WO2019164778A1

WO2019164778A1 - Process for preparing 1-arylsulfonyl-pyrrolidine-2-carboxamide transient receptor potential channel antagonist compounds and crystalline forms thereof

Info

Publication number: WO2019164778A1
Application number: PCT/US2019/018407
Authority: WO
Inventors: Kyle Bradley Pascual CLAGG; Francis Gosselin; Chong Han; James Levi KNIPPEL; Joseph LUBACH; Scott Savage
Original assignee: Genentech, Inc.; F. Hoffmann-La Roche Ag
Priority date: 2018-02-20
Filing date: 2019-02-18
Publication date: 2019-08-29
Also published as: TW202000201A; AR114585A1

Abstract

The invention relates generally to methods of preparing 1-arylsulfonyl-pyrrolidine-2-carboxamide Transient Receptor Potential channel antagonist compounds of the following structure (I): (I) The invention further relates to solvate and co-crystal polymorphs of crystalline formula (I), and methods of preparation thereof.

Description

PROCESS FOR PREPARING 1-ARYLSULFONYL-PYRROLIDINE-2-CARBOXAMIDE TRANSIENT RECEPTOR POTENTIAL CHANNEL ANTAGONIST COMPOUNDS

AND CRYSTALLINE FORMS THEREOF

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to United States Provisional Application No. 62/632,653 filed on February 20, 2018, the contents of which are incorporated by reference herein.

BACKGROUND OF THE INVENTION

[0002] The field of the invention relates generally to methods of preparing 1- arylsulfonyl-pyrrolidine-2-carboxamide Transient Receptor Potential channel antagonist compounds of the following structure (I):

The field of the invention further relates to solvate and co-crystal polymorphs of crystalline formula (I), and methods of preparation thereof.

[0003] Transient Receptor Potential (TRP) channels are a class of ion channels found on the plasma membrane of a variety of human (and other animal) cell types. There are at least 28 known human TRP channels which are broken into a number of families or groups based upon sequence homology and function. Transient receptor potential cation channel, subfamily A, member 1 (TRPA1) is a non-selective cation conducting channel that modulates membrane potential via flux of sodium, potassium and calcium. TRPA1 has been shown to be highly expressed in the human dorsal root ganglion neurons and peripheral sensory nerves. In humans, TRPA1 is activated by a number of reactive compounds such as acrolein, allylisothiocyanate, ozone as well as unreactive compounds such as nicotine and menthol and is thus thought to act as a chemosensor.

[0004] Many of the known TRPA1 agonists are irritants that cause pain, irritation and neurogenic inflammation in humans and other animals. Therefore, it would be expected that TRPA1 antagonists or agents that block the biological effect of TRPA1 channel activators would be useful in the treatment of diseases such as asthma and its exacerbations, chronic cough and related maladies as well as being useful for the treatment of acute and chronic pain.

Recently, it has also been shown that products of tissue damage and oxidative stress (e.g., 4- hydroxynonenal and related compounds) activate the TRPA1 channel. This finding provides additional rationale for the utility of small molecule TRPA1 antagonists in the treatment of diseases related to tissue damage, oxidative stress and bronchial smooth muscle contraction such as asthma, chronic obstructive pulmonary disease (COPD), occupational asthma, and virally- induced lung inflammation. Moreover, recently findings have correlated activation of TRPA1 channels with increased pain perception (Kosugi et al, J. Neurosci 27, (2007) 4443-4451; Kremayer et al, Neuron 66 (2010) 671-680; Wei et al., Pain 152 (2011) 582-591); Wei et al., Neurosci Lett 479 (2010) 253-256)), providing additional rationale for the utility of small molecule TRPA1 inhibitors in the treatment of pain disorders

[0005] The TRP channel antagonist compound (25',4i?,55)-4-fluoro-l-((4- fluorophenyl)sulfonyl)-5-methyl-/V-((5-(trifluoromethyl)-2-(2-(trifluoromethyl)pyrimi din-5- yl)pyridin-4-yl)methyl) pyrrolidine-2-carboxamide of the following structure 1(a):

is known from International Publication Number WO 2016/128529, which is incorporated by reference in its entirety. Alternative names for (25'.4//.55')-4-riuoro- 1 -((4-fluorophenyl) sulfonyl)-5-methyl-/V-((5-(trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyri din-4- yl)methyl) pyrrolidine-2-carboxamide can be used, but the shown chemical structure controls. The WO 2016/128529 publication discloses as useful method for preparing compound 1(a). The method is shown in FIG. 4. However, the intermediate produced by step 4 of the prior art method is isolated as an HC1 salt and the yield for the combination of steps 3 and 4 is about 17%. Further, the compound 1(a) is isolated as an amorphous solid in the prior art process. Yet further, the prior art method requires multiple chromatographic purification steps to achieve desired purity. [0006] A need therefore exists for improved methods for preparing TRP antagonist compounds of structure (I), such as (2ri',4i?,5ri -4-fluoro-l-((4-fluorophenyl)sulfonyl)-5-methyl- iV-((5-(trinuoromethyl)-2-(2-(tririuoromethyl)pyrimidin-5-yl)pyridin-4-yl)methyl)pyrrolidine-2- carboxamide, and intermediate compounds therefore.

[0007] A need further exists for crystalline forms of compound (I) that can provide for improved properties, such as, for instance, one or more of, stability, solubility, dissolution rate, hardness, compressibility and melting point.

BRIEF DESCRIPTION OF THE INVENTION

[0008] In some embodiments, a process for preparing compound 3 is provided. The process comprises reacting compound 1 with a sulfonating reagent in a solvent to form compound 2 according to step 1 below where Y is an arylsulfonyl or alkylsulfonyl group:

[0009] The process further comprises reacting compound 2 with a nitrogen source in a solvent to form compound 3 according to step 2 below:

p

[0010] Compound 3 is a free base. The yield of compound 3 based on compound 1 is at least 30%. R¹ is selected from halo, halo-Ci-4 alkyl-, halo-Ci-4 alkoxy-, and -CN. R² is selected from H and cyclopropyl-.

[0011] The group Y may be introduced by reaction of compound 1 with sulfonating reagents such as sulfonate esters, arylsulfonyl halides or lower alkylsulfonyl halides. Exemplary sulfonating reagents include tosylate (tosyl) chloride and mesylate (mesyl) chloride. The nitrogen source may be ammonia or an ammonium salt which is reacted with Compound 2 to displace the Y-O- group and afford amine compound 3.

[0012] In some other embodiments, a process for preparing crystalline compound I, or a solvate or co-crystal thereof, is provided. The process comprises reacting compound 6 (as an acid salt), compound 7, and a base, in a solvent system in a reaction step to form compound (I) as follows

[0013] R¹ is selected from halo, halo-Ci-4 alkyl-, halo-Ci-4 alkoxy-, and -CN. R² is selected from H and -cyclopropyl. R³ is C alkyl- and R⁴ is selected from H and -F, or R³ and R⁴ together with the ring atoms to which they are attached form a three-membered carbocyclic ring. R⁵ is halo. Xi and X₂ are each C, or one of Xi and X₂ is N and the other is C. n is 1 or 2. Each asterisk represents a chiral center.

[0014] The process further comprises forming a solution of compound (I) by solvent exchange transfer of compound (I) from the solvent system of the reaction step into an organic solvent selected from: (a) a non-polar solvent having a dielectric constant of greater than 2; (b) a polar aprotic solvent; or (c) a polar protic solvent.

[0015] The process further comprises contacting the solution of compound (I) with an anti-solvent to form a slurry of crystalline compound (I). [0016] In some other embodiments, a crystalline (2L'.4//.5L')-4-PIIOGO- 1 -(4- fluorophenylsulfonyl)-5-methyl-/V-((5-(trifluoromethyl)-2-(2-(trifluoromethyl)pyrimi din-5- yl)pyridine-4-yl)methyl)pyrrolidine-2-carboxamide compound is provided.

[0017] In some other embodiments, a pharmaceutical composition comprising a compound of the present disclosure and at least one pharmaceutically acceptable excipient, diluent and/or carrier is provided.

[0018] In some other embodiments, a compound (2ri',4i?,5ri -4-fluoro-l-(4- fluorophenylsulfonyl)-5-methyl-/V-((5-(trifluoromethyl)-2-(2-(trifluoromethyl)pyrimi din-5- yl)pyridine-4-yl)methyl)pyrrolidine-2-carboxamide in free base anhydrate crystalline Type E form is provided characterized by X-ray powder diffraction peaks containing three, four or five peaks selected from 7.5°±0.2°, 8.2°±0.2°, 12.6°±0.2°, 13.1°±0.2°, 13.4°±0.2°, l4.7°±0.2°, l5. l°±0.2°, l5.5°±0.2°, l6. l°±0.2°, l6.6°±0.2°, l8.2°±0.2°, l8.9°±0.2°, l9.9°±0.2°, 20.4°±0.2°, 2l.0°±0.2°, 2l.5°±0.2°, 2l.8°±0.2°, 22.4°±0.2°, 22.7°±0.2°, 24.3°±0.2°, 25.0°±0.2°, 25.4°±0.2°, and 28.4°±0.2°.

[0019] In some other embodiments, a pharmaceutical composition comprising

(2_<S',4i?,5_<S)-4-fluoro-l-(4-fluorophenylsulfonyl)-5-methyl- V-((5-(trifluoromethyl)-2-(2- (trifluoromethy l)pyrimi din-5 -yl)pyridine-4-yl)methyl)pyrrolidine-2-carboxamide in free base anhydrate crystalline Type E form and at least one pharmaceutically acceptable excipient, diluent and/or carrier is provided.

[0020] In some other embodiments, a method of preparing (2ri',4i?,5ri -4-fluoro-l-(4- fluorophenylsulfonyl)-5-methyl-/V-((5-(trifluoromethyl)-2-(2-(trifluoromethyl)pyrimi din-5- yl)pyridine-4-yl)methyl)pyrrolidine-2-carboxamide in free base anhydrate crystalline Type E is provided.

[0021] The method comprises mixing (2ri',4i?,5ri)-4-fluoro-l-(4-fluorophenylsulfonyl)- 5-methyl-/V-((5-(trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridine-4- yl)methyl)pynOlidine-2-carboxamide free base starting material with dichloromethane to form a solution having a (2ri',4i?,5ri)-4-fluoro-l-(4-fluorophenylsulfonyl)-5-methyl- V-((5- (trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridine-4-yl)methyl)pyrrohdine-2- carboxamide concentration of at least 50 mg/mL.

[0022] The method further comprises combining the solution of (2ri',4i?,5ri)-4-fluoro-l- (4-fluorophenylsulfonyl)-5-methyl-/V-((5-(trifluoromethyl)-2-(2-(trifluoromethyl)pyrimi din-5- yl)pyridine-4-yl)methyl)pyrrolidine-2-carboxamide with a non-polar anti-solvent having a dielectric constant of less than 2 to a total volume ratio of dichloromethane to anti-solvent of from about 1 : 1.5 to about 1 : 10 to form a slurry comprising free base anhydrate crystalline Type E (2ri',4i?,5ri -4-fluoro-l-(4-fluorophenylsulfonyl)-5-methyl-/V-((5-(trifluoromethyl)-2-(2- (trifluoromethyl)pyrimidin-5-yl)pyridine-4-yl)methyl)pyrrobdine-2-carboxamide.

[0023] The method further comprises isolating the free base anhydrate crystalline Type E (2ri',4i?,5ri -4-fluoro-l-(4-fluorophenylsulfonyl)-5-methyl-/V-((5-(trifluoromethyl)-2-(2- (trifluoromethyl)pyrimidin-5-yl)pyridine-4-yl)methyl)pyrrolidine-2-carboxamide from the slurry.

BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 shows one method of the present disclosure for preparing TRP antagonist compound (I).

[0025] Figure 2 shows one method of the present disclosure for preparing intermediate compound 1 and one method of the present disclosure for preparing intermediate compound 8.

[0026] Figure 3 shows one method of the present disclosure for preparing intermediate compound 4(a) corresponding to compound 4 of FIG. 1 wherein R³ is -CH₃, R⁴ is F and PG is /er/-butyloxy carbonyl (BOC).

[0027] Figure 4 shows a prior art process for preparing amorphous (2ri',4i?,5ri -4-fluoro- l-((4-fluorophenyl) sulfonyl)-5-methyl-/V-((5-(trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin- 5-yl)pyridin-4-yl)methyl) pyrrolidine-2-carboxamide (Compound 1(a)).

[0028] Figure 5 shows the inter-conversion relationship between crystalline forms of Compound 1(a).

[0029] Figure 6 shows an XRPD pattern of crystalline Compound 1(a) Type A.

[0030] Figure 7 shows TGA and DSC curves for crystalline Compound 1(a) Type A.

[0031] Figure 8 shows a ^XH NMR spectrum of crystalline Compound 1(a) Type A.

[0032] Figure 9 shows a DVS plot of crystalline Compound 1(a) Type A.

[0033] Figure 10 shows an XRPD pattern of crystalline Compound 1(a) Type E.

[0034] Figure 11 shows TGA and DSC curves for crystalline Compound 1(a) Type E. [0035] Figure 12 shows a 1H NMR spectrum of crystalline Compound 1(a) Type E.

[0036] Figure 13 shows a DVS plot of crystalline Compound 1(a) Type E.

[0037] Figure 14 shows an XRPD overlay of samples from slurries of Compound 1(a) Type A and Type E.

[0038] Figure 15 shows an XRPD pattern of crystalline Compound 1(a) Type E.

[0039] Figure 16 shows TGA and DSC curves for crystalline Compound 1(a) Type E.

[0040] Figure 17 shows an XRPD pattern of crystalline Compound 1(a) Type E before and after jet milling.

[0041] Figure 18 shows a DSC curve of crystalline Compound 1(a) Type E after jet milling.

[0042] Figure 19 shows an XRPD overlay of crystalline Compound 1(a) Type B before and after air drying.

[0043] Figure 20 shows an XRPD overlay of re-prepared crystalline Compound 1(a) Type A before and after drying.

[0044] Figure 21 shows TGA and DSC curves for re-prepared crystalline Compound 1(a) Type A.

[0045] Figure 22 shows an XRPD pattern of re-prepared crystalline Compound 1(a)

Type E.

[0046] Figure 23 shows TGA and DSC curves for re-prepared crystalline Compound 1(a) Type E.

[0047] Figure 24 shows an XRPD pattern of crystalline Compound 1(a) Type AO. [0048] Figure 25 shows an XRPD pattern of crystalline Compound 1(a) Type C. [0049] Figure 26 shows TGA and DSC curves for crystalline Compound 1(a) Type C. [0050] Figure 27 shows a 1H NMR spectrum of crystalline Compound 1(a) Type C. [0051] Figure 28 shows an XRPD pattern of crystalline Compound 1(a) Type D. [0052] Figure 29 shows TGA and DSC curves for crystalline Compound 1(a) Type D. [0053] Figure 30 shows a 1H NMR spectrum of crystalline Compound 1(a) Type D.

[0054] Figure 31 shows an XRPD overlay of crystalline Compound 1(a) Type D before and after heating.

[0055] Figure 32 shows an XRPD pattern of crystalline Compound 1(a) Type F.

[0056] Figure 33 shows TGA and DSC curves for crystalline Compound 1(a) Type F.

[0057] Figure 34 shows a 1H NMR spectrum of crystalline Compound 1(a) Type F.

[0058] Figure 35 shows an XRPD overlay of crystalline Compound 1(a) Type F before and after heating.

[0059] Figure 36 shows an XRPD pattern of crystalline Compound 1(a) Type G.

[0060] Figure 37 shows TGA and DSC curves for crystalline Compound 1(a) Type G.

[0061] Figure 38 shows a 'H NMR spectrum of crystalline Compound 1(a) Type G.

[0062] Figure 39 shows an XRPD overlay of crystalline Compound 1(a) Type G before and after heating.

[0063] Figure 40 shows an XRPD pattern of crystalline Compound 1(a) Type H.

[0064] Figure 41 shows TGA and DSC curves for crystalline Compound 1(a) Type H.

[0065] Figure 42 shows a 'H NMR spectrum of crystalline Compound 1(a) Type H.

[0066] Figure 43 shows an XRPD overlay of crystalline Compound 1(a) Type H before and after heating.

[0067] Figure 44 shows an XRPD pattern of crystalline Compound 1(a) Type I.

[0068] Figure 45 shows TGA and DSC curves for crystalline Compound 1(a) Type I. [0069] Figure 46 shows a 1H NMR spectrum of crystalline Compound 1(a) Type I. [0070] Figure 47 shows an XRPD pattern of crystalline Compound 1(a) Type J.

[0071] Figure 48 shows TGA and DSC curves for crystalline Compound 1(a) Type J. [0072] Figure 49 shows a 1H NMR spectrum of crystalline Compound 1(a) Type J. [0073] Figure 50 shows an XRPD pattern of crystalline Compound 1(a) Type K. [0074] Figure 51 shows TGA and DSC curves for crystalline Compound 1(a) Type K.

[0075] Figure 52 shows a ' H NMR spectrum of crystalline Compound 1(a) Type K.

[0076] Figure 53 shows an XRPD pattern of crystalline Compound 1(a) Type L.

[0077] Figure 54 shows TGA and DSC curves for crystalline Compound 1(a) Type L.

[0078] Figure 55 shows a 1H NMR spectrum of crystalline Compound 1(a) Type L.

[0079] Figure 56 shows an XRPD pattern of crystalline Compound 1(a) Type M.

[0080] Figure 57 shows TGA and DSC curves for crystalline Compound 1(a) Type M.

[0081] Figure 58 shows a 1H NMR spectrum of crystalline Compound 1(a) Type M.

[0082] Figure 59 shows an XRPD pattern for amorphous Compound 1(a) prepared by a prior art process.

[0083] Figure 60 shows TGA and DSC curves for amorphous Compound 1(a) free base prepared by a prior art process.

[0084] Figure 61 shows an XRPD pattern for amorphous Compound 1(a) free base prepared by a prior art process.

[0085] Figure 62 shows an TGA and mDSC curves for amorphous Compound 1(a) prepared by a prior art process.

[0086] Figure 63 shows an HPLC chromatograph for amorphous Compound 1(a) prepared by a prior art process.

[0087] Figure 64 shows XRPD patterns for crystalline Compound 1(a) Type E and Type E seed material.

[0088] Figure 65 shows TGA and DSC curves for crystalline Compound 1(a) Type E.

[0089] Figure 66 shows an XRPD overlay of gentisic acid-Compound 1(a) co-crystal Type A.

[0090] Figure 67 shows a TGA and DSC curves for gentisic acid-Compound 1(a) co crystal Type A. [0091] Figure 68 shows a ' H NMR spectrum of gentisic acid-Compound 1(a) co-crystal Type A.

[0092] Figure 69 shows an XRPD overlay of gentisic acid-Compound 1(a) co-crystal Types A and B.

[0093] Figure 70 shows a TGA and DSC curves for gentisic acid-Compound 1(a) co crystal Type A.

[0094] Figure 71 shows an XPRD overlay of patterns for crystalline Compound 1(a) Type E before and after DVS testing.

[0095] Figure 72 shows a TGA and DSC curves for gentisic acid-Compound 1(a) co crystal Type B.

[0096] Figure 73 shows a 'H NMR spectrum of gentisic acid-Compound 1(a) co-crystal Type B.

[0097] Figure 74 shows an XRPD overlay of picolinamide Compound 1(a) co-crystal Type A.

[0098] Figure 75 shows TGA and DSC curves for picolinamide Compound 1(a) co crystal Type A.

[0099] Figure 76 shows a 1H NMR spectrum of picolinamide Compound 1(a) co-crystal Type A.

[0100] Figure 77 shows an XRPD overlay of picolinamide Compound 1(a) co-crystal Type A before and after heating.

[0101] Figure 78 shows an XRPD pattern of picolinamide Compound 1(a) co-crystal Type A.

[0102] Figure 79 shows TGA and DSC curves for picolinamide Compound 1(a) co crystal Type A.

[0103] Figure 80 shows a 1H NMR spectrum of picolinamide Compound 1(a) co-crystal Type A.

[0104] Figure 81 shows an XRPD pattern of crystalline Compound 1(a) Type AL.

[0105] Figure 82 shows TGA and DSC curves for crystalline Compound 1(a) Type AL. [0106] Figure 83 shows a ' H NMR spectrum of crystalline Compound 1(a) Type AL.

[0107] Figure 84 shows an XRPD overlay of crystalline Compound 1(a) Type BO and Type BN.

[0108] Figure 85 shows TGA and DSC curves for crystalline Compound 1(a) Type BO.

[0109] Figure 86 shows a 'H NMR spectrum of crystalline Compound 1(a) Type BO.

[0110] Figure 87 shows an XRPD pattern of crystalline Compound 1(a) Type BP.

[0111] Figure 88 shows TGA and DSC curves for crystalline Compound 1(a) Type BP.

[0112] Figure 89 shows a 'H NMR spectrum of crystalline Compound 1(a) Type BP.

[0113] Figure 90 shows an XRPD pattern of crystalline Compound 1(a) Type BK.

[0114] Figure 91 shows TGA and DSC curves for crystalline Compound 1(a) Type BK.

[0115] Figure 92 shows a 'H NMR spectrum of crystalline Compound 1(a) Type BK.

[0116] Figure 93 shows an XRPD pattern of crystalline Compound 1(a) Type AX.

[0117] Figure 94 shows TGA and DSC curves for crystalline Compound 1(a) Type AX.

[0118] Figure 95 shows a 'H NMR spectrum of crystalline Compound 1(a) Type AX.

[0119] Figure 96 shows an XRPD pattern of crystalline Compound 1(a) Type Q.

[0120] Figure 97 shows TGA and DSC curves for crystalline Compound 1(a) Type Q.

[0121] Figure 98 shows a 'H NMR spectrum of crystalline Compound 1(a) Type Q.

[0122] Figure 99 shows an XRPD pattern of crystalline Compound 1(a) Type P.

[0123] Figure 100 shows TGA and DSC curves for crystalline Compound 1(a) Type P.

[0124] Figure 101 shows a 'H NMR spectrum of crystalline Compound 1(a) Type P.

