Method for preparing AG-10, its intermediates, and its salts.

Abstract

To propose an improved synthesis method for AG-10, and to provide other forms of AG-10 that confer advantageous pharmacokinetic properties. [Solution] An improved method for preparing compounds of formula IX is provided. pharmaceutically acceptable salts of formulas I and Ib. JPEG2026127822000103.jpg35146 and the crystalline form of formula IX (AG-10) are also provided. The methods described herein offer improved yields and efficiencies, and the pharmaceutically acceptable salts and their crystalline forms offer unexpected pharmacokinetic properties. Other features and aspects of this disclosure will be apparent to those skilled in the art by reading the remainder of the specification.

Description

[Background technology]

[0001] [Cross-reference to related applications] This application is in accordance with U.S. Provisional Application No. 62 / 460,576 filed on 17 February 2017, under Section 119 of the U.S. Patent Act. Priority is claimed pursuant to section e), and the disclosure thereof is incorporated herein by reference in its entirety.

[0002] [Referencing the rights to inventions developed under federal government support] Not applicable.

[0003] [References to the "arrangement list," table, or computer program listing on the compact disc, submitted as an appendix.] Not applicable.

[0004] [Background of the Invention] Abnormal protein interactions and aggregation, resulting from incorrect protein folding and excessive activation of signaling pathways, are underlying causes of numerous human degenerative diseases. Therefore, targeting protein-protein interactions (PPIs) is therapeutically important.

[0005] To date, approved PPI inhibitors are proteins, not small molecule inhibitors. For example, therapeutic monoclonal antibodies (mAbs) are used to treat cancer, autoimmune diseases, infections, and neurodegenerative diseases. Therapeutic mAbs are expensive to manufacture, require administration by injection, and can trigger an immune response in patients. For these reasons, the development of small molecule inhibitors of PPIs is of interest.

[0006] One example of abnormal protein aggregation is the soluble protein transthyretin (TTR or prealbumin). TTR is a 55 kDa homotetrameric protein present in the blood and cerebrospinal fluid. Upon dissociation from its homotetrameric form, the TTR dimer can misfold into an amyloid-forming monomer. This has been observed in wild-type TTR as well as in over 100 different mutants. Previous studies have shown that stabilizing the tetrameric form of TTR suppresses the misfolding of the amyloid-forming monomer and subsequent TTR amyloid formation.

[0007] Recent studies have identified 3-(3,5-dimethyl-1H-pyrazole-4-yl)propoxy)-4-fluorobenzoic acid (AG-10) as a promising candidate for the treatment of TTR amyloid-related diseases, such as TTR amyloid cardiomyopathy. This compound is disclosed in WO 2014 / 100227. In particular, this disclosure does not provide any additional forms of AG-10, and the described synthetic method would not be suitable for industrial production.

[0008] Therefore, there is a need to propose an improved synthesis method for AG-10 and to provide other forms of AG-10 that confer favorable pharmacokinetic properties. This invention addresses these requirements and also provides the relevant advantages. [Overview of the project]

[0009] 〔overview〕 In one embodiment, the present disclosure relates to an improved method for preparing compounds of formula IX,

[0010] [ka]

[0011] (a) Compound of formula II

[0012] [ka]

[0013] Compound of formula III

[0014] [ka]

[0015] Contact with a first base and a first organic solvent to provide the compound of formula IV.

[0016] [ka]

[0017] (Here each R 1 These are independently halogenated or sulfonic acid esters; (b) The compound of formula IV is contacted with hydrazine and a second organic solvent to provide the compound of formula V.

[0018] [ka]

[0019] (c) Contact a compound of formula V with a sulfonating agent or halogenating agent to provide a compound of formula VI.

[0020] [ka]

[0021] (R here) 2 It is a halogen or sulfonic acid ester;

[0022] (d) Compound of formula VI to compound of formula VII

[0023] [ka]

[0024] , contact with a second base and a third organic solvent to provide the compound of formula VIII.

[0025] [ka]

[0026] (R here) 3 is C1~C 12 Alkyl, C2~C 12 Alkenyl, C1~C 12 A selection from the group consisting of alkynyl, C3-C8 cycloalkyl, heterocycloalkyl, aryl, and heteroaryl molecules, each of which may be substituted as needed. (e) The compound of formula VIII is brought into contact with a third base to give the compound of formula IX. To provide a method that includes the following.

[0027] In a second aspect, the disclosure provides pharmaceutically acceptable salts represented by formula I or Ib:

[0028] [ka]

[0029] (Here, X is a pharmaceutically acceptable anion of a protonic acid, and Y is a polyprotic acid.)

[0030] From a third perspective, this disclosure discloses crystal forms A to K of formula IX.

[0031] Other features, elements, and aspects of this disclosure will be evident from the accompanying drawings and the detailed description below. [Brief explanation of the drawing]

[0032] [Figure 1] Figure 1 shows the scheme described herein for the preparation of AG-10 and its intermediates. [Figure 2A-2F]Figures 2A-2F show pharmacokinetic results demonstrating the high bioavailability of AG-10 from various species. [Figure 3A-3F] Figures 3A-3F show pharmacokinetic results demonstrating the high bioavailability of AG-10 in male and female dogs at different dosages. [Figure 4] Figure 4 shows the powder X-ray diffraction (XRPD) pattern of the mesylate of formula IX. [Figure 5] Figure 5 shows the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) plots of the mesylate of formula IX. [Figure 6] Figure 6 shows the powder X-ray diffraction (XRPD) pattern of the edisylate of formula IX. [Figure 7] Figure 7 shows the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) plots of the edisylate of formula IX. [Figure 8] Figure 8 shows the powder X-ray diffraction (XRPD) pattern of the besylate of formula IX. [Figure 9] Figure 9 shows the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) plots of the besylate of formula IX. [Figure 10] Figure 10 shows the powder X-ray diffraction (XRPD) pattern of the tosylate of formula IX. [Figure 11] Figure 11 shows the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) plots of the tosylate of formula IX. [Figure 12] Figure 12 shows the powder X-ray diffraction (XRPD) pattern of the esylate of formula IX. [Figure 13] Figure 13 shows the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) plots of the esylate of formula IX. [Figure 14] Figure 14 shows the powder X-ray diffraction (XRPD) pattern of the bromide salt of formula IX. [Figure 15] Figure 15 shows the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) plots of the bromide salt of formula IX. [Figure 16] Figure 16 shows the powder X-ray diffraction (XRPD) pattern of the a-form of the nitrate of formula IX. [Figure 17] Figure 17 shows the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) plots of form a of nitrate of formula IX. [Figure 18] Figure 18 shows the powder X-ray diffraction (XRPD) pattern of the b-form nitrate of formula IX. [Figure 19] Figure 19 shows the powder X-ray diffraction (XRPD) pattern of the sulfate of formula IX. [Figure 20] Figure 20 shows the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) plots of the sulfate of formula IX. [Figure 21] Figure 21 shows the powder X-ray diffraction (XRPD) pattern of the oxalate of formula IX. [Figure 22] Figure 22 shows the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) plots of the oxalate of formula IX. [Figure 23] Figure 23 shows the powder X-ray diffraction (XRPD) pattern of the maleate of formula IX, form a. [Figure 24] Figure 24 shows thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) plots of form a of maleate of formula IX. [Figure 25] Figure 25 shows the powder X-ray diffraction (XRPD) pattern of the b-form maleate of formula IX. [Figure 26] Figure 26 shows thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) plots of form b of the maleate of formula IX. [Figure 27] Figure 27 shows the powder X-ray diffraction (XRPD) pattern of the acetate of formula IX. [Figure 28] Figure 28 shows the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) plots of the acetate of formula IX. [Figure 29] Figure 29 shows the powder X-ray diffraction (XRPD) pattern of L-malate of formula IX. [Figure 30] Figure 30 shows the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) plots of L-malate of formula IX. [Figure 31]Figure 31 shows the powder X-ray diffraction (XRPD) patterns of crystal form A of formula IX (three different samples). [Figure 32] Figure 32 shows the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) plots for crystal form A of equation IX. [Figure 33] Figure 33 shows the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) plots for crystal form A of equation IX. [Figure 34] Figure 34 shows the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) plots for crystal form A of equation IX. [Figure 35] Figure 35 shows a polarized light microscopy (PLM) image of crystal form A of formula IX. [Figure 36] Figure 36 shows the asymmetric unit structure of crystal form A of formula IX. [Figure 37] Figure 37 shows the dynamic vapor sorption (DVS) data for crystal form A of equation IX. [Figure 38] Figure 38 shows the powder X-ray diffraction (XRPD) patterns of crystal form A of formula IX before (bottom) and after (top) DVS. [Figure 39] Figure 39 shows a summary of the interconversions between the identified crystal forms A, B, C, E, G, H, I, and J. [Figure 40] Figure 40 shows the powder X-ray diffraction (XRPD) pattern of crystal form B of formula IX. [Figure 41] Figure 41 shows the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) plots for crystal form B of equation IX. [Figure 42] Figure 42 shows the powder X-ray diffraction (XRPD) patterns of crystal form B and reference crystal form I (bottom) before heating (top), after heating to 100°C (second from top), and after heating to 170°C (second from bottom). Upon heating, crystal form B transforms to crystal form I. [Figure 43] Figure 43 shows the powder X-ray diffraction (XRPD) pattern of the crystal form C of formula IX. [Figure 44] Figure 44 shows the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) plots for the crystal form C of equation IX. [Figure 45] Figure 45 shows the powder X-ray diffraction (XRPD) patterns of crystal form D of formula IX (upper plot) and crystal form F of formula IX (lower plot). [Figure 46] Figure 46 shows the powder X-ray diffraction (XRPD) pattern of crystal form E of formula IX. [Figure 47] Figure 47 shows the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) plots for crystal form E of equation IX. [Figure 48] Figure 48 shows the powder X-ray diffraction (XRPD) patterns of crystal form E of formula IX before heating (top), heated to 195°C (middle), and for reference crystal form I (bottom). Upon heating, form E transforms to form I. [Figure 49] Figure 49 shows the powder X-ray diffraction (XRPD) pattern of the crystal form G of formula IX. [Figure 50] Figure 50 shows the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) plots for crystal form G of equation IX. [Figure 51] Figure 51 shows the powder X-ray diffraction (XRPD) pattern of the H-type crystal form of formula IX. [Figure 52] Figure 52 shows the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) plots for the crystal form H of equation IX. [Figure 53] Figure 53 shows the 1H-NMR spectrum of the H-type crystal form of formula IX. [Figure 54] Figure 54 shows the powder X-ray diffraction (XRPD) patterns of the crystal form H of formula IX before heating (top), after heating at 120°C (middle), and for the reference crystal form I (bottom). Upon heating, the H form transforms to the I form. [Figure 55] Figure 55 shows the powder X-ray diffraction (XRPD) pattern of crystal form I of formula IX. [Figure 56] Figure 56 shows the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) plots for crystal form I of equation IX. [Figure 57]Figure 57 shows the powder X-ray diffraction (XRPD) patterns of crystal form I of formula IX (reference, top), before N2 purging (second from the top), after 1.5 hours of N2 purging (second from the bottom), and the reference crystal form B (bottom). Upon N2 purging, form I transforms to form B. [Figure 58] Figure 58 shows the thermogravimetric analysis (TGA) plot of the crystal form I of equation IX. [Figure 59] Figure 59 shows the powder X-ray diffraction (XRPD) pattern of the crystal form J of formula IX. [Figure 60] Figure 56 shows the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) plots for the crystal form J of equation IX. [Figure 61] Figure 61 shows the 1H NMR spectrum of the crystal form J of formula IX. [Figure 62] Figure 62 shows the powder X-ray diffraction (XRPD) patterns of crystal form J of formula IX before heating (top), after heating to 130°C (second from the top), reference crystal form A (second from the bottom), and reference crystal form I (bottom). Upon heating, form J transforms into a mixture of form A and form I. [Figure 63] Figure 63 shows the powder X-ray diffraction (XRPD) pattern of the K-type crystal form of formula IX. [Figure 64] Figure 64 shows the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) plots for the crystal form K of equation IX. [Modes for carrying out the invention]

[0033] [Detailed explanation] I. General Overview

[0034] This disclosure, in part, provides an improved method for preparing the compound of formula IX (AG-10) and its intermediates. The method newly described herein provides high yield and improved potency.

[0035] A complete synthesis scheme is provided in the abstract of the invention and in Scheme 1 (Figure 1), but those skilled in the art will understand that certain steps of this method are novel and can be carried out regardless of the origin of the starting materials or intermediates.

[0036] pharmaceutically acceptable salts of formulas I and Ib are also provided. These pharmaceutically acceptable salts possess remarkable pharmacokinetic properties that improve the bioavailability of the compounds of formula IX. Without being bound by any particular theory, the pharmaceutically acceptable salts of formulas I and Ib provide protonated pyrazoles on the compounds of formula IX that pair with protonic or polyprotonic anions. Unlike the pharmaceutically acceptable salts of formulas I and Ib, salts prepared from alkali hydroxides such as NaOH, or amphoteric ions of the compounds of formula IX, do not offer the beneficial properties described herein. In certain embodiments, the compounds of formula I are represented by the compounds of formula Ia, which are HCl salts of formula I. II. Definition

[0037] The term "compound of formula IX" refers to 3-(3-(3,5-dimethyl-1H-pyrazole-4-yl)propoxy)-4-fluorobenzoic acid, also known as AG-10, which has the following structure:

[0038] [ka]

[0039] This refers to compounds that possess [a certain characteristic].

[0040] In this specification, the terms “a” or “an” or “the” include not only embodiments having a single element but also embodiments having multiple elements. For example, the singular forms “a,” “an,” and “the” include multiple referents unless the context clearly indicates otherwise. For example, “a cell” includes multiple cells, and “the drug” includes one or more drugs known to those skilled in the art.

