivalents) was added to the organic phase while maintaining the temperature at 25 ± 5 °C, and the steps of stirring the two-phase mixture, stopping the stirring to allow the phases to settle, draining and sampling the phases, and returning the organic phase to the reactor were once again repeated. Vacuum was applied, and the reaction mixture was distilled to a total of 3 volumes while maintaining the internal temperature at or below 35 °C, followed by the addition of dichloromethane (4.0 volumes, 5.31 w / w equivalents) and sampling the residual ethanol and water content (repeated 3 times). Next, the mixture was heated to 35 ± 5 °C and stirred for not less than 15 minutes, n-heptane (2.6 volumes, 1.78 w / w equivalents) was added, and then heated to 40 ± 5 °C. While maintaining the temperature at 40 ± 5 °C, n-heptane (2.0 volumes, 1.37 w / w equivalents) was again added over not less than 30 minutes, the batch was stirred for not less than 30 minutes, and the formation of nucleated solids was monitored. If solids nucleated, n-heptane (7.7 volumes, 5.27 w / w equivalents) was added over not less than 12 hours. If solids did not nucleate, the batch was cooled to 35 ± 5 °C and stirred for not less than 1 hour, and then n-heptane was added over not less than 12 hours.The batch is cooled to 20 ± 5 °C over not less than 7 hours, then stirred at 20 ± 5 °C for not less than 2 hours. The solids are isolated by filtration or centrifugation, and the mother liquor is sampled. A wash solution is prepared by mixing dichloromethane (0.75 volumes, 0.995 w / w equivalents) and n-heptane (2.25 volumes, 1.54 w / w equivalents). The wet cake is washed with the prepared wash solution, and both the wash and the wet cake are sampled. To the wet cake is added n-heptane (3.0 volumes, 2.05 w / w equivalents), vacuum is applied, and the wash is sampled (repeat twice). After drying, the solids are dried under vacuum at a jacket temperature of 50 ± 5 °C, the jacket is cooled, and the solids are discharged. The solids, H8, are sampled for palladium and copper analysis. The maximum batch volume in Step IB is 14 volumes by water wash and 17 volumes in the crystallization process.

[0501] Step 2B: Synthesis of 5-(4-fluorophenyl)-6-isopropyl-1,5-dihydropyrrolo[2,3- f]indazole (T3)