[0125] Figure 102 shows an XRPD pattern of crystalline Compound 1(a) Type AQ.

[0126] Figure 103 shows TGA and DSC curves for crystalline Compound 1(a) Type

[0127] Figure 104 shows a 'H NMR spectrum of crystalline Compound 1(a) Type AQ. DETAILED DESCRIPTION OF THE INVENTION

[0128] Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. While the invention will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents which may be included within the scope of the present invention as defined by the claims. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like, this application controls. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0129] The present disclosure provides for improved methods for preparing compound

(I):

p

[0130] The present disclosure further provides for crystalline forms of Compound (I). The present disclosure still further provides for various crystalline polymeric forms of compound (I). The present disclosure yet further provides for improved processes for preparing compound (I) and for process for preparing various crystalline polymeric forms of compound

(I)· [0131] Definitions

[0132] When indicating the number of substituents, the terms“at least one” and "one or more" refer to the range from one substituent to the highest possible number of substitution, i.e. replacement of one hydrogen up to replacement of all hydrogens by substituents. The term "substituent" denotes an atom or a group of atoms replacing a hydrogen atom on the parent molecule. The term "substituted" denotes that a specified group bears one or more substituents. Where any group may carry multiple substituents and a variety of possible substituents is provided, the substituents are independently selected and need not to be the same. The term "unsubstituted" means that the specified group bears no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted by one or more substituents, independently chosen from the group of possible substituents. When indicating the number of substituents, the terms“at least one” and "one or more" mean from one substituent to the highest possible number of substitution, i.e. replacement of one hydrogen up to replacement of all hydrogens by substituents.

[0133] As used herein,“alkyl" refers to a monovalent linear or branched saturated hydrocarbon moiety, consisting solely of carbon and hydrogen atoms, having from one to twelve carbon atoms. "Lower alkyl" refers to an alkyl group of one to six carbon atoms, or from one to four carbon atoms, such as Ci_-4 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like. Alkyl groups may optionally be substituted with one or more substituents.

[0134] As used herein, the terms“halo” and“halogen” refer to chlorine, fluorine, bromine and iodine.

[0135] As used herein, the term“haloalkyl" refers to an alkyl as defined herein in which one or more hydrogen atoms have been replaced with the same or a different halogen. Exemplary haloalkyls include halo-Ci-₄ alkyl, for instance, -CH₂Cl, -CH₂CF₃, -CH₂CCI₃, -CF₃, and -CHF₂.

[0136] As used herein, the term“alkoxy" refers to a moiety of the structure -OR, wherein R is an alkyl moiety as defined herein. Examples of alkoxy moieties include, but are not limited to, methoxy, ethoxy and isopropoxy.

[0137] As used herein, the term“haloalkoxy” refers to an alkoxy as defined herein in which one or more hydrogen atoms have been replaced with the same or a different halogen. Exemplary haloalkoxys include halo-Ci-4 alkoxy, for instance, -OCH₂CI, -OCH₂CF₃, - OCH₂CCI₃, -OCF₃, and -OCHF₂.

[0138] As used herein, the terms“cycloalkyl” and“carbocyclic” refer to a monovalent saturated carbocyclic moiety comprising from 3 to 12 carbon atoms and consisting of mono- or bicycbc rings. Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, including partially unsaturated (cycloalkenyl) derivatives thereof.

[0139] As used herein,“leaving group” refers to an atom or a group of atoms that is displaced in a chemical reaction as stable species. Suitable leaving groups are well known in the art, e.g., see, March's Advanced Organic Chemistry, 5.sup.th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001 and T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991, the entire contents of each are hereby incorporated by reference. Such leaving groups include, but are not limited to, halogen, alkoxy, sulphonyloxy, optionally substituted alkylsulphonyl, optionally substituted alkenylsulfonyl, optionally substituted arylsulfonyl, and diazonium moieties. Examples of some leaving groups include chloro, iodo, bromo, fluoro, methanesulfonyl (mesyl), tosyl, triflate, nitro- phenylsulfonyl (nosyl), and bromo-phenylsulfonyl (brosyl).

[0140] As used herein“protecting group” refers to group used for protection of remote functionality (e.g., primary or secondary amine) of intermediates. The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. Suitable amino-protecting groups include acetyl trifluoroacetyl, t- butoxy carbonyl (BOC), benzyloxy carbonyl (Cbz) and 9-fluorenylmethyleneoxy carbonyl (Fmoc ). For a general description of protecting groups and their use, see March and Green.

[0141] As used herein,“deprotecting reagent” refers to a compound that will cleave a protecting group as defined herein.

[0142] As used herein,“coupling reagent” refers to a reagent that promotes the formation of an amide from an amine and a carboxylic acid. Examples of coupling reagents include, but are not limited to, propane phosphonic acid anhydride (T3P®); 1- [Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid

hexafluorophosphate (HATU); 2-(lH-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium

hexafluorophosphate (HBTU); N,N'-dicyclohexylcarbodiimide (DCC); benzotriazol-l- yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP); benzotriazol-l-yl- oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP); l,r-carbonyldiimidazole (CDI); l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and hydroxybenzotriazole (HOBt); and EDC and 4-dimethylaminopyridine (DMAP).

[0143] As used herein, the term“free base” refers to parent compound (I) as distinct from any salt thereof.

[0144] As used herein, the term“organic base” refers to an organic compound containing one or more nitrogen atoms, and which acts as a base. Examples of organic bases include, but are not limited to, tertiary amine bases. Examples of organic bases include, but are not limited to, N-methyl-morpholine (NMM), diisopropylethylamine (DIPEA) and triethylamine (TEA).

[0145] As used herein, the term“inorganic base” refers to a base comprising an inorganic component. Examples of inorganic bases include, but are not limited to, alkali metal hydroxide, ammonium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate, and sodium bicarbonate.

[0146] As used herein, the term“organic acid” refers to an organic compound that acts an acid. Examples of organic acids include, but are not limited carboxylic acids. Examples of organic acids include, but are not limited to, formic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, butanedioic acid, adipic acid, tartaric acid and citric acid.

[0147] As used herein, the term“inorganic acid” refers to an acid comprising an inorganic component. Examples of inorganic acids include mineral acids including, but not limited to hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and boric acid.

[0148] As used herein, the term“polar aprotic solvent” refers to any polar solvent not having a proton-donating ability. Examples include, without any limitation, 2- methyltetrahydrofuran, tetrahydrofuran, ethyl acetate, propyl acetate (e.g., isopropyl acetate), acetone, dimethylsulfoxide, N,N-dimethylformamide, acetonitrile, N,N-dimethylacetamide, N- methylpyrrobdone, hexamethylphosphoramide , and propylene carbonate.

[0149] As used herein, the term“polar probe solvent” refers to any polar solvent having a proton-donating ability. Examples include, without limitation, water, methanol, ethanol, 1- propanol, 2-propanol, 1 -butanol, formic acid, nitromethane and acetic acid. An organic polar protic solvent excludes any effective amount of water.

[0150] As used herein, the term“polar organic solvent” refers to both polar aprotic solvents and polar protic solvents excluding water.

[0151] As used herein, the term“non-polar solvent” refers to solvents that contain bonds between atoms with similar electronegativities, such as carbon and hydrogen, such that the electric charge on the molecule is evenly distributed. Non-polar solvents are characterized as having a low dielectric constant. Examples include, without limitation, pentane (e.g., «- pentane), hexane (e.g., «-hexane), heptane (e.g., «-heptane), cyclopentane, methyl tert-butyl ether, diethyl ether, toluene, benzene, l,4-dioxane, carbon tetrachloride, chloroform and dichloromethane (DCM). In some aspects, the non-polar solvent has a dielectric constant of less than 2, examples of which include, without limitation, «-pentane, «-hexane and «-heptane. As compared to other non-polar solvents, DCM exhibits some degree of polarity at the bond level (i.e., between carbon and chlorine), but only a small degree of polarity at the molecular level due to symmetry-based cancellation of polarity.

[0152] As used herein, the term“solvent” refers to any of polar aprotic solvents, polar protic solvents, and non-polar solvents.

[0153] As used herein, the term“anti-solvent” refers to a solvent in which the referenced compound is poorly soluble and which induces precipitation or crystallization of said compound from solution.

[0154] As used herein,“ammonium salt” refers to salts having an ammonium cation. Examples include, without limitation, ammonium carbonate, ammonium chloride and ammonium nitrate.

[0155] As used herein, a“polymorph” or“polymorphism” refers to the ability of a substance to exist in more than one crystal form, where the different crystal forms of a particular substance are referred to as“polymorphs.” In general, it is believed that polymorphism may be affected by the ability of a molecule of a substance to change its conformation or to form different intermolecular or intra-molecular interactions, particularly hydrogen bonds, which is reflected in different atom arrangements in the crystal lattices of different polymorphs. The different polymorphs of a substance may possess different energies of the crystal lattice and, thus, in solid state they may show different physical properties such as form, density, melting point, color, stability, solubility, dissolution rate, etc., which may, in turn, affect properties such as, and without limitation, the stability, dissolution rate and/or bioavailability of a given polymorph and its suitability for use as a pharmaceutical and in pharmaceutical compositions.

[0156] As used herein,“morphology” refers to the external shape of the crystal and the planes present, without reference to the internal structure. Crystals can display different morphology based on different conditions, such as, for example, growth rate, stirring, and the presence of impurities.

[0157] As used herein,“solvate” refers to refers to any form of compound (I) that is bound by a non-covalent bond to another molecule (such as a polar solvent). Such solvates are typically crystalline solids having a substantially fixed molar ratio of solute and solvent.

Representative solvents include «-heptane, N,N-dimethylacetamide, anisole, ethanol, toluene, 2- propanol, 1 -butanol, 2-methyltetrahydrofuran, tetrahydrofuran, isobutyl alcohol, and dimethyl sulfoxide.

[0158] As used herein, the term“seed” can be used as a noun to describe one or more crystals of a crystalline compound (I) (e.g., compound 1(a) polymorph Type E). The term “seed” can also be used as a verb to describe the act of introducing said one or more crystals of a crystalline compound (I) into an environment (including, but not limited to e.g., a solution, a mixture, a suspension, or a dispersion) thereby resulting in the formation of more crystals of the crystalline compound (I).

[0159] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed

"stereoisomers." Diastereomers are stereoisomers with opposite configuration at one or more chiral centers which are not enantiomers. Stereoisomers bearing one or more asymmetric centers that are non-superimposable mirror images of each other are termed "enantiomers." When a compound has an asymmetric center, for example, if a carbon atom is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center or centers and is described by the R- and S- sequencing rules of Cahn, Ingold and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)- isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture". In certain embodiments the compound is enriched by at least about 90% by weight with a single diastereomer or enantiomer. In other embodiments the compound is enriched by at least about 95%, 98%, or 99% by weight with a single diastereomer or enantiomer.

[0160] The compounds of the invention may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention. In some instances, the stereochemistry has not been determined or has been provisionally assigned. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane- polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s).

[0161] As used herein, the term“approximately” and“about” refers to a value of 90%, 95% or 99% of a referenced value.

[0162] The term "a therapeutically effective amount" of a compound means an amount of compound that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is within the skill in the art. The therapeutically effective amount or dosage of a compound according to this invention can vary within wide limits and may be determined in a manner known in the art.

[0163] Methods for preparing compound (I)

[0164] In accordance with one aspect of the present disclosure, TRP antagonist compound (I) may be prepared according to the method shown in FIG. 1.

[0165] In some aspects, compound 3 having a 5-(pyridin-2-yl)pyrimidine core may be prepared from compound 1 by steps 1 and 2 as follows.

[0166] In step 1, a compound 1 is reacted with a sulfonating reagent, that is the source of the moiety Y, in a solvent to form compound 2 as follows:

Compound 1 Compound 2

[0167] R¹ is selected from halo, halo-Ci-4 alkyl-, halo-Ci-4 alkoxy-, and -CN. In some aspects, R¹ is selected from -F, -CF₃, -CHF₂, -OCF₃, -OCHF₂, -OCH₂CF₃, and -CN. In some other aspects, R¹ is -CF₃.

[0168] R² is selected from H and -cyclopropyl. In some aspects, R² is H.

[0169] The group Y may be, for example, arylsulfonyl or alkylsulfonyl, and may be introduced by reaction of compound 1 with an arylsulfonyl halide reagent such as tosyl (toluenesulfonyl) chloride, or a lower alkylsulfonyl halide reagent such as mesyl (methanesulfonyl) chloride.

[0170] In some aspects, the step 1 solvent comprises or is a polar aprotic solvent. In some such aspects, the solvent is selected from one or more of 2-methyltetrahydrofuran (MeTHF), tetrahydrofuran (THF), ethyl acetate, propyl acetate, acetone, dimethylformamide (DMF), acetonitrile, and dimethyl sulfoxide (DMSO). In some aspects, the polar aprotic solvent is selected from MeTHF and THF. In some aspects, the polar aprotic solvent is MeTHF.

[0171] Generally, the polar aprotic solvent may be charged to a vessel, such as a jacketed reactor, followed by addition of compound 1 with stirring. The concentration of compound 1 may suitably be from about 0.05 to about 2 kg/L, such about 1 kg/L. The organic base may then be charged with stirring and the reactor contents cooled to a temperature of less than about 25 °C, such as from about 0 °C to about 10 °C. The base may generally be present in molar excess of compound 1. The arylsulfonyl halide or lower alkylsulfonyl halide source of group Y may then be added with stirring to form a reaction mixture while maintaining the temperature. The arylsulfonyl halide or lower alkylsulfonyl halide may generally be present in molar excess of compound 1, and the base may be in molar excess of the source of the leaving group. The reaction mixture may be maintained at temperature with stirring and reacted until a step 1 reaction product mixture comprising compound 2 is formed containing less than 5%, less than 2%, less than 1% or less than 0.5% of starting compound 1. Analysis may be done by HPLC as described elsewhere herein. [0172] The step 1 reaction product mixture comprising compound 2 may be washed at least once with an aqueous acid, an aqueous salt solution, or sequential washes thereof in any order. In some such aspects, the reaction product mixture comprising compound 2 may be washed with from about 2 wt % to about 10 wt %, such as about 5 wt %, aqueous acid (e.g., citric acid). In some aspects, the volume ratio of aqueous acid to reaction product mixture may suitably be from about from about 0.5: 1 to about 5: 1, about 0.5: 1 to about 2:1, such as about 1 : 1. In some aspects, the reaction product mixture comprising compound 2 may be washed with from about 5 wt % to about 40 wt %, such as about 25 wt %, aqueous salt solution (e.g., sodium chloride). In some aspects, the volume ratio of aqueous salt solution to reaction product mixture may suitably be from about from about 0.5:1 to about 3: 1, about 0.5: 1 to about 2: 1, such as about 0.75: 1.

[0173] In some aspects, solvent exchange from the polar aprotic solvent in the step 1 reaction product mixture to second solvent may be done. In some aspects the second solvent is a polar aprotic solvent. In some particular aspects, the second solvent comprises or is ethyl acetate. In some aspects, the second solvent can be added to the step 1 reaction product mixture followed by one or more optional wash steps as described elsewhere herein, such as after an acid wash and before a salt wash. The volume ratio of the second solvent to the solvent in the step 1 may suitably be from about 1.5: 1 to about 5: 1, such as about 3: 1. In some aspects, after the addition of a second solvent to the step 1 reaction product mixture and at least one wash step, additional second solvent can be added followed by distillation. In some such aspects, the volume ratio of the second solvent to the solvent in step 1 may be from about 0.5: 1 to about 2: 1, such as about 0.75: 1. Distillation may be done under reduced pressure to produce a mixture comprising concentrated compound 2, for instance, a compound 2 concentration of from about 0.25 g/mL to about 1 g/mL, such as about 0.5 g/mL. Distillation temperature may suitably be less than about 50 °C.

[0174] Solid compound 2 may be formed by addition of an anti-solvent to the reaction product mixture comprising compound 2 or any solution of compound 2. In some aspects, the anti-solvent has a dielectric constant of less than 2. In some aspects, the anti-solvent is selected from one or more of «-pentane, «-hexane, «-heptane and cyclopentane. In some aspects, the anti-solvent comprises or is «-heptane. In some-aspects, distillation is done after the anti solvent addition. In some such distillation aspects, a volume ratio of anti-solvent to the solvent in the step 1 may suitably be from about 0.25: 1 to about 2: 1, from about 0.25: 1 to about 1: 1 such as about 0.5: 1. Distillation may be done under reduced pressure to produce a mixture comprising concentrated compound 2, for instance, a compound 2 concentration of from about 0.25 g/mL to about 1 g/mL, such as about 0.5 g/mL. The distillation step may be repeated one or more times. After the final distillation step, anti-solvent may be added to produce a slurry that may be easily transferred and filtered. For instance, the compound 2 concentration in the slurry may suitably be about 0.05 to about 0.5 g/mL, about 0.1 to about 0.3 g/mL such as about 0.2 g/mL.

[0175] Solid compound 2 may be isolated by techniques known in the art including filtration, centrifugation, and settling. Isolated solid compound 2 may be optionally washed with the anti-solvent and/or mother liquor and then optionally dried. Drying may be done by techniques known in the art including vacuum drying at elevated temperature, such as from about 30°C to about 50°C.

[0176] Compound 2 yield based on compound 1 is at least 85%, at least 90% or at least 95%, for instance, 90% or 95%. Purity as measured by HPLC methods described elsewhere herein is at least 95%, at least 96%, or at least 97%, such as about 97% or about 97.5%.

[0177] In some aspects, compound 1 is compound 1(a), (5-(trifluoromethyl)-2-(2- (trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methanol, below:

[0178] In some aspects, compound 2 is compound 2(a), (5-(trifluoromethyl)-2-(2- (trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methyl methanesulfonate, below:

Compound 2(a)

[0179] In step 2, compound 2 and a nitrogen source in a solvent are reacted to form compound 3 as follows: R²

Compound 3

[0180] R¹ and R² are as previously described.

[0181] In step 2, compound 2 is combined with the solvent in a reactor with stirring until a solution is formed. In some aspects, the solvent comprises or is a polar organic solvent.

In some aspects, the polar organic solvent may be selected from one or more of methanol, ethanol, 1 -propanol, 2-propanol, 1 -butanol, formic acid, acetic acid, MeTHF, THF, ethyl acetate, propyl acetate, acetone, DMF, acetonitrile, and DMSO. In some aspects, the polar organic solvent is selected from one or more of THF and MeTHF. In some aspects the solvent is THF. In some aspects, the nitrogen source is ammonia or an ammonium salt. The concentration of compound 2 in solution may suitably be from about 0.05 to about 1.0 g/mL, from about 0.05 to about 0.5 g/mL, or from about 0.1 to about 0.3 g/mL, such as about 0.2 g/mL. The solution of compound 2 is combined with ammonia or an ammonium salt to form a reaction mixture comprising compound 2. In some aspects, the ammonia or ammonium salt may be in solution in an organic polar protic solvent selected from methanol, ethanol, 1- propanol, 2-propanol, 1 -butanol, formic acid, nitromethane and acetic acid. In some aspects the organic polar protic solvent is selected from methanol, ethanol, 1 -propanol and 2-propanol. In some aspects the organic polar protic solvent comprises or is methanol. In any such aspect, the solution may be from about 3 molar to about 9 molar, such as about 7 molar ammonia or ammonium salt. The volume of ammonia or ammonium salt solution to compound 2 solution may be from about 1 :1 to about 10: 1 or from about 4: 1 to about 8: 1, such as about 5: 1, such as about 6: 1. The reaction mixture is heated to form a reaction product mixture comprising compound 3. A suitable reaction temperature may be from about from about 30 °C to about 60 °C, from about 30 °C to about 50 °C, or from about 35 °C to about 45 °C. The reaction mixture is maintained at temperature with stirring and reacted until a step 2 reaction product mixture comprising compound 3 is formed containing less than 0.5%, less than 0.2%, or less than 0.1% of compound 2. Analysis may be done by HPLC as described elsewhere herein.

[0182] In some aspects, step 2 may optionally comprise a purification step. In some such aspects, the purification step may comprise: (i) solvent exchange from the step 2 solvent to a non-polar solvent having a dielectric constant of greater than 2 to form a first solution of compound 3 in the non-polar solvent; (ii) precipitation of solid compound 3 from solution by addition of an acid followed by isolation of solid compound 3 and optional washing of isolated solid compound 3; (iii) dissolution of compound 3 in a non-polar solvent having a dielectric constant of greater than 2 by addition of a base to form a second solution of compound 3 in the non-polar solvent; (iv) precipitation of solid compound 3 free base from the second solution by addition of an anti-solvent, concentration by non-polar solvent removal, or a combination thereof; and (v) isolation of purified compound 3 free base.