[0041] The term "alkyl" refers to a straight-chain or branched-chain, saturated aliphatic group having the indicated number of carbon atoms. Alkyl can contain any number of carbon atoms, for example C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 1-7 , C 1-8 , C 1-9 , C 1-10 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6 can be included. For example, C 1-6 alkyl includes, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, etc. Alkyl can refer to an alkyl group having 20 or fewer carbon atoms, for example, but not limited to, heptyl, octyl, nonyl, decyl, etc. The alkyl group may be substituted or unsubstituted. Specific substituents include hydroxyl, halogen, alkoxy, and amino groups. One of ordinary skill in the art will know that various substituents can be added to the alkyl group without departing from the teachings herein.

[0042] The term "alkenyl" refers to a straight-chain or branched-chain hydrocarbon having at least 2 carbon atoms and at least 1 double bond. Alkenyl can have any number of carbons, for example C2, C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 2-7 , C 2-8 , C 2-9 , C 2-10 , C3, C 3-4 , C 3-5 , C 3-6 , C4, C 4-5 , C4-6 , C5, C 5-6 and C6 may be included. The alkenyl group may have a suitable number of double bonds, for example, 1, 2, 3, 4, 5 or more, but is not limited to these. Examples of alkenyl groups include, but are not limited to, vinyl(ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexadienyl. The alkenyl group, like the alkyl group, may be substituted or unsubstituted.

[0043] The term "alkynyl" refers to a straight-chain or branched-chain hydrocarbon having at least two carbon atoms and at least one triple bond. Alkynnyls can have any number of carbon atoms, e.g., C2, C2 2-3 , C 2-4 , C 2-5 , C 2-6 , C 2-7 , C 2-8 , C 2-9 , C 2-10 , C3, C 3-4 , C 3-5 , C 3-6 , C4, C 4-5 , C 4-6 , C5, C 5-6 , and C6 may be included. Examples of alkynyl groups include, but are not limited to, acetylenyl, propynyl, 1-butynyl, 2-butynyl, isobutynyl, sec-butynyl, butadiinyl, 1-pentynyl, 2-pentynyl, isopentinyl, 1,3-pentadinyl, 1,4-pentadinyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadinyl, 1,4-hexadinyl, 1,5-hexadinyl, 2,4-hexadinyl, or 1,3,5-hexatriinyl. The alkynyl group, like the alkyl groups described above, may be substituted or unsubstituted.

[0044] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic, fused bicyclic, or bridging polycyclic ring system (assembly) containing 3 to 12 ring atoms or the number of atoms indicated. A cycloalkyl can contain any number of carbon atoms, for example, C 3-6 , C 4-6 , C 5-6 , C 3-8 , C 4-8 , C 5-8 , C 6-8 , C 3-9 , C 3-10 , C 3-11 , and C 3-12 This may include saturated monocyclic cycloalkyl rings, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl groups can also be partially unsaturated, having one or more double or triple bonds in the ring. 3-8 When the group is cycloalkyl, typical groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The cycloalkyl group may be substituted or unsubstituted. Those skilled in the art will understand that a number of different substituents can be included in the cycloalkyl group without departing from the teachings herein.

[0045] The term "heterocycloalkyl" refers to a saturated ring system having 3 to 12 ring members and 1 to 4 heteroatoms such as N, O, and S. Additional heteroatoms are also useful and include, for example, B, Al, Si, and P, but are not limited to these. Heteroatoms may be oxidized and can be, for example, -S(O)- and -S(O)2-, but are not limited to these. Heterocycloalkyl groups can contain any number of ring members, e.g., 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12. Any suitable number of heteroatoms, e.g., 1, 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4 heteroatoms can be included in a heterocycloalkyl group. Heterocycloalkyl groups, like cycloalkyl groups described above, may be substituted or unsubstituted.

[0046] The term "aryl" refers to an aromatic ring system having any appropriate number of ring atoms and any appropriate number of rings. An aryl group can contain any appropriate number, e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 ring atoms and 6-10, 6-12, or 6-14 ring members. An aryl group can be monocyclic, condense to form a bicyclic or tricyclic group, or be linked by bonds to form a biaryl group. Typical aryl groups include phenyl, naphthyl, and biphenyl. Other aryl groups include benzyl with a methylene linkage. Certain aryl groups have 6-12 ring members and can be, for example, phenyl, naphthyl, or biphenyl. Another aryl group has 6-10 ring members and can be, for example, phenyl or naphthyl. Some other aryl groups have 6 ring members and can be, for example, phenyl. Like the cycloalkyl groups described above, aryl groups may be substituted or unsubstituted.

[0047] The term "heteroaryl" refers to a monocyclic, fused bicyclic, or tricyclic aromatic ring system containing 5 to 16 ring atoms, where 1 to 5 of the ring atoms are heteroatoms such as N, O, or S. Additional heteroatoms, such as non-limited heteroatoms such as B, Al, Si, and P, are also useful. Heteroatoms may be oxidized and can be, for example, -S(O)- and -S(O)2-. A heteroaryl group can contain any number of ring atoms, e.g., 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitable number of heteroatoms, e.g., 1, 2, 3, 4, or 5, 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5 heteroatoms can be included in a heteroaryl group. A heteroaryl group may have 5 to 8 ring members and 1 to 4 heteroatoms, or 5 to 8 ring members and 1 to 3 heteroatoms, or 5 to 6 ring members and 1 to 4 heteroatoms, or 5 to 6 ring members and 1 to 3 heteroatoms. Heteroaryl groups can include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine, thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. Like the cycloalkyl groups described above, heteroaryl groups may be substituted or unsubstituted.

[0048] The term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0049] The term “hydration” refers to a chemical reagent containing water. In relation to the chemical transformation of step (a), “hydration” refers to a chemical reagent having a sufficient amount of water to complete the indicated chemical transformation. In certain embodiments, the hydrating reagent contains at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, or 20% by weight of water.

[0050] III. Embodiments of Disclosure A. Method for preparing the compound of formula IX In one embodiment, the present disclosure relates to an improved method for preparing compounds of formula IX,

[0051] [ka]

[0052] (a) Compound of formula II

[0053] [ka]

[0054] Compound of formula III

[0055] [ka]

[0056] Contact with a first base and a first organic solvent to provide a compound of formula IV.

[0057] [ka]

[0058] (Here each R 1 These are independently halogenated or sulfonic acid esters; (b) The compound of formula IV is brought into contact with hydrazine and a second organic solvent to obtain the compound of formula V.

[0059] [ka]

[0060] Provided; (c) Contact a compound of formula V with a sulfonating agent or halogenating agent to provide a compound of formula VI.

[0061] [ka]

[0062] (R here) 2 It is a halogen or sulfonic acid ester; (d) Compound of formula VI to compound of formula VII

[0063] [ka]

[0064] , contact with a second base and a third organic solvent to provide the compound of formula VIII.

[0065] [ka]

[0066] (R here) 3 is C 1-12 Alkyl, C 2-12 Alkenil, C 1-12 Alkinyl, C 3-8 Selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups, each of which may be substituted; and (e) A method is provided comprising contacting a compound of formula VIII with a third base to obtain a compound of formula IX.

[0067] Step (a) involves mixing the first base with an organic solvent to form the compound of formula II.

[0068] [ka]

[0069] and compounds of formula III

[0070] [ka]

[0071] When brought into contact with the compound of formula IV

[0072] [ka]

[0073] This includes providing.

[0074] Those skilled in the art will recognize that the compound of formula IV possesses both a nucleophilic and an electrophilic site, and that intramolecular transformation is possible depending on the reaction conditions. For example, under certain conditions, the alcohol group of formula IV can be added to one of the carbonyl carbons to form a six-membered ring (formula IVa). When the above addition is coupled with a subsequent elimination reaction, the compound of formula IV has the structure of formula IVb. It will be obvious to those skilled in the art that the compound of formula IV may exist as an enol-replacement isomer of formula IVc.

[0075] [ka]

[0076] The compounds of formulas IV, IVa, IVb, and IVc interconvert, and depending on the reaction conditions, varying concentrations of these compound species exist. In some embodiments, only a single species is present.

[0077] Many suitable bases exist that can be used in this conversion. For example, in some embodiments, the first base is an alkali metal carbonate, an alkali metal bicarbonate, or a combination thereof. Examples of alkali metal carbonates, but not limited to, include Li2CO3, Na2CO3, and K2CO3; and examples of alkali metal bicarbonates, but not limited to, include LiHCO3, NaHCO3, and KHCO3. In some embodiments, the alkali metal carbonate is K2CO3.

[0078] The organic solvent in step (a) is a solvent that adequately dissolves both compounds of formula II and formula III in solution and is miscible with the base used. Those skilled in the art will recognize that there are numerous organic solvents that satisfy these specific requirements. In some embodiments, the first organic solvent is a polar organic solvent. In some embodiments, the polar organic solvent is selected from the group consisting of acetone, ethyl acetate, dichloromethane, tetrahydrofuran, dimethylformamide, and acetonitrile. In some embodiments, the organic solvent is acetone.

[0079] The transformation in step (a) also includes at least one equivalent of water to produce the hydroxyl-containing compound of formula IV. Often, this equivalent of water is provided by a reagent or solvent in the reaction mixture, such as a first base or an organic solvent, rather than by direct addition of water. The use of a hydrated base in the chemical transformation in step (a) provides a very efficient transformation. For this reason, in some embodiments, the first base in the transformation of step (a) is a hydrated base (hydrated base). In some embodiments, the first base is a hydrated alkali metal carbonate. In some embodiments, the first base is hydrated K2CO3.

[0080] The compound of formula III has two R 1 The compound contains a group, each independently selected from the group consisting of chlorides, bromides, tosylates, and mesylates. In some embodiments, each R 1 That is bromide.

[0081] Each R 1 The group acts as a leaving group in the transformation of step (a); here, those skilled in the art will recognize that other leaving groups are also useful in the present invention and that they do not depart from the teachings herein.

[0082] In some embodiments, the compound of formula IV obtained in step (a) is used directly in the transformation in step (b) without purification.

[0083] Moving on to step (b), the chemical transformation described is the compound of formula IV.

[0084] [ka]

[0085] The method involves contacting with hydrazine (N2H4) and a second organic solvent to provide a compound of formula V.

[0086] [ka]

[0087] Those skilled in the art will understand that a wide variety of solvents can be used as the second organic solvent in this conversion. In some embodiments, the second organic solvent is a polar protic organic solvent. In some embodiments, the polar protic organic solvent is C 1-8 It is -OH. In some embodiments, the polar protic organic solvent is ethanol.

[0088] In some embodiments, the compound of formula V obtained in step (b) is used directly in the conversion in step (c) without purification.

[0089] The chemical transformation in step (c) includes providing a compound of formula (VI) by substituting a halogen with a hydroxyl component in the compound of formula V, or by converting the hydroxyl component to a sulfonic acid ester.

[0090] [ka]

[0091] Although sulfonating agents or halogenating agents are particularly envisioned as starting materials for this conversion, those skilled in the art will know that in addition to halogens and sulfonic acid esters, there are many other types of leaving groups, R 2 You will understand that it is a suitable substituent of R. 2 Any starting material capable of generating a suitable leaving group at the appropriate position falls within the scope of the present invention.

[0092] Numerous solvents are suitable for this conversion; however, since a particular solvent is not suitable for all starting materials, those skilled in the art will recognize that the solvent chosen for this chemical conversion will depend on the selection of the sulfonating agent or halogenating agent. For example, polar organic solvents are particularly useful when contacting the compound of formula V with a halogenating agent. In one embodiment, the polar organic solvent is 1,2-dichloroethane.

[0093] Examples of halogenating agents useful for the conversion in step (c) include, but are not limited to, PBr3, PCl3, PCl5, SOBr2, PBr5, and SOCl2. Examples of sulfonating agents for the conversion in step (c) include, but are not limited to, mesyl chloride (MsCl) and tosyl chloride (TsCl). In some embodiments, the halogenating agent is PBr3.

[0094] R 2 The nature of R depends on the starting material selected for the chemical transformation in step (c). For example, if a sulfonating agent is selected, 2 The characteristic of is the corresponding sulfate. In one embodiment, R 2 These are chlorides, bromides, tosylates, and mesylates. In one embodiment, R 2 That is Br. Focusing on step (d), the compound of formula VI

[0095] [ka]

[0096] and the compound of formula VII

[0097] [ka]

[0098] When these are contacted in the presence of a base and a third organic solvent, they provide a compound of formula VIII:

[0099] [Chemical formula]

[0100] The chemical transformation of step (d) can be carried out using a variety of bases. For example, in some embodiments, the second base is an alkali metal carbonate, an alkali metal bicarbonate, or a combination thereof. Non-limiting examples of alkali metal carbonates include Li2CO3, Na2CO3, and K2CO3, and non-limiting examples of alkali metal bicarbonates include LiHCO3, NaHCO3, and KHCO3. In some embodiments, the alkali metal carbonate is K2CO3.

[0101] The organic solvent for step (d) is one that appropriately dissolves both compounds of Formula VI and Formula VII in solution and is miscible with the base used. Those skilled in the art will recognize that there are numerous organic solvents that meet these criteria. In some embodiments, the third organic solvent is a polar aprotic organic solvent. In some embodiments, the polar organic solvent is selected from the group consisting of acetone, ethyl acetate, dichloromethane, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, and acetonitrile. In some embodiments, the third organic solvent is dimethylformamide. In some embodiments, the third organic solvent is dimethyl sulfoxide.

[0102] R 3 Suitable substituents for the group include those that do not interfere with the chemical transformation of step (e) described in detail below. Such substituents include, but are not limited to, C 1-8 alkyl, C 3-8 cycloalkyl, C 3-12 heterocycloalkyl, aryl, heteroaryl, and the like. Those skilled in the art will recognize that numerous other ester substituents for R 3 are suitable without departing from the teachings of this specification. In some embodiments, R 3 is C 1-8 alkyl. In some embodiments, R 3 is methyl.

[0103] In some embodiments, the method of step (d) provides the compound of formula VIII in a yield (moles / moles) of at least 70% with respect to the amount of formula VII.

[0104] Regarding step (e), the compound of formula VIII

[0105] [ka]

[0106] It is contacted with a third base to provide the compound of formula IX.