[0502] Sodium tert-butoxide (NaOtBu) was combined with ethanol (8.0 volumes, 6.31 w / w equivalents), stirring was initiated, and the mixture was cooled to 20 ± 5 °C. H8 from Step IB was added to the mixture, followed by the addition of 4-fluoroaniline (1.13 equivalents, 0.477 w / w equivalents), and the mixture was added to the reactor. Stirring was initiated, and the temperature was adjusted to 20 ± 5 °C, the initial reactor and lines were rinsed with ethanol. The reaction mixture was deoxygenated with four vacuum-nitrogen cycles. tBuXPhos Pd G3 (0.03 equivalents, 0.091 w / w equivalents) was added to the mixture as a catalyst, and the mixture was deoxygenated twice more as described above. The reaction mixture was heated to 65 ± 5 °C and stirred at the same temperature for not less than 2.5 hours, then sampled for reaction completion. The mixture was cooled to 55 ± 5 °C, acetic acid (4.75 equivalents, 1.08 w / w equivalents) was added while maintaining the batch temperature not greater than 60 °C, the mixture was stirred at 55 ± 5 °C for not less than 4 hours, and sampled for reaction completion. The mixture was cooled to 20 ± 5 °C, 2-methyltetrahydrofuran (2-MeTHF) (8.0 volumes, 6.83 w / w equivalents) was added to the reactor, and the mixture was stirred at 20 ± 5 °C for not less than 30 minutes. The slurry was filtered with Celite to obtain a filtrate. The reactor and wet cake were rinsed with 2-MeTHF (2.0 volumes, 1.71 w / w equivalents), and vacuum was applied to obtain a rinsed filtrate. The filtrates were combined, then sampled. The solution was then heated to 50 ± 5 °C with stirring. A saturated aqueous sodium bisulfite solution was prepared for 2 aqueous washes by stirring sodium bisulfite in water until it dissolved (not less than 20 volumes). Half of the prepared saturated sodium bisulfite solution (10.0 volumes) was added to a vessel maintained at 50 ± 5 °C, and the mixture was stirred at 50 ± 5 °C for not less than 1 hour. Stirring was stopped, the phases were allowed to settle for not less than 30 minutes, then the bottom aqueous layer was drained. Both the organic and aqueous phases were sampled. The mixture was treated with the second half of the sodium bisulfite solution, and the steps of allowing the phases to settle without stirring, sampling the phases, and draining the bottom aqueous layer were also repeated. Next, the organic layer was stirred and cooled to 20 ± 5 °C, toluene (1.5 volumes, 1.30 w / w equivalents) was added to the reactor, followed by water (10.0 volumes) while maintaining the temperature at 20 ± 5 °C, the mixture was stirred at 20 ± 5 °C for not less than 30 minutes. Then, the steps of allowing the phases to settle without stirring, sampling the phases, and draining the bottom aqueous layer were repeated. The organic layer was stirred again, and water (10.0 volumes) was added to the reactor while maintaining the temperature at 20 ± 5 °C, the steps of allowing the phases to settle without stirring, sampling the phases, and draining the bottom aqueous layer were again repeated. The organic layer was fine filtered to remove any remaining solids, then the solution was transferred to a clean dry vessel. The filtered organic phase was then sampled.Apply agitation and vacuum and distill the reaction mixture to a total of 4.0 volumes while maintaining the jacket temperature at or below 40 °C, then add toluene (6.0 volumes, 5.20 w / w equivalents for the first two distillations, then 5.0 volumes, 4.34 w / w equivalents for the third distillation) (repeat 3 times). After the second and third distillations, sample the mixture for residual 2-MeTHF and ethanol. Stir the solution and heat to 90 ± 5 °C, then cool to 75 ± 3 °C, then stir the solution at 75 ± 2 °C for not less than 1 hour. If no self-nucleation is observed, heat the solution to 70 ± 3 °C and stir for an additional 1 hour, then proceed to the next step, which is to cool the reaction mixture to 20 ± 5 °C over 12 hours. Stir the resulting slurry at 20 ± 5 °C for not less than 5 hours, then sample by microscopy. Isolate the solids from the slurry by filtration or centrifugation, and sample the mother liquor. Add toluene (4.0 volumes, 3.47 w / w equivalents) to the crystallizer, then apply to the wet cake. Sample both the wash and the wet cake. Transfer the wet cake to a drying apparatus and dry at not more than 50 ± 5 °C until a constant loss on drying (LOD) is obtained. Sample the dried solids T3. The maximum volumes used in Step 2B are: water wash 31 volumes, crystallization 9 volumes.

[0503] Step 3-5: Synthesis of (E)-3-(5-(4-fluorophenyl)-6-isopropyl-1,5-dihydropyrrolo[2,3- f]indazol-7-yl)acrylic acid methyl ester (II), 3-(5-(4-fluorophenyl)-6-isopropyl-1,5- dihydropyrrolo[2,3-f]indazol-7-yl)propanoic acid methyl ester (H36), and Compound 2

[0504] The remaining steps 3, 4, and 5 of the method described in Scheme 8 are as described above (i.e., steps 3, 4, and 5 of the method described in Scheme 7B).

[0505] Optional recrystallization of Compound 2 for form conversion

[0506] The recrystallization step also applies to Compound 2 prepared using the method described in Scheme 8.