[0183] In some such purification aspects, a step 2 reaction product solvent

exchange/wash step from the polar organic solvent to a non-polar solvent having a dielectric constant of greater than 2 may be done. Suitable non-polar solvents include methyl /er/-butyl ether (MTBE), diethyl ether, toluene, benzene, l,4-dioxane, carbon tetrachloride, chloroform and dichloromethane. In some aspects, the non-polar solvent comprises or is MTBE. In such aspects, the step 2 reaction product mixture may be admixed with the non-polar solvent at a volume ratio to the polar organic solvent of from about 1.25: 1 to about 4: 1, from about 1 :5: 1 to about 3: 1, such as about 2: 1. The resulting combination may be further admixed with an aqueous inorganic base solution. In some aspects, the base is selected from alkali metal hydroxide, ammonium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate, and sodium bicarbonate. In some aspects, the base may be potassium bicarbonate or sodium bicarbonate. The aqueous inorganic base solution may suitably be from about 2 wt % to about 30 wt % base. For a weak base such as potassium bicarbonate or sodium bicarbonate, the concentration may suitably be from about from about 15 wt % to about 30 wt %, or about 20 wt % to about 25 wt %. In such aspects, the phases are allowed to separate, and the lower aqueous phase is removed. The aqueous phase may be washed at least once with the non-polar solvent at a volume ratio of the non-polar solvent to the polar organic solvent used to form the step 2(a) reaction mixture of from about 0.5: 1 to about 4: 1, from about 1 :5: 1 to about 3: 1, such as about 0.5: 1 or 2: 1. The organic phases from each washing step are combined. In some aspects, two washing steps at a solvent volume ratio of about 2: 1 followed by one washing step at a solvent volume ratio of about 0.5: 1 are done. The combined organic layers comprising compound 3 may be distilled under reduced pressure to concentrate compound 3 to a concentration of such as from about 0.03 g/mL to about 0.2 g/mL, such as about 0.07 g/mL. A distillation temperature of less than about 50°C is suitable for the practice of the present disclosure. [0184] In some such purification aspects step compound 3 or a concentrate thereof may be admixed with a solution of an acid, such as an organic acid, in a solvent, such as a non polar solvent. In some aspects, the organic acid is a carboxylic acid. In some aspects, the carboxylic acid is selected from one or more of formic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, butanedioic acid, and adipic acid. In some aspects, the organic acid comprises or is oxalic acid. The non-polar solvent is as described elsewhere herein. In some aspects, the non-polar solvent comprises or is MTBE. The organic acid concentration in the non-polar solvent may suitably be from about 0.02 g/mL to about 0.1 g/mL, such as about 0.03 g/mL such as about 0.04 g/mL. The admixture may be agitated for at least about 1 hour at about room temperature to form solid compound 3. Solid compound 3 may be isolated by a method described elsewhere herein, and optionally washed with the non-polar solvent.

[0185] In some such purification aspects, solid compound 3 may be combined with stirring with additional non-polar solvent (e.g., MTBE) to a compound 3 concentration of from about 0.05 g/mL to about 0.5 g/mL, or from about 0.1 g/mL to about 0.2 g/mL. The compound 3 mixture may be washed with an aqueous inorganic base solution as previously described at a volume ratio of inorganic base solution to additional non-polar solvent of from about 0.5: 1 to about 5: 1, from about 1 : 1 to about 3 : 1 or from about 1 : 1 to about 1.5: 1. The phases are allowed to separate, and the lower aqueous phase is removed and is optionally washed with additional non-polar solvent as previously described at least one time. The combined organic phases containing compound 3 are distilled under reduced pressure to produce a mixture comprising concentrated compound 3, for instance, a compound 3 concentration of from about 0.25 g/mL to about 1 g/mL, such as about 0.5 g/mL. Distillation temperature is suitably less than about 50°C.

[0186] In a final purification step, an anti-solvent, such as a non-polar anti-solvent having a dielectric constant of less than 2 as described elsewhere herein (e.g., «-heptane), is added to the compound 3 concentrate to form a compound 3 free base slurry having a compound 3 concentration of from about 0.05 to about 0.5 g/mL, about 0.1 to about 0.3 g/mL, such as about 0.2 g/mL.

[0187] In some aspects, compound 3 is compound 3(a), (5-(trifluoromethyl)-2-(2- (trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methanamine, below

Compound 3(a)

[0188] In some aspects, solid compound 3 may be isolated by a method described elsewhere herein. Isolated compound 3 may be optionally washed with non-polar solvent. The compound 3 solids may be optionally dried by techniques known in the art including vacuum drying at elevated temperature, such as from about 20 °C to about 50 °C.

[0189] Compound 3 yield based on compound 2 is at least 70%, at least 75% or at least 80%, for instance, 80% or 85%. Assay percent (w/w) as measured by HPLC methods described elsewhere herein is at least 90% or at least 95%, such as about 95% or about 96%. Purity as measured by HPLC methods described elsewhere herein is at least 97%, at least 98%, or at least 99%, such as about 99% or about 99.5%.

[0190] Compound 3 yield based on compound 1 is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80%.

[0191] In step 3, compound 3, compound 4, and a coupling reagent are reacted in a solvent to form compound 5 according to step 3 as follows:

Compound 5

[0192] R¹ and R² are as previously described.

[0193] In some aspects, R³ is -C i alkyl. In some aspects, R³ is -CH₃.

[0194] In some aspects, R⁴ is selected from H and F. In some other aspects, R⁴ is F. [0195] In some other aspects, R³ and R⁴ together with the ring atoms to which they are attached form a three-membered carbocyclic ring.

[0196] Each asterisk refers to a chiral center.

[0197] PG refers to an amine protecting group. In some aspects, PG is selected from acetyl trifluoroacetyl, t-butoxy carbonyl (BOC), benzyloxy carbonyl (CBz) and 9- fluorenylmethyleneoxy carbonyl (Fmoc). In some aspects, PG is BOC.

[0198] In some aspects, compound 4 is compound 4(a), (2S,4R,5S)-l-(tert- butoxycarbonyl)-4-fluoro-5-methylpynOlidine-2-carboxylic acid, below:

Compound 4(a)

[0199] In some aspects, compound 5 is compound 5(a), (2S,3R,5S)-tert-butyl 3-fluoro- 2-methyl-5-((5-(trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4- yl)methylcarbamoyl)pyrrolidine- 1 -carboxylate below:

Compound 5(a)

[0200] In some aspects, the coupling reagent may be selected from: propane phosphonic acid anhydride (T3P®); l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (HATU); 2-(lH-benzotriazol-l-yl)-l, 1,3,3- tetramethyluronium hexafluorophosphate (HBTU); N,N'-dicyclohexylcarbodiimide (DCC); benzotriazol- 1 -y loxy )tris(dimethy lamino)phosphonium hexafluorophosphate (BOP);

benzotriazol-l-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP); 1,1'- carbonyldiimidazole (CDI); 1 -ethyl-3 -(3 -dimethylaminopropyl)carbodiimide (EDC) and hydroxybenzotriazole (HOBt); and EDC and 4-dimethylaminopyridine (DMAP). In some aspects, the coupling reagent is T3P®. The coupling agent may optionally be in solution in an organic solvent, for instance, at 50 wt % solution of T3P® in ethyl acetate.

[0201] In some aspects, the reaction mixture for forming compound 5 further comprises a base. In some aspects, the base is an organic base. In some other aspects, the base is a tertiary amine base. In some other aspects, the base is selected from N-methyl-morpholine (NMM), diisopropylethylamine (DIPEA) and triethylamine (TEA). In some other aspects, the base comprises or is NMM.

[0202] In some aspects, the solvent for the reaction mixture for forming compound 5 comprises or is a polar aprotic solvent. In some aspects, the polar aprotic solvent is selected from one or more of MeTHF, THF, ethyl acetate, propyl acetate, isopropyl acetate, acetone, DMF, acetonitrile, and DMSO. In some aspects, the polar aprotic solvent is selected from one or both of ethyl acetate and propyl acetate.

[0203] The reaction mixture for step 3 may by formed by combining compound 3, compound 4 and the solvent in a reactor with stirring until a solution is formed. The order of addition is not narrowly critical. An approximately stoichiometric equivalent ratio of compounds 3 and 4 may be used for the reaction. The concentration of compound 3 may suitably be from about 0.03 g/mL to about 0.3 g/mL, from about 0.05 g/mL to about 0.15 g/mL, such as about 0.1 g/mL. Base is then added to the solution of compounds 3 and 4. The base is typically present in molar excess to compound 3, such as a molar ratio of between 1: 1 and 3: 1, from about 1.1 : 1 to about 2: 1, from about 1.2: 1 to about 1.5: 1, such as about 1.3: 1. The coupling reagent is then added to form a reaction mixture. In some aspects, the equivalents of base and the coupling reagent are present in approximately stoichiometric equal amounts.

[0204] The reaction mixture is heated, such as to at least 40 °C, such as from about 40 °C to about 70 °C, or from about 50 °C to about 60 °C. The reaction mixture may be maintained at temperature with stirring and reacted until a step 3(a) reaction product mixture comprising compound 5 is formed containing less than 5%, less than 2%, less than 1% or less than 0.5% of starting compound 4 and/or compound 3. Analysis may be done by HPLC as described elsewhere herein. Reaction time is typically at least 1 hour, at least 2 hours, or at least 3 hours. If the reaction product mixture comprises in excess of 5% compound 4, additional coupling agent can be added and the reaction can be continued. [0205] In some aspects, step 3 may further comprise: (i) a solvent exchange step from the solvent for the compound 5 reaction mixture (e.g., a polar aprotic solvent) to a second solvent (e.g., a polar protic solvent); and (ii) a precipitation step where solid compound 5 is produced the addition of an anti-solvent. In some aspects, the solvent exchange step may comprise a base, such as an inorganic base. In some aspects, the base is selected from one or more of an alkali metal hydroxide, ammonium hydroxide, potassium carbonate and sodium carbonate. In some aspects, the base is a strong base. In some aspects, the base is sodium hydroxide or potassium hydroxide. In some aspects, the base is in aqueous solution.

[0206] In some aspects, the second solvent in the solvent exchange is a polar protic solvent. In such aspects, the polar protic solvent may be selected from one or more of methanol, ethanol, 1 -propanol, 2-propanol, 1 -butanol, formic acid and acetic acid. In some aspects, the polar protic solvent is selected from one or more of methanol, ethanol, 1 -propanol and 2- propanol. In some aspects, the polar protic solvent comprises or is ethanol.

[0207] In the solvent exchange step, base in aqueous solution may optionally be added to the step 3 reaction product mixture comprising compound 5 with stirring. Stirring is stopped and the phases are allowed to separate, and the lower aqueous phase is removed from the reactor. The remaining organic phase containing compound 5 is distilled under reduced pressure while charging polar protic solvent in a solvent exchange step while maintaining an approximately constant volume. The solvent exchange is continued until the polar aprotic solvent content is less than 2% measured by GC as described elsewhere herein. Compound 5 is generated as a solid by water addition. Water may then be charged to the reactor and the reaction product mixture may be heated, such as to at least 40 °C, such as from about 40 °C to about 75 °C, or from about 50 °C to about 70 °C. The amount of water based on starting compound 3 weight may suitably be from about 0.5 mL/g to about 2 mL/g, from about 0.5 mL/g to about 1.5 mL/g, such as about 1 mL/g. The reaction product mixture may then be cooled to less than about 35 °C, such as from about 5 °C to about 30 °C, or from about 10 °C to about 25 °C. Additional water may then be added wherein the amount of water based on starting compound 3 weight may suitably be from about 2 mL/g to about 10 mL/g, from about 4 mL/g to about 8 mL/g, such as about 6 mL/g.

[0208] Solid compound 5 may be isolated by techniques known in the art as described elsewhere herein. Isolated solid compound 5 may be optionally washed with the polar protic solvent and water, and then optionally dried. Drying may be done by techniques known in the art including vacuum drying at elevated temperature, such as from about 40 °C to about 60 °C.

[0209] Compound 5 yield based on compound 3 is at least 80%, at least 85% or at least 90%, for instance, 85% or 90%. Purity as measured by HPLC methods described elsewhere herein is at least 95%, at least 97%, or at least 99%, such as about 99% or about 99.5%.

[0210] In step 4 a compound 5 and an acidic deprotecting reagent are reacted in a solvent to deprotect compound 5 and form compound 6 as follows:

[0211] PG, R¹, R², R³ and R⁴ are as previously described.

[0212] In some aspects, compound 5 is compound 5(a) disclosed elsewhere herein. In some such aspects, compound 6 is an acid salt of compound 6(a), (2S,4R,5S)-4-fluoro-5-methyl- N-((5-(trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methyl)pyrrohdine-2- carboxamide, below:

Compound 6(a)

[0213] The acidic deprotecting reagent may be an organic acid or an inorganic acid. In some aspects, the acidic deprotecting reagent is an acyl halide or a mineral acid. In some aspects, the acidic deprotecting reagent is an acyl chloride selected from acetyl chloride, formyl chloride, propionyl chloride and butyryl chloride, or is a mineral acid selected from hydrochloric acid and sulfuric acid. In some aspects, the acidic deprotecting reagent is acetyl chloride such that compound 6(a) is an acetate salt. In certain embodiments, the acidic deprotecting reagent is hydrochloric acid such that compound 6(a) is a hydrochloride salt. [0214] In some aspect, the solvent used in step 4 comprises or is a polar protic solvent. In some aspects, the polar protic solvent is selected from one or more of methanol, ethanol, 1- propanol, 2-propanol, 1 -butanol, formic acid and acetic acid. In some aspects, the polar protic solvent is selected from one or more of methanol, ethanol, 1 -propanol and 2-propanol. In some aspects, the polar protic solvent comprises or is 1 -propanol.

[0215] In step 4, the solvent, compound 5, and the acidic deprotecting reagent are combined in a reactor with stirring to form a reaction mixture. The acidic deprotecting reagent is in equivalent excess of compound 5. In some aspects the mole ratio of the acidic deprotecting reagent to compound 5 may be between 1: 1 and 5: 1, from about 1.5: 1 to about 4: 1 or from about 2: 1 to about 3: 1, such as about 2.5: 1. The concentration of compound 5 in the reaction mixture may suitably be from about 0.05 g/mL to about 1 g/mL, from about 0. 075 g/mL to about 0.5 g/mL, or from about 0.1 g/mL to about 0.3 g/mL, such as about 0.2 g/mL. The reaction mixture is heated with stirring to at least 40 °C, such as from about 40 °C to about 75 °C or from about 50 °C to about 70 °C and held until the a reaction product mixture comprising compound 6 is formed containing less than 5%, less than 2%, less than 1% or less than 0.5% of starting compound 5. Analysis may be done by HPLC as described elsewhere herein. Reaction time is typically at least 1 hour, at least 2 hours, or at least 3 hours.

[0216] In some aspects, the reaction product mixture comprising compound 6 may be distilled under reduced pressure while charging a non-polar anti-solvent having a dielectric constant of less than 2 (e.g., «-heptane), and while maintaining an approximately constant volume. Addition of the anti-solvent forms solid compound 6 in the reaction product mixture. Distillation is continued until about a volume ratio of non-polar anti-solvent to polar protic solvent present in the step 4 reaction mixture of at least 0.5: 1, 0.75: 1 or 1: 1 is achieved, such as from about 1 : 1 to about 4:1, from about 1.5 : 1 to about 3: 1, such as about 2: 1. The reactor contents are then cooled to less than about 40 °C, such as from about 5 °C to about 30 °C, and the compound 6 solids are isolated by a method as described elsewhere herein. The isolated compound 6 solids may optionally be washed with a combination of the polar protic solvent and the non-polar anti-solvent.

[0217] The compound 6 solids may be optionally dried. Drying may be done by techniques known in the art including vacuum drying at elevated temperature, such as from about 30 °C to about 40 °C. [0218] Compound 6 yield based on compound 5 is at least 80%, at least 85% or at least 90%, for instance, 85% or 90%. Purity as measured by HPLC methods described elsewhere herein is at least 96%, at least 97%, or at least 98%, such as about 98% or about 98.5%.

[0219] In step 5, compound 6 acid salt, compound 7, and a base are reacted in a solvent system to form compound (I) as follows:

[0220] R¹, R², R³ and R⁴ are as previously described.

[0221] R⁵ is halo. In some aspects, R⁵ is F.

[0222] n is 1 or 2. In some aspect, n is 1.

[0223] Xi and X₂ are each C, or one of Xi and X₂ is N and the other is C. In some aspects, Xi and X₂ are each C. In some aspects, Xi is C and X₂ is N. In some aspects, Xi is N and X₂ is C.

[0224] In some aspects, compound 6 is compound 6(a) disclosed elsewhere herein. In some such aspects, compound (I) is compound 1(a), (2S,4R,5S)-4-fluoro-l-(4- fluorophenylsulfonyl)-5-methyl-N-((5-(trifluoromethyl)-2-(2-(trifluoromethyl)pyrimi din-5- yl)pyridin-4-yl)methyl)pyrrolidine-2-carboxamide below:

[0225] In step 5, compound 6, the solvent system comprising a non-polar solvent, a base, and compound 7 are combined with stirring to form a reaction mixture followed by reaction thereof to form a reaction product mixture comprising compound (I). In some aspects the reaction mixture is formed by combining compound 6 with the non-polar solvent, followed by optional addition of the polar protic solvent, and then addition of an aqueous base.

[0226] The base for step 5 may be an organic base or an inorganic base. In some aspects, the base is an inorganic base. In some aspects, the base is an aqueous solution of an inorganic base. In some such aspects, the base is selected from an aqueous solution of alkali metal hydroxide, ammonium hydroxide, potassium carbonate and, sodium carbonate. In some aspects, the base is an aqueous solution of potassium carbonate or sodium carbonate.

[0227] The solvent system for step 5 comprises a non-polar solvent having a dielectric constant of greater than 2. In some aspects, the non-polar solvent is selected from one or more of methyl tert-butyl ether, diethyl ether, l,4-dioxane and chloroform. In some aspects, the non polar solvent is selected from methyl tert-butyl ether and diethyl ether. In some aspects, the solvent comprises or is methyl tert-butyl ether. The solvent system may optionally further comprise a polar protic solvent selected from one or more of methanol, ethanol, 1 -propanol, 2- propanol, 1 -butanol, formic acid and acetic acid. In some aspects, the polar protic solvent is selected from one or more of methanol, ethanol, 1 -propanol and 2-propanol. In some aspects, the polar protic solvent comprises or is ethanol. A volume ratio of non-polar solvent to optional polar protic solvent may suitably be from about 1 : 1 to about 20: 1, from about 1:2 to about 20: 1, from about 5: 1 to about 15: 1, such as about 10: 1. The equivalent ratio of base to compound 6 may be greater than 1: 1, between about 1 : 1 and about 4: 1, from about 1.5: 1 to about 3: 1, such as about 2: 1.

[0228] In the reaction mixture, the concentration of compound (I) in the non-polar solvent may suitably be from about 0.05 g/mL to about 1 g/mL, from about 0.1 g/mL to about 0.75 g/mL, from about 0.15 g/mL to about 0.4 g/mL, from about 0.2 g/mL to about 0.3 g/mL, such as about 0.25 g/mL. In aspects directed to an aqueous solution of an inorganic base, the volume ratio of water to non-polar solvent in the reaction mixture may suitably be from about 0.25: 1 to about 4: 1, from about 0.5: 1 to about 2: 1, such as about 1: 1.

[0229] The reaction mixture is maintained at temperature for a period of time sufficient to generate a reaction product mixture comprising compound (I) and less than about 5% compound 6 as measured by HPLC as described elsewhere herein. Reaction temperature is suitably from about from about 10 °C to about 60 °C, from about 10 °C to about 50 °C, or from about 15 °C to about 40 °C. Reaction time is typically at least 1 hour, at least 2 hours, or at least 3 hours.

[0230] In aspects of the disclosure where the reaction product mixture comprises water, the phases are allowed to separate, and the lower aqueous phase is removed. In any of the various aspects, water may be added with stirring to the organic mixture in the reactor, the phases allowed to separate, and the lower aqueous phase removed. Additional water wash steps or wash steps with an aqueous salt are within the scope of the present disclosure. The remaining organic phase comprising compound (I) may be distilled under reduced pressure to reduce the volume and form a reaction product mixture concentrate comprising compound (I). In some aspects, distillation may be continued until a minimum stir volume is reached.

[0231] A solvent exchange step may be done to exchange the solvent in reaction product mixture concentrate comprising compound (I) to new solvent selected from: (i) a second non-polar solvent having a dielectric constant of greater than 2 as described elsewhere herein;

(ii) a polar aprotic solvent as described elsewhere herein; or (iii) a polar protic solvent as described elsewhere herein, and thereby form a solution of compound (I) in the new solvent. Solvent exchange may suitably be done by adding the new solvent to the reaction product mixture concentrate comprising compound (I) followed by distillation at reduced pressure while charging the new solvent and while maintaining an approximately constant volume.

[0232] A non-polar anti-solvent as described elsewhere herein (e.g., «-heptane) may then be added with stirring to the distillation mixture comprising compound (I) and the admixture may suitably be heated to from about 40 °C to about 85 °C, or from about 50 °C to about 80°C followed by cooling to less than 20 °C, such as from about -l0°C to about 15 °C, or from about -5 °C to about 10 °C to form solid crystalline compound (I) as a solvate of the second non-polar solvent having a dielectric constant of greater than 2, the polar aprotic solvent, or the polar protic solvent that was exchange for the solvent in the step 5 reaction mixture. A suitable concentration of compound (I) in the anti-solvent may be from about 0.025 to about 1 g/mL, or about 0.05 to about 0.5 g/mL. Crystalline compound (I) may be isolated by methods described elsewhere herein. Isolated compound (I) may be dried by techniques known in the art described elsewhere herein at elevated temperature, such as from about 30 °C to about 70 °C, or from about 40 °C to about 60 °C, such as from about 50 °C to about 60 °C. Compound (I) may be dried until the non-polar anti-solvent content is less than 0.5% as measured by GC as described elsewhere herein. Compound (I) yield based on compound 6 is at least 80%, at least 85% or at least 90%, for instance 85% or 90%. Assay measured by HPLC methods described elsewhere is at least 85% or at least 90%, such as about 90% or about 92%. Purity as measured by HPLC methods described elsewhere herein is at least 97%, at least 98%, or at least 99%, such as about 98.5% or about 99%.

[0233] In aspects where the new solvent in the solvent exchange step is DMAc, crystalline compound (I) is a DMAc solvate designated Type C. In aspects where the new solvent is anisole, crystalline compound (I) is an anisole solvate designated Type D. In aspects where the new solvent is ethanol, crystalline compound (I) is an ethanol solvate designated Type F. In aspects where the new solvent is toluene, crystalline compound (I) is a toluene solvate designated Type G. In aspects where the new solvent is 2-propanol, crystalline compound (I) is a 2-propanol solvate designated Type H. In aspects where the new solvent is 1 -butanol, crystalline compound (I) is a 1 -butanol solvate designated Type I. In aspects where the new solvent is MeTHF, crystalline compound (I) is a MeTHF solvate designated Type J. In aspects where the new solvent is THF, crystalline compound (I) is a THF solvate designated Type K. In aspects where the new solvent is isobutyl alcohol, crystalline compound (I) is an isobutyl alcohol solvate designated Type L. In aspects where the new solvent is DMSO, crystalline compound (I) is a DMSO solvate designated Type M. In aspects where the new solvent is 2- pentanol, crystalline compound (I) is a 2-pentanol solvate designated Type BK. In aspects where the new solvent is isopropyl acetate, crystalline compound (I) is an isopropyl acetate solvate designated Type BK.