[0107] [ka]

[0108] The third base used in the chemical transformation of step (e) can be a number of different bases. For example, in some embodiments, the third base is a metal hydroxide. In some embodiments, the metal hydroxide is an alkali metal hydroxide. In some embodiments, the alkali metal hydroxide is selected from the group consisting of LiOH, NaOH, KOH, RbOH, and CsOH. In some embodiments, the alkali metal hydroxide is LiOH. In some embodiments, the alkali metal hydroxide is NaOH.

[0109] Those skilled in the art will know that a wide variety of solvents can be used as the solvent for the transformation in step (e). For example, in some embodiments, the second organic solvent is a polar protic organic solvent or water. In some embodiments, the polar organic solvent is C 1-8 It is -OH. In some embodiments, the polar protic organic solvent is methanol. In some embodiments, the solvent is water. In some embodiments, the solvent is a combination of methanol and water.

[0110] In some embodiments, the process of step (e) is further (ei) Remove the solvent to obtain the residue; (e-ii) Dissolve the residue in water to produce a solution; (e-iii) Acidify the solution to form a precipitate; and (e-iv) The above solution is filtered to provide formula IX isolated from the solution. This further includes the fact that steps (ei) to (e-iv) are performed after step (e).

[0111] Step (ei) can be carried out using any suitable removal step, such as reduced pressure, increased temperature, or a combination of both. In some embodiments, the solvent is removed by distillation under reduced pressure. In some embodiments, a solid is produced in step (e), and the solvent is removed by filtration. Furthermore, the addition of water in steps (e-ii) can be carried out before step (ei). In such cases, the removal of the solvent under reduced pressure provides a concentrated aqueous component (i.e., water is not removed). Reordering steps (ei) and (e-ii) does not deviate from the scope of the method described herein.

[0112] In step (e-iii), the solution can be acidified using any suitable acid. In some embodiments, the suitable acid is HCl. In some embodiments, the solution is acidified to a pH of 3 or less, 0-3, or 2-3 or less. In some embodiments, the solution is acidified to a pH of about 2. In some embodiments, the solution is acidified to a pH of 2 or less, 0-2, or 1-2. In some embodiments, the solution is acidified to a pH of about 1.4-1.6.

[0113] The pH of the acidification steps (e-iii) determines the dominant species produced. In some embodiments, the pH of the acidification steps is in the range of 5 to 6, and the amphoteric form of formula IX is produced. In some embodiments, the pH is acidified with HCl to less than about 2 or in the range of 1.4 to 1.6 to produce the HCl salt of formula IX (i.e., the compound of formula Ia).

[0114] The process described in step (e) can produce a compound of formula IX in high yield and high purity. In some embodiments, the yield of step (e) is greater than 85%, 90%, 93%, or 95% (mol / mol) based on the compound of formula VIII. In some embodiments, the purity of the compound of formula IX produced in step (e) is higher than 80%, 85%, 90%, 95%, or 97% (mol / mol).

[0115] In another embodiment, a method for preparing a compound of formula IX,

[0116] [ka]

[0117] (a) Compound of formula II

[0118] [ka]

[0119] Compound of formula III

[0120] [ka]

[0121] The adduct is provided by contacting it with a first base and a first organic solvent. Here each R 1 These are independently halogens or sulfonic acid esters; (b) The adduct is brought into contact with hydrazine and a second organic solvent to form a compound of formula V. Provide

[0122] [ka]

[0123] (c) Contact a compound of formula V with a sulfonating agent or halogenating agent to provide a compound of formula VI.

[0124]

Chem.

[0125] (where R 2 is a halogen or a sulfonic acid ester); (d) contacting the compound of formula VI with the compound of formula VII

[0126]

Chem.

[0127] in the presence of a second base and a third organic solvent to provide a compound of formula VIII

[0128]

Chem.

[0129] where R 3 is selected from the group consisting of C 1-12 alkyl, C[[ID=4"]] 2-12 alkenyl, C 1-12 alkynyl, C 3-8 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, each of which groups is optionally substituted; and (e) contacting the compound of formula VIII with a third base to provide a compound of formula IX A method is provided which comprises the above.

[0130] In some embodiments, the adduct formed in step (a) is a compound of formula IV, formula IVa, formula IVb, and / or formula IVc.

[0131] [[ID=]59]

Chem.

[0132] Those skilled in the art will understand that the compounds listed above are interchangeable and that the relative amounts of each compound depend on the experimental conditions.

[0133] As described above, those skilled in the art will understand that certain steps of the method can be carried out regardless of the origin of the starting materials or intermediates. B. Pharmaceutically acceptable salts of formula I

[0134] In a second embodiment, the present disclosure provides a pharmaceutically acceptable salt represented by formula I.

[0135] [ka]

[0136] (Here, X is a pharmaceutically acceptable salt of a protonic acid.)

[0137] A variety of protons are suitable for producing pharmaceutically acceptable salts of formula I. It is understood that the pharmaceutically acceptable salt of a proton depends on the proton used. For example, protons useful in this disclosure include hydrochloric acid, hydrobromic acid, sulfonic acid, tosylic acid (p-toluenesulfonic acid), methanesulfonic acid, nitric acid, or acetic acid. Thus, pharmaceutically acceptable anions of protons include chloride ions (Cl-) and bromide ions (Br-). - ), sulfonate ion (HS(O)2O - ), tosylate ion (TsO) - ), mesylate ion (MsO) - ), besylate ion (BeO - ), ethanesulfonate ion (EtSO3 - ), nitrate ion (NO3 - ), acetate ion (CH3C(O)O - ), glycolate ion (HO-CH2-C(O)O - ), or a combination thereof.

[0138] In some embodiments, the pharmaceutically acceptable anion of the protonic acid is the mesylate ion. In some embodiments, the mesylate salt of Formula IX characterized by the powder X-ray diffraction pattern substantially coincides with FIG. 4.

[0139] In some embodiments, the pharmaceutically acceptable anion of the protonic acid is the besylate ion. In some embodiments, the besylate salt of Formula IX characterized by the powder X-ray diffraction pattern substantially coincides with FIG. 8.

[0140] In some embodiments, the pharmaceutically acceptable anion of the protonic acid is the tosylate ion. In some embodiments, the tosylate salt of Formula IX characterized by the powder X-ray diffraction pattern substantially coincides with FIG. 10.

[0141] In some embodiments, the pharmaceutically acceptable anion of the protonic acid is the esylate ion. In some embodiments, the esylate salt of Formula IX characterized by the powder X-ray diffraction pattern substantially coincides with FIG. 12.

[0142] In some embodiments, the pharmaceutically acceptable anion of the protonic acid is the bromide ion. In some embodiments, the bromide salt of Formula IX characterized by the powder X-ray diffraction pattern substantially coincides with FIG. 14.

[0143] In some embodiments, the pharmaceutically acceptable anion of the protonic acid is the nitrate ion. In some embodiments, the nitrate salt of Formula IX characterized by the powder X-ray diffraction pattern substantially coincides with FIG. 18.

[0144] In some embodiments, the pharmaceutically acceptable anion of the protonic acid is the chloride ion, and the pharmaceutically acceptable salt of Formula I is represented by Formula (Ia):

[0145]

Chemical formula

[0146] In some embodiments, the salt of formula Ia is crystalline form A. In some embodiments, crystalline form A of formula I is characterized by a powder X-ray diffraction pattern having peaks at 12.0, 21.8, 25.9, 26.7 and 27.9° 2θ (±0.2° 2θ). In some embodiments, the powder X-ray diffraction pattern further comprises one or more peaks at 7.0, 10.3, 13.9, 15.6 and / or 17. Crystalline form A of formula Ia is characterized by a powder X-ray diffraction pattern that substantially coincides with FIG. 31.

[0147] In some embodiments, a polyprotic acid, such as a diprotic or triprotic acid, is used to produce a pharmaceutically acceptable salt of formula IX. In such embodiments, the pharmaceutically acceptable salt is represented by formula Ib:

[0148]

Chemical formula

[0149] (where Y is a polyprotic acid).

[0150] In some embodiments, Y is selected from the group consisting of ethanedisulfonic acid, sulfuric acid, citric acid, maleic acid, malic acid, tartaric acid, and oxalic acid. In some embodiments, Y is L-malic acid or L-tartaric acid.

[0151] In some embodiments, Y is ethanedisulfonic acid. In some embodiments, the edisylate of formula IX is characterized by an XRPD pattern that substantially coincides with FIG. 6.

[0152] In some embodiments, Y is sulfuric acid. In some embodiments, the sulfate of formula IX is characterized by an XPRD pattern that substantially coincides with FIG. 19.

[0153] In some embodiments, Y is oxalic acid. In some embodiments, the oxalate of formula IX is characterized by an XPRD pattern substantially consistent with that in Figure 21.

[0154] In some embodiments, Y is maleic acid. In some embodiments, the maleate of formula IX is characterized by an XPRD pattern substantially consistent with that of Figure 23. In some embodiments, the maleate of formula IX is characterized by an XRPD pattern substantially consistent with that of Figure 25.

[0155] In some embodiments, Y is acetic acid. In some embodiments, the acetate of formula IX is characterized by an XRPD pattern substantially consistent with that of Figure 27.

[0156] In some embodiments, Y is L-malate. In some embodiments, the L-malate of formula IX is characterized by an XRPD pattern substantially consistent with that in Figure 29.

[0157] The molar ratio of AG-10 to Y in formula Ib can vary depending on the polyprotic acid used. For example, if Y is maleic acid, the molar ratio of AG-10 to Y is 1:1; if Y is edisyl acid, the molar ratio of AG-10 to Y is 2:1; and if Y is malic acid, the molar ratio of AG-10 to Y is 1.8:1.

[0158] pharmaceutically acceptable salts of formula I can be prepared using a number of conventional methods of the prior art. For example, the free acid form of the compound of formula I can be brought into contact with a stoichiometric amount of a suitable acid in water, an organic solvent, or a mixture of the two. In some embodiments, pharmaceutically acceptable salts of formula I are formed in a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. In some embodiments, pharmaceutically acceptable salts of formula I are formed by dissolving the compound of formula IX in water, adding a suitable amount of HX to form a mixture, and then adding a non-aqueous solvent, such as the non-aqueous medium described above, to crystallize the salt. In some embodiments, the suitable amount of HX is a stoichiometric amount. It will be understood that HX contains hydrogen and X is a pharmaceutically acceptable anion of the protic acid as defined above.

[0159] Similar to the pharmaceutically acceptable salts of formula I, pharmaceutically acceptable salts of formula Ib can also be prepared using a number of conventional methods of the prior art. In non-limiting examples, a pharmaceutically acceptable salt of formula Ib can be prepared by contacting the free acid form of a compound of formula Ib with a stoichiometric or quasi-stoichiometric amount of a suitable polyprotic acid in water, an organic solvent, or a mixture of the two. C. Crystal form of formula IX

[0160] In another embodiment, the crystal form of formula IX is provided.

[0161] [ka]

[0162] This disclosure describes 11 crystalline forms of formula IX, namely 6 HCl salt forms (A, B, E, H, I, and J), 3 free base forms (K, C, and G), and 2 unidentified forms (D and F). A summary of the properties of the identified forms is given in Tables 1 and 2.

[0163] In some embodiments, the crystalline form of Formula IX provided herein is substantially free of other crystalline forms. The term "substantially free of" means that the amount of the other crystalline form is 10% or less, preferably 8%, 5%, 4%, 3%, 2%, 1%, 0.5% or less.

[0164]

Table 1

[0165]

Table 2

[0166] In some embodiments, crystalline Form A of Formula IX is provided. In some embodiments, crystalline Form A of Formula IX is characterized by a powder X-ray diffraction pattern that includes peaks at 7.0, 10.4, 12.0, 13.0 and 13.9° 2θ (±0.2° 2θ). In some embodiments, crystalline Form A of Formula IX is characterized by a powder X-ray diffraction pattern that includes peaks at 12.0, 21.8, 25.9, 26.7 and 27.9° 2θ (±0.2° 2θ). In some embodiments, the powder X-ray diffraction pattern further includes one or more peaks at 7.0, 10.3, 13.9, 15.6, and / or 17. In some embodiments, crystalline Form A of Formula IX is characterized by a powder X-ray diffraction pattern that substantially follows FIG. 31. In some embodiments, crystalline Form A of Formula IX is substantially free of other crystalline forms.

[0167] In some embodiments, crystalline Form A of Formula IX is characterized by a weight loss in the range of about 0.7% to about 1.9% upon heating to near 150° C as measured by thermogravimetric analysis. In some embodiments, the weight loss is about 1.3% when measured by thermogravimetric analysis.

[0168] In some embodiments, crystalline form A of formula IX is characterized by a moisture absorption of approximately 1.6% at 25°C / 80%RH after undergoing a dynamic vapor sorption cycle including a pre-equilibrium at 0% relative humidity (RH). In some embodiments, crystalline form A of formula IX is characterized by an increase of less than 2.5% by weight after undergoing a dynamic vapor sorption cycle from approximately 0% relative humidity (RH) to approximately 90% RH. In some embodiments, crystalline form A of formula IX has a dynamic vapor sorption profile substantially as shown in Figure 37.

[0169] In some embodiments, crystal form A of formula IX is characterized by a differential scanning calorimetry thermogram containing endothermic peaks around 211–214°C and 237–239°C. In some embodiments, the differential scanning calorimetry thermogram contains endothermic peaks around 11.7, 212.6, and 237.3°C.

[0170] In some embodiments, crystal form B of formula IX is provided. In some embodiments, crystal form B of formula IX is characterized by a powder X-ray diffraction pattern containing peaks at 12.0, 13.8, 17.2, 17.7, and 19.8°2θ (±0.2°2θ). In some embodiments, crystal form B of formula IX is characterized by a powder X-ray diffraction pattern containing peaks at 12.1, 13.9, 19.8, 23.3, and 24.4°2θ (±0.2°2θ). In some embodiments, crystal form B of formula IX is characterized by a powder X-ray diffraction pattern substantially consistent with Figure 40. In some embodiments, crystal form B of formula IX substantially does not include any other crystal forms.