[0507] Example 7: Assays for detecting and measuring AAT modulator properties

[0508] A. AAT functional assay (MSD Assay NL20-SI cell line)

[0509] α-1 antitrypsin (AAT) is a SERPIN (serine protease inhibitor) that inactivates the enzyme by covalent binding. This assay measures the amount of functionally active AAT in a sample in the presence of either compound 1 or compound 2 by determining the ability of AAT to form an irreversible complex with human neutrophil elastase (hNE). In practice, the sample (cell supernatant, blood sample, or others) is incubated with an excess of hNE to allow the formation of an AAT-elastase complex with all functional AAT in the sample. This complex is then captured using a microplate coated with an anti-AAT antibody. The complex on the captured plate is detected with a labeled anti-elastase antibody and quantified using a set of AAT standards spanning the concentration range present in the sample. A Meso Scale Discovery (MSD) plate reader, sulfonated labeling, and microplates are used to provide high sensitivity and a wide dynamic range.

[0510] Materials :

[0511] Reagent / plate concentration

[0512] Goat anti-human α-1-antitrypsin at 1 mg / mL

[0513] Under polyclonal antibody, 1 mL

[0514] Use at 5 μg / mL in phosphate-buffered saline (PBS)

[0515] 100 μg of human neutrophil elastase lyophilized

[0516] Store at 3.4 μM (0.1 mg + 1 mL PBS).

[0517] 1% bovine serum albumin (BSA) was measured in MSD buffer.

[0518] μg / mL (34nm) is effective

[0519] Mouse anti-human neutrophil elastase monoclonal antibody 900 μg / mL

[0520] Using MSDGold sulfonyl labeling

[0521] N-hydroxysuccinimide (NHS) ester was subjected to sulfonation at a ratio of 12:1.

[0522] Note: 0.45 μg / mL in MSD assay buffer (1% BSA).

[0523] use

[0524] M-AAT (α-1-antitrypsin) 5mg lyophilized

[0525] MSD Blocker A (BSA) 250 mL

[0526] 5% solution in PBS for blocking

[0527] 1% solution in PBS for assay buffer

[0528] MSD Read Buffer T with surfactant (4X) 1 L or 250 mL MSD 384 High Binding Plates

[0529] Polypropylene for dilution of 384 well plates

[0530] Black-well 384 well plates for tissue culture handling

[0531] Instruments :

[0532] Meso Sector S600

[0533] Bravo

[0534] Washer dispenser

[0535] Multidrop Combi

[0536] Assay Protocol

[0537] Day 1 cell culture

[0538] 1. Harvest NL20 human bronchial epithelial cells expressing human Z-AAT in OptiMEM with Pen / Strep (P / S). TM

[0539] 2. Seed at 16,000 cells / well in 30 pL (384 well plate).

[0540] 3. Centrifuge plates briefly (1200 rpm) and place in 37 °C incubator overnight.

[0541] Day 2: Compound addition and plate coating with capture antibody

[0542] Compound addition:

[0543] 1. Using multidrop Combi in a fume hood, dispense 40 pL of OptiMEM with doxycycline (1:1000 stock = 0.1 pM final) into each well of the compound plate. TM

[0544] 2. Remove cell plate from incubator, invert / suck dry and immediately take to Bravo to transfer compounds ​​

[0545] 3. Place plates back in the incubator overnight.

[0546] Coat MSD plates

[0547] 1. Dilute capture antibody (polyclonal goat anti-AAT) to 5 pg / mL (1 :200) in PBS (no BSA).

[0548] 2. Use Multidrop equipped with standard tips to dispense 25 pL of diluted capture antibody to all wells of the MSD 384-well high binding plate.

[0549] 3. Incubate overnight at 4°C.

[0550] Prepare Blocker A (BSA) solution

[0551] 1. Follow manufacturer’s instructions to prepare a 5% MSD Blocker A (BSA) solution.

[0552] 2. Further dilute 5% MSD Blocker A in PBS to 1% (Blocker A) as needed.