[0234] Is some aspects, Type F may be obtained by slow evaporation of a solution of compound (I) in ethanol. In some other aspects, Type H may be obtained by slow evaporation of a solution of compound (I) in IPA or by slow evaporation of a solution of compound (I) in MTBE and IPA. [0235] In some aspects of the disclosure, crystalline compound (I) Type E may be prepared from amorphous compound (I) or from any of the various crystalline hydrate types. In such aspects, compound (I) is dissolved in DCM at a temperature of less than about 50 °C to form a solution. The temperature is suitably from about 5 °C to about 50 °C, from about 10 °C to about 40 °C, or from about 10 °C to about 30 °C. The concentration of compound (I) in DCM may suitably be from about 0.05 g/mL to about 2 g/mL, from about 0.1 g/mL about 1 g/mL, or from about 0.1 g/mL to about 0.5 g/mL. A non-polar anti-solvent having a dielectric constant of less than 2 as described elsewhere herein (e.g. «-heptane) is added to the compound (I) solution to induce crystallization of crystalline compound (I) Type E and form a slurry thereof. The volume ratio of total anti-solvent to DCM may suitably be from about 1 : 1 and about 5: 1, from about 1.5 : 1 to about 4: 1 or from about 1.5 : 1 to about 3: 1, such as about 2: 1. In some aspects, an initial anti-solvent addition is done followed by further additions in increments over an addition time period, such as from about 1 hour to about 5 hours, or from about 2 hours to about 4 hours. Crystalline compound (I) Type E seed crystals may optionally be added after the initial anti-solvent addition and prior to one or more further anti-solvent additions.

[0236] Solid crystalline compound (I) Type E may be isolated from the slurry by techniques known in the art as described elsewhere herein with concomitant generation of a mother liquor. The isolated solid may be optionally washed with the mother liquor and/or anti solvent solvent and then optionally dried. The crystalline compound (I) Type E may be dried by techniques known in the art described elsewhere herein at elevated temperature, such as from about 30 °C to about 70 °C, or from about 40 °C to about 60 °C, such as from about 45 °C to about 55 °C. Compound (I) is dried until the DCM content is less than 600 ppm and the non polar anti-solvent content is less than 0.45% as measured by GC as described elsewhere herein. Compound (I) yield based on compound 6 is at least 80%, at least 85% or at least 90%, for instance 85% or 90%. Purity as measured by HPLC methods described elsewhere herein is at least 98%, at least 99%, or at least 99.5%, such as about 99%, about 99.5% or about 99.9%.

[0237] Compound 1 may be prepared according to the three-step method shown in FIG. 2, and with further reference to the Examples.

[0238] In a first step, compound 10A, an alkyl ester forming reagent, and a base are reacted in a solvent to form compound 10B according to the following:

[0239] The alkyl ester forming reagent may be an alkylating agent, and in many embodiments may be a methylating reagent such as methyl tosylate.

[0240] A reaction mixture is formed from compound 10A, the solvent, an alkylating agent methylating reagent, and base, and the reaction mixture is reacted at a temperature of from about 25 °C to about 60 °C, or from about 30 °C to about 50 °C, to form a reaction product mixture comprising compound 1B. In some aspects the solvent comprises or is a polar aprotic solvent. R¹ and R², the polar aprotic solvent, the methylating reagent and the base are as describe elsewhere herein. In some aspects, the polar aprotic solvent comprises or is DMF. In some aspects, the alkylating agent is a methylating reagent which may be selected from methyl iodide, methyl tosylate, and methyl mesylate. In some aspects, the base is an inorganic base, or is an inorganic base selected from potassium carbonate, potassium bicarbonate, sodium carbonate, and sodium bicarbonate. The reaction product mixture may be combined with water and a non-polar solvent having a dielectric constant greater than 2 as described elsewhere herein (e.g., MTBE) followed by phase separation to remove the aqueous phase. The aqueous phase may be washed one or more times with additional non-polar solvent. The organic phases comprising compound 1B may be combined with a polar aprotic solvent (e.g., THF) and distilled to a compound 1B concentration of from about 0.1 to about 2 g/mL, or from about 0.25 to about 0.75 g/mL.

[0241] In certain embodiments the methylating reagent may be replaced with other lower alkyl reagents such that compound 10B is a lower alkyl ester other than a methyl ester as shown.

[0242] In a second step, compound 1B and a reducing agent are reacted to in a solvent form compound 1C according to the following:

[0243] A reaction mixture comprising compound 1B in solvent (e.g., THF), additional solvent (e.g., THF), water, and a reducing agent is formed and reacted at a temperature below 25 °C, such as from about 5 °C to about 20 °C to form a reaction product mixture comprising compound 1C. In some aspects, the solvent is a polar aprotic solvent. R¹ and R², and the polar aprotic solvent are as described elsewhere herein. In some aspects, the reducing agent is a borohydride compound such as sodium borohydride, NaBH₄. The pH of the reaction product mixture is adjusted to about 1 with a mineral acid (e.g., HC1) and the adjusted reaction product mixture is stirred at temperature, for instance, for at least 1 hour or at least 4 hours. The phases are allowed to separate, and the lower aqueous phase is removed leaving an organic phase comprising compound 1C. The aqueous phase may be washed at least one additional time with a polar aprotic solvent as described elsewhere herein (e.g., ethyl acetate). The combined organic phases comprising compound 1C may be washed one or more times with an aqueous inorganic base solution (e.g., sodium bicarbonate or potassium bicarbonate) and/or an aqueous salt solution (e.g., NaCl). The washed organic phase is combined with a non-polar solvent having a dielectric constant of less than 2 as described elsewhere herein (e.g., «-heptane) followed by distillation at reduced pressure at a temperature of less than about 70 °C. Additional non-polar solvent may be added and the mixture is cooled to less than about 20 °C, such as from about -5 °C to about 5 °C. Solid compound 1C may be isolated from the slurry by techniques known in the art as described elsewhere herein. The isolated solid may be optionally washed with anti solvent solvent and then optionally dried by techniques known in the art described elsewhere herein. Compound 1C yield based on compound 1B is at least 70%, at least 75% or at least 80%, for instance 80%. Purity as measured by HPLC methods described elsewhere herein is at least 98%, or at least 99%, such as about 99% or about 99.4%.

[0244] In a third step, compound 1C, compound 8, a catalyst, and a base are reacted in a solvent to form compound 1 according to the following:

[0245] A reaction mixture comprising compound 1C, compound 8, a solvent, a catalyst, and a base is formed and reacted at a temperature of from about 65 °C to about 90 °C, from about 70 °C to about 85 °C, or from about 75 °C to about 80 °C to form a reaction product mixture comprising compound 1. In some aspects, the solvent is a non-polar solvent having a dielectric constant of greater than 2. R¹ and R², the base and the non-polar solvent are as describe elsewhere herein. In some aspects, the solvent comprises or is l,4-dioxane. In some aspects, the base is an inorganic base, or is selected from potassium bicarbonate and sodium bicarbonate. In some aspects, the catalyst is a palladium catalyst, such as, for instance and without limitation, Pd(dppf)Cl2. The reaction is continued until the compound 1C content is less than 5% as measured by HPLC as described elsewhere herein. After reaction completion, the reaction product mixture may be distilled to reduce the volume and the resulting concentrate comprising compound 1 is combined with water and a non-polar solvent having a dielectric constant of greater than 2 (e.g., MTBE). The phases are allowed to separate, and the lower aqueous phase is removed leaving an organic phase comprising compound 1. The aqueous phase may be washed at least one additional time with a non-polar solvent having a dielectric constant of greater than 2 (e.g., MTBE). The combined organic phases are mixed with a non polar anti-solvent having a dielectric constant of less than 2 as described elsewhere herein (e.g., «-heptane) followed by distillation at reduced pressure at a temperature of less than about 70 °C to reduce the volume. At least one additional non-polar anti-solvent addition and distillation step may be done. Additional non-polar solvent (e.g., DCM) may be added and the mixture is cooled to less than about 40 °C, such as from about 20 °C to about 35 °C. Solid compound 1 may be isolated from the slurry by techniques known in the art as described elsewhere herein. The isolated solid may be optionally washed with the anti-solvent solvent and the non-polar solvent having a dielectric constant of greater than 2. Compound 1 may then be optionally dried by techniques known in the art described elsewhere herein. Compound 1 yield based on compound 1C is at least 70% or at least 75%, for instance 75% or 78%. Purity as measured by HPLC methods described elsewhere herein is at least 97%, at least 98%, or at least 98.5%, such as about 98% or about 98.7%. [0246] In some aspects, compound 10A is compound l0A(i), 2-chloro-5- methylisonicotinic acid, as follows:

[0247] In some aspects, compound 10B is compound lOB(i), methyl 2-chloro-5- methylisonicotinate, as follows:

[0248] In some aspects, compound 10C is compound l0C(i), (2-chloro-5- methylpyridin-4-yl)methanol, as follows:

10C(i)

[0249] Compound 8 below may be prepared from compound 8 A, 5-bromo-2- iodopyrimidine, by introducing a trifluoromethyl group to form compound 8(b) (5-bromo-2- (trifluoromethyl)pyrimidine), which in turn is converted to boronate compound 8 according to the two-step method shown in FIG. 2, and with further reference to the Examples as follows:

[0250] The polar aprotic solvent is described elsewhere herein. In some aspect, the solvent for step 1 comprises or is DMF and the solvent for step 2 comprises or is THF.

[0251] In some aspects of the disclosure, compound 4(a) (2S,4R,5S)-l-(tert- butoxycarbonyl)-4-fluoro-5-methylpynOlidine-2-carboxylic acid may be prepared from compound 4A according to the 7 step method shown in FIG. 3, and with further reference to the Examples.

[0252] Polymorphs of compound (I) and methods of preparation

[0253] Provided herein are crystalline forms of compound (I) (e.g., compound 1(a)) and pharmaceutical compositions comprising crystalline forms of compound (I). Certain crystalline polymorphic salts of compound (I) are also within the scope of the present disclosure. It has been found that crystalline forms of compound (I) can be prepared as one or more polymorph forms, including hydrate, solvate, and salt forms. These polymorph forms exhibit new physical properties as compared to the prior art amorphous form that can be exploited in order to obtain new pharmacological properties, and that may be utilized in drug substance and drug product development. More particularly, crystalline forms of compound (I) and pharmaceutical compositions thereof are useful for the prevention, amelioration or treatment of diseases mediated by TRPA1.

[0254] In contrast to an amorphous form of compound (I) free base, a crystalline form is characterized by the presence of observable peaks in a powder x-ray diffraction (PXRD) pattern measured on the crystalline form. The PXRD patterns measured or calculated for the salts and crystalline forms reported herein represent a fingerprint that can be compared to other experimentally determined patterns to find a match. Identity of the respective crystalline forms is established by overlap or match of an experimentally determined PXRD pattern with the PXRD pattern of the crystalline forms reported herein. In various embodiments, the salts and crystalline forms are characterized by exhibiting at least one of the PXRD peaks reported here. Thus, in various embodiments, a salt or crystalline form is characterized by a match of two or more peaks, a match of 3 or more peaks, 4 or more peaks, or 5 or more peaks, and so on, from the respective PXRD patterns.

[0255] In some embodiments, the percent crystallinity of any of the salt or crystalline forms of compound (I) described herein can vary with respect to the total amount of compound (I). In particular, certain embodiments provide for the percent crystallinity of a salt or crystalline form of compound (I) being at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least, 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99%.

In some embodiments, the percent crystallinity can be substantially 100%, where substantially 100% indicates that the entire amount of compound (I) appears to be crystalline as best can be determined using methods known in the art. Accordingly, pharmaceutical compositions and therapeutically effective amounts of compound (I) can include amounts that vary in crystallinity. These include instances where compound (I) is used as an active pharmaceutical ingredient (API) in various formulations and solid forms, including where an amount of compound (I) in a solid form is subsequently dissolved, partially dissolved, or suspended or dispersed in a liquid.

[0256] As noted, in some embodiments API compositions are provided that comprise compound (I), wherein at least a portion of the compound (I) in the API composition is in one of the salt or crystalline forms. For example, an API composition containing compound (I) has at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% or at least 99% of the compound of the composition in one of the salt or crystalline forms. In some embodiments, essentially 100% of the compound (I) of an API formulation is in a salt or crystalline form as described herein.

[0257] Any of the crystalline forms of compound (I), including salts and solvated forms, can be useful as an API for preparation of pharmaceutical compositions. Solvated forms can be, as indicated above, useful as process intermediates in preparation of solvent-free forms. Compound (I) salts and crystalline forms can be used in preparation of pharmaceutical compositions suitable for various routes of administration, including oral, to a subject in need thereof. Thus, in some embodiments, a pharmaceutical composition is provided, comprising a crystalline form of compound (I) and one or more pharmaceutically acceptable excipients.

[0258] In some embodiments, the salt or crystalline form of compound (I) includes those of: (1) compound (I) free base hydrate having PXRD pattern A; (2) compound (I) free base anhydrate having PXRD pattern E; (3) compound (I) free base N,N-dimethylacetamide solvate having PXRD pattern C; (4) compound (I) free base anisole solvate having PXRD pattern D; (5) compound (I) free base ethanol solvate having pattern F; (6) compound (I) free base toluene solvate having PXRD pattern G; (7) compound (I) free base 2-propanol solvate having PXRD pattern H; (8) compound (I) free base 1 -butanol solvate having PXRD pattern I; (9) compound (I) free base 2-methyltetrahydrofuran solvate having PXRD pattern J; (10) compound (I) free base tetrahydrofuran solvate having PXRD pattern K; (11) compound (I) isobutyl alcohol solvate having PXRD pattern L; (12) compound (I) DMSO solvate having PXRD pattern M; (13) compound (I) anhydrate gentisic acid co-crystal having co-crystal PXRD pattern A; (14) compound (I) anhydrate gentisic acid co-crystal having co-crystal PXRD pattern B; (15) compound (I) hydrate picolinamide co-crystal having co-crystal PXRD pattern C; (16) compound (I) free base anhydrate having PXRD pattern AL; (17) compound (I) free base hydrate having PXRD pattern BO; (18) compound (I) free base «-heptane solvate PXRD pattern BP; (19) compound (I) free base 2-pentanol solvate PXRD pattern BK; (20) compound (I) free base l-propanol solvate PXRD pattern AX; (21) compound (I) free base m-xylene solvate PXRD patern Q; (22) compound (I) free base 2-methoxy ethanol solvate PXRD patern P; and (23) compound (I) free base vec-butyl ethanol solvate PXRD pattern AQ.

[0259] Based on certain atributes, and in some aspects, crystalline compound 1(a) free base anhydrate Type E is a preferred polymorphic form. For instance, Type E it is the only discovered anhydrate. Milling evaluations indicate that Type E does not form any significant of amorphous material after jet milling. Type E shows good physical and chemical stability under conditions of 80 °C (closed)/24 hrs, 25°C/60%RH/6 days and 40 °C/75%RH/6 days when evaluated by XRPD and HPLC. Further, Type E showed no form change after DVS evaluation at 25 °C. Yet further, Type E production may readily be scaled up by anti-solvent crystallization in DCM/n-heptane at room temperature.

[0260] In certain embodiments of the processes described herein, solvate forms of compound (I) may obtained by exposing the compound to sequential solvents in order to form compound (I) crystals. For instance, and without limitation, compound (I) may be dissolved in first solvent (e.g., dichloromethane), and then crystallization may be induced by addition of an anti-solvent (e.g., «-heptane). In any of the various aspects, the crystals may be isolated by techniques known in the art including filtration, centrifugation, and setling. Isolated crystals may be optionally washed with the anti-solvent solvent and then dried. Drying may be done by techniques known in the art including vacuum drying at elevated temperature, such as from about 35 °C to about 60 °C.

[0261] Compound (I) (e.g., compound 1(a)) free base anhydrate Type E may be prepared from a solution of compound (I) free base in dichloromethane (DCM). The compound (I) concentration in solution is suitably at least 50 g/L at room temperature, such as about 200 g/L, about 150 g/L, about 300 g/L, about 350 g/L, or about 400 g/L, and ranges thereof, such as from about 200 g/L to about 400 g/L or from about 250 g/L to about 350 g/L. «-heptane is then charged at a volume: volume ratio of DCM to «-heptane of from about 1 :2, about 1 :2.5, about 1:3, about 1:3.5, about 1 :4 or about 1 :5, and ranges thereof, such as from about 1:2 to about 1 :5, or from about 1:2.5 to about 1 :3.5. Compound (I) Type E seed crystals may optionally be added to induce and/or enhance crystallization. [0262] Optionally, crystalline compound (I) (e.g., compound 1(a)) free base anhydrate Type E may be prepared by solid phase transition. In one such aspect, Type E may be prepared by heating solid compound (I) free base anisole Type D solvate to greater than about 100 °C, such as about 110 °C. In another such aspect, Type E may be prepared by heating solid compound (I) free base ethanol Type F solvate to greater than about 100 °C, such as about 105 °C. In another such aspect, Type E may be prepared by heating solid compound (I) free base toluene Type G solvate to greater than about 100 °C, such as about 1 l0°C. In another such aspect, Type E may be prepared by heating solid compound (I) free base 2-propanol Type H solvate to greater than about 110 °C, such as about 125 °C.

[0263] In aspects where the crystalline compound 1(a) is a free base anhydrate designated Type E, Type E is identifiable on the basis of characteristic peaks in an XRPD analysis. In one such aspect, Type E exhibits an XRPD pattern having characteristic peaks expressed in degrees 2-theta at angles of 7.5°±0.2°, 8.2°±0.2°, 12.6°±0.2°, l3.l°±0.2°,

13.4°±0.2°, 14.7°±0.2°, 15.1°±0.2°, 15.5°±0.2°, 16.1°±0.2°, 16.6°±0.2°, 18.2°±0.2°, l8.9°±0.2°, l9.9°±0.2°, 20.4°±0.2°, 2l.0°±0.2°, 2l.5°±0.2°, 2l.8°±0.2°, 22.4°±0.2°, 22.7°±0.2°, 24.3°±0.2°, 25.0°±0.2°, 25.4°±0.2°, and 28.4°±0.2°. The endotherm (onset) for Type E was determined to be 147.0 °C. In another aspect, the Type E free base anhydrate exhibits an XRPD pattern substantially in accordance with FIG. 10. In another aspect, Type E exhibits TGA and DSC spectrum curves substantially in accordance with FIG. 11. In another aspect, Type E exhibits an NMR spectrum substantially in accordance with FIG. 12. In another aspect, Type E exhibits a DVS isotherm plot substantially in accordance with FIG. 13.

[0264] Crystalline compound (I) free base hydrate Type A may be prepared from solution by dissolving Form E or amorphous material in methanol at 125 mg/mL at 60 °C, followed by addition of 5-20% (v/v) water and subsequent cooling to 10 °C. Solids are then collected via vacuum filtration and dried under ambient room temperature and pressure.

[0265] In aspects where the crystalline compound 1(a) is a free base hydrate Type A, it is identifiable on the basis of characteristic peaks in an XRPD analysis. In one such aspect,

Type A exhibits an XRPD pattern having characteristic peaks expressed in degrees 2-theta at angles of 7.2°±0.2°, 12.2°±0.2°, 14.0°±0.2°, 14.2°±0.2°, 15.5°±0.2°, 15.8°±0.2°, l7.0°±0.2°, l7.2°±0.2°, l8.4°±0.2°, 2l.3°±0.2°, 2l.6°±0.2°, 22.2°±0.2°, 23.4°±0.2°, 24.4°±0.2°, and 25.2°±0.2°. The endotherm (onset) for Type A was determined to be 98.0°C. In another aspect, Type A free base hydrate exhibits an XRPD pattern substantially in accordance with FIG. 6. In another aspect, Type A exhibits TGA and DSC spectrum curves substantially in accordance with FIG. 7. In another aspect, Type A exhibits an NMR spectrum substantially in accordance with FIG. 8. In another aspect, Type A exhibits a DVS isotherm plot substantially in accordance with FIG. 9.

[0266] Crystalline compound (I) free base N,N-dimethylacetamide (DMAc) solvate Type C may be prepared from a solution of compound (I) in DMAc by addition of water anti solvent. Optionally, Type C crystals may be prepared by evaporation of DMAc from the solution and/or by cooling the solution to less than about 10 °C, such as about 0 °C to about 5 °C. Compound (I) DMAc solvate Type C seed crystals may optionally be added to induce and/or enhance crystallization.

[0267] In aspects where the crystalline compound 1(a) is a DMAc solvate Type C, it is identifiable on the basis of characteristic peaks in an XRPD analysis. In one such aspect, Type C exhibits an XRPD pattern having characteristic peaks expressed in degrees 2-theta at angles of l0.8°±0.2°, 12.1°±0.2°, 12.3°±0.2°, 13.6°±0.2°, 13.8°±0.2°, 14.9°±0.2°, 16.0°±0.2°, l6.2°±0.2°, l7. l°±0.2°, l8.2°±0.2°, 2l.2°±0.2°, 2l.5°±0.2°, 22.4°±0.2°, 2l.2°±0.2°, 23.5°±0.2°, 24.2°±0.2°, 25.2°±0.2°, 27.2°±0.2°, and 27.9°±0.2°. The endotherm (onset) for Type C was determined to be 100.4 °C. In another aspect, Type C DMAc solvate exhibits an XRPD pattern substantially in accordance with FIG. 25. In another aspect, Type C exhibits TGA and DSC spectrum curves substantially in accordance with FIG. 26. In another aspect, Type C exhibits an NMR spectrum substantially in accordance with FIG. 27.

[0268] Crystalline compound (I) (e.g., compound 1(a)) free base anisole solvate Type D may be prepared from a solution of compound (I) in anisole by addition «-heptane anti solvent. In some aspects, the solution of compound (I) in anisole may be contacted with n- heptane vapor to form water. Optionally, Type D crystals may be prepared by evaporation of anisole from the solution and/or by cooling the solution to less than about 10 °C, such as about 0 °C to about 5 °C. Compound (I) anisole solvate Type D seed crystals may optionally be added to induce and/or enhance crystallization.