[0171] In some embodiments, crystal form B of formula IX is characterized by a weight loss in the range of approximately 0.6% to approximately 2.0% when heated to around 150°C, as measured by thermogravimetric analysis. Crystal form B of formula IX is characterized by a weight loss of approximately 1.2% when heated to around 150°C, as measured by thermogravimetric analysis.

[0172] In some embodiments, the crystal form B of formula IX is characterized by a differential scanning calorimetry thermogram that includes endothermic peaks around 161.4°C, 232.2°C, and 262.3°C.

[0173] In some embodiments, crystal form E of formula IX is provided. In some embodiments, crystal form E of formula IX is characterized by a powder X-ray diffraction pattern containing peaks at 11.8, 14.0, 15.1, 19.9 and 24.0°2θ (±0.2°2θ). In some embodiments, crystal form E of formula IX is characterized by a powder X-ray diffraction pattern containing peaks at 11.9, 14.0, 15.1 and 25.8°2θ (±0.2°2θ). In some embodiments, crystal form E of formula IX is characterized by a powder X-ray diffraction pattern substantially consistent with Figure 46. In some embodiments, crystal form E of formula IX substantially does not include any other crystal forms.

[0174] Crystal form E of formula IX is characterized by a weight loss in the range of approximately 0.5% to approximately 2.5% when heated to around 150°C, as measured by thermogravimetric analysis. In some embodiments, crystal form E of formula IX is characterized by a weight loss of approximately 1.5% when heated to around 150°C, as measured by thermogravimetric analysis.

[0175] In some embodiments, the crystal form E of formula IX is characterized by a differential scanning calorimetry thermogram that includes endothermic peaks around 182.0°C and 242.7°C.

[0176] In some embodiments, crystal form I of formula IX is provided. In some embodiments, crystal form I of formula IX is characterized by a powder X-ray diffraction pattern containing peaks at 11.4, 12.1, 12.4, 13.6, and 13.9°²θ (±0.2°²θ). In some embodiments, crystal form I of formula IX is characterized by a powder X-ray diffraction pattern containing peaks at 12.5, 17.3, 23.4, 25.0, and 25.4°²θ (±0.2°²θ). In some embodiments, crystal form I of formula IX is characterized by a powder X-ray diffraction pattern substantially consistent with Figure 55. In some embodiments, crystal form I of formula IX substantially does not include any other crystal forms.

[0177] In some embodiments, crystal form I of formula IX is characterized by a weight loss in the range of approximately 2.5% to approximately 3.5% when heated to around 120°C, as measured by thermogravimetric analysis. In some embodiments, crystal form I of formula IX is characterized by a weight loss of approximately 3.0% when heated to around 120°C, as measured by thermogravimetric analysis.

[0178] In some embodiments, the crystal form I of formula IX is characterized by a differential scanning calorimetry thermogram that includes endothermic peaks around 62.0°C, 158.4°C, and 215.7°C.

[0179] In some embodiments, the H-form of formula IX is provided. In some embodiments, the H-form of formula IX is characterized by a powder X-ray diffraction pattern containing peaks at 11.8, 12.3, 13.8, 15.7, and 16.9°²θ (±0.2°²θ). In some embodiments, the H-form of formula IX is characterized by a powder X-ray diffraction pattern containing peaks at 11.9, 12.3, 21.7, 23.3, and 25.8°²θ (±0.2°²θ). In some embodiments, the H-form of formula IX is characterized by a powder X-ray diffraction pattern substantially according to Figure 51. In some embodiments, the H-form of formula IX substantially does not include any other crystal forms.

[0180] In some embodiments, the H-type crystalline form of formula IX is characterized by a weight loss in the range of approximately 3.5% to approximately 5.5% when heated to around 150°C, as measured by thermogravimetric analysis. In some embodiments, the H-type crystalline form of formula IX is characterized by a weight loss of approximately 4.6% when heated to around 150°C, as measured by thermogravimetric analysis.

[0181] In some embodiments, the H-type crystal form of formula IX is characterized by a differential scanning calorimetry thermogram that includes endothermic peaks around 90.4°C, 200.5°C, and 232.3°C.

[0182] In some embodiments, crystal form J of formula IX is provided. In some embodiments, crystal form J of formula IX is characterized by a powder X-ray diffraction pattern containing peaks at 4.6, 11.8, 12.8, 13.8, and 14.6°2θ (±0.2°2θ). In some embodiments, crystal form J of formula IX is characterized by a powder X-ray diffraction pattern containing peaks at 13.8, 14.7, 22.9, 26.2, and 27.7°2θ (±0.2°2θ). In some embodiments, crystal form J of formula IX is characterized by a powder X-ray diffraction pattern substantially consistent with Figure 59. In some embodiments, crystal form J of formula IX substantially does not include any other crystal forms.

[0183] Crystal form J of formula IX is characterized by a weight loss in the range of approximately 17.5% to 24% when heated to around 120°C, as measured by thermogravimetric analysis. In some embodiments, crystal form J of formula IX is characterized by a weight loss of approximately 21.5% when heated to around 120°C, as measured by thermogravimetric analysis.

[0184] In some embodiments, the J-type crystal form of formula IX is characterized by differential scanning calorimetry thermograms that include endothermic peaks around 120.8°C, 197.8°C, and 221.5°C.

[0185] In some embodiments, the K-form of formula IX is provided. In some embodiments, the K-form of formula IX is characterized by a powder X-ray diffraction pattern containing peaks at 7.5, 9.8, 13.9, 15.9 and 19.3°²θ (±0.2°²θ). In some embodiments, the K-form of formula IX is characterized by a powder X-ray diffraction pattern containing peaks at 7.2, 7.6, 9.9, 14.0 and 19.3°²θ (±0.2°²θ). In some embodiments, the K-form of formula IX is characterized by a powder X-ray diffraction pattern substantially consistent with Figure 59. In some embodiments, the K-form of formula IX substantially does not include any other crystal forms.

[0186] In some embodiments, the K-type crystal form of formula IX is characterized by a weight loss in the range of approximately 5.0% to approximately 7.0% when heated to around 120°C, as measured by thermogravimetric analysis. In some embodiments, the K-type crystal form of formula IX is characterized by a weight loss of approximately 6.1% when heated to around 120°C, as measured by thermogravimetric analysis.

[0187] In some embodiments, the K-type crystal form of formula IX is characterized by differential scanning calorimetry thermograms that include endothermic peaks around 159.3°C, 176.2°C, and 278.4°C.

[0188] In some embodiments, crystal form C of formula IX is provided. In some embodiments, crystal form C of formula IX is characterized by a powder X-ray diffraction pattern containing peaks at 9.5, 11.7, 12.3, 13.4 and 14.6°2θ (±0.2°2θ). In some embodiments, crystal form C of formula IX is characterized by a powder X-ray diffraction pattern containing peaks at 14.6, 16.8, 19.5, 20.7 and 22.5°2θ (±0.2°2θ). In some embodiments, crystal form C of formula IX is characterized by a powder X-ray diffraction pattern substantially consistent with Figure 43. In some embodiments, crystal form C of formula IX substantially does not include any other crystal forms.

[0189] In some embodiments, the crystalline form C of formula IX is characterized by a weight loss in the range of approximately 2.0% to approximately 4.0% when heated to around 150°C, as measured by thermogravimetric analysis. In some embodiments, the crystalline form C of formula IX is characterized by a weight loss of approximately 3.1% when heated to around 150°C, as measured by thermogravimetric analysis.

[0190] In some embodiments, the C-type crystal form of formula IX is characterized by a differential scanning calorimetry thermogram that includes endothermic peaks around 91.2°C and 173.0°C.

[0191] In some embodiments, crystal form G of formula IX is provided. In some embodiments, crystal form G of formula IX is characterized by a powder X-ray diffraction pattern containing peaks at 9.8, 12.2, 13.1, 13.4, and 14.6°2θ (±0.2°2θ). In some embodiments, crystal form G of formula IX is characterized by a powder X-ray diffraction pattern containing peaks at 12.3, 13.2, 13.4, 17.8, and 26.6°2θ (±0.2°2θ). In some embodiments, crystal form G of formula IX is characterized by a powder X-ray diffraction pattern substantially consistent with Figure 43. In some embodiments, crystal form G of formula IX substantially does not include any other crystal forms.

[0192] In some embodiments, the G-type crystal form of formula IX is characterized by a weight loss in the range of approximately 1.7% to approximately 2.7% when heated to around 200°C, as measured by thermogravimetric analysis. In some embodiments, the G-type crystal form of formula IX is characterized by a weight loss of approximately 3.7% when heated to around 200°C, as measured by thermogravimetric analysis.

[0193] In some embodiments, the G-type crystal form of formula IX is characterized by a differential scanning calorimetry thermogram that includes an endothermic peak around 231.1°C.

[0194] In some embodiments, crystal form D of formula IX is provided. In some embodiments, crystal form D of formula IX is characterized by a powder X-ray diffraction pattern substantially consistent with Figure 45 (plot above). In some embodiments, crystal form D of formula IX substantially does not include any other crystal forms.

[0195] In some embodiments, crystal form F of formula IX is provided. In some embodiments, crystal form F of formula IX is characterized by a powder X-ray diffraction pattern substantially consistent with Figure 45 (plot below). In some embodiments, crystal form F of formula IX substantially does not include any other crystal forms.

[0196] The methods for producing the described crystal types will be explained in more detail in the examples of this specification. Crystallization conditions used to produce types A to K include the addition of a poor solvent, slow evaporation, slow cooling, slurry conversion at room temperature, slurry conversion at 50°C, solid-phase vapor diffusion, and liquid-phase vapor diffusion. [Examples]

[0197] IV. Examples Example 1: Preparation of 3-(3-hydroxypropyl)pentane-2,4-dione (compound of formula IV)

[0198] [ka]

[0199] Compound IIIa (100 g, 495 mmol, 1.0 equivalent) was dissolved in acetone (1 L). Compound II (49.59 g, 495 mmol, 1.0 equivalent) was added to the solution, and then K2CO3 (82.14 g, 594.38 mmol, 1.2 equivalents) and KI (41.11 g, 247 mmol, 0.5 equivalents) were added while stirring at room temperature. The reaction mixture was heated to 60±5°C and stirred at this temperature for 40 hours. The reaction mixture was filtered and then concentrated under reduced pressure to obtain compound IV (102 g) as a viscous orange liquid.

[0200] Example 2: Preparation of 3(3,5-dimethyl-1H-pyrazole-4-yl)propan-1-ol (compound of formula V).

[0201] [ka]

[0202] The compound of formula IV (100 g, 632 mmol, 1.0 equivalent) was dissolved in ethanol (1 L). To the solution, hydrazine hydrate (87 g, 1738 mmol, 2.75 equivalents) and concentrated HCl (4.6 mL, 0.2 equivalents) were added at room temperature. The reaction mixture was heated to 75±5°C and stirred at this temperature for 3 hours. After confirming the completion of the reaction by observing the product peak in the TLC (70% ethyl acetate: visible in n-hexane and iodine) and mass spectrum, the reaction mixture was concentrated under reduced pressure to give the compound of formula V (70 g) as a colorless liquid syrup, which was used directly in the next step.

[0203] Example 3: Preparation of 4-(3-bromopropyl)-3,5-dimethyl-1H-pyrazole (compound of formula VIa)

[0204] [ka]

[0205] The compound of formula V (35 g, 227 mmol, 1.0 equivalent) was dissolved in 1,2-dichloroethane (525 mL). PBr3 (64.67 mL, 681 mmol, 3 equivalents) was added in small amounts at room temperature over 30 minutes. The reaction mixture was heated to 75±5°C and stirred at this temperature for 3 hours. After confirming the completion of the reaction by observing the product peak in the mass spectrum and performing TLC (50% ethyl acetate: visible in n-hexane and iodine), the reaction mixture was diluted with dichloromethane (350 mL) and quenched to pH=7-8 with saturated NaHCO3 solution. The organic and aqueous phases were separated and both were collected. The organic phase was dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to obtain the compound of formula VIa (38 g) as a viscous orange liquid.

[0206] Example 4: Preparation of 3-[3-(3,5-dimethyl-1H-pyrazole-4-yl)propoxy]-4-fluorobenzoate methyl ester (compound of formula VIIIa)

[0207] [ka]

[0208] The compound of formula VIIa (19 g, 111 mmol, 1.0 equivalent) was dissolved in DMF (190 mL). The compound of formula VIa (31.5 g, 145.14 mmol, 1.3 equivalents) was followed by K2CO3 (38.6 g, 279.18 mmol, 2.5 equivalents) at room temperature under stirring conditions. The reaction mixture was stirred at room temperature for 16-18 hours. After confirming the completion of the reaction by TLC (50% ethyl acetate:n-hexane), the reaction mixture was diluted with water (190 mL) and ethyl acetate (95 mL). The organic phase and aqueous phase were separated and both were collected. The aqueous phase was extracted with ethyl acetate (190 mL). The combined organic extract was washed with water (95 mL) and brine (95 mL), dried over Na2SO4, and filtered. The filtered organic phase was concentrated under reduced pressure to obtain a crude, viscous orange liquid (40 g). The crude product was further purified by column chromatography using silica gel, while varying the amount of ethyl acetate in hexane, to obtain a pure product, the compound of formula VIIIa (25 g), as an off-white solid.

[0209] Example 5: Preparation of 3-[3-(3,5-dimethyl-1H-pyrazole-4-yl)propoxy]-4-fluorobenzoate methyl ester (compound of formula VIIIa)

[0210] [ka]

[0211] 4-(3-bromopropyl)-3,5-dimethyl-1H-pyrazole hydrobromide (VIa) and DMSO were placed in a container and stirred at 20±10°C for 10 minutes. The mixture was then heated to 55±5°C while stirring. A stirred solution containing 4-fluoro-3-hydroxybenzoate methyl ester (VIIa), potassium carbonate, and anhydrous DMSO was transferred to this mixture. The DMSO solution of alkyl bromide was slowly added to maintain the internal temperature at 55.0±5°C. The addition was completed after 6 hours, and the mixture was stirred for a further 1 hour at 55.0±5°C. The mixture was cooled to 25±5°C over 30 minutes, and water was added while maintaining the temperature below 25°C. The mixture was extracted with ethyl acetate, and the aqueous phase was back-extracted with ethyl acetate. The combined ethyl acetate solution was washed with brine. The combined ethyl acetate washing solution was concentrated under reduced pressure to the minimum volume, heptane was added, and VIIIa was precipitated. The mixture was heated to 75±5°C and allowed to mature for 1 hour with stirring. The mixture was cooled to 25±5°C over 2 hours, and the resulting solid was collected by filtration. The filtered cake was washed with ethyl acetate (30%) in heptane. The isolated solid was dried under a stream of nitrogen. The solid was placed in a container and mixed with ethyl acetate and heptane. The resulting mixture was heated to 75±5°C to dissolve the solid. The solution was cooled to 25±5°C over 2 hours, and the resulting solid was collected by filtration. The solid was washed with a 30% ethyl acetate / heptane solvent mixture and vacuum-dried in an oven at 55°C to obtain VIIIa with >99.5% purity.