[0553] Day 3: Run MSD assay

[0554] Block plates

[0555] 1. Wash plates lx with 50 pL wash buffer (PBS + 0.5% Tween 20) and add 35 pL of 5% Blocker A buffer to block non-specific binding on the washer dispenser.

[0556] 2. Spin plates at 600 rpm for 1 hour on a shaker.

[0557] Prepare M-AAT standards

[0558] 1. Dilute M-AAT stock to 1.6 pg / mL in 1% BSA Blocker A (stored at -70°C); then prepare 12 x 1 :2 serial dilutions in 1% Blocker A.

[0559] 2. Highest starting final concentration on MSD plates is 320 ng / mL. These dilutions correspond to concentrations of 320, 160, 80, 40, 20, 10, 5, 2.5, 1.25, 0.625, 0.312, 0.156 ng / mL.

[0560] Dilute plates

[0561] 1. Add 80 pL of 1% assay buffer to all wells except column 1 / 24 (standards) using Multidrop Combi.

[0562] 2. Add diluted standards to columns 1 and 24.

[0563] 3. Centrifuge dilution plate at 1200 rpm briefly.

[0564] Cell plate

[0565] 1. Aspirate columns containing standards from cell plate using 16 needle aspirator in fume hood.

[0566] Prepare human neutrophil elastase (hNE)

[0567] 1. Prepare 1 pg / mL human neutrophil elastase by diluting in 1% Blocker A.

[0568] a. Small 100 pg tube - add 1 mL PBS (100 pg / mL)

[0569] i. This can then be diluted 1 : 100 in 1% assay buffer to a final 1 pg / mL concentration.

[0570] MSD - Add hNE (20 pL / well)

[0571] 1. After MSD plate has been blocked for at least 1 hour, wash plate 1x with 50 pL. Wash buffer (PBS + 0.5% Tween 20) then add 20 pL hNE to each well.

[0572] Bravo - Cell plate - Dilution plate - MSD plate

[0573] Use Bravo to aspirate 10 pL from cell plate, transfer to dilution plate (9-fold dilution).

[0574] 1. Mix 25 pL 3x, then aspirate 5 pL, transfer to MSD plate (5-fold dilution).

[0575] 2. Mix 10 pL 3x. Total dilution is 45-fold.

[0576] 3. Shake plate at 600 rpm for 1.5 hours.

[0577] Add functional detection hNE antibody

[0578] 1. Wash plate 1x with wash buffer.

[0579] 2. Add 25 pL sulfotag labeled anti-elastase (monoclonal mouse anti-elastase) diluted to 0.45 pg / mL (1 :2000) in 1% Blocker A to all wells of functional active MSD plate using washer / dispensers.

[0580] NotesThe dilution required to achieve sufficient signal for each new lot of labeled antibody must be determined.

[0581] 3. Incubate at room temperature with shaking at 600 rpm for 1 hour.

[0582] Final wash and MSD imager readout

[0583] 1. Wash the plate lx and add 25 μL wash buffer to the plate.

[0584] 2. Prepare 2x read buffer.

[0585] 3. Remove wash buffer from the MSD plate.

[0586] 4. Transfer 35 μL 2x read buffer to the MSD plate using Bravo and immediately read the MSD.

[0587] Data analysis and EC values in MSD Discovery Workbench 4.0 software 50 Values determined using Genedata.

[0588] B. Biochemical Assay (Z-AAT Elastase Activity Assay)

[0589] This assay measures the modulation of Z-AAT SERPIN activity by Compound 1 or Compound 2 using purified Z-AAT and purified human neutrophil elastase (hNE). Normally, when the active monomer Z-AAT encounters a protease such as trypsin or elastase, it forms a 1 : 1 covalent "suicide" complex in which both the AAT and the protease are irreversibly inactivated. However, binding of a compound to Z-AAT can result in decreased SERPIN activity. In such cases, when the protease encounters the compound-bound Z-AAT, the protease cleaves and inactivates the Z-AAT without being inactivated itself.