[0269] In aspects where the crystalline compound 1(a) is a free base anisole solvate designated Type D, it is identifiable on the basis of characteristic peaks in an XRPD analysis. In one such aspect, Type D exhibits an XRPD pattern having characteristic peaks expressed in degrees 2-theta at angles of 5.7°±0.2°, 12.8°±0.2°, 15.4°±0.2°, 17.1°±0.2°, 18.1°±0.2° and 20.8°±0.2°. The endotherm (onset) for Type D was determined to be 94.9°C. In another aspect, the Type D anisole solvate exhibits an XRPD pattern substantially in accordance with FIG. 28. In another aspect, Type D exhibits TGA and DSC spectrum curves substantially in accordance with FIG. 29. In another aspect, Type D exhibits an NMR spectrum substantially in accordance with FIG. 30.

[0270] Crystalline compound (I) (e.g., compound 1(a)) free base ethanol solvate Type F may be prepared from a solution of compound (I) in ethanol by addition of «-heptane anti solvent. Optionally, Type F crystals may be prepared by evaporation of ethanol from the solution and/or by cooling the solution to less than about 10 °C, such as about 0 °C to about 5 °C. Compound (I) ethanol solvate Type F seed crystals may optionally be added to induce and/or enhance crystallization.

[0271] In aspects where the crystalline compound 1(a) is a free base ethanol solvate designated Type F, it is identifiable on the basis of characteristic peaks in an XRPD analysis. In one such aspect, Type F exhibits an XRPD pattern having characteristic peaks expressed in degrees 2-theta at angles of l l.7°±0.2°, 12.9°±0.2°, 13.3°±0.2°, 17.4°±0.2°, 18.5°±0.2°, 19.4°±0.2°, 23.5°±0.2°, 24.3°±0.2° and 25.9°±0.2°. The endotherm (onset) for Type F was determined to be 100.3 °C and 36.4 °C. In another aspect, the Type F free base ethanol solvate exhibits an XRPD pattern substantially in accordance with FIG. 32. In another aspect, Type F exhibits TGA and DSC spectrum curves substantially in accordance with FIG. 33. In another aspect, Type F exhibits an NMR spectrum substantially in accordance with FIG. 34.

[0272] Crystalline compound (I) (e.g., compound 1(a)) free base toluene solvate Type G may be prepared from a solution of compound (I) in toluene by cooling of the solution to less than about 10 °C, such as about 0 °C to about 5 °C. Optionally, Type G crystals may be prepared by evaporation of toluene from the solution followed by cooling. Compound (I) toluene solvate Type G seed crystals may optionally be added to induce and/or enhance crystallization.

[0273] In aspects where the crystalline compound 1(a) is a free base toluene solvate designated Type G, it is identifiable on the basis of characteristic peaks in an XRPD analysis. In one such aspect, Type G exhibits an XRPD pattern having characteristic peaks expressed in degrees 2-theta at angles of 13.8°±0.2°, 16.7°±0.2°, 17.6°±0.2°, 17.8°±0.2°, 18.8°±0.2°, 22.5°±0.2° and 25.1°±0.2°. The endotherm (onset) for Type G was determined to be 106.3 °C.

In another aspect, the Type G free base toluene solvate exhibits an XRPD pattern substantially in accordance with FIG. 36. In another aspect, Type G exhibits TGA and DSC spectrum curves substantially in accordance with FIG. 37. In another aspect, Type G exhibits an NMR spectrum substantially in accordance with FIG. 38.

[0274] Crystalline compound (I) (e.g., compound 1(a)) free base 2-propanol solvate Type H may be prepared from a solution of compound (I) in MTBE by addition of 2-propanol anti-solvent. Compound (I) 2-propanol solvate Type H seed crystals may optionally be added to induce and/or enhance crystallization.

[0275] In aspects where the crystalline compound 1(a) is a free base 2-propanol solvate designated Type H, it is identifiable on the basis of characteristic peaks in an XRPD analysis. In one such aspect, Type H exhibits an XRPD pattern having characteristic peaks expressed in degrees 2-theta at angles of l l.5°±0.2°, 12.8°±0.2°, 13.1°±0.2°, 17.5°±0.2°, 18.2°±0.2°, 22.3°±0.2°, 23.2°±0.2° and 24.0°±0.2°. The endotherm (onset) for Type H was determined to be 116.3 °C. In another aspect, the Type H free base 2-propanol solvate exhibits an XRPD pattern substantially in accordance with FIG. 40. In another aspect, Type H exhibits TGA and DSC spectrum curves substantially in accordance with FIG. 41. In another aspect, Type H exhibits an NMR spectrum substantially in accordance with FIG. 42.

[0276] Crystalline compound (I) (e.g., compound 1(a)) free base l-butanol solvate Type I may be prepared from a slurry of Type A crystals at a temperature of greater than about 35 °C, such about 40 °C, about 50 °C, or about 60 °C. Compound (I) l-propanol solvate Type I seed crystals may optionally be added to induce and/or enhance crystallization.

[0277] In aspects where the crystalline compound 1(a) is a free base l-butanol solvate designated Type I, it is identifiable on the basis of characteristic peaks in an XRPD analysis. In one such aspect, Type I exhibits an XRPD pattern having characteristic peaks expressed in degrees 2-theta at angles of 12.0°±0.2°, 12.4°±0.2°, 12.6°±0.2°, 13.3°±0.2°, 14.0°±0.2°, 15.1°±0.2°, 17.2°±0.2°, 17.9°±0.2°, 18.3°±0.2°, 19.7°±0.2°, 19.9°±0.2°, 23.1°±0.2°, 24.3°±0.2°, 25.4°±0.2°, 25.9°±0.2° and 27.3°±0.2°. The endotherm (onset) for Type I was determined to be 90.0 °C. In another aspect, the Type I free base l-butanol solvate exhibits an XRPD pattern substantially in accordance with FIG. 44. In another aspect, Type I exhibits TGA and DSC spectrum curves substantially in accordance with FIG. 45. In another aspect, Type I exhibits an NMR spectrum substantially in accordance with FIG. 46.

[0278] Crystalline compound (I) (e.g., compound 1(a)) free base 2- methyltetrahydrofuran (MeTHF) solvate Type J may be prepared from a slurry of Type A crystals in MeTHF and «-heptane at about room temperature. A suitable volume ratio of MeTHF to «-heptane is from about 1: 1.1 to about 1 :5, such as about 1 : 1.15, 1:2, 1 :2.5 or 1:3. Compound (I) MeTHF solvate Type J seed crystals may optionally be added to induce and/or enhance crystallization.

[0279] In aspects where the crystalline compound 1(a) is a free base MeTHF solvate designated Type J, it is identifiable on the basis of characteristic peaks in an XRPD analysis. In one such aspect, Type J exhibits an XRPD pattern having characteristic peaks expressed in degrees 2-theta at angles of l l.8°±0.2°, 13.1°±0.2°, 14.5°±0.2°, 16.8°±0.2°, 18.4°±0.2°, 19.4°±0.2°, 20.7°±0.2°, 21.8°±0.2°, 24.3°±0.2° and 26.4°±0.2°. The endotherm (onset) for Type J was determined to be 82.2°C. In another aspect, the Type J free base MeTHF solvate exhibits an XRPD pattern substantially in accordance with FIG. 47. In another aspect, Type J exhibits TGA and DSC spectrum curves substantially in accordance with FIG. 48. In another aspect, Type J exhibits an NMR spectrum substantially in accordance with FIG. 49.

[0280] Crystalline compound (I) (e.g., compound 1(a)) free base THF solvate Type K may be prepared from a slurry of Type A crystals in THF and «-heptane at about room temperature. A suitable volume ratio of THF to «-heptane is from about 1 : 1.1 to about 1:5, such as about 1: 1.15, 1 :2, 1:2.5 or 1:3. Compound (I) THF solvate Type K seed crystals may optionally be added to induce and/or enhance crystallization.

[0281] In aspects where the crystalline compound 1(a) is a free base THF solvate designated Type K, it is identifiable on the basis of characteristic peaks in an XRPD analysis. In one such aspect, Type K exhibits an XRPD pattern having characteristic peaks expressed in degrees 2-theta at angles of l l.0°±0.2°, 12.0°±0.2°, 12.4°±0.2°, 12.6°±0.2°, 13.3°±0.2°, 13.5°±0.2°, 14.1°±0.2°, 14.7°±0.2° , 17.2°±0.2°, 18.5°±0.2°, 19.5°±0.2°, 20.9°±0.2°,

21.4°±0.2°, 21.6°±0.2°, 22.0°±0.2°, 22.2°±0.2°, 22.9°±0.2°, 24.8°±0.2°, 27.1°±0.2°, 27.4°±0.2° and 28.3°±0.2°. The endotherm (onset) for Type K was determined to be 86.8 °C. In another aspect, the Type K free base THF solvate exhibits an XRPD pattern substantially in accordance with FIG. 50. In another aspect, Type K exhibits TGA and DSC spectrum curves substantially in accordance with FIG. 51. In another aspect, Type K exhibits an NMR spectrum substantially in accordance with FIG. 52.

[0282] Crystalline compound (I) (e.g., compound 1(a)) free base isobutyl alcohol solvate Type L may be prepared from a slurry of anhydrous compound (I) or Type A crystals in isobutyl alcohol at about room temperature. Compound (I) isobutyl alcohol solvate Type L seed crystals may optionally be added to induce and/or enhance crystallization.

[0283] In aspects where the crystalline compound 1(a) is a free base isobutyl alcohol solvate designated Type , it is identifiable on the basis of characteristic peaks in an XRPD analysis. In one such aspect, Type L exhibits an XRPD pattern having characteristic peaks expressed in degrees 2-theta at angles of l l.6°±0.2°, 12.8°±0.2°, 13.1°±0.2°, l4.2°±0.2°, l7.5°±0.2°, l8.l°±0.2°, 22.8°±0.2°, 23. l°±0.2°, 24.0°±0.2° and 25.3°±0.2°. The endotherm (onset) for Type L was determined to be 106.8 °C. In another aspect, the Type L free base isobutyl alcohol solvate exhibits an XRPD pattern substantially in accordance with FIG. 53. In another aspect, Type L exhibits TGA and DSC spectrum curves substantially in accordance with FIG. 54. In another aspect, Type L exhibits an NMR spectrum substantially in accordance with FIG. 55.

[0284] Crystalline compound (I) (compound 1(a)) free base DMSO solvate Type M may be prepared from a slurry of Type E crystals in DMSO and water at about room

temperature. A suitable volume ratio of THF to «-heptane is from about 1:2 to about 2: 1, such as about 1:2, 1: 1.5, 1 : 1, 1.5: 1 or 2: 1. Compound (I) DMSO solvate Type M seed crystals may optionally be added to induce and/or enhance crystallization.

[0285] In aspects where the crystalline compound 1(a) is a free base DMSO solvate designated Type M, it is identifiable on the basis of characteristic peaks in an XRPD analysis.

In one such aspect, Type M exhibits an XRPD pattern having characteristic peaks expressed in degrees 2-theta at angles of 12.1°±0.2°, 13.4°±0.2°, 14.7°±0.2°, 18.4°±0.2°, 20.9°±0.2°, 21.5°±0.2°, 24.9°±0.2°, 26.8°±0.2° and 27.6°±0.2°. The endotherm (onset) for Type M was determined to be 110.7 °C. In another aspect, the Type M free base DMSO solvate exhibits an XRPD pattern substantially in accordance with FIG. 56. In another aspect, Type M exhibits TGA and DSC spectrum curves substantially in accordance with FIG. 57. In another aspect, Type M exhibits an NMR spectrum substantially in accordance with FIG. 58.

[0286] Crystalline compound (I) (e.g., compound 1(a)) free base anhydrate Type AL may be prepared from a slurry of Type E crystals in EtOAc and n-heptane. A suitable volume ratio of EtOAc to «-heptane may be from about 2: 1 to about 1:5, such as about 2: 1, 1 : 1, 1:2, 1 :3, 1:4 or 1 :5. Compound (I) Type AL seed crystals may optionally be added to induce and/or enhance crystallization. Crystallization temperature may suitably be from about 15 °C to about 60 °C or from about 50 °C to about 60 °C, such as about 15 °C, 25 °C, 35 °C, 45 °C, 50 °C, 55 °C or 60 °C. Crystallization time may be at least about 12 hours, such as 12 hours, 1 day, 3 days, 5 days or more.

[0287] In aspects where the crystalline compound 1(a) is a free base anhydrate designated Type AL, it is identifiable on the basis of characteristic peaks in an XRPD analysis. In one such aspect, Type AL exhibits an XRPD pattern having characteristic peaks expressed in degrees 2-theta at angles of 7.6°±0.2°, 8.4°±0.2°, 13.2°±0.2°, 13.8°±0.2°, l4.8°±0.2°, l5.2°±0.2°, l5.6°±0.2°, l5.9°±0.2°, l6.9°±0.2°, l8. l°±0.2°, 20.5°±0.2°, and 2l.3°±0.2°. The endotherm (onset) for Type AL was determined to be 93.3 °C and 147.5 °C. In another aspect, the Type M free base anhydrate exhibits an XRPD pattern substantially in accordance with FIG. 81. In another aspect, Type AL exhibits TGA and DSC spectrum curves substantially in accordance with FIG. 82. In another aspect, Type AL exhibits an NMR spectrum substantially in accordance with FIG. 83.

[0288] Crystalline compound (I) (e.g., compound 1(a)) free base hydrate Type BO may be prepared from a solution of Type E crystals in methanol and water. A suitable volume ratio of methanol to water may be from about 3: 1 to about 1:3, such as about 3: 1, 2: 1, 1 : 1, 1:2, or 1 :3. Dissolution temperature may be from about 30 °C to about 70 °C or from about 50 °C to about 60 °C, such as about 30 °C, 40 °C, 50 °C, 55 °C, 60 °C, 65 °C or 70 °C. Crystallization temperature may less than about 60 °C, such as about 60 °C, 50 °C, 40 °C, 30 °C, 20 °C, 10 °C or 5 °C. Crystallization time may be at least about 12 hours, such as 12 hours, 1 day, 2days, 3 days or more. Based on XPRD comparison, the compound 1(a) crystals were determined to be Type BN in accordance with FIG. 84. Type BO was obtained after drying the Type BN crystals at ambient conditions for at least about an hour.

[0289] In aspects where the crystalline compound 1(a) is a free base hydrate designated Type BO, it is identifiable on the basis of characteristic peaks in an XRPD analysis. In one such aspect, Type BO exhibits an XRPD pattern having characteristic peaks expressed in degrees 2- theta at angles of 12.1°±0.2°, 12.4°±0.2°, 13.9°±0.2°, 15.0°±0.2°, 15.4°±0.2°, 17.1°±0.2°, 18.3°±0.2°, 21.5°±0.2°, 22.1°±0.2°, 24.4°±0.2°, 25.1°±0.2°, 26.2°±0.2°, and 26.3°±0.2°. The endotherm (onset) for Type BO was determined to be 86.2 °C and 148.3 °C and an exotherm peak was determined to be at 136.4 °C. In another aspect, the Type BO free base hydrate exhibits an XRPD pattern substantially in accordance with FIG. 84. In another aspect, Type BO exhibits TGA and DSC spectrum curves substantially in accordance with FIG. 85. In another aspect, Type BO exhibits an NMR spectrum substantially in accordance with FIG. 86. [0290] Crystalline compound (I) (e.g., compound 1(a)) free base «-heptane solvate Type BP may be prepared from a slurry of Type E crystals in (i) isopropyl acetate and «-heptane followed by (ii) isobutyl acetate and «-heptane. A suitable volume ratio for each of isopropyl acetate to «-heptane and of isobutyl acetate to «-heptane may be from about 3: 1 to about 1 :3, such as about 3: 1, 2: 1, 1 : 1, 1:2, or 1 :3. Slurry temperature may be from about 30 °C to about 80 °C, or 65 °C to about 75 °C, such as about 30 °C, 40 °C, 50 °C, 60 °C, 65 °C, 70 °C, 75 °C or 80 °C.

[0291] In aspects where the crystalline compound 1(a) is a free base «-heptane solvate Type BP, it is identifiable on the basis of characteristic peaks in an XRPD analysis. In one such aspect, Type BP exhibits an XRPD pattern having characteristic peaks expressed in degrees 2- theta at angles of 8.5°±0.2°, l2.9°±0.2°, l7.6°±0.2°, l8.l°±0.2°, l9.4°±0.2°, 20.8°±0.2°, 2l.2°±0.2°, 22.9°±0.2°, and 24.0°±0.2°. The endotherm (onset) for Type BP was determined to be 122.5 °C and 147.3 °C. In another aspect, the Type BP free base «-heptane solvate exhibits an XRPD pattern substantially in accordance with FIG. 87. In another aspect, Type BP exhibits TGA and DSC spectrum curves substantially in accordance with FIG. 88. In another aspect, Type BP exhibits an NMR spectrum substantially in accordance with FIG. 89.

[0292] Crystalline compound (I) (e.g., compound 1(a)) free base 2-pentanol solvate Type BK may be prepared from a slurry of Type E crystals in 2-pentanol and «-heptane. A suitable volume ratio for each of isopropyl acetate to «-heptane and of isobutyl acetate to «- heptane may be from about 4: 1 to about 1:2, such as about 4: 1, 3: 1, 2: 1, 1 : 1, or 1 :2. Slurry temperature may be from about 30 °C to about 70 °C or from about 45 °C to about 55 °C, such as about 30 °C, 40 °C, 45 °C, 50 °C, 55 °C, 60 °C or 70 °C.

[0293] In aspects where the crystalline compound 1(a) is a free base 2-pentanol solvate Type BK, it is identifiable on the basis of characteristic peaks in an XRPD analysis. In one such aspect, Type BK exhibits an XRPD pattern having characteristic peaks expressed in degrees 2- theta at angles of l l.9°±0.2°, 13.0°±0.2°, 14.4°±0.2°, 14.7°±0.2°, 16.9°±0.2°, l7.9°±0.2°, l9.3°±0.2°, 2l.8°±0.2°, 22.7°±0.2°, 23.9°±0.2°, 24.6°±0.2°, and 26. l°±0.2°. The endotherm (onset) for Type BK was determined to be 71.5 °C. In another aspect, the Type BK free base 2- pentanol solvate exhibits an XRPD pattern substantially in accordance with FIG. 90. In another aspect, Type BK exhibits TGA and DSC spectrum curves substantially in accordance with FIG. 91. In another aspect, Type BK exhibits an NMR spectrum substantially in accordance with FIG. 92. [0294] Crystalline compound (I) (e.g., compound 1(a)) free base 1 -propanol solvate Type AX may be prepared from rapid evaporation of a solution of compound (I) in a solution of 1 -propanol and isopropyl acetate. A suitable volume ratio for 1 -propanol to isopropyl acetate may be from about 3: 1 to about 1:3, such as about 3: 1, 2: 1, 1.25: 1, 1: 1, 1 :2, or 1 :3. Evaporation may be done under partial vacuum and evaporation temperature may be from about 15 °C to about 60 °C or from about 20 °C to about 35 °C, such as about 15 °C, 20 °C, 25 °C, 30 °C, 35 °C, 40 °C, 50 °C or 60 °C.

[0295] In aspects where the crystalline compound 1(a) is a free base 1 -propanol solvate Type AX, it is identifiable on the basis of characteristic peaks in an XRPD analysis. In one such aspect, Type AX exhibits an XRPD pattern having characteristic peaks expressed in degrees 2- theta at angles of l l.5°±0.2°, l2.9°±0.2°, l3. l°±0.2°, l7.4°±0.2°, l8.2°±0.2°, 23. l°±0.2°, 23.9°±0.2°, and 25.9°±0.2°. The endotherm (onset) for Type AX was determined to be 113.5 °C and 122.0 °C. In another aspect, the Type AX free base 1 -propanol solvate exhibits an XRPD pattern substantially in accordance with FIG. 93. In another aspect, Type AX exhibits TGA and DSC spectrum curves substantially in accordance with FIG. 94. In another aspect, Type AX exhibits an NMR spectrum substantially in accordance with FIG. 95.

[0296] Crystalline compound (I) (e.g., compound 1(a)) free base m-xylene solvate Type Q may be prepared from rapid evaporation of a solution of compound (I) in a solution of methyl acetate and m-xylene. A suitable volume ratio for methyl acetate to m-xylene may be from about 3: 1 to about 1 :3, such as about 3: 1, 2:1, 1.25: 1, 1 : 1, 1:2, or 1:3. Evaporation may be done under partial vacuum and evaporation temperature may be from about 15 °C to about 60 °C or from about 20 °C to about 35 °C, such as about 15 °C, 20 °C, 25 °C, 30 °C, 35 °C, 40 °C, 50 °C or 60 °C.

[0297] In aspects where the crystalline compound 1(a) is a free base /«-xylene solvate Type Q, it is identifiable on the basis of characteristic peaks in an XRPD analysis. In one such aspect, Type Q exhibits an XRPD pattern having characteristic peaks expressed in degrees 2- theta at angles of 5.5°±0.2°, l2.5°±0.2°, l5.0°±0.2°, l7.6°±0.2°, 20.2°±0.2°, 22. l°±0.2°, 22.8°±0.2°, and 26.6°±0.2°. The endotherm (onset) for Type Q was determined to be 78.8 °C.

In another aspect, the Type Q free base /«.-xylene solvate exhibits an XRPD pattern substantially in accordance with FIG. 96. In another aspect, Type Q exhibits TGA and DSC spectrum curves substantially in accordance with FIG. 97. In another aspect, Type Q exhibits an NMR spectrum substantially in accordance with FIG. 98. [0298] Crystalline compound (I) (e.g., compound 1(a)) free base 2-methoxy ethanol (EGME) solvate Type P may be prepared from rapid evaporation of a solution of compound (I) in EGME and «-heptane. A suitable volume ratio for EGME to «-heptane may be from about 3: 1 to about 1 :3, such as about 3: 1, 2: 1, 1.25: 1, 1 : 1, 1 :2, or 1:3. Evaporation may be done under partial vacuum and evaporation temperature may be from about 15 °C to about 60 °C or from about 20 °C to about 35 °C, such as about 15 °C, 20 °C, 25 °C, 30 °C, 35 °C, 40 °C, 50 °C or 60 °C.