[0212] Example 6: Preparation of 3-[3-(3,5-dimethyl-1H-pyrazole-4-yl)propoxy]-4-fluorobenzoic acid (compound of formula IX)

[0213] [ka]

[0214] The compound of formula VIIIa (19 g, 62 mmol, 1 equivalent) was dissolved in methanol (95 mL, 5 volumes) at room temperature. A solution of LiOH·H2O (6.5 g, 155 mmol, 2.5 equivalents) in water (57 mL) was added in small amounts over 10-15 minutes at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After confirming the completion of the reaction by TLC (70% ethyl acetate:n-hexane), the reaction mixture was concentrated under reduced pressure at 45°C or below to give the solid residue of formula IX.

[0215] Example 7: Preparation of a pharmaceutically acceptable salt of Formula I The solid residue of formula IX was dissolved in water (57 mL), stirred for 10 minutes, and cooled to 0±5°C. The aqueous solution was acidified to pH=2 with concentrated HCl (20-25 mL) and stirred at 0±5°C for 30 minutes. A precipitate was observed, which was filtered and dried at room temperature to obtain the pure product, compound Ia (17.5 g), as an off-white solid.

[0216] Example 8: Additional preparation of pharmaceutically acceptable salts of Formula I

[0217] [ka]

[0218] Water and concentrated HCl were placed in a container and cooled to 10±5°C while stirring. The compound of formula IX and water were placed in a second container and cooled to 10±5°C while stirring. The HCl solution in container 1 was transferred to the container containing the mixture of compound IX over a maximum of 15 minutes while maintaining the temperature at ≤25°C. The resulting slurry was aged at 20±5°C for 44 hours with stirring. The solid was collected by filtration, washed with 0.2 N HCl (3×), and vacuum-dried at ≥55°C to obtain Ia as a white solid with >99.8% purity.

[0219] Example 9: Preparation of 3-[3-(3,5-dimethyl-1H-pyrazole-4-yl)propoxy]-4-fluorobenzoate (compound Ia) from VIIIa

[0220] [ka]

[0221] A jacketed glass container was loaded with the compound of formula VIIIa (1.0 equivalent) and methanol. The mixture was cooled to 10±5°C with stirring, and an aqueous solution of sodium hydroxide (3 equivalents) was added over 20 minutes. The mixture was aged at 20±5°C with stirring for at least (NLT) 2 hours, at which point the reaction was complete. Stirring was stopped, and water was added. Methanol was then removed by vacuum distillation at an internal temperature not exceeding 35°C (NMT). The resulting concentrated clear aqueous solution was cooled to 10°C, and concentrated HCl was added until the pH dropped to between 1.4 and 1.6 (pH meter value) to precipitate the HCl salt. The solid was collected by filtration, washed with 0.2 N HCl, and vacuum-dried at 50°C to obtain the compound of formula Ia with a purity of at least (NLT) 99.5%.

[0222] Example 10: Preparation of 3-[3-(3,5-dimethyl-1H-pyrazole-4-yl)propoxy]-4-fluorobenzoic acid (compound of formula IX) from VIIIa

[0223] [ka]

[0224] Methyl 3-[3-(3,5-dimethyl-1H-pyrazole-4-yl)propoxy]-4-fluorobenzoate (compound of formula VIIIa) and methanol were placed in a container and stirred at 20±5°C until the resulting mixture dissolved. The solution was cooled to 10±5°C, and sodium hydroxide solution was added over 20 minutes while maintaining the temperature at ≤25°C. The temperature of the mixture was adjusted to 25±5°C and aged for 18 hours with stirring. The reaction mixture was then filtered. Water was added to the filtrate and the mixture was concentrated under reduced pressure until the volume was minimized. Water was added again and the resulting mixture was concentrated under reduced pressure until the volume was minimized. The pH of the aqueous mixture was adjusted to 5.5±0.5 by adding concentrated hydrochloric acid followed by 0.5 N HCl. The temperature of the mixture was adjusted to 7±5°C and aged for a further 1 hour with stirring. The solid was collected by filtration, washed with water, and partially dried under vacuum at ≥55°C to obtain the compound of formula IX as a white solid with >99.5% HPLC purity.

[0225] Example 11: Conversion from hydrochloride to free base 10.0 g, 30.4 mmol, 1.0 equivalent of 3-[3-(3,5-dimethyl-1H-pyrazole-4-yl)propoxy]-4-fluorobenzoic acid salt was placed in 30.0 mL of deionized water at room temperature and cooled to 10±5°C. Saturated sodium bicarbonate was added to this mixture to a pH of approximately 6-7, and the mixture was stirred at this temperature for 30 minutes. The resulting off-white precipitate was filtered and washed with 20 mL of deionized water. The solid compound was dried at room temperature to obtain 3-[3-(3,5-dimethyl-1H-pyrazole-4-yl)propoxy]-4-fluorobenzoic acid (compound of formula IX) (7.40 g, 83.2%) as an off-white solid.

[0226] Example 12: Oral administration using a pharmaceutically acceptable salt of Formula I The following examples describe the pharmacokinetic measurements of compounds of formula IX in various salt and amphoteric forms. The results shown here indicate that compounds of formula I have a remarkably high pharmacokinetic profile.

[0227] Rats or dogs were orally administered AG-10 in the amphoteric, sodium, or HCl forms. The forms and dosages of AG-10 used are noted in Table 3. Plasma samples from each rat / dog were measured at 0 hours and 96 hours after administration of the specific form of AG-10. After isolation from the animals, proteins were precipitated by adding 0.1% formamide in 500 μL of acetonitrile to each sample (50 μL). After adding the formamide solution, the samples were voldex-mixed and centrifuged at 1400 rpm for 15 minutes at 4°C. 100 μL of the supernatant was taken and diluted with 100 μL of water. 5 μL of the diluted sample was injected into LC-MS / MS analysis. Pharmacokinetic data were reported as shown in Table 3. max The calculation was performed using the values ​​and exposure amount (0-24 h, ng.h / mL).

[0228] [Table 3]

[0229] As can be seen from Table 3, the HCl salt of formula I, compared to the amphoteric ions and Na salts, is C in dogs and rats. max The values ​​showed a significant and substantial improvement. Compare row 3 with row 1 and row 6 with row 4 in the table. Thus, to achieve the same level of bioavailability, the HCl salt of formula I requires a significantly lower dose.

[0230] Example 13: Intravenous administration of a pharmaceutically acceptable salt of Formula I The following examples describe the pharmacokinetic measurements of various salt and amphoteric forms of the compound of formula IX after intravenous administration to rats and dogs. The results shown here demonstrate that the compound of formula I has an unpredictably high pharmacokinetic profile, whether administered orally or intravenously.

[0231] Mice, rats, or dogs were intravenously administered AG-10 in its amphoteric, sodium, or HCl form. The forms and doses of AG-10 are shown in Table 4. Plasma samples from each mouse / rat / dog were measured at 0 hours and 24 hours after administration of the specific form of AG-10. After isolation from the animals, proteins were precipitated by adding 0.1% formamide in 500 μL of acetonitrile to each sample (50 μL). After adding the formamide solution, the samples were stirred with a Bordex and centrifuged at 1400 rpm for 15 minutes at 4°C. 100 μL of the supernatant was taken and diluted with 100 μL of water. 5 μL of the diluted sample was injected into LC-MS / MS analysis. Pharmacokinetic data were reported as shown in Table 4. max The calculation was performed using the values ​​and exposure amount (0-24 h, ng.h / mL).

[0232] [Table 4]

[0233] Example 14: High bioavailability of AG-10 in multiple species Figure 2 shows pharmacokinetic results demonstrating the high bioavailability of AG-10 in dogs, rats, and mice. Mean plasma concentrations of AG-10 were measured 0–24 hours after intravenous administration of 1 mg / kg of AG-10 and oral administration of 5 mg / kg of AG-10. The calculated pharmacokinetic data are shown in Figure 2.

[0234] Example 15: High bioavailability of AG-10 in dogs Figure 3 shows pharmacokinetic results demonstrating the high bioavailability of AG-10 in male / female dogs at different dose levels. Mean plasma concentrations of AG-10 were measured 2–24 hours after oral administration of 5 mg / kg or 20 mg / kg of AG-10. The calculated pharmacokinetic data are shown in Figure 3.

[0235] Example 16: Salt and cocrystal screening Numerous salts and co-crystal states were tested for various pharmaceutically acceptable salts targeting different species. Details of the experiments are shown in Tables 5 and 6. Experiments were carried out using various crystallization techniques, including cooling, evaporation, slurrying, and solvent-based grinding. Solids obtained from salt and co-crystal screening experiments were observed using polarized light microscopy (PLM) and analyzed by XRPD. The XRPD patterns of isolated solids were compared to those of known AG-10 forms and counterions / cohomers.

[0236] The confirmed AG10 salts were identified through experiments targeting salt formation using strong acids, particularly methanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, ethanesulfonic acid, sulfuric acid, hydrogen bromide, and nitric acid.

[0237] Salts or cocrystals of AG10 were also isolated from experiments targeting salt / cocrystal formation using weak organic acids such as citric acid, acetic acid, maleic acid, oxalic acid, and malic acid.

[0238] Experiments targeting L-tartaric acid, glycolic acid, and fumaric acid were also planned; however, experiments aimed at isolating these substances as single-crystal phases were unsuccessful, instead producing physical mixtures of the starting material or unique additional peaks with the starting material.

[0239] Attempts to form salts / cocrystals of AG10 with L-aspartic acid, benzoic acid, gentisic acid, and succinic acid were unsuccessful.

[0240] [Table 5]

[0241] [Table 6]

[0242] [Table 7]

[0243] [Table 8]

[0244] [Table 9]

[0245] [Table 10]

[0246] Example 17: Preparation of mesylate of formula IX The mesylate of formula IX was produced by adding 1 molar equivalent of methanesulfonic acid to a solution of AG-10 MEK:DMF = 2:0.3 (v / v) at high temperature. The suspension was kept at high temperature for approximately 20 minutes, cooled to room temperature, and the solid was isolated.

[0247] The XRPD pattern is shown in Figure 4, which shows the separation of peaks indicating a crystalline material. An attempt was made to index the XRPD pattern, but no solution for indexing was found, possibly because the sample contains a mixture of crystalline phases or because of low peak resolution.

[0248] 1 The 1H NMR spectrum was consistent with AG-10 mesylate in a 1:1 molar ratio, referenced to the 2.37 ppm peak. Trace amounts of DMF and an additional unknown peak were also observed in the spectrum.

[0249] The DSC thermogram (Figure 5) shows a single endothermic reaction at approximately 233°C (maximum peak), which is thought to be due to melting. No significant weight loss is observed in the TGA (Figure 5) up to approximately 200°C, which suggests that the substance is likely unsolvated / anhydrous.

[0250] Example 18: Preparation of edisylate of formula IX The edisylate of formula IX was prepared by adding 1 molar equivalent of 1,2-ethanedisulfonic acid to an AG10 acetone:DMA solution at high temperature. The suspension was cooled to ambient temperature, and the solid was isolated.

[0251] According to XRPD, the edisylate of formula IX consists of crystalline material (Figure 6). 1 The 1H NMR spectrum is consistent with that of AG-10 edisylate in a 2:1 molar ratio, with the 2.7 ppm peak as the reference. Approximately 1 mole of DMA was also observed, suggesting that it is the AG-10 edisylate DMA (2:1:1) solvate.

[0252] The DSC thermogram (Figure 7) shows a broad feature at ~139°C associated with an 11% weight loss based on TGA (Figure 7) data, which is likely due to desolvation. A sharp endothermic peak is observed at 313°C (maximum peak), which is thought to be due to the melting / decomposition of the desolvated substance. Hot stage microscopy is recommended to further understand the behavior of the substance with heating.

[0253] When a sample of edisylate of formula IX was dried at 180°C for 10 minutes, no change in physical morphology was observed based on XRPD.

[0254] Example 19: Preparation of besylate of formula IX The besilate of formula IX was prepared by cooling a THF solution containing equimolar equivalents of AG-10 and benzenesulfonic acid.

[0255] The besylate of formula IX is composed of crystalline material, and its XRPD pattern is shown in Figure 8. 1 The 1H NMR spectrum generally matches that of AG-10 besylate in a ratio of approximately 1:1. Trace amounts of THF were also observed in the spectrum, with a 3.6 ppm peak as the reference.

[0256] The DSC thermogram shows two endothermic peaks with maximum peaks at approximately 158°C and 177°C (Figure 9). A weight loss of 0.2% is observed between 42°C and 127°C (Figure 9).

[0257] Example 20: Preparation of tosylate of formula IX The tosylate of formula IX was prepared by adding 1 molar equivalent of p-toluenesulfonic acid to an AG-10 acetonitrile solution at high temperature.

[0258] According to XRPD, the tosylate of formula IX is composed of crystalline material (Figure 10). The pattern is indexed favorably, indicating that the material consists mainly or exclusively of a single-crystal phase. The unit cell volume obtained from the indexing solution, when molecular volume is taken into account, is consistent with that of the AG10 tosylate (1:1) salt.

[0259] 1 The 1H NMR spectrum generally agrees with AG10 tosylate at a molar ratio of approximately 1:1, based on the 2.28 ppm peak.