[0590] Materials

[0591] Reagents

[0592] PBS buffer (medium formulation) + 0.01% BRIJ 35 detergent (Calbiochem catalog # 203728)

[0593] Opti-MEM medium (Fisher catalog # 11058-021)

[0594] Human neutrophil elastase (hNE, Athens Research catalog # 16-14-051200)

[0595] 3.4 mM stock (0.1 mg / mL) prepared in 50 mM sodium acetate, pH 5.5, 150 mM NaCl, stored at -80 °C

[0596] Elastase Substrate V (ES V, fluorescent peptide substrate MeOSuc-Ala-Ala-Pro-Val-AMC, Calbiochem Cat# 324740)

[0597] 20 mM stock in DMSO, stored at -20 °C

[0598] Z-AAT protein purified from human plasma;

[0599] 12.9 mM (0.67 mg / mL) Z-AAT Vertex Cambridge sample 4942 from patient #061-SSN, stored at -80 °C

[0600] Plate

[0601] Corning 4511 (384-well black low volume)

[0602] Instrument

[0603] EnVision TM

[0604] Assay Protocol

[0605] Pre-incubation of Z-AAT with compounds

[0606] 1. 7.5 pL of Z-AAT (20 nM) was incubated with Compound 1 or Compound 2 in GCA plate for 1 hour at room temperature.

[0607] Addition of hNE

[0608] 1. 7.5 pL of HNE solution (3 nM in PBS + 0.01% BRIJ35) was added to the GCA plate.

[0609] 2. The plate was incubated for 30 minutes to allow Z-AAT / HNE suicide complex formation.

[0610] Addition of substrate and reading of the plate on PE Envision

[0611] 1. 7.5 pL of substrate (300 pM solution of Elastase Substrate (ES V) in PBS + 0.01% BRIJ35) was dispensed into each well of the GCA plate.

[0612] 2. Immediately read on Envision.

[0613] C. IC50values for Compound 1 and Compound 2 50 and EC50values for Compound 1 and Compound 2 50 Data

[0614] Compound 1 and Compound 2 are useful as modulators of AAT activity. The IC50value for Compound 1 50 (Z-AAT elastase activity) is greater than 1.0 M, the EC50value for Compound 1 50 (NL20 function) is less than 0.4 μM. The IC50value for Compound 2 50 (Z-AAT elastase activity) is greater than 1.0 μM. The EC50value for Compound 2 50 (NL20 function) is less than 0.4 μM.

[0615] Other Embodiments

[0616] The present disclosure provides only exemplary embodiments of the disclosed subject matter. Those skilled in the art will readily recognize from the disclosure and associated drawings herein, that changes and modifications can be made thereto without departing from the spirit and scope of the subject matter defined in the following claims.

Claims

1. A process for preparing Compound 1 in solid form: or a pharmaceutically acceptable salt thereof, comprising: and (a) reacting or a pharmaceutically acceptable salt thereof with to form or a pharmaceutically acceptable salt thereof. (b) de-esterifying C58B, or a pharmaceutically acceptable salt thereof, to obtain Compound 1 in solid form, or a pharmaceutically acceptable salt thereof.

2. The process of claim 1, wherein step (a) comprises reacting B1, or a pharmaceutically acceptable salt thereof, with D1 in the presence of a palladium-phosphine complex-based catalyst, which is bis(tri-tert-butylphosphine)Pd, and a base, which is potassium carbonate.

3. The process of claim 1 or claim 2, wherein step (a) comprises reacting B1, or a pharmaceutically acceptable salt thereof, with D1 in the presence of a solvent, which is 2-methyltetrahydrofuran.

4. The process of claim 1 or claim 2, wherein step (a) comprises reacting B1, or a pharmaceutically acceptable salt thereof, with D1 at 75 °C.

5. The process of claim 1 or claim 2, wherein step (b) comprises de-esterifying C58B, or a pharmaceutically acceptable salt thereof, with a base, which is sodium hydroxide, in the presence of a solvent, which is tetrahydrofuran.