[0299] In aspects where the crystalline compound 1(a) is a free base EGME solvate Type P, it is identifiable on the basis of characteristic peaks in an XRPD analysis. In one such aspect, Type P exhibits an XRPD pattern having characteristic peaks expressed in degrees 2- theta at angles of l l.9°±0.2°, l2.3°±0.2°, l2.7°±0.2°, l4.0°±0.2°, l7. l°±0.2°, 20.0°±0.2°, 23.9°±0.2°, 24.l°±0.2°, 25.5°±0.2°, 25.8°±0.2°, and 27.2°±0.2°. The endotherm (onset) for Type P was determined to be 104.7 °C and 142.0 °C. In another aspect, the Type P free base EGME solvate exhibits an XRPD pattern substantially in accordance with FIG. 99. In another aspect, Type P exhibits TGA and DSC spectrum curves substantially in accordance with FIG.

100. In another aspect, Type P exhibits an NMR spectrum substantially in accordance with FIG.

101

[0300] Crystalline compound (I) (e.g., compound 1(a)) free base sec-butyl alcohol solvate Type AQ may be prepared from rapid evaporation of a solution of compound (I) in sec- butyl alcohol and MTBE. A suitable volume ratio for .sec-butyl alcohol and MTBE may be from about 3: 1 to about 1 :3, such as about 3: 1, 2:1, 1.25: 1, 1 : 1, 1:2, or 1:3. Evaporation may be done under partial vacuum and evaporation temperature may be from about l5°C to about 60 °C or from about 20 °C to about 35 °C, such as about 15 °C, 20 °C, 25 °C, 30 °C, 35 °C, 40 °C, 50 °C or 60 °C.

[0301] In aspects where the crystalline compound 1(a) is a free base .vec-butyl alcohol solvate Type AQ, it is identifiable on the basis of characteristic peaks in an XRPD analysis. In one such aspect, Type AQ exhibits an XRPD pattern having characteristic peaks expressed in degrees 2-theta at angles of l l.5°±0.2°, 12.7°±0.2°, 12.9°±0.2°, 14.1°±0.2°, 17.4°±0.2°, 17.9°±0.2°, 21.9°±0.2°, 22.7°±0.2°, 23.1°±0.2°, 23.5°±0.2°, 23.9°±0.2°, 25.5°±0.2°, and 27.6°±0.2°. The endotherm (onset) for Type AQ was determined to be 99.7 °C and 110.8 °C. In another aspect, the Type AQ free base .vec-butyl alcohol solvate exhibits an XRPD pattern substantially in accordance with FIG. 102. In another aspect, Type AQ exhibits TGA and DSC spectrum curves substantially in accordance with FIG. 103. In another aspect, Type AQ exhibits an NMR spectrum substantially in accordance with FIG. 104.

[0302] Compound (I) (e.g., compound 1(a)) gentisic acid anhydrate co-crystal Type A may be prepared from a solution of compound (I) free base and gentisic acid in ethyl acetate (EtOAc). The concentration of compound (I) is suitably from about 20 g/L to about 100 g/L, from about 30 g/L to about 75 g/L, or about 50 /L. Compound (I) and gentisic acid are present in approximately stoichiometric amounts. An anti-solvent, such as «-heptane, is added to the solution to induce crystallization. The volume ratio of EtOAc to anti-solvent is suitably from about 1 : 1.1 to about 1:5, such as about 1: 1.15, 1:2, 1 :2.5 or 1:3. Compound (I) gentisic acid anhydrate co-crystal Type A seed crystals may optionally be added to induce and/or enhance crystallization. The slurry may be cooled, such as to less than 10 °C, such as about 0 °C to about 5 °C to induce further crystallization. The Compound (I) gentisic acid anhydrate co-crystal Type A may be collected by methods known in the art as described elsewhere herein, and dried at about room temperature as described elsewhere herein.

[0303] In another aspect, the compound 1(a) gentisic acid anhydrate co-crystal Type A exhibits an XRPD pattern substantially in accordance with FIG. 66. In another aspects, characteristic peaks are at degrees 2-theta at angles of 12.5°±0.2°, 13.0°±0.2°, l4.4°±0.2°, l5.7°±0.2°, l7.5°±0.2°, 2l.7°±0.2°, 25.5°±0.2°, and 26.3°±0.2°. In another aspect, co-crystal Type A exhibits TGA and DSC spectrum curves substantially in accordance with FIG. 67. In another aspect, co-crystal Type A exhibits an NMR spectrum substantially in accordance with FIG. 68.

[0304] Compound (I) (e.g., compound 1(a)) gentisic acid anhydrate co-crystal Type B may be prepared from a solution of compound (I) free base and gentisic acid in THF. The concentration of compound (I) is suitably from about 20 g/L to about 100 g/L, from about 30 g/L to about 75 g/L, or about 50 /L. Compound (I) and gentisic acid are present in

approximately stoichiometric amounts. An anti-solvent, such as «-heptane, is added to the solution to induce crystallization. The volume ratio of THF to anti-solvent is suitably from about 1 : 1.1 to about 1:5, such as about 1: 1.15, 1:2, 1 :2.5 or 1:3. Compound (I) gentisic acid anhydrate co-crystal Type B seed crystals may optionally be added to induce and/or enhance crystallization. The slurry may be cooled, such as to less than l0°C, such as about 0°C to about 5°C to induce further crystallization. The Compound (I) gentisic acid anhydrate co-crystal Type B may be collected by methods known in the art as described elsewhere herein, and dried at about room temperature as described elsewhere herein.

[0305] In another aspect, the compound 1(a) gentisic acid anhydrate co-crystal Type B exhibits an XRPD pattern substantially in accordance with FIG. 69. In another aspect, characteristic peaks are at degrees 2-theta angles of 6.6°±0.2°, 7.9°±0.2°, l2.2°±0.2°, l2.4°±0.2°, l4.0°±0.2°, l5. l°±0.2°, l6.3°±0.2°, 2l.l°±0.2°, 25.3°±0.2°, and 25.6°±0.2°. In another aspect, co-crystal Type B exhibits TGA and DSC spectrum curves substantially in accordance with FIG. 72. In another aspect, co-crystal Type B exhibits an NMR spectrum substantially in accordance with FIG. 73.

[0306] Compound (I) (e.g., compound 1(a)) picolinamide hydrate co-crystal Type A may be prepared from a solution of compound (I) free base and picolinamide in EtOAc. The concentration of compound (I) is suitably from about 20 g/L to about 100 g/L, from about 30 g/L to about 75 g/L, or about 50 /L. Compound (I) and picolinamide are present from approximately stoichiometric amounts to a slight molar excess of picolinamide, such as from about 1 : 1 to about 1 :4, such as about 1:2. An anti-solvent, such as «-heptane, is added to the solution to induce crystallization. The volume ratio of EtOAc to anti-solvent is suitably from about 1 : 1.1 to about 1:5, such as about 1: 1.15, 1:2, 1 :2.5 or 1 :3. Compound (I) hydrate co crystal Type A seed crystals may optionally be added to induce and/or enhance crystallization. The slurry may be cooled, such as to less than 10 °C, such as about 0 °C to about 5 °C to induce further crystallization. The Compound (I) picolinamide hydrate co-crystal Type A may be collected by methods known in the art as described elsewhere herein, and dried at about room temperature as described elsewhere herein.

[0307] In another aspect, the compound 1(a) picolinamide hydrate co-crystal Type A exhibits an XRPD pattern substantially in accordance with FIG. 74. Characteristic peaks at degrees 2-theta were at angles of 12.1°±0.2°, 12.4°±0.2°, 14.5°±0.2°, 15.8°±0.2°, 18.1°±0.2°, 19.1°±0.2°, 22.0°±0.2°, 24.5°±0.2°, 25.6°±0.2°, and 26.6°±0.2°,Ih another aspect, co-crystal Type A exhibits TGA and DSC spectrum curves substantially in accordance with FIG. 75. In another aspect, co-crystal Type A exhibits an NMR spectrum substantially in accordance with FIG. 76. [0308] Pharmaceutical Compositions

[0309] The disclosure also provides for compositions and medicaments comprising a compound (I) and at least one pharmaceutically acceptable carrier. The compositions of the invention can be used to selectively inhibit TRPA1 in patients (e.g., humans). The term "composition" as used herein, is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0310] In one aspect, the invention provides for pharmaceutical compositions or medicaments comprising a compound (I) (e.g., compound 1(a)) or an embodiment thereof, (and its stereoisomers, solvates, metabolites, or pharmaceutically acceptable salts thereof) and a pharmaceutically acceptable carrier, diluent or excipient. In another embodiment, the invention provides for preparing compositions (or medicaments) comprising compounds of the invention. In another embodiment, the invention provides for administering compound (I) (e.g., compound 1(a)) or its embodiments and compositions comprising compound (I) or an embodiment thereof to a patient (e.g., a human patient) in need thereof.

[0311] Compositions are formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. The effective amount of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to inhibit TRPA1 activity as required to prevent or treat the undesired disease or disorder, such as for example, pain. For example, such amount may be below the amount that is toxic to normal cells, or the mammal as a whole.

[0312] The compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, intracerebral, intraocular, intralesional or subcutaneous administration. [0313] As an API, a crystalline form of compound (I) free base or mixtures thereof can have advantages over an amorphous form. For example, purification of API to the high degree of purity required by most regulatory authorities can be more efficient and therefore cost less where the API is in crystalline form as opposed to amorphous form. Physical and chemical stability, and therefore shelf-life of the API solid, can also be better for crystalline than amorphous forms. Ease of handling can be improved over the amorphous form, which can be oily or sticky. Drying can be more straightforward and more easily controlled in the case of the crystalline material, which can have a well-defined drying or desolvation temperature, than in the case of the amorphous material, which can have greater affinity for organic solvents and no well-defined drying temperature. Downstream processing using crystalline API can further permit enhanced process control. In preparing a liquid formulation, for example a solution in a lipid carrier, crystalline compound (I) can dissolve faster and can have a reduced tendency to form a gel during dissolution. These advantages are illustrative and non-limiting.

[0314] Pharmaceutical compositions comprising crystalline compound (I) free base, or prepared using crystalline compound (I) free base or salts of compound (I) as API, contain compound (I) in an amount that can be therapeutically effective when the composition is administered to a subject in need thereof according to an appropriate regimen. Dosage amounts are expressed herein as free base equivalent amounts unless the context requires otherwise. Typically, a unit dose (the amount administered at a single time), which can be administered at an appropriate frequency, e.g., twice daily to once weekly, in the case of oral or parenteral administration to adult humans weighing approximately 70 Kg, a daily dosage of from about 0.1 mg to about 5,000 mg, from about 1 mg to about 1,000 mg, from about 7 mg to about 1,400 mg or from about 1 mg to 100 mg may be appropriate, although the lower and upper limits may be exceeded when indicated. Alternatively stated, the therapeutically effective amount of the compound of the invention administered parenterally per dose will be in the range of about 0.01- 100 mg/kg, about 0.01-100 mg/kg, or about e.g., 0.1 to 20 mg/kg of patient body weight per day, with the typical initial range of compound used being 0.3 to 15 mg/kg/day. This dosage regimen may be adjusted to provide the optimal therapeutic response. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, it may be given as continuous infusion.

[0315] The compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents.

[0316] An example of a suitable oral administration form is a tablet containing about 1 mg, 5 mg, 10 mg, 25 mg, 30 mg, 50 mg, 80 mg, 100 mg, 150 mg, 250 mg, 300 mg and 500 mg of the compound of the invention compounded with about 90-30 mg anhydrous lactose, about 5- 40mg sodium croscarmellose, about 5-30 mg polyvinylpyrrolidone (PVP) K30, and about 1-10 mg magnesium stearate. The powdered ingredients are first mixed together and then mixed with a solution of the PVP. The resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using conventional equipment. An example of an aerosol formulation can be prepared by dissolving the compound, for example 5-400 mg, of the invention in a suitable buffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g. a salt such sodium chloride, if desired. The solution may be filtered, e.g., using a 0.2 micron filter, to remove impurities and contaminants.

[0317] For treatment of the eye or other external tissues, e.g., mouth and skin, the formulations are preferably applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w. When formulated in an ointment, the active ingredient can be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients can be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base can include a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane l,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof. The topical formulations can desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include DMSO and related analogs.

[0318] For topical formulations, it is desired to administer an effective amount of a pharmaceutical composition according to the invention to target area, e.g., skin surfaces, mucous membranes, and the like, which are adjacent to peripheral neurons which are to be treated. This amount will generally range from about 0.0001 mg to about 1 g of a compound of the invention per application, depending upon the area to be treated, whether the use is diagnostic, prophylactic or therapeutic, the severity of the symptoms, and the nature of the topical vehicle employed. A preferred topical preparation is an ointment, wherein about 0.001 to about 50 mg of active ingredient is used per cc of ointment base. The pharmaceutical composition can be formulated as transdermal compositions or transdermal delivery devices ("patches"). Such compositions include, for example, a backing, active compound reservoir, a control membrane, liner and contact adhesive. Such transdermal patches may be used to provide continuous pulsatile, or on demand delivery of the compounds of the present invention as desired.

[0319] The compositions comprising compound (I) are normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. A typical formulation is prepared by mixing a compound of the present invention and a diluent, carrier or excipient. Suitable diluents, carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004;

Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005.

[0320] The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament). Suitable carriers, diluents and excipients are well known to those skilled in the art and include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine;

monosaccharides, disaccharides and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG).

Compound (I) of the disclosure can also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example,

hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington: The Science and Practice of Pharmacy: Remington the Science and Practice of Pharmacy (2005) 2lst Edition, Lippincott Williams & Wilkins, Philadelphia, PA.

The particular carrier, diluent or excipient used will depend upon the means and purpose for which a compound of the present invention is being applied. Solvents are generally selected based on solvents recognized by persons skilled in the art as safe (GRAS) to be administered to a mammal. In general, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400, PEG 300), etc. and mixtures thereof. Acceptable diluents, carriers, excipients and stabilizers are nontoxic to recipients at the dosages and concentrations employed.

[0321] Sustained-release preparations of a compound (I) of the invention can be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing compound (I), which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxy ethyl-methacrylate), or poly(vinyl alcohol)), polylactides (U.S. Patent No. 3,773,919), copolymers of L-glutamic acid and gamma-ethyl-L- glutamate (Sidman et al., Biopolymers 22:547, 1983), non-degradable ethylene-vinyl acetate (Langer et al, J. Biomed. Mater. Res. 15: 167, 1981), degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT™ (injectable microspheres composed of lactic acid- glycolic acid copolymer and leuprolide acetate) and poly-D-(-)-3-hydroxybutyric acid (EP 133,988A). Sustained release compositions also include liposomally entrapped compounds, which can be prepared by methods known per se (Epstein et al, Proc. Natl. Acad. Sci. U.S. A. 82:3688, 1985; Hwang et al, Proc. Natl. Acad. Sci. U.S. A. 77:4030, 1980; U.S. Patent Nos. 4,485,045 and 4,544,545; and EP 102,324A). Ordinarily, the liposomes are of the small (about 200-800 Angstroms) unilamelar type in which the lipid content is greater than about 30 mol % cholesterol, the selected proportion being adjusted for the optimal therapy.

[0322] In one example, compound (I) may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form. The pH of the formulation depends mainly on the particular use and the concentration of compound, but preferably ranges anywhere from about 3 to about 8. In one example, a compound (I) may be formulated in an acetate buffer, at pH 5. In another embodiment, compound (I) is sterile. The compound may be stored, for example, as a solid or amorphous composition, as a lyophibzed formulation or as an aqueous solution.

[0323] Formulations of compound (I) that are suitable for oral administration can be prepared as discrete units such as pills, capsules, cachets or tablets each containing a predetermined amount of a compound of the invention.

[0324] Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets can optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient therefrom.

[0325] Tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, e.g., gelatin capsules, syrups or elixirs can be prepared for oral use. Formulations of compound (I) intended for oral use can be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.

Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients can be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets can be uncoated or can be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax can be employed. [0326] An example of a suitable oral administration form is a tablet containing about 1 mg, 5 mg, 10 mg, 25 mg, 30 mg, 50 mg, 80 mg, 100 mg, 150 mg, 250 mg, 300 mg and 500 mg of the compound of the invention compounded with about 90-30 mg anhydrous lactose, about 5- 40mg sodium croscarmellose, about 5-30 mg polyvinylpyrrolidone (PVP) K30, and about 1-10 mg magnesium stearate. The powdered ingredients are first mixed together and then mixed with a solution of the PVP. The resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using conventional equipment. An example of an aerosol formulation can be prepared by dissolving the compound, for example 5-400 mg, of the invention in a suitable buffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g. a salt such sodium chloride, if desired. The solution may be filtered, e.g., using a 0.2 micron filter, to remove impurities and contaminants.

[0327] The formulations can be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injection immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.

[0328] When the binding target is located in the brain, certain embodiments of the invention provide for compound (I) capable of traversing the blood-brain barrier. Certain neurodegenerative diseases are associated with an increase in permeability of the blood-brain barrier, such that compound (I) can be readily introduced to the brain. When the blood-brain barrier remains intact, several art-known approaches exist for transporting molecules across it, including, but not limited to, physical methods, lipid-based methods, and receptor and channel- based methods.

[0329] Physical methods of transporting compound (I) across the blood-brain barrier include, but are not limited to, circumventing the blood- brain barrier entirely, or by creating openings in the blood-brain barrier.

[0330] Circumvention methods include, but are not limited to, direct injection into the brain (see, e.g., Papanastassiou et al, Gene Therapy 9:398-406, 2002), interstitial

infusion/convecti on-enhanced delivery (see, e.g., Bobo et al., Proc. Natl. Acad. Sci. U.S.A. 91 :2076-2080, 1994), and implanting a delivery device in the brain (see, e.g., Gill et al, Nature Med. 9:589-595, 2003; and Gliadel Wafers™, Guildford.

[0331] Methods of creating openings in the barrier include, but are not limited to, ultrasound (see, e.g., U.S. Patent Publication No. 2002/0038086), osmotic pressure (e.g., by administration of hypertonic mannitol (Neuwelt, E. A., Implication of the Blood-Brain Barrier and its Manipulation, Volumes 1 and 2, Plenum Press, N.Y., 1989)), and permeabilization by, e.g., bradykinin or permeabilizer A- 7 (see, e.g., U.S. Patent Nos. 5,112,596, 5,268,164, 5,506,206, and 5,686,416).

[0332] Lipid-based methods of transporting compound (I) across the blood-brain barrier include, but are not limited to, encapsulating the compound (I) in liposomes that are coupled to antibody binding fragments that bind to receptors on the vascular endothelium of the blood- brain barrier (see, e.g., U.S. Patent Application Publication No. 2002/0025313), and coating compound (I) in low-density lipoprotein particles (see, e.g., U.S. Patent Application Publication No. 2004/0204354) or apobpoprotein E (see, e.g., U.S. Patent Application

Publication No. 2004/0131692).

[0333] Receptor and channel-based methods of transporting compound (I) across the blood-brain barrier include, but are not limited to, using glucocorticoid blockers to increase permeability of the blood-brain barrier (see, e.g., U.S. Patent Application Publication Nos. 2002/0065259, 2003/0162695, and 2005/0124533); activating potassium channels (see, e.g.,

U.S. Patent Application Publication No. 2005/0089473), inhibiting ABC drug transporters (see, e.g., U.S. Patent Application Publication No. 2003/0073713); coating compound (I) with a transferrin and modulating activity of the one or more transferrin receptors (see, e.g., U.S. Patent Application Publication No. 2003/0129186), and cationizing the antibodies (see, e.g., U.S.

Patent No. 5,004,697).

[0334] For intracerebral use, in certain embodiments, the compounds can be administered continuously by infusion into the fluid reservoirs of the CNS, although bolus injection may be acceptable. The inhibitors can be administered into the ventricles of the brain or otherwise introduced into the CNS or spinal fluid. Administration can be performed by use of an indwelling catheter and a continuous administration means such as a pump, or it can be administered by implantation, e.g., intracerebral implantation of a sustained-release vehicle. More specifically, the inhibitors can be injected through chronically implanted cannulas or chronically infused with the help of osmotic minipumps. Subcutaneous pumps are available that deliver proteins through a small tubing to the cerebral ventricles. Highly sophisticated pumps can be refilled through the skin and their delivery rate can be set without surgical intervention. Examples of suitable administration protocols and delivery systems involving a subcutaneous pump device or continuous intracerebroventricular infusion through a totally implanted drug delivery system are those used for the administration of dopamine, dopamine agonists, and cholinergic agonists to Alzheimer's disease patients and animal models for Parkinson's disease, as described by Harbaugh, J. Neural Transm. Suppl. 24:271, 1987; and DeYebenes et al, Mov. Disord. 2: 143, 1987

[0335] Indications and Methods of Treatment

[0336] Representative compounds of the invention have been shown to modulate TRPAlactivity (see, e.g., WO 2016/128529). Accordingly, the compounds of the invention are useful for treating diseases and conditions mediated by TRPA1 activity. Such diseases and conditions include but are not limited to: pain (acute, chronic, inflammatory, or neuropathic pain); itch or various inflammatory disorders; inner ear disorders; fever or other disorders of thermoregulation; tracheobronchial or diaphragmatic dysfunction; gastrointestinal or urinary tract disorders; chronic obstructive pulmonary disease; incontinence; and disorders associated with reduced blood flow to the CNS or CNS hypoxia.

[0337] In a specific embodiment, compounds of the invention can be administered to treat pain, including but not limited to neuropathic and inflammatory pain, among others.