[0260] The DSC thermogram shows a single endothermic temperature at approximately 205°C (maximum peak), which is thought to be due to melting (Figure 11). No significant weight loss was observed in the TGA up to approximately 160°C, suggesting that the substance is likely unsolvated / anhydrous (Figure 11).

[0261] Example 21: Preparation of ethylate of formula IX The esylate of formula IX precipitated at 50°C from a THF solution containing AG-10 and ethanesulfonic acid (1:1 molar ratio). The suspension was cooled and the solid was isolated.

[0262] The esylate of formula IX consists of crystalline material, as confirmed by XRPD (Figure 12). 1 The 1H NMR spectrum is consistent with AG-10 ethylate in a 1:1 molar ratio, based on a 2.4 ppm peak. Approximately 0.1 moles of THF were observed in the spectrum.

[0263] The DSC thermogram shows one endothermic peak at 199°C (maximum peak), likely due to melting (Figure 13). There is no significant weight loss even when heated to melting, suggesting that the substance is either unsolvated or anhydrous (Figure 13).

[0264] Example 22: Preparation of bromide salt of formula IX The bromide salt of formula IX was prepared by adding equimolar amounts of hydrogen bromide to an AG-10 MIBK:DMSO 2:0.4 (v / v) solution at ~60°C. This resulted in the formation of a yellow solution and oil. The sample was placed in a vacuum oven at room temperature for 3 days, yielding oil containing solid matter. MEK was added to the sample while sonicating, and the mixture was heated to 60°C and then cooled twice. The solid matter remaining in the resulting suspension was isolated and analyzed.

[0265] The bromide salt of formula IX consists of crystalline material (Figure 14). 1 The 1H NMR spectrum is consistent with the chemical structure of AG-10. Based on a peak at 2.54 ppm, approximately 1 mole of DMSO was also observed.

[0266] The bromide content was found to be 17.7% by mass based on IC, which is consistent with the calculated bromide content (17.7%) of AG-10 bromide DMSO (1:1:1) solvate.

[0267] Endothermic activity (peak maximum) at ~105°C, followed by exothermic activity (peak maximum) at 155°C, and then endothermic activity at ~214°C are observed in the DSC data (Figure 15). A weight loss of 19.9% ​​is observed when heated to approximately 182°C, which is likely related to the decrease in solvent or the possibility of recrystallization into a non-solvated form (Figure 15).

[0268] Example 23: Preparation of nitrate of formula IX Two nitrate forms of formula IX have been identified. These two forms are referred to as form a and form b. • Nitrate, type A The nitrate form a of formula IX precipitated from a DMSO solution containing AG-10 and nitric acid in equimolar ratios. Based on favorable indexing of XRPD patterns, AG-10 nitrate substance A consists of a single-crystal phase (Figure 16).

[0269] Solution of AG10 nitrate, form A 1 The 1H NMR spectrum is consistent with the chemical structure of AG-10. Based on the 2.54 ppm peak, approximately 0.8 moles of DMSO are present. Water and a small additional peak are also observed.

[0270] The DSC thermogram shows a broad endothermic curve around 117°C, which is associated with a 2.5% weight loss, likely due to the loss of volatile substances (Figure 17). This broad endothermic curve is followed by an exothermic peak with a maximum peak at ~173°C, which is associated with a ~16% weight loss, likely due to melting / decomposition (Figure 17).

[0271] The nitrate content was found to be 7.5% by mass based on IC, which does not match the calculated nitrate content predicted for the non-solvated 1:1 nitrate (theoretical nitrate content: 17.5%), nor does it match the calculated nitrate content predicted for the 1:1:1 AG-10 nitrate DMSO solvate (theoretical nitrate content: 14.3%).

[0272] • Nitrate, type B The b-form of the nitrate of formula IX was prepared by evaporating a THF solution containing equimolar ratios of AG-10 and nitric acid. The XRPD pattern of this solid is shown in Figure 18. Solution of AG-10 nitrate substance B 1 The 1H NMR spectrum matches the chemical structure of AG-10.

[0273] The nitrate content was found to be 16.9% by mass based on IC, which is generally consistent with AG-10 nitrate at a ratio of approximately 1:1.

[0274] Example 24: Preparation of sulfate of formula IX The sulfate of formula IX is prepared by evaporating an ethanol solution containing equimolar amounts of AG-10 and sulfuric acid, and then cooling it (from 60°C to 2-8°C). The sulfate of formula IX consists of crystalline material (Figure 19).

[0275] 1 The 1H NMR spectrum confirmed the presence of AG-10 and indicated approximately 1 mole of ethanol based on peaks at 1.06 ppm and 3.4 ppm. Additional unknown peaks were also observed in the spectrum.

[0276] The sulfate content was found to be 15.9% by mass based on IC, which corresponds to an AG-10:sulfate ratio of 1:0.58. A 6.4% weight loss was observed in the TGA thermogram between ~30°C and 96°C, which is equivalent to 1 mole of ethanol and was presumed to be the AG10 sulfate 2:1 salt (Figure 20). Broad features were observed by DSC (Figure 20).

[0277] Example 25: Preparation of citrate of formula IX After evaporating an IPA solution saturated with citric acid and containing AG-10 at room temperature, a single crystal of the citrate of formula IX was obtained. After collecting a suitable single crystal for SCXRD, the sample was further evaporated, and the collected solid, based on XRPD, consisted of a mixture of AG-10 citrate and citric acid. The structure of AG-10 citrate was successfully determined. The crystal system is triclinic, and the space group is

[0278]

number

[0279] The unit cell parameters and calculated volume are as follows:

[0280] [ka]

[0281] The formula weight is 484.43 g mol. -1 Therefore, Z=2, and as a result, the computational density is 1.435 g cm³. -3 That is the case.

[0282] A second experiment was conducted with the aim of obtaining a bulk solid of AG10 citrate as a single-crystal phase for further characterization. This experiment also yielded a physical mixture of AG10 citrate and citric acid.

[0283] Example 26: Preparation of oxalate of formula IX The oxalate of formula IX precipitated at 50°C from a DMA solution containing AG-10 and oxalic acid (in a 1:1 molar ratio). The sample was cooled to room temperature, and the solid was isolated for characterization.

[0284] According to XRPD, the oxalate of formula IX consists of crystalline material (Figure 21). The XRPD pattern of this sample was well indexed, indicating that the sample consists mainly or exclusively of a single-crystal phase. The indexed volume is consistent with that of AG-10 hemi-oxalate based on considerations of molecular volume.

[0285] 1 The 1H NMR spectrum matches the chemical structure of AG-10. Approximately 0.1 moles of DMA and water were also present in the spectrum.

[0286] IC determined the oxalate content of the sample to be 13.7%, confirming the approximately 2:1 stoichiometry of AG-10 hemioxalate.

[0287] Based on the TGA data, a single endothermic event is observed in the DSC data at ~225°C (peak maximum), which is thought to be due to melting / decomposition (Figure 22). The TGA thermogram is probably 1 The initial weight loss of 0.9% during heating between 33°C and 169°C is observed by 1H NMR, due to the loss of residual surface solvents such as DMA (Figure 22).

[0288] Example 27: Preparation of maleate of formula IX Two maleate forms of formula IX have been identified. These two forms are referred to as form a and form b. • Maleate, type A When a nitromethane solution of maleic acid (2.2 molar equivalents) was added to AG-10 at 70°C, a suspension was formed. This suspension was cooled to room temperature and then reheated twice to 60°C, after which the solid was isolated.

[0289] Based on XRPD analysis, form a of maleate of formula IX consists of a crystalline material (Figure 23). The XRPD pattern is not indexable, suggesting that the material is not composed of a single-crystal phase and is a mixture of possible forms. XRPD analysis suggests that form a of maleate of formula IX was isolated as a mixture with form b of maleate of formula IX.

[0290] Sample 1 The 1H NMR spectrum contained AG-10:maleic acid in a molar ratio of approximately 1:1, based on the 6.23 ppm peak. Based on the presence of the 4.42 ppm peak, approximately 1.3 moles of nitromethane were observed for every mole of AG-10. An additional small, unknown peak was also observed in the spectrum.

[0291] Endothermic activity is observed in the DSC data at ~160°C (peak maximum) (Figure 24). When heated to 110°C, a weight loss of 8.4% is observed, which is thought to be due to a decrease in solvent (Figure 24). When a sample of maleate form a of formula IX was dried at 110°C for approximately 7 minutes, a disordered substance was produced that had a peak corresponding to maleate form b of formula IX based on XRPD.

[0292] The sample is XRPD and 1 Based on the 1H NMR data, it appears to consist of a mixture of the maleate of formula IX (form b) plus a possible nitromethane solvate.

[0293] • Maleate, type B The b-form of the maleate of formula IX was prepared from a temperature-controlled slurry experiment containing AG-10 and maleic acid (1:1) in p-dioxane. The XRPD pattern of the b-form of the maleate of formula IX (Figure 25) was well indexed, indicating that the substance consists mainly or exclusively of a single-crystal phase. The indexed amounts are consistent with those of the 1:1 AG-10 maleate.

[0294] Sample 1 The 1H NMR spectrum is consistent with AG-10 and maleic acid in a 1:1 molar ratio. Approximately 0.3 moles of p-dioxane were also observed in the spectrum.

[0295] A single endothermic reaction is observed at approximately 171°C (peak maximum) in the DSC thermogram (Figure 26). No significant weight loss is observed when the sample is heated between 33°C and 120°C (Figure 26).

[0296] Example 28: Preparation of acetate of formula IX The acetate of formula IX was prepared by directly grinding AG-10 together with acetic acid in a 1:1 molar ratio.

[0297] According to XRPD, the acetate of formula IX is composed of crystalline material, as shown in Figure 27. The XRPD pattern was successfully indexed, indicating that the sample consists mainly or exclusively of a single-crystal phase. 1 The 1H NMR spectrum, which shows the presence of approximately 0.9 moles of acetic acid, is consistent with the chemical structure of AG-10.

[0298] The DSC thermogram showed a broad endothermic peak at ~113°C, which is associated with a ~16% weight loss that may be due to the loss of acetic acid (Figure 28). This was followed by endothermic peaks at 186°C and 192°C (peak maximum), which are thought to be due to the melting of the free form of AG-10 (Figure 28).

[0299] Example 29: Preparation of L-malate of formula IX A saturated solution of L-malic acid in nitromethane was added to AG-10 at 60°C, and the resulting solution was cooled to produce a solid at a temperature below ambient temperature. The XRPD pattern consists of a unique crystalline substance called L-malate of formula IX (Figure 29).

[0300] 1 The 1H NMR spectrum indicated a peak at 4.2 ppm, suggesting a malic acid content of 1.8 moles per mole of AG-10. Small amounts of ACN and water were also observed in the spectrum.

[0301] In the DSC data, two broad endothermic phases are observed, with peak maximums at ~89°C and 199°C (Figure 30). A weight loss of 0.2% is observed between 33°C and 107°C (Figure 30).

[0302] Example 30: Crystal form A of formula IX The substance of formula Ia (HCl salt of formula IX) prepared in Example 7 was characterized by powder X-ray diffraction (XRPD) (Figure 31), thermogravimetric analysis (TGA) (Figures 32-34), differential scanning calorimetry (DSC) (Figures 32-34), and polarizing microscope (PLM) (Figure 35). This substance was referred to as crystal form A of formula IX. Three different XRPD plots showing the three different preparations obtained according to Example 7 are superimposed in Figure 31. The representative peak values ​​for the XRPD plot shown in Figure 31 are given in Table 7 below.

[0303] [Table 11]

[0304] Figures 32–35 show three individual TGA / DSC plots for crystal form A of formula IX. Thermogravimetric analysis measured a weight loss of approximately 0.7%–1.9% when heated to approximately 150°C, and further characterization using differential scanning calorimetry revealed at least two endothermic peaks at approximately 211–214°C and 237–239°C. The HPLC purity of crystal form A of formula IX was determined to be 98.76 area%.

[0305] Figure 36 shows the asymmetric unit of crystalline form A of formula IX. This contains one cation and one chloride ion of the free base of compound AG10 (the HCl molecule has transferred a proton to the N1 atom of the free base), indicating that form A is in the form of the anhydrous monoHCl salt.

[0306] To evaluate the hygroscopicity and physical stability of crystalline form A of formula IX under different humidity conditions, samples were pre-equilibrated at 0% RH to remove unbound water (free water), and then dynamic vapor sorption (DVS) data was collected at 25°C. The DVS results (Figure 37) showed a water absorption rate of 1.6% at 25°C / 80% RH, which suggests that crystalline form A of formula IX is slightly hygroscopic. Furthermore, the XRPD results (Figure 38) showed no morphological change before and after the DVS test.

[0307] Example 31: Polymorphic screening of AG-10 Using crystal form A of formula IX as the starting material, polymorphism screening experiments were performed under 98 different conditions using vapor diffusion, poor solvent addition, slurry conversion, slow evaporation, and slow cooling methods. From the polymorphism screening and follow-up, a total of 10 additional crystal forms were obtained: 6 HCl salt forms (A / B / E / H / I / J types), 2 free base forms (C / G type), and 2 currently unidentified forms (D / F type). The crystal forms of A / B / E types were identified as anhydrous. Type I was identified as a hydrate. Types H and J were identified as MeOH solvate and DMAc solvate, respectively. The methods used and the identified crystal forms are summarized in Table 8.

[0308] [Table 12]

[0309] Poor solvent addition A total of 24 poor solvent addition experiments were performed. For each experiment, approximately 15 mg of crystalline form A of formula IX was weighed into a 20 mL glass vial, followed by the addition of 0.125–0.63 mL of the corresponding solvent. The mixture was then magnetically stirred at 750 RPM at room temperature to obtain a clear solution. Subsequently, the corresponding poor solvent was added to the solution to induce precipitation, or until the total volume of the poor solvent reached 10.0 mL. The clear solution was made into a slurry at 5°C. If no precipitation occurred, the solution was transferred to rapid evaporation at RT or vacuum drying at RT. The solid was isolated for XRPD analysis. The results summarized in Table 9 show that forms A, C, D, E, and form A with additional peaks were obtained.