6. The process of claim 1 or claim 2, wherein step (b) comprises de-esterifying C58B, or a pharmaceutically acceptable salt thereof, at 55-65 °C.

7. The process of claim 1, wherein the process further comprises:

8. The process of claim 7, wherein the process further comprises: (a2) reacting or a pharmaceutically acceptable salt thereof, with 4-fluorophenylboronic acid to form B1 or a pharmaceutically acceptable salt thereof.

9. The process of claim 8, wherein step (al) comprises reacting A0, or a pharmaceutically acceptable salt thereof, with pivaloyl chloride in the presence of a base, which is sodium tert-pentoxide, and a solvent, which is tetrahydrofuran. (a1) reacting or a pharmaceutically acceptable salt thereof, with pivaloyl chloride to form A1 or a pharmaceutically acceptable salt thereof.

10. The process of claim 8 or claim 9, wherein step (al) comprises reacting A0, or a pharmaceutically acceptable salt thereof, with pivaloyl chloride at 10-20 °C.

11. The process of any one of claims 7 to 9, wherein step (a2) comprises reacting A1, or a pharmaceutically acceptable salt thereof, with 4-fluorophenylboronic acid in the presence of a phospholane oxide catalyst, which is hexamethyloxophospholane, and a solvent, which is toluene.

12. The process of any one of claims 7 to 9, wherein step (a2) comprises reacting A1, or a pharmaceutically acceptable salt thereof, with 4-fluorophenylboronic acid in the presence of a reducing agent, which is dimethylsilyloxy(dimethyl)silane.

13. The process of any one of claims 7 to 9, wherein step (a2) comprises reacting A1, or a pharmaceutically acceptable salt thereof, with 4-fluorophenylboronic acid at 90 °C.

14. The process of any one of claims 1, 2, and 7 to 9, wherein the process further comprises:

15. The process of claim 14, wherein the process further comprises: (b2) reacting the compound of formula (D1) with a compound of formula (D2) with an aqueous sodium chloride solution to produce D1.

16. The process of claim 14, wherein step (b2) comprises reacting E1 with the aqueous sodium chloride solution at 150 °C. (b1) reacting with oxan-4-carbonyl chloride to form E1. ​ 17. The method of claim 14, wherein step (b2) comprises reacting E1 with the aqueous sodium chloride solution in the presence of a solvent, the solvent being dimethyl sulfoxide.

18. The method of claim 15, wherein step (bl) comprises reacting Fl with oxan-4- carbonyl chloride in the presence of a base and a solvent, the base being potassium tert- butoxide, the solvent being tetrahydrofuran.

19. A method for preparing Compound 1 in solid form: or a pharmaceutically acceptable salt thereof, comprising: and (i) reacting or a pharmaceutically acceptable salt thereof with trimethyl((tetrahydro-2H-pyran-4- yl)ethynyl)silane to form or a pharmaceutically acceptable salt thereof. (ii) reacting C13, or a pharmaceutically acceptable salt thereof, with benzenesulfonyl chloride to form or a pharmaceutically acceptable salt thereof. (iii) halogenating C15, or a pharmaceutically acceptable salt thereof, to form or a pharmaceutically acceptable salt thereof. (iv) reacting S6, or a pharmaceutically acceptable salt thereof, with (4- (ethoxycarbonyl)phenyl)boronic acid to form or a pharmaceutically acceptable salt thereof. (v) de-esterifying C57, or a pharmaceutically acceptable salt thereof, to obtain the Compound 1 in solid form, or a pharmaceutically acceptable salt thereof.