Certain types of pain may be considered a disease or disorder, while other types may be considered symptoms of various diseases or disorders, and pain may include various etiologies. Exemplary types of pain treatable with a TRPA1 -modulating agent according to the invention include pain associated with, arising from, or caused by: osteoarthritis, rotator cuff disorders, arthritis (e.g., rheumatoid arthritis or inflammatory arthritis; see, Barton et al. Exp. Mol. Pathol. 2006, 81(2), 166-170), fibromyalgia, migraine and headache (e.g. cluster headache, sinus headache, or tension headache; see, Goadsby Curr. Pain Headache Reports 2004, 8, 393), sinusitis, oral mucositis, toothache, dental trauma, dental extractions, dental infections, bum (Bolcskei et al, Pain 2005, 117(3), 368-376), sunburn, dermatitis, psoriasis, eczema, insect sting or bite, musculoskeletal disorders, bony fractures, ligamentous sprains, plantar fasciitis, costochondritis, tendonitis, bursitis, tennis elbow, pitcher's elbow, patellar tendonitis, repetitive strain injury, myofascial syndrome, muscle strain, myositis, temporomandibular joint disorder, amputation, low back pain, spinal cord injury, neck pain, whiplash, bladder spasms, GI tract disorders, cystitis, interstitial cystitis, cholecystitis, urinary tract infection, urethral colic, renal colic, pharyngitis, cold sores, stomatitis, external otitis, otitis media (Chan et al, Lancet, 2003, 361, 385), burning mouth syndrome, mucositis, esophageal pain, esophageal spasms, abdominal disorders, gastroesophageal reflux disease, pancreatitis, enteritis, irritable bowel disorder, inflammatory bowel disease, Crohn's disease, ulcerative colitis, colon distension, abdominal constriction, diverticulosis, diverticulitis, intestinal gas, hemorrhoids, anal fissures, anorectal disorders, prostatitis, epididymitis, testicular pain, proctitis, rectal pain, labor, childbirth, endometriosis, menstrual cramps, pelvic pain, vulvodynia, vaginitis, orolabial and genital infections (e.g. herpes simplex), pleurisy, pericarditis, non- cardiac chest pain, contusions, abrasions, skin incision (Honore, P. et al, J Pharmacal Exp Ther., 2005, 314, 410-21), postoperative pain, peripheral neuropathy, central neuropathy, diabetic neuropathy, acute herpetic neuralgia, post-herpetic neuralgia, trigeminal neuralgia, glossopharyngeal neuralgia, atypical facial pain, gradiculopathy, HIV associated neuropathy, physical nerve damage, causalgia, reflex sympathetic dystrophy, sciatica, cervical, thoracic or lumbar radiculopathy, brachial plexopathy, lumbar plexopathy, neurodegenerative disorders, occipital neuralgia, intercostal neuralgia, supraorbital neuralgia, inguinal neuralgia, meralgia paresthetica, genitofemoral neuralgia, carpal tunnel syndrome, Morton's neuroma, post-mastectomy syndrome, post-thoracotomy syndrome, post-polio syndrome, Guillain-Barre syndrome, Raynaud's syndrome, coronary artery spasm (Printzmetal's or variant angina), visceral hyperalgesia (Pomonis, J.D. et al. J. Pharmacal. Exp. Ther. 2003, 306, 387; Walker, K.M. et al, J. Pharmacal. Exp. Ther. 2003, 304(1), 56-62), thalamic pain, cancer (e.g. pain caused by cancer, including osteolytic sarcoma, by treatment of cancer by radiation or chemotherapy, or by nerve or bone lesions associated with cancer (see, Menendez, L. et al, Neurosci. Lett. 2005, 393 (1), 70-73; Asai, H. et al., Pain 2005, 117, 19-29), or bone destruction pain (see, Ghilardi, J.R. et al, J. Neurosci. 2005, 25, 3126-31)), infection, or metabolic disease. Additionally, the compounds may be used to treat pain indications such as visceral pain, ocular pain, thermal pain, dental pain, capsaicin-induced pain (as well as other symptomatic conditions induced by capsaicin such as cough, lachrymation, and bronchospasm).

[0338] In another specific embodiment, compounds of the invention can be

administered to treat itch, which may arise from various sources, such as dermatological or inflammatory disorders.

[0339] In another specific embodiment, compounds of the invention can be

administered to treat inflammatory disorders, including disorders selected from the group consisting of: renal or hepatobiliary disorders, immunological disorders, medication reactions and unknown/idiopathic conditions. Inflammatory disorders treatable with an inventive agent include, for example, inflammatory bowel disease (IBO), Crohn's disease, and ulcerative colitis (Geppetti, P. et al, Br. J. Pharmacal. 2004, 141, 1313-20; Yiangou, Y. et al, Lancet200l, 357, 1338-39; Kimball, E.S. et al, Neurogastroenterol. Motif., 2004,16, 811), osteoarthritis (Szabo, A. et al, J. Pharmacal. Exp. Ther. 2005, 314, 111-119), psoriasis, psoriatic arthritis, rheumatoid arthritis, myasthenia gravis, multiple sclerosis, scleroderma, glomerulonephritis, pancreatitis, inflammatory hepatitis, asthma, chronic obstructive pulmonary disease, allergic rhinitis, uveitis, and cardiovascular manifestations of inflammation including atherosclerosis, myocarditis, pericarditis, and vasculitis.

[0340] In another specific embodiment, compounds of the invention can be

administered to treat inner ear disorders. Such disorders include, for example, hyperacusis, tinnitus, vestibular hypersensitivity, and episodic vertigo.

[0341] For example, compounds of the invention can be administered to treat tracheobronchial and diaphragmatic dysfunctions including, for example, asthma and allergy- related immune responses (Agopyan, N. et al, Am. J. Physiol. Lung Cell Mol. Physiol. 2004, 286, L563-72; Agopyan, N. et al, Toxicol. Appl. Pharmacal. 2003, 192, 21-35), cough (e.g., acute or chronic cough, or cough caused by irritation from gastroesophageal reflux disease; see, Lalloo, U.G. et al, J. Appl. Physiol. 1995, 79(4), 1082-7), bronchospasm, chronic obstructive pulmonary disease, chronic bronchitis, emphysema, and hiccups (hiccoughs, singultus).

[0342] In another specific embodiment, compounds of the invention can be

administered to treat gastrointestinal and urinary tract disorders such as, bladder overactivity, inflammatory hyperalgesia, visceral hyperreflexia of the urinary bladder, hemorrhagic cystitis (Dinis, P. et al, J Neurosci., 2004, 24, 11253-11263), interstitial cystitis (Sculptoreanu, A. et al., Neurosci Lett., 2005, 381, 42-46), inflammatory prostate disease, prostatitis (Sanchez, M. et al, Eur J Pharmacal, 2005, 515, 20-27), nausea, vomiting, intestinal cramping, intestinal bloating, bladder spasms, urinary urgency, defecation urgency and urge incontinence.

[0343] In another specific embodiment, compounds of the invention can be

administered to treat disorders associated with reduced blood flow to the CNS or CNS hypoxia. Such disorders include, for example, head trauma, spinal injury, thromboembolic or

hemorrhagic stroke, transient ischaemic attacks, cerebral vasospasm, hypoglycaemia, cardiac arrest, status epilepticus, perinatal asphyxia, Alzheimer's disease, and Huntington's Disease. [0344] In other embodiments, compounds of the invention can be administered to treat other diseases, disorders, or conditions mediated through TRPA1 activity, such as anxiety; learning or memory disorders; eye-related disorders (such as glaucoma, vision loss, increased intraocular pressure, and conjunctivitis); baldness (e.g., by stimulating hair growth); diabetes (including insulin-resistant diabetes or diabetic conditions mediated by insulin sensitivity or secretion); obesity (e.g., through appetite suppression); dyspepsia; biliary colic; renal colic; painful bladder syndrome; inflamed esophagus; upper airway disease; urinary incontinence; acute cystitis; and envenomations (such as marine, snake, or insect stings or bites, including jellyfish, spider, or stingray envenomations).

[0345] In one specific embodiment, compounds of the invention are administered to treat pain (including but not limited to acute, chronic, neuropathic and inflammatory pain), arthritis, itch, cough, asthma, or inflammatory bowel disease.

[0346] In another embodiment, the invention provides for a method for treating neuropathic pain or inflammatory pain, comprising the step of administering a therapeutically effective amount of a compound as described herein to a subject in need thereof.

[0347] In another embodiment, the invention provides for a compound as described herein or a pharmaceutically acceptable salt thereof for modulating TRPA1 activity.

[0348] In another embodiment, the invention provides for a compound as described herein or a pharmaceutically acceptable salt thereof for use in medical therapy.

[0349] In another embodiment, the invention provides for a method for treating a respiratory disorder selected from chronic obstructive pulmonary disorder (COPD), asthma, allergic rhinitis and bronchospasm, comprising the step of administering a therapeutically effective amount of a compound as described herein to a subject in need thereof.

[0350] In another embodiment, the invention provides for a compound as described herein or a pharmaceutically acceptable salt thereof for the treatment or prophylaxis of a respiratory disorder.

[0351] In another embodiment, the invention provides for the use of a compound as described herein or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment or prophylaxis of a respiratory disorder. [0352] In another embodiment, the invention provides for a method for treating a respiratory disorder in a mammal (e.g., a human) comprising administering a compound as described herein or a pharmaceutically acceptable salt thereof to the mammal.

[0353] In another embodiment, the invention provides for a method for modulating TRPA1 activity, comprising contacting TRPA1 with a compound as described herein or a pharmaceutically acceptable salt thereof.

[0354] In another embodiment, the invention provides for a compound as described herein or a pharmaceutically acceptable salt thereof for the treatment or prophylaxis of a disease or condition mediated by TRPA1 activity. Within aspects of this embodiment, the disease or condition is pain (including but not limited to acute, chronic, neuropathic and inflammatory pain), itch, an inflammatory disorder, an inner ear disorder, fever or another disorder of thermoregulation, tracheobronchial or diaphragmatic dysfunction, a gastrointestinal or urinary tract disorder, chronic obstructive pulmonary disease, incontinence, or a disorder associated with reduced blood flow to the CNS or CNS hypoxia. Within certain aspects of this embodiment, wherein the disease or condition is pain (including but not limited to acute, chronic, neuropathic and inflammatory pain), arthritis, itch, cough, asthma, inflammatory bowel disease, or an inner ear disorder.

[0355] In another embodiment, the invention provides for the use of a compound as described herein or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment or prophylaxis of a disease or condition that is mediated by TRPA1 activity. Within aspects of this embodiment, the disease or condition is pain (including but not limited to acute, chronic, neuropathic and inflammatory pain), itch, an inflammatory disorder, an inner ear disorder, fever or another disorder of thermoregulation, tracheobronchial or diaphragmatic dysfunction, a gastrointestinal or urinary tract disorder, chronic obstructive pulmonary disease, incontinence, or a disorder associated with reduced blood flow to the CNS or CNS hypoxia. Within aspects of this embodiment, the disease or condition is pain (including but not limited to acute, chronic, neuropathic and inflammatory pain), arthritis, itch, cough, asthma, inflammatory bowel disease, or an inner ear disorder.

[0356] In another embodiment, the invention provides for a method for treating a disease or condition mediated by TRPA1 activity in a mammal (e.g., a human), comprising administering a compound as described herein or a pharmaceutically acceptable salt thereof to the mammal. Within certain aspects of this embodiment, the disease or condition is pain (including but not limited to acute, chronic, neuropathic and inflammatory pain), itch, an inflammatory disorder, an inner ear disorder, fever or another disorder of thermoregulation, tracheobronchial or diaphragmatic dysfunction, a gastrointestinal or urinary tract disorder, chronic obstructive pulmonary disease, incontinence, or a disorder associated with reduced blood flow to the CNS or CNS hypoxia. Within certain aspects of this embodiment, the disease or condition is pain (including but not limited to acute, chronic, neuropathic and inflammatory pain), arthritis, itch, cough, asthma, inflammatory bowel disease, or an inner ear disorder. In some embodiments, the disease or condition is asthma.

[0357] Combination Therapy

[0358] The compounds of the invention may be usefully combined with one or more other compounds of the invention or one or more other therapeutic agent or as any combination thereof, in the treatment of ion channel-mediated diseases and conditions. For example, a compound of the invention may be administered simultaneously, sequentially or separately in combination with other therapeutic agents, including, but not limited to the following.

[0359] Opiate analgesics, e.g., morphine, heroin, cocaine, oxymorphine, levorphanol, levallorphan, oxycodone, codeine, dihydrocodeine, propoxyphene, nalmefene, fentanyl, hydrocodone, hydromorphone, meripidine, methadone, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine and pentazocine.

[0360] Non-opiate analgesics, e.g., acetomeniphen, and salicylates ( e.g., aspirin).

[0361] Nonsteroidal antiinflammatory drugs (NSAIDs), e.g., ibuprofen, naproxen, fenoprofen, ketoprofen, celecoxib, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin and zomepirac.

[0362] Anticonvulsants, e.g., carbamazepine, oxcarbazepine, lamotrigine, valproate, topiramate, gabapentin and pregabalin.

[0363] Antidepressants such as tricyclic antidepressants, e.g., amitriptyline, clomipramine, despramine, imipramine and nortriptyline.

[0364] COX-2 selective inhibitors, e.g., celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, and lumiracoxib. [0365] Alpha-adrenergics, e.g., doxazosin, tamsulosin, clonidine, guanfacine, dexmetatomidine, modafmil, and 4-amino-6,7-dimethoxy-2-(5- methane sulfonamido-l,2,3,4- tetrahydroisoquinol-2-yl)-5-(2-pyridyl) quinazoline.

[0366] Barbiturate sedatives, e.g., amobarbital, aprobarbital, butabarbital, butabital, mephobarbital, metharbital, methohexital, pentobarbital, phenobartital, secobarbital, talbutal, theamylal and thiopental.

[0367] Tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-l antagonist, e.g., (aR, 9R)-7-[3,5-bis(trifluoromethyl)benzyl)]-8,9,l0,l l-tetrahydro-9-methyl-5-(4- methylphenyl)-7H-[l,4]diazocino[2,l-g][l,7]-naphthyridine-6-l3-dione (TAK-637), 5-[[2R,3S)- 2-[(lR)-l-[3,5-bis(trifluoromethylphenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]- l,2-dihydro-3H-l,2,4-triazol-3-one (MK-869), aprepitant, lanepitant, dapitant or 3-[[2- methoxy5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine (2S,3S).

[0368] Coal-tar analgesics, e.g., paracetamol.

[0369] Serotonin reuptake inhibitors, e.g., paroxetine, sertraline, norfluoxetine

(fluoxetine desmethyl metabolite), metabolite demethylsertraline, '3 fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcitalopram, escitalopram, d,l -fenfluramine, femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericlamine, trazodone and fluoxetine.

[0370] Noradrenaline (norepinephrine) reuptake inhibitors, e.g., maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, buproprion, buproprion metabolite hydroxybuproprion, nomifensine and viloxazine (Vivalan®)), especially a selective noradrenaline reuptake inhibitor such as reboxetine, in particular (S,S)-reboxetine, and venlafaxine duloxetine neuroleptics sedative/anxiolytics.

[0371] Dual serotonin-noradrenaline reuptake inhibitors, such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine, milnacipran and imipramine.

[0372] Acetylcholinesterase inhibitors, e.g., donepezil.

[0373] 5-HT3 antagonists, e.g., ondansetron.

[0374] Metabotropic glutamate receptor (mGluR) antagonists. [0375] Local anaesthetics, e.g., mexiletine and lidocaine.

[0376] Corticosteroids, e.g., dexamethasone.

[0377] Antiarrhythimics, e.g., mexiletine and phenytoin.

[0378] Muscarinic antagonists, e.g., tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium.

[0379] Cannabinoids.

[0380] Vanilloid receptor agonists ( e.g., resinferatoxin) or antagonists ( e.g., capsazepine).

[0381] Sedatives, e.g., glutethimide, meprobamate, methaqualone, and

dichloralphenazone.

[0382] Anxiolytics, e.g., benzodiazepines.

[0383] Antidepressants, e.g., mirtazapine.

[0384] Topical agents, e.g., lidocaine, capsacin and resiniferotoxin.

[0385] Muscle relaxants, e.g., benzodiazepines, baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol and orphrenadine.

[0386] Anti -histamines or Hl antagonists.

[0387] NMD A receptor antagonists.

[0388] 5-HT receptor agonists/antagonists.

[0389] PDEV inhibitors.

[0390] Tramadol®.

[0391] Cholinergic (nicotine) analgesics.

[0392] Alpha-2-delta ligands.

[0393] Prostaglandin E2 subtype antagonists.

[0394] Leukotriene B4 antagonists.

[0395] 5-lipoxygenase inhibitors. [0396] 5-HT3 antagonists.

[0397] As used herein "combination" refers to any mixture or permutation of one or more compounds of the invention and one or more other compounds of the invention or one or more additional therapeutic agent. Unless the context makes clear otherwise, "combination" may include simultaneous or sequentially delivery of a compound of the invention with one or more therapeutic agents. Unless the context makes clear otherwise, "combination" may include dosage forms of a compound of the invention with another therapeutic agent. Unless the context makes clear otherwise, "combination" may include routes of administration of a compound of the invention with another therapeutic agent. Unless the context makes clear otherwise, "combination" may include formulations of a compound of the invention with another therapeutic agent. Dosage forms, routes of administration and pharmaceutical compositions include, but are not limited to, those described herein.

[0398] Examples

[0399] Example 1: Preparation of (2S,4R,5S)-4-fluoro-l-(4-fluorophenylsulfonyl)-5- methyl-N-((5-(trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4- yl)methyl)pyrrolidine-2-carboxamide of formula (I)

[0400] Example 1A: Preparation of Compound formula (I) from compound 1.

[0401] Example 1A Analytical Methods

[0402] In reference to FIG. 1, compound 1(a) was prepared from compound 1 according to steps 1 to 5 as follows.

[0403] Example 1A Step 1 : Mesylation

[0404] Compound 2(a) (5-(4-(methoxymethyl)-5-(trifluoromethyl)pyridin-2-yl)-2- (trifluoromethyl)pyrimidine) was prepared from compound 1(a) ((5-(trifluoromethyl)-2-(2- (trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methanol), where MS represents mesyl (methanesulfonyl), as follows:

[0405] 2-Methyltetrahydrofuran (147.7 kg, 8.54 kg/kg compound 1(a)) was charged to an inerted reactor with stirring followed by the addition of compound 1(a) (17.3 kg, 53.53 mol). Triethylamine (7.03 kg, 0.407 kg/kg compound 1(a)) was charged to the reactor and the contents were cooled to from 0 °C to 10 °C. Methanesulfonyl (mesyl) chloride (7.36 kg, 0.425 kg/kg compound 1(a)) was charged slowly to the reactor to maintain the temperature below lO°C. The reactor contents were agitated at temperature for at least 2 hours. The reactor contents were sampled and tested for compound 1(a) content by HPLC Method-0l2. Sampling and LC testing was continued (with 1 hour intervals) until the compound 1(a) content was less than 5.0%.

[0406] 5% Aqueous citric acid (173 kg, 10 kg/kg compound 1(a)) was charged to the reactor and the reactors contents were stirred for at least 30 minutes at 25 °C. Ethyl acetate (77.6 kg, 5.94 kg/kg compound 1(a)) was charged to the reactor and the reactor contents were stirred for at least 30 minutes. Stirring was stopped to allow for phase separation, and the lower aqueous phase was removed. 25% NaCl aqueous solution (102.8 kg, 5.94 kg/kg compound 1(a)) was charged to the organic phase in the reactor and the reactor contents were stirred for at least 10 minutes. Stirring was stopped to allow for phase separation, and the lower aqueous phase was removed. The remaining organic phase was distilled under reduced pressure at a temperature of less than 50 °C to a volume of 2 liters/kg compound 1(a). Ethyl acetate (77.6 kg, 5.94 kg/kg compound 1(a)) was charged to the reactor with stirring and the reactor contents were distilled under reduced pressure at a temperature of less than 50 °C to a volume of 2 liters/kg compound 1(a). «-heptane (59.2 kg, 3.42 kg/kg compound 1(a)) was charged to the reactor with stirring and the reactor contents were distilled under reduced pressure at a temperature of less than 50 °C to a volume of 2 liters/kg compound 1(a). «-heptane addition and distillation was repeated two times «-heptane (47.3 kg, 2.73 kg/kg compound 1(a)) was added to the reactor and the contents were stirred for at least 2 hours at from 25 °C to 30 °C. The reactor contents were filtered to collect solid compound 2(a), and the reactor was washed with «-heptane (23.7 kg, 1.37 kg/kg compound 1(a)) forward through the collected compound 2(a) solids. Solid compound 2(a) was dried in a vacuum oven at from 30 °C to 40 °C for at least 14 hours to yield compound 2(a) (21.85 kg, 95% yield). HPLC purity by method HPLC-012 was 97.66% with 2.61% impurities.

[0407] Example 1A Step 2: Amine Formation

[0408] Compound 3(a) (5-(trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5- yl)pyridin-4-yl)methanamine was prepared from compound 2(a) 5-(4-(methoxymethyl)-5- (trifluoromethyl)pyridin-2-yl)-2-(trifluoromethyl)pyrimidine as follows:

Step 2

[0409] Compound 2(a) (11 kg, 27.41 moles) was charged to an inerted reactor followed by THF (48.9 kg, 4.45 kg/kg) with stirring until a solution was formed. The solution of compound 2(a) was combined with NTb/MeOH (7M in methanol, 257.1 kg, 23.4 kg/kg) with stirring, slowly heated to 35 °C to 45 °C, and aged at temperature for at least 2 hours to form compound 3. The reactor contents were sampled and tested for compound 2(a) content by HPLC Method-0l4. Sampling and LC testing was continued (with 1 hour intervals) until the compound 1(a) content was less than 5.0%.