[0310] [Table 13]

[0311] Slow evaporation Slow evaporation experiments were conducted under seven conditions. For each experiment, approximately 15 mg of crystalline form A of formula IX was weighed into a 3 mL glass vial, followed by the addition of the corresponding solvent or solvent mixture to obtain a clear solution. The vial was then covered with Parafilm having 3-4 pinholes, and the solution was kept at room temperature to allow for slow evaporation. The isolated solids were tested by XRPD. Forms A and H were produced, as summarized in Table 10.

[0312] [Table 14]

[0313] Slow cooling Slow cooling experiments were conducted in eight solvent systems. For each experiment, approximately 15–35 mg of crystalline form A of formula IX was suspended at room temperature in 0.8–2.0 mL of the corresponding solvent in a 3 mL glass vial. The suspension was made into a slurry at 750 RPM at 50°C using a magnetic stirrer. The sample was equilibrated at 50°C for 1 hour and then filtered through a 0.45 μm PTFE membrane. The filtrate was then slowly cooled from 50°C to 5°C at a rate of 0.1°C / min. If no precipitate formed, the solution was transferred to rapid evaporation at room temperature or vacuum drying at room temperature. The results summarized in Table 11 show that forms A, E, and J were obtained.

[0314] [Table 15]

[0315] Slurry conversion in RT Slurry conversion experiments were conducted at room temperature in different solvent systems. For each experiment, approximately 15–35 mg of crystalline form A of formula IX was suspended in 0.3–2.0 mL of the corresponding solvent in a 1.5 mL glass vial. After magnetic stirring of the suspension at room temperature for 4 days, the remaining solid was isolated for XRPD analysis. The results summarized in Table 12 show that forms A, C, and G were obtained.

[0316] [Table 16]

[0317] Slurry conversion at 50°C Slurry conversion experiments were conducted at 50°C in different solvent systems. For each experiment, approximately 15 mg of crystalline form A of formula IX was suspended in 1.0 mL of the corresponding solvent in a 1.5 mL glass vial. The suspension was magnetically stirred at 50°C for 4 days, and the remaining solid was isolated for XRPD analysis. The results summarized in Table 13 show that forms A and F were obtained.

[0318] [Table 17]

[0319] Solid vapor diffusion Solid-phase vapor diffusion experiments were conducted using 13 different solvents. For each experiment, approximately 15 mg of crystalline form A of formula IX was weighed into a 3 mL vial and placed in a 20 mL vial together with 4 mL of the corresponding solvent. The 20 mL vial was sealed with a lid and maintained at room temperature for 39 days to allow the solvent vapor to interact with the solid sample. The isolated solid was tested by XRPD. The results summarized in Table 14 show that crystalline form A and form A with extra peaks were obtained.

[0320] [Table 18]

[0321] Liquid-phase vapor diffusion Twenty-one liquid-phase vapor diffusion experiments were conducted. For each experiment, approximately 15 mg of crystalline form A of formula IX was dissolved in 0.125–0.6 mL of the corresponding solvent in a 3 mL vial to obtain a clear solution. This solution was then placed in a 20 mL vial together with 4 mL of the corresponding poor solvent. The 20 mL vial was sealed with a lid and kept at room temperature for a sufficient amount of time for the solvent vapor to interact with the solution. If no precipitate formed, the solution was then rapidly evaporated at room temperature. The solid was isolated for XRPD analysis. The results summarized in Table 15 show that form A was obtained.

[0322] [Table 19]

[0323] A chart summarizing the interchangeability between the identified crystal forms is shown in Figure 39. Abbreviation for solvent

[0324] [Table 20]

[0325] Equipment and methods XRPD A PANalytical powder X-ray diffractometer was used for XRPD analysis. The XRPD parameters used are listed in Table 17.

[0326] [Table 21]

[0327] TGA and DSC TGA data was collected using a TA Q500 / Q5000 TGA from TA Instruments. DSC was performed using a TA Q200 / Q2000 DSC from TA Instruments. The detailed parameters used are listed in Table 18.

[0328] [Table 22]

[0329] 1 1H NMR 1 ¹H NMR data were collected using a Bruker 400M NMR spectrometer with DMSO-d6.

[0330] DVS DVS was measured using the DVS Intrinsic from SMS (Surface Measurement Systems). The parameters for the DVS test are listed in Table 19.

[0331] [Table 23]

[0332] HPLC An Agilent 1100 / 1260 HPLC was used to analyze purity and solubility. Detailed procedures are shown in Table 20.

[0333] [Table 24]

[0334] I C Cl - The IC method used for content measurement is listed in Table 21.

[0335] [Table 25]

[0336] Example 32: Preparation of crystal form B of formula IX Crystal form B of formula IX was obtained by heating a sample of crystal form A to 212°C, cooling to 30°C under nitrogen protection, and then exposing it to air conditioning. The HPLC purity and stoichiometry (acid:free base (FB)) of crystal form B were determined to be 97.86 area% and 0.86, respectively. The XRPD pattern is shown in Figure 40, and the TGA / DSC curve is shown in Figure 41. The results indicated that form B is a crystal with a 1.2% weight loss before 150°C in TGA and three endothermic peaks at 161.4, 232.2, and 262.3°C (peaks) in DSC. Due to the limited TGA weight loss before 150°C and the neat DSC, form B was inferred to be an anhydrous. Heating experiments were performed to investigate the thermal signals. As shown in Figure 42, after heating to 100°C or 170°C, cooling to 30°C under nitrogen protection, and then exposure to air, type B was converted to type I (type I will be described in more detail in Example 38). The peak values ​​of the XRPD plot shown in Figure 40 are given in Table 22 below.

[0337] [Table 26]

[0338] Example 33: Preparation of crystal form C of formula IX The crystalline form C of formula IX was obtained at room temperature by adding a poor solvent in DMSO / H2O, and its XRPD is shown in Figure 43. The TGA and DSC results shown in Figure 44 showed a 3.1% weight loss up to 150°C and two endothermic peaks at 91.2°C and 173.0°C. - The content was 0.17% (theoretical Cl of monoHCl salt). - (The content is 10.8%), so it was confirmed that type C is in the free base form. The peak values ​​of the XRPD plot shown in Figure 43 are given in Table 23 below.

[0339] [Table 27]

[0340] Example 34: Preparation of crystal forms D and F of formula IX Crystalline form D of formula IX was obtained by adding a poor solvent to a MeOH / IPAc system at room temperature. Form F of formula IX was obtained by slurring form A in toluene at 50°C. Their XRPD patterns are shown in Figure 45 (form D, upper plot; form F, lower plot). The peak values ​​for the XRPD plots (Type D and Type F) shown in Figure 45 are provided in Tables 24 and 25 below.

[0341] [Table 28]

[0342] [Table 29]

[0343] Example 35: Preparation of crystal form E of formula IX Crystalline form E of formula IX was obtained by slow evaporation in CHCl3 / EtOH at room temperature. The HPLC purity and stoichiometry (acid:FB) of crystalline form E of formula IX were determined to be 98.60 area% and 0.91, respectively. The XRPD pattern is shown in Figure 46, and the TGA / DSC curve is plotted in Figure 47. The results showed that crystalline form E had a weight loss of 1.5% by 130°C in TGA, and two endothermic peaks at 182.0°C and 242.7°C in DSC (peak). Due to the limited TGA weight loss and the neat (smooth) DSC before 170°C, it was inferred that form E is an anhydrous. To investigate the thermal signal at 182.0°C (peak) in DSC, a heating experiment was performed. As shown in Figure 48, form E was converted to the hydrate form I after heating to 195°C, cooling to 30°C under nitrogen protection, and then exposure to air. Based on thermal data and heating experiments, the anhydrous E-type was converted to a novel anhydrous form (the endothermic signal in the DSC ~180°C may be a morphological transition signal), and this anhydrous form then changed to the hydrated I-type through interaction with water when exposed to ambient conditions. The peak values ​​of the XRPD plot shown in Figure 46 are provided in Table 26 below.

[0344] [Table 30]

[0345] Example 36: Preparation of crystal form G of formula IX The G-type crystalline form of formula IX was obtained at room temperature via slurrying in DMAc / H2O (v:v, 1:3), and its XRPD is shown in Figure 49. The TGA and DSC results shown in Figure 50 showed a 3.7% weight loss up to 200°C and a single sharp endothermic signal at 231.1°C (peak). Cl of the G-type sample - The content was 0.14% (theoretical Cl of monoHCl salt) - (The content is 10.8%), so it was confirmed that the G type is in the free base form. The peak values ​​of the XRPD plot shown in Figure 49 are provided in Table 27 below.

[0346] [Table 31]

[0347] [Table 32]

[0348] Example 37: Preparation of the crystal form H of formula IX The H-form of formula IX was obtained by slow evaporation in an acetone / MeOH system at RT, and its XRPD is shown in Figure 51. The HPLC purity and stoichiometry (acid:FB) of the H-form (810119-11-A4) were determined to be 98.47 area% and 0.91, respectively. The TGA and DSC curves (Figure 52) showed a 4.6% weight loss before 120°C and three endothermic peaks at 90.4, 200.5, and 232.3°C (peaks). 1 As shown in the 1H NMR spectrum (Figure 53), 0.36 equivalents of MeOH (~3.40 wt%) were detected. Combined with the fact that a change in crystal form to form I was observed after heating form H to 120°C under nitrogen protection, cooling to 30°C, and then exposure to ambient conditions (Figure 54), form H was predicted to be the MeOH solvate. The peak values ​​of the XRPD plot shown in Figure 51 are given in Table 28 below.

[0349] [Table 33]

[0350] Example 38: Preparation of crystal form I of formula IX Crystalline form I of formula IX was obtained by heating crystalline form B of formula IX to 100°C, cooling to 30°C under nitrogen protection, and then exposing it to air. Its XRPD is shown in Figure 55. The HPLC purity and stoichiometry (acid: FB) of crystalline form I of formula IX were determined to be 97.94 area% and 0.86, respectively. Crystalline form I was obtained via a solid-phase transition of anhydrous form B, and a 3.0% weight loss (equivalent to 0.5 moles of water) with an endothermic peak (peak, Figure 56) was observed at 62.0°C, so it was presumed that form I is a hydrate. The peak values ​​of the XRPD plot shown in Figure 55 are given in Table 29 below.

[0351] [Table 34]

[0352] [Table 35]

[0353] To further identify crystalline form I and investigate its dehydration behavior, in-situ XRPD analysis using N2 flow was performed to observe the dehydrated form of type I, and a KF (Karl Fischer) test was conducted to confirm whether the TGA weight loss was caused by moisture. As shown in Figure 57, crystalline form I underwent approximately 1.5 hours of N2 purging (30°C / 16%RH) and morphological change to anhydrous crystalline form B was observed. As shown in Figure 58, a weight loss of 2.6% was observed in crystalline form I up to 120°C. Based on the KF results, a moisture content of approximately 3.48% was observed in the crystalline form I sample. Combined with the morphological change to anhydrous form B under N2 flow, type I was identified as a hydrate.

[0354] Example 39: Preparation of crystal form J of formula IX The J-form of formula IX was obtained by slow evaporation in a MEK / DMAc system followed by vacuum drying at 50°C. Its XRPD is shown in Figure 59. The HPLC purity and stoichiometry (acid:FB) of the J-form of formula IX were determined to be 91.69 area% and 0.90, respectively. The TGA and DSC results in Figure 60 showed a 21.5% weight loss up to 120°C and three endothermic peaks at 120.8, 197.8, and 221.5°C (peaks). 1 As shown in the 1H NMR spectrum (Figure 61), 4.9 equivalents of DMAc (~56.51 wt%) were detected. Combined with the fact that a morphological change (highlighted) into a mixture of crystalline forms I and A was observed after heating crystalline form J to 130°C, cooling to 30°C under nitrogen protection, and exposure to ambient conditions (Figure 62), it was inferred that form J is a DMAc solvate.

[0355] The peak values ​​of the XRPD plot shown in Figure 59 are given in Table 30 below. [Table 36]

[0356] [Table 37]

[0357] Example 40: Preparation of the K-type crystal form of formula IX The free base material prepared in Example 11 was characterized by XRPD (Figure 63), TGA (Figure 64), and DSC (Figure 64). This material was referred to as the K-form of formula IX. A weight loss of 6.1% was observed by TGA up to 150°C, and the DSC results showed endothermic peaks at 159.3, 176.2, and 278.4°C. The HPLC purity of the K-form of formula IX was determined to be 99.12 area%. The peak values ​​of the XRPD plot shown in Figure 63 are given in Table 31 below.

[0358] [Table 38]

[0359] For clarity and understanding, the above has been described in some detail by description and examples, but those skilled in the art will understand that certain changes and modifications can be made within the scope of the appended claims. Furthermore, each of the references provided herein is incorporated by reference in whole to the same extent as each of the references is incorporated by reference individually.

Claims

1. Formula I: 【Chemistry 1】 (Here, X is the pharmaceutically acceptable anion of a protonate.) A pharmaceutically acceptable salt represented by [this].

2. The pharmaceutically acceptable salt according to claim 1, wherein the pharmaceutically acceptable anion of the proton acid is selected from the group consisting of chloride ions, bromide ions, sulfate ions, tosylate ions, mesylate ions, nitrate ions, and acetate ions, and combinations thereof.

3. The pharmaceutically acceptable salt according to claim 2, wherein the pharmaceutically acceptable anion of the proton acid is the mesylate ion.

4. The pharmaceutically acceptable salt according to claim 2, wherein the pharmaceutically acceptable anion of the proton acid is the tosylate ion.

5. The pharmaceutically acceptable salt according to claim 2, wherein the pharmaceutically acceptable anion of the proton acid is a chloride ion.

6. Formula Ib: 【Chemistry 2】 (Here, Y is a polyprotonic acid.) A pharmaceutically acceptable salt represented by [this].

7. A pharmaceutically acceptable salt according to claim 2, wherein Y is selected from the group consisting of ethane-1,2-disulfonic acid, sulfuric acid, citric acid, maleic acid, malic acid, tartaric acid, and oxalic acid.