20. A method for preparing Compound 1 in solid form: or a pharmaceutically acceptable salt thereof, comprising: and (v) de-esterifying C58A, or a pharmaceutically acceptable salt thereof, or C58B, or a pharmaceutically acceptable salt thereof, to obtain the Compound 1 in solid form, or a pharmaceutically acceptable salt thereof. (i) reacting or a pharmaceutically acceptable salt thereof with trimethyl((tetrahydro-2H-pyran-4- yl)ethynyl)silane to form or a pharmaceutically acceptable salt thereof. (ii) reacting C13, or a pharmaceutically acceptable salt thereof, with pivaloyl chloride to form or a pharmaceutically acceptable salt thereof. (iii) halogenating C14, or a pharmaceutically acceptable salt thereof, to form or a pharmaceutically acceptable salt thereof; (iv) reacting S4, or a pharmaceutically acceptable salt thereof, with (4- (ethoxycarbonyl)phenyl)boronic acid to form or a pharmaceutically acceptable salt thereof; or alternatively reacting S4, or a pharmaceutically acceptable salt thereof, with (4-(methoxycarbonyl)phenyl)boronic acid to form or a pharmaceutically acceptable salt thereof; 21. The method of claim 19 or 20, wherein step (i) comprises reacting B1, or a pharmaceutically acceptable salt thereof, with trimethyl((tetrahydro-2H-pyran-4-yl)ethynyl)silane in the presence of a base, copper iodide, a palladium-phosphine complex-based catalyst, an alcohol, and an acid, the base being potassium hydroxide, the palladium-phosphine complex-based catalyst being bis(triphenylphosphine)palladium dichloride, the alcohol being 2-propanol, the acid being acetic acid.

22. The method of claim 19 or 20, wherein step (ii) comprises reacting C13, or a pharmaceutically acceptable salt thereof, with benzenesulfonyl chloride or pivaloyl chloride in the presence of a base and a solvent, the base being potassium tert-butoxide, the solvent being tetrahydrofuran.

23. The method of claim 19 or 20, wherein step (iii) comprises reacting C15, or a pharmaceutically acceptable salt thereof, or C14, or a pharmaceutically acceptable salt thereof, with l-iodopyrrolidine-2,5-dione in the presence of a solvent, the solvent being dichloromethane.

24. The method of claim 19 or 20, wherein step (iv) comprises reacting S6, or a pharmaceutically acceptable salt thereof, or S4, or a pharmaceutically acceptable salt thereof, with (4-(ethoxycarbonyl)phenyl)boronic acid or (4-(methoxycarbonyl)phenyl)boronic acid in the presence of a palladium-phosphine complex-based catalyst, optionally complexed with dichloromethane, and in the presence of a base selected from triethylamine, sodium carbonate, and potassium carbonate.

25. The method of claim 19 or 20, wherein step (v) comprises reacting C57, or a pharmaceutically acceptable salt thereof, C58A, or a pharmaceutically acceptable salt thereof, or C58B, or a pharmaceutically acceptable salt thereof, with a base in the presence of a solvent, the base being sodium hydroxide, the solvent being piperidine.

26. A method for preparing Compound 1 in solid form: or a pharmaceutically acceptable salt thereof, comprising: ​ ​ ​ (i) forming by a method comprising the steps of or a pharmaceutically acceptable salt thereof: (a) reacting 5-bromo-6-iodo-lH-indazole with trimethyl((tetrahydro-2H-pyran-4- yl)ethynyl)silane to form 5-bromo-6-((tetrahydro-2H-pyran-4-yl)ethynyl)-lH- indazole; (b) reacting 5-bromo-6-((tetrahydro-2H-pyran-4-yl)ethynyl)-lH-indazole with 4- fluoroaniline to form N-(4-fluorophenyl)-6-((tetrahydro-2H-pyran-4- yl)ethynyl)-lH-indazol-5-amine; and (c) reacting N-(4-fluorophenyl)-6-((tetrahydro-2H-pyran-4-yl)ethynyl)-lH- indazol-5-amine with AcOH to form C13, or a pharmaceutically acceptable salt thereof; and (ii) reacting C13, or a pharmaceutically acceptable salt thereof, with benzenesulfonyl chloride to form or a pharmaceutically acceptable salt thereof. (iii) halogenating C15, or a pharmaceutically acceptable salt thereof, to form or a pharmaceutically acceptable salt thereof. (iv) reacting S6, or a pharmaceutically acceptable salt thereof, with (4- (ethoxycarbonyl)phenyl)boronic acid to form or a pharmaceutically acceptable salt thereof. (v) de-esterifying C57, or a pharmaceutically acceptable salt thereof, to obtain the solid form of Compound 1, or a pharmaceutically acceptable salt thereof.

27. A method for preparing a solid form of Compound 1: or a pharmaceutically acceptable salt thereof, comprising: (a) reacting 5-bromo-6-iodo-lH-indazole with trimethyl((tetrahydro-2H-pyran-4- yl)ethynyl)silane to form 5-bromo-6-((tetrahydro-2H-pyran-4-yl)ethynyl)-lH- indazole; (i) forming by a method comprising the steps of or a pharmaceutically acceptable salt thereof: (b) reacting 5-bromo-6-((tetrahydro-2H-pyran-4-yl)ethynyl)-lH-indazole with 4- fluoroaniline to form N-(4-fluorophenyl)-6-((tetrahydro-2H-pyran-4- yl)ethynyl)-lH-indazol-5-amine; and (c) reacting N-(4-fluorophenyl)-6-((tetrahydro-2H-pyran-4-yl)ethynyl)-lH- indazol-5-amine with AcOH to form C13, or a pharmaceutically acceptable salt thereof; and (v) de-esterifying C58A, or a pharmaceutically acceptable salt thereof, or C58B, or a pharmaceutically acceptable salt thereof, to obtain the solid form of Compound 1, or a pharmaceutically acceptable salt thereof. (ii) reacting C13, or a pharmaceutically acceptable salt thereof, with pivaloyl chloride to form a pharmaceutically acceptable salt thereof. (iii) halogenating C14, or a pharmaceutically acceptable salt thereof, to form or a pharmaceutically acceptable salt thereof. (iv) reacting S4, or a pharmaceutically acceptable salt thereof, with (4- (ethoxycarbonyl)phenyl)boronic acid to form or a pharmaceutically acceptable salt thereof; or alternatively reacting S6, or a pharmaceutically acceptable salt thereof, with (4-(methoxycarbonyl)phenyl)boronic acid to form or a pharmaceutically acceptable salt thereof; 28. The method of claim 26 or 27, wherein step (ii) comprises reacting C13, or a pharmaceutically acceptable salt thereof, with benzenesulfonyl chloride or pivaloyl chloride in the presence of a base, which is potassium tert-butoxide, and a solvent, which is tetrahydrofuran.

29. The method of claim 26 or 27, wherein step (iii) comprises reacting C15, or a pharmaceutically acceptable salt thereof, or C14, or a pharmaceutically acceptable salt thereof, with l-iodopyrrolidine-2,5-dione in the presence of a solvent, which is dichloromethane.

30. The method of claim 26 or 27, wherein step (iv) comprises reacting S6, or a pharmaceutically acceptable salt thereof, or S4, or a pharmaceutically acceptable salt thereof, with (4-(ethoxycarbonyl)phenyl)boronic acid or (4- (methoxycarbonyl)phenyl)boronic acid in the presence of a palladium-phosphine complex-based catalyst, which is [l,l’-bis(diphenylphosphino)ferrocene]palladium(II) dichloride optionally complexed with dichloromethane, and a base selected from triethylamine, sodium carbonate, and potassium carbonate. ​ ​ 31. The method of claim 26 or 27, wherein step (v) comprises reacting C57, or a pharmaceutically acceptable salt thereof, C58A, or a pharmaceutically acceptable salt thereof, or C58B, or a pharmaceutically acceptable salt thereof, with a base, which is sodium hydroxide, in the presence of a solvent, which is piperidine.

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