8. Formula IX: 【Transformation 3】 A method for preparing the compound, (a) Equation II: 【Chemistry 4】 The compound is given by formula III: 【Transformation 5】 The compound is brought into contact with a first base and a first organic solvent, and formula IV: 【Transformation 6】 (Here each R 1 (These are independently halogenated compounds or sulfonic acid esters.) Provides compounds of the same name; (b) The compound of formula IV is brought into contact with hydrazine and a second organic solvent, and formula V: 【Transformation 7】 Provides the compound, (c) Contact the compound of formula V with a sulfonating agent or halogenating agent to obtain formula VI: 【Transformation 8】 Provides the compound, (d) Compound of formula VI is formula VII: 【Chemistry 9】 The compound is brought into contact with a second base and a third organic solvent, and formula VIII: 【Chemistry 10】 (Here, R 3 is C 1 to C 12 alkyl, C 2 to C 12 alkenyl, C 1 to C 12 alkynyl, C 3 to C 8 selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl, each of which is optionally substituted). It provides compounds of; and (e) Contacting the compound of formula VIII with a third base to give the compound of formula IX. Methods that include...

9. Each R 1 The method according to claim 8, wherein is independently selected from the group consisting of chloride, bromide, tosylate, and mesylate.

10. Each R 1 The method according to claim 9, wherein bromide is used.

11. The method according to any one of claims 8 to 10, wherein the first base is an alkali metal carbonate, an alkali metal bicarbonate, or a combination thereof.

12. The alkali metal carbonate is Li 2 CO 3 kaNa 2 CO 3 and K 2 CO 3 The method according to claim 9, selected from the group consisting of the following.

13. The alkali metal carbonate is K 2 CO 3 The method according to claim 12.

14. The alkali metal bicarbonate is LiHCO 3 NaHCO 3 and KHCO 3 The method according to claim 11, selected from the group consisting of the following.

15. The method according to any one of claims 8 to 14, wherein the first organic solvent is a polar aprotic organic solvent.

16. The method according to claim 15, wherein the polar organic solvent is selected from the group consisting of acetone, ethyl acetate, dichloromethane, tetrahydrofuran, dimethylformamide, and acetonitrile.

17. The method according to claim 16, wherein the polar organic solvent is acetone.

18. The method according to any one of claims 8 to 17, wherein the second organic solvent is a polar protic organic solvent.

19. The polar protic organic solvent is C 1-10 The method according to claim 18, wherein the result is -OH.

20. The method according to claim 19, wherein the polar protic organic solvent is ethanol.

21. The method according to any one of claims 8 to 20, wherein the sulfonating agent is mesyl chloride or tosyl chloride.

22. The halogenating agent is PBr 3 , PCl 3 , PCl 5 , SOBr 2 PBr 5 and SOCl 2 A method according to any one of claims 8 to 20, selected from the group consisting of the following.

23. The halogenating agent is PBr 3 The method according to claim 22.

24. R 2 The method according to any one of claims 8 to 23, wherein is selected from the group consisting of chloride, bromide, tosylate, and mesylate.

25. R 2 The method according to claim 24, wherein is Br.

26. The method according to any one of claims 8 to 25, wherein the second base is selected from the group consisting of alkali metal carbonates, alkali metal bicarbonates, or combinations thereof.

27. The alkali metal carbonate is Li 2 CO 3 kaNa 2 CO 3 and K 2 CO 3 The method according to claim 25, selected from the group consisting of a combination thereof.

28. The alkali metal carbonate is K 2 CO 3 The method according to claim 27.

29. The alkali metal bicarbonate is LiHCO 3 NaHCO 3 and KHCO 3 The method according to claim 25, selected from the group consisting of a combination thereof.

30. The method according to any one of claims 8 to 29, wherein the third organic solvent is a polar aprotic organic solvent.

31. The method according to claim 30, wherein the polar organic solvent is selected from the group consisting of acetone, ethyl acetate, dichloromethane, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, and acetonitrile.

32. The method according to claim 31, wherein the polar organic solvent is dimethylformamide.

33. The method according to claim 31, wherein the polar organic solvent is dimethyl sulfoxide.

34. R 3 C 1-8 The method according to any one of claims 8 to 32, wherein the alkyl group is alkyl.

35. R 3 The method according to claim 34, wherein is methyl.

36. The method according to any one of claims 8 to 35, wherein the third base is a metal hydroxide.

37. The method according to claim 36, wherein the metal hydroxide is an alkali metal hydroxide.

38. The method according to claim 37, wherein the alkali metal hydroxide is selected from the group consisting of LiOH, NaOH, KOH, RbOH, and CsOH.

39. The method according to claim 38, wherein the alkali metal hydroxide is LiOH.

40. The method according to claim 38, wherein the alkali metal hydroxide is NaOH.

41. Crystal form A of formula IX, characterized by a powder X-ray diffraction pattern with peaks at 12.0, 21.8, 25.9, 26.7, and 27.9°²θ (±0.2°²θ).

42. Crystal form A of formula IX, characterized by a powder X-ray diffraction pattern that substantially matches Figure 31.

43. Crystal form A of formula IX according to claim 41 or 42, substantially free from other crystal forms or amorphous forms of formula IX.

44. Crystal form A of formula IX according to any one of claims 41 to 42, further characterized by a weight loss in the range of approximately 0.7% to approximately 1.9% when heated to around 150°C, as measured by thermogravimetric analysis.

45. The crystal form A of formula IX according to claim 44, wherein the weight reduction is approximately 1.3%.

46. Crystal form A of formula IX, characterized by a water absorption rate of approximately 1.6% at 25°C / 80%RH, after undergoing dynamic vapor sorption circulation including pre-equilibrium at 0% relative humidity (RH).

47. Crystalline form A of formula IX, characterized by a weight increase of less than 2.5 wt% after undergoing dynamic vapor sorption circulation from approximately 0% relative humidity (RH) to approximately 90% RH.

48. Crystal form A of formula IX, having substantially the same dynamic vapor sorbation profile as shown in Figure 37.

49. Crystal form A of formula IX according to any one of claims 41 to 45, further characterized by a differential scanning calorimetry thermogram including endothermic peaks around 211–214°C and 237–239°C.

50. The crystal form A of formula IX according to claim 49, wherein the differential scanning calorimetry thermogram includes endothermic peaks around 11.7°C, 212.6°C, and 237.3°C.

51. Crystal form B of formula IX, characterized by a powder X-ray diffraction pattern with peaks at 12.1, 13.9, 19.8, 23.3, and 24.4°²θ (±0.2°²θ).

52. Crystal form B of formula IX, characterized by a powder X-ray diffraction pattern that substantially matches Figure 40.

53. Crystal form B of formula IX according to claim 51 or 52, substantially free from other crystal forms or amorphous forms of formula IX.

54. Crystal form B of formula IX according to claim 51 or 52, further characterized by a weight loss in the range of approximately 0.6% to approximately 2.0% when heated to around 150°C, as measured by thermogravimetric analysis.

55. Crystal form B of formula IX according to claim 51 or 52, further characterized by a weight loss of approximately 1.2% when heated to around 150°C, as measured by thermogravimetric analysis.

56. Crystal form B of formula IX according to any one of claims 51 to 54, further characterized by a differential scanning calorimetry thermogram including endothermic peaks around 161.4°C, 232.2°C, and 262.3°C.

57. Crystal form E of formula IX, characterized by a powder X-ray diffraction pattern with peaks at 11.9, 14.0, 15.1, and 25.8°2θ (±0.2°2θ).

58. Crystal form E of formula IX, characterized by a powder X-ray diffraction pattern that substantially matches Figure 46.

59. Crystal form E of formula IX according to claim 57 or 58, substantially comprising no other crystal forms or amorphous forms of formula IX.

60. Crystal form E of formula IX according to claim 57 or 58, further characterized by a weight loss in the range of approximately 0.5% to approximately 2.5% when heated to around 150°C, as measured by thermogravimetric analysis.

61. Crystal form E of formula IX according to claim 57 or 58, further characterized by a weight loss of approximately 1.5% when heated to around 150°C, as measured by thermogravimetric analysis.

62. Crystal form E of formula IX according to any one of claims 57 to 60, further characterized by a differential scanning calorimetry thermogram including endothermic peaks around 182.0°C and 242.7°C.

63. Crystal form I of formula IX, characterized by a powder X-ray diffraction pattern with peaks at 12.5, 17.3, 23.4, 25.0, and 25.4°2θ (±0.2°2θ).

64. Crystal form I of formula IX, characterized by a powder X-ray diffraction pattern that substantially matches that of Figure 55.

65. Crystal form I of formula IX according to claim 63 or 64, substantially free from other crystal forms or amorphous forms of formula IX.

66. Crystal form I of formula IX according to claim 63 or 64, further characterized by a weight loss in the range of approximately 2.5% to approximately 3.5% when heated to around 120°C, as measured by thermogravimetric analysis.

67. Crystal form I of formula IX according to claim 63 or 64, further characterized by a weight loss of approximately 3.0% when heated to around 120°C, as measured by thermogravimetric analysis.

68. Crystal form I of formula IX according to any one of claims 63 to 66, further characterized by a differential scanning calorimetry thermogram including endothermic peaks around 62.0°C, 158.4°C, and 215.7°C.

69. The H-type crystal form of formula IX is characterized by a powder X-ray diffraction pattern having peaks at 11.9, 12.3, 21.7, 23.3, and 25.8°²θ (±0.2°²θ).

70. The H-type crystal form of formula IX is characterized by a powder X-ray diffraction pattern that substantially matches Figure 51.

71. The H-type crystalline form of formula IX according to claim 69 or 70, which substantially does not include other crystalline or amorphous forms of formula IX.

72. The crystal form H of formula IX according to claim 69 or 70, further characterized by a weight loss in the range of approximately 3.5% to approximately 5.5% when heated to around 150°C, as measured by thermogravimetric analysis.

73. The crystal form H of formula IX according to claim 69 or 70, further characterized by a weight loss of approximately 4.6% when heated to around 150°C, as measured by thermogravimetric analysis.

74. Crystalline form H of formula IX according to any one of claims 69 to 73, further characterized by a differential scanning calorimetry thermogram including endothermic peaks around 90.4°C, 200.5°C, and 232.3°C.

75. Crystal form J of formula IX, characterized by a powder X-ray diffraction pattern with peaks at 13.8, 14.7, 22.9, 26.2, and 27.7°2θ (±0.2°2θ).

76. Crystal form J of formula IX, characterized by a powder X-ray diffraction pattern that substantially matches Figure 59.

77. The crystal form J of formula IX according to claim 75 or 76, which substantially does not include other crystal forms or amorphous forms of formula IX.

78. Crystal form J of formula IX according to claim 75 or 76, further characterized by a weight loss in the range of approximately 17.5% to approximately 24% when heated to around 120°C, as measured by thermogravimetric analysis.

79. Crystal form J of formula IX according to claim 75 or 76, further characterized by a weight loss of approximately 21.5% when heated to around 120°C, as measured by thermogravimetric analysis.

80. Crystal form J of formula IX according to any one of claims 75 to 79, further characterized by a differential scanning calorimetry thermogram including endothermic peaks around 120.8°C, 197.8°C, and 221.5°C.

81. The crystal form K-type of formula IX is characterized by a powder X-ray diffraction pattern with peaks at 7.2, 7.6, 9.9, 14.0, and 19.3°2θ (±0.2°2θ).

82. Crystal form K of formula IX, characterized by a powder X-ray diffraction pattern that substantially matches Figure 59.

83. The K-type crystalline form of formula IX according to claim 81 or 82, which substantially does not include other crystalline or amorphous forms of formula IX.

84. The crystal form K of formula IX according to claim 81 or 82, further characterized by a weight loss in the range of approximately 5.0% to approximately 7.0% when heated to around 120°C, as measured by thermogravimetric analysis.

85. The crystal form K of formula IX according to claim 81 or 82, further characterized by a weight loss of approximately 6.1% when heated to around 120°C, as measured by thermogravimetric analysis.

86. Crystal form K of formula IX according to any one of claims 81 to 85, further characterized by differential scanning calorimetry thermograms including endothermic peaks around 159.3°C, 176.2°C, and 278.4°C.

87. Crystal form C of formula IX, characterized by a powder X-ray diffraction pattern with peaks at 14.6, 16.8, 19.5, 20.7, and 22.5°²θ (±0.2°²θ).

88. Crystal form C of formula IX, characterized by a powder X-ray diffraction pattern that substantially matches that of Figure 43.

89. The crystalline form C of formula IX according to claim 87 or 88, which substantially does not include other crystalline or amorphous forms of formula IX.

90. Crystal form C of formula IX according to claim 87 or 88, further characterized by a weight loss in the range of approximately 2.0% to approximately 4.0% when heated to around 150°C, as measured by thermogravimetric analysis.

91. Crystal form C of formula IX according to claim 87 or 88, further characterized by a weight loss of approximately 3.1% when heated to around 150°C, as measured by thermogravimetric analysis.

92. Crystal form C of formula IX according to any one of claims 87 to 91, further characterized by a differential scanning calorimetry thermogram including endothermic peaks around 91.2°C and 173.0°C.

93. Crystal form G of formula IX, characterized by a powder X-ray diffraction pattern with peaks at 12.3, 13.2, 13.4, 17.8 and 26.6°2θ (±0.2°2θ).

94. Crystal form G of formula IX, characterized by a powder X-ray diffraction pattern that substantially matches that of Figure 43.

95. The crystal form G of formula IX according to claim 93 or 94, which substantially does not include other crystalline or amorphous forms of formula IX.

96. Crystal form G of formula IX according to claim 93 or 94, further characterized by a weight loss in the range of approximately 1.7% to approximately 2.7% when heated to around 200°C, as measured by thermogravimetric analysis.

97. Crystal form G of formula IX according to claim 93 or 94, further characterized by a weight loss of approximately 3.7% when heated to around 200°C as measured by thermogravimetric analysis.

98. Crystal form G of formula IX according to any one of claims 93 to 97, further characterized by a differential scanning calorimetry thermogram containing an endothermic peak around 231.1°C.

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