[0410] The reactor contents comprising compound 3 were combined with stirring with MTBE (81.4 kg, 7.4 kg/kg compound 2(a)) and 20% aqueous KHCO₃ (27.3 kg, 2.48 kg/kg compound 2(a)). Stirring was stopped and the mixture was allowed to phase separate for at least 10 minutes. The lower aqueous phase was removed and was combined with stirring with MTBE (81.4 kg, 7.4 kg/kg compound 2(a)), and mixed for at least 10 minutes. Stirring was stopped and the mixture was allowed to phase separate for at least 10 minutes. In a second wash step, the lower aqueous phase was removed and was combined with Stirring with MTBE (81.4 kg, 7.4 kg/kg compound 2(a)), and mixed for at least 10 minutes. Stirring was stopped and the mixture was allowed to phase separate for at least 10 minutes. In a third wash step, the lower aqueous phase was removed and was combined with stirring with MTBE (40.7 kg, 3.7 kg/kg compound 2(a)), and mixed for at least 10 minutes. Stirring was stopped, the mixture was allowed to phase separate for at least 10 minutes, and the lower aqueous phase was removed.

[0411] The four organic phases comprising compound 3 were combined in a reactor and distilled under reduced pressure at a temperature of less than 50 °C to reach a volume of l5L/kg compound 2(a). A solution of oxalic acid (1.73 kg, 0.157 kg/kg compound 2(a)) in MTBE (40.7 kg, 3.7 kg/kg) was combined with the distilled organic phase over 3 hours while maintaining the temperature at 20 °C to 30 °C to form a slurry comprising solid compound 3, followed by aging for at least 20 minutes after completion of the oxalic acid addition. The slurry was filtered to collect solid crude compound 3 oxalic acid salt, and the reactor was washed forward through the collected solids with MTBE (16.3 kg, 1.48 kg/kg compound 2(a)). [0412] Crude compound 3 was combined with MTBE (81.4 kg, 7.4 kg/kg compound 2(a)) in a reactor with stirring followed by addition with stirring of 25% aqueous w/w KHCO₃ (57.1 kg, 5.19 kg/kg compound 2(a)) while maintaining the temperature at 20 °C to 30 °C. The reactors contents were aged with stirring for 30 minutes, stirring was stopped, and the mixture was allowed to phase separate for at least 10 minutes. The lower aqueous phase was removed and was combined with stirring with MTBE (81.4 kg, 7.4 kg/kg compound 2(a)), and mixed for at least 10 minutes. In a second wash step, the lower aqueous phase was removed and was combined with stirring with MTBE (40.7 kg, 3.7 kg/kg compound 2(a)), and mixed for at least 10 minutes. Stirring was stopped, the mixture was allowed to phase separate for at least 10 minutes, and the lower aqueous phase was removed.

[0413] The three organic phases comprising compound 3 were combined in a reactor and distilled under reduced pressure at a temperature of less than 50 °C to reach a volume of 2L/kg compound 2(a). «-heptane (30.1 kg, 2.74 kg/kg compound 2(a)) was added with stirring to the reactor and the reactor contents were distilled under reduced pressure at a temperature of less than 50 °C to reach a volume of 2L/kg compound 2(a). «-heptane (30.1 kg, 2.74 kg/kg compound 2(a)) was added with stirring to the reactor and the reactor contents were held at 20 °C to 30 °C for 3 hours. The reactor contents were filtered to isolate solid compound 3, and the reactor was washed forward through the collected solids with «-heptane (15 kg, 2.74 kg/kg compound 2(a)). Solid compound 3 was dried in a vacuum oven at 30 °C to 40 °C for at least 14 hours to yield compound 3 (7.2 kg, 82% yield) as a light brown solid. Identity by 1H NMR indicated that compound 3 was consistent with a compound 3 standard. HPLC assay was 95.9% and HPLC purity was 99.42%.

[0414] Example 1A Step 3: Condensation reaction to form an amide

[0415] Compound 5(a), (2S,3R,5S)-tert-butyl 3-fluoro-2-methyl-5-((5- (trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4- yl)methylcarbamoyl)pyrrolidine-l-carboxylate, was prepared from compound 3(a) (5- (trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methanamine and compound 4(a) (2S,4R,5S)-l -(tert-butoxycarbonyl)-4-fluoro-5-methylpyrrolidine-2-carboxylic acid as follows:

Step 3

[0416] Compound 3(a) (13 g, 40.4 mmol) and compound 4(a) (10.0 g, 40.4 mmol) were combined with isopropyl acetate (90 mL, 9.0 mg/kg compound 4(a)) in a reactor with stirring until a solution formed. N-methylmorpholine (5.3 g, 0.58 mL/g compound 4, 52.5 mmol) was charged to the reactor with stirring followed by T3P® in ethyl acetate (33.4 g, 3.12 mL/g compound 4(a), 3.34 g/g compound 4, 52.5 mmol). The reactor contents were heated to 50°C to 60 °C. The reactor was rinsed with isopropyl acetate (10 mL, 1.0 mL/g compound 3(a), 0.87 g/g compound 4(a)) and the reactor contents were held at temperature for at least 3 hours to form compound 5(a). The reactor contents were sampled and tested for compound 3(a) content by LC Method-Vl.O. Sampling and LC testing was continued (with 1 hour intervals) until the compound 3(a) content was less than 5.0%.

[0417] The reactor contents comprising compound 5(a) were combined with stirring with 2N NaOH (54 g, 5.4 g/g compound 4(a)) and mixed for at least 10 minutes at 40°C to 60°C. Stirring was stopped and the mixture was allowed to phase separate for at least 10 minutes 40°C to 60°C. The lower aqueous phase was removed. The reactor contents were distilled under reduced pressure (100-400 mbar) to a total volume of 9-11 mL/g compound 4(a). The reactor contents were further distilled under reduced pressure (100-400 mbar) while charging ethanol (300 mL, 30 mL/g compound 4(a)) while maintaining a constant volume of 9- 11 mL/g compound 4(a). The reactor contents were sampled and tested for Isopropyl acetate content by GC. Solvent exchange with ethanol was continued until the Isopropyl acetate content was less than 2.0%.

[0418] Water (57 mL, 5.7 mL/g compound 4(a)) at 20°C to 55°C was charged to the reactor with stirring and heating to 55°C to 65°C for at least 10 minutes, followed by cooling to l5°C to 25°C over 1-3 hours. The reactor contents were held with stirring at l5°C to 25°C for 1 hour to form a slurry comprising solid compound 5(a). The solids were collected by filtration and the collected solids were washed with the mother liquor. The reactor was washed forward through the collected solids with ethanol 50 v/v% in water (4 mL/g compound 4(a)). Washed solid compound 5(a) was dried in a vacuum oven (<100 mbar, at 30°C) for at least 6 hours. Compound 5(a) was sampled and tested for water by Karl Fischer method. Drying was continued until the water content was less than 1. Identity by 1H NMR indicated that compound 5(a) was consistent with a compound 5(a) standard. Compound 5(a) (20.1 g, 90% yield) was produced as a brown/orange solid. Purity by HPLC was 99.28%.

[0419] Example 1A Step 4: Deprotection

[0420] Compound 6(a), (2S,4R,5S)-4-fluoro-5-methyl-N-((5-(trifluoromethyl)-2-(2- (trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methyl)pynOlidine-2-carboxamide hydrochloride salt was prepared from compound 5(a) (2S,3R,5S)-tert-butyl 3-fluoro-2-methyl-5-((5- (trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4- yl)methylcarbamoyl)pyrrolidine-l-carboxylate as follows:

[0421] l-Propanol (58.6 mL, 3.77 mL/g compound 5(a)) was charged to a reactor and cooled to -5 °C to 5 °C followed by addition of acetyl chloride (5.3 mL, 73.4 mmol, 0.34 mL/g compound 5(a)) with stirring while maintaining the temperature to less than 40 °C. The mixture was aged at temperature for at least 10 minutes. Compound 5(a) (15.56 g, 28.2 mmol) was added to the reactor followed by additional l-propanol (31 mL, 2 mL/g compound 5(a)). The reaction mixture was heated to 55 °C to 65 °C with stirring and held at temperature for at least 3 hours to produce compound 6. The reactor contents were sampled and tested for compound 5(a) content by LC Method-Vl.0. Sampling and LC testing was continued (with 1 hour intervals) until the compound 5(a) content was less than 5.0%.

[0422] The reactor contents were distilled under reduced pressure (100-400 mbar) while charging «-heptane (187 mL, 12 mL/g compound 5(a)) while maintaining a constant volume of about 7 mL/g compound 5(a). The reactor contents were sampled and tested for 1- propanol content by GC. The reactor contents were cooled to 15 °C to 25 °C and stirred for at least 1 hour. The reactor contents were filtered to collect solid compound 6(a), and the reactor was washed with mother liquor forward through the collected compound 6(a) solids. The collected solids were further washed with a mixture of l-propanol (10.9 mL, 0.7 mL/g compound 5(a)) and «-heptane (43.6 mL, 2.8 mL/g compound 5(a)). Solid compound 6(a) was dried in a vacuum oven (less than 100 mbar) at 50°C for at least 6 hours to yield compound 6(a) (20.1 g, 90% yield) as a brown/orange solid. HPLC purity by method HPLC-012 was 97.66% with 2.61% impurities. The dried material was sampled and tested for 2-propanol and «-heptane content by GC. Drying was continued until the l-propanol and «-heptane content was each less than 0.5%. Compound 6(a) purity by HPLC was 98.81%.

[0423] Example 1A Step 5: Preparation of Compound (I)a

[0424] Compound (I)(a), (2S,4R,5S)-4-fluoro-l-(4-fluorophenylsulfonyl)-5-methyl-N- ((5-(trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methyl)pynOhdine-2- carboxamide was prepared as an ethanol solvate from compound 6(a) (2S,4R,5S)-4-fluoro-5- methyl-N-((5-(trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyri din-4- yl)methyl)pyrrolidine-2-carboxamide hydrochloride salt and compound 7(a) 4-fluorobenzene-l- sulfonyl chloride as follows:

[0425] Compound 6(a) (10 g, 20.5 mmol) and MTBE (15 mL, 1.5 ml g compound 6a)) were charged to a reactor with stirring. Ethanol (4 mL, 0.4 mL/g compound 6(a)) and 10% aqueous K₂CO₃ (38.2 mL, 3.82 mL/g compound 6(a)) were charged to the reactor with stirring followed by addition of a solution of compound 7(a) in MTBE (4.4 g compound 7(a), 0.44 g/g compound 6(a), 22.6 mmol; 21 mL MTBE 2.6 mL/g compound 6(a)). The reaction mixture was mixed at 15 °C to 40 °C for at least 2 hours to form compound 1(a). The reactor contents were sampled and tested for compound 6(a) content by LC Method-Vl.O. Sampling and LC testing was continued (with 1 hour intervals) until the compound 6(a) content was less than 5.0%. Stirring was stopped to allow for phase separation, and the lower aqueous phase was removed. Water (20 mL, 2.0 mL/g compound 6(a)) was charged to the reactor with stirring and was mixed for at least 10 minutes. Stirring was stopped to allow for phase separation, and the lower aqueous phase was removed.

[0426] The reactor contents comprising compound 1(a) were distilled under reduced pressure (100-400 mbar) to a minimum stir volume. Ethanol (10-50 mL, 1-5 mL/g compound 6(a)) was charged to the reactor to a total volume of 4-5 mL/g compound 6(a). The reactor contents were distilled under reduced pressure (100-400 mbar) while charging ethanol (60 mL, 6.0 mL/g compound 6(a)) to maintain a constant volume of about 4.5 mL/g compound (a). The reactor contents were sampled and evaluated for MTBE by GC. «-heptane (100 mL, 10.0 mL/g compound 6(a)) was added to the reactor and heated to 60 °C to 70 °C followed by stirring for at least 15 minutes. The reaction mixture was cooled to -5 °C to 5 °C over 1-3 hours and aged with stirring for 30 minutes. The reactor contents were filtered to collect solid compound 1(a), and the reactor was washed with the mother liquor forward through the collected compound 1(a) solids. The reactor was washed forward with «-heptane (20 mL, 2 mL/g compound 6(a)) forward through the collected compound 6(a) solids. Solid compound 1(a) was dried in a vacuum oven at from 50 °C to 60 °C for at least 18 hours to yield compound 1(a) (11.7 g, 94% yield) as an off-white to tan solid. The dried material was sampled and tested for «-heptane content by GC. Drying was continued until the «-heptane content was less than 0.5%.

Compound 1(a) assay by HPLC was 92.81% and purity by HPLC was 98.99%. Compound 1(a) was identified as the crystalline free base ethanol solvate of compound 1(a) of Type F.

[0427] Example 1A: Preparation of crystalline compound 1(a) free base anhydrate

Type E

[0428] Solid crystalline free base compound 1(a) ethanol solvate (10.0 g) and DCM (25 mL, 2.5 mL/g compound 1(a)) were stirred at 15 °C to 25 °C to form a solution. The solution was filtered through a 0.45 pm filter cartridge into a reactor where it was combined with «- heptane (22 mL, 2.2 mL/g compound 1(a)) with stirring. Crystalline compound 1(a) free base anhydrate Type E seed crystals were added to the reactor with stirring at 15 °C to 25 °C for at least 30 minutes «-heptane (16 mL, 1.6 mL/g compound 6(a)) was added to the reactor over 2.5 to 3.5 hours with stirring. Additional «-heptane (16 mL, 1.6 mL/g compound 6(a)) was added to the reactor over 1.5 to 2.5 hours with stirring. Additional «-heptane (16 mL, 1.6 mL/g compound 6(a)) was added to the reactor over 0.5 to 1.5 hours with stirring. The crystalline compound 1(a) free base anhydrate Type E solids were collected by filtration and the reactor was washed forward through the collected solids with the mother liquor. The reactor was washed forward through the collected solids with «-heptane (20 mL/g, 2.0 mL/g compound 6(a)).

Washed crystalline compound 1(a) free base anhydrate Type E was dried in a vacuum oven (<20 mbar, at 45 °C to 55 °C) for at least 18 hours. The dried material (8.4 g, 90% yield) was sampled and tested for DCM and «-heptane content by GC. Drying was continued until the DCM content was less than 600 ppm and the «-heptane content was less than 0.45%. Identity by 1H NMR indicated that compound 1(a) free base anhydrate was consistent with a compound 1(a) free base anhydrate standard. HPLC purity was 99.87%.

[0429] Example 1B: Preparation of (5-(trifluoromethyl)-2-(2- (trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methanol of compound 1(c).

[0430] Compound 1(c) was prepared according to the method depicted in FIG. 2.

[0431] Example 1B Analytical Methods

[0432] In reference to FIG. 2, compound 1(a) was prepared from compound 10A and compound 8 according to steps 1 to 3 as follows.

[0433] Example 1B Step 1

[0434] Compound lOB(i) methyl 2-chloro-5-methylisonicotinate was prepared from compound lOA(i) 2-chloro-5-methylisonicotinic acid as follows: polar aprotic solvent,

[0435] Dimethylformamide was charged (99.3 kg, 4.75 kg/kg compound l0A(i)) into an inerted first reactor and stirred. Compound l0A(i) was charged (20.9 kg, 92.7 mol) into the reactor followed by sodium bicarbonate (15.6 kg, 0.745 kg/kg compound lOA(i)), and methyl tosylate (22.4 kg, 1.07 kg/kg compound lOA(i)). The reaction mixture was heated to 35-45 °C and held at temperature for at least 4 hours. A sample was removed from the reaction mixture and diluted with acetonitrile. The reactor contents were sampled and tested for compound lOA(i) content by HPLC Method-008. Sampling and LC testing was continued (with 1 hour intervals) until the compound lOA(i) content was less than 5.0%. The reaction mixture was cooled to 20-30°C.

[0436] Water was charged (313.5 kg, 15.0 kg/kg compound lOA(i)) into an inerted second reactor and stirred. The contents of the first reactor were charged into the second reactor over a period of 1 hour while the temperature was maintained below 25 °C. The mixture was stirred for at least 10 minutes before methyl /-butyl ether was added (77.3 kg, 3.70 kg/kg compound l0A(i)), after which the mixture was allowed to settle for 10 minutes. The bottom aqueous layer was removed and transferred to a first vessel, and the organic layer was drained and transferred to a second vessel. The contents of the first vessel containing aqueous phase was charged into the second reactor, followed by addition of methyl /-butyl ether (77.3 kg, 3.70 kg/kg compound l0A(i)) into the second reactor. This mixture was stirred for at least 10 minutes, agitation was stopped, and the mixture was allowed to settle for at least 10 minutes.

The bottom aqueous layer was removed and transferred to the first vessel, and the organic layered was drained and transferred to the second vessel. The contents of the first vessel containing aqueous phase were charged into the second reactor, followed by addition of methyl /-butyl ether (77.3 kg, 3.70 kg/kg compound l0A(i)) into the second reactor. This mixture was stirred for at least 10 minutes, agitation was stopped, and the mixture was allowed to settle for at least 10 minutes. The bottom aqueous layer was removed and transferred to the first vessel.

[0437] The organic phase in the second vessel was charged into the second reactor, followed by a brine solution (3.4 M sodium chloride, 125 kg, 5.98 kg/kg compound l0A(i)).

The contents of the second reactor were stirred for at least 10 minutes before the mixture was allowed to settle for at least 10 minutes. The bottom aqueous layer was removed and transferred as waste. A brine solution (3.4 M sodium chloride, 125 kg, 5.98 kg/kg compound l0A(i)) was charged into the second reactor and the contents of the second reactor were stirred for at least 10 minutes before the mixture was allowed to settle for at least 10 minutes. The bottom aqueous layer was removed and transferred as waste.

[0438] The contents of the second reactor were distilled under reduced pressure to a volume of 2 L/kg while maintaining the temperature of the reactor below 45 °C.

Tetrahydrofuran was charged (37.2 kg, 1.78 kg/kg compound l0A(i)) into the second reactor, and the reactor contents were distilled under reduced pressure in order to reach a volume of 2 L/kg wherein compound lOB(i) was in solution while maintaining the temperature of the reactor below 45 °C. The temperature was held at 20-30 °C for the next step.

[0439] Example 1B Step 2

[0440] Compound l0C(i) (2-chloro-5-methylpyridin-4-yl)methanol was prepared from compound l0B(i) methyl 2-chloro-5-methylisonicotinateas follows: polar aprotic solvent,

reducing agent

- ►

Step 2

10C(i)

[0441] Compound l0B(i) was charged as a tetrahydrofuran solution (42 L, 1.9 L/kg) into a stirred, inerted reactor. Tetrahydrofuran (167.4 kg, 7.6 kg/kg compound l0B(i)) and water (14.6 kg, 0.7 kg/kg compound lOB(i)) was charged into the reactor and the mixture was cooled to 10-20 °C. Lithium chloride was charged (5.9 kg, 0.265 kg/kg compound l0B(i)) into the reactor while the temperature was maintained below 25 °C, followed by batchwise addition of sodium borohydride (3.5 kg, 0.16 kg/kg compound l0B(i)) over a period of 2 hours while the temperature was maintained below 25 °C. The reaction mixture was held for at least 5 hours at 15-25 °C. The reactor contents were sampled and tested for compound l0B(i) content by HPLC Method-008. Sampling and LC testing was continued (with 1 hour intervals) until the compound l0B(i) content was less than 5.0%

[0442] The reactor was charged with hydrochloric acid (2N, 230 L, 10.4 L/kg) to obtain a pH value of ~l while the reactor temperature was maintained below 20 °C and stirred for at least 4 hours. Agitation was stopped and the mixture was allowed to settle for at least 10 minutes. The aqueous layer was transferred to a first vessel and the organic layer was transferred to a second vessel. The aqueous layer was charged into the reactor followed by ethyl acetate (94 kg, 4.2 kg/kg compound l0B(i)), and the mixture was stirred for at least 10 minutes. Agitation was stopped, the mixture was allowed to settle for at least 10 minutes, and the aqueous phase was drained to waste. Sodium bicarbonate (115 kg, 5.18 kg/kg compound l0B(i)) into the reactor and the mixture was stirred for at least 10 minutes. Agitation was stopped and the mixture was allowed to settle for at least 10 minutes. The aqueous layer was transferred to the first vessel and the organic layer was transferred to the second vessel. The aqueous layer was charged into the reactor followed by ethyl acetate (94 kg, 4.2 kg/kg compound l0B(i)), and the mixture was stirred for at least 10 minutes. Agitation was stopped, the mixture was allowed to settle for at least 10 minutes, and the aqueous phase was drained to waste.

[0443] The organic phase in the second vessel was charged into the reactor followed by a brine solution (3.4 M sodium chloride, 125 kg, 5.63 kg/kg compound lOB(i)). The mixture was stirred for at least 10 minutes, agitation was stopped, and the mixture was allowed to settle for at least 10 minutes. The aqueous layer was removed and transferred to waste. This drying process was repeated a second time. The contents of the reactor were distilled under reduced pressure in order to reach a volume of 2 L/kg while maintaining the temperature of the reactor below 60 °C. The reactor was charged with heptane (71 kg, 3.2 L/kg, 3.2 kg/kg compound l0B(i)) and the reactor contents was distilled under reduced pressure to a volume of 2 L/kg while maintaining the temperature of the reactor below 60 °C. The reactor was charged with heptane (71 kg, 3.2 L/kg, 3.2 kg/kg compound l0B(i)), the reactor contents were cooled to 0 °C and aged for at least 1 hour while the reaction temperature was maintained between -5 and 5 °C. The solids were filtered and the reactor and filter cake was twice washed with heptane (14.2 kg, 3.2 L/kg, 0.64 kg/kg compound l0B(i)). The product was dried in a vacuum oven to a constant weight of compound l0C(i) (15.8 kg, 81% yield over two steps) as an off-white solid. The purity of the compound l0C(i) product was determined to be 99.38 A% using analytical HPLC Method-009.

[0444] Example 1B Step 3

[0445] Compound 1(a) (5-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4- yl)methanol was prepared from compound l0C(i) (2-chloro-5-methylpyridin-4-yl)methanol and compound 8 2-(trifluoromethy l)pyrimi din-5 -ylboronic acid as follows:

Step 3

[0446] l,4-dioxane (52.73 kg, 7.22 kg/kg compound l0C(i)) and water (36.5 kg, 5 kg/kg compound l0C(i)) was charged into a first inerted, stirred reactor and stirred. Potassium carbonate (11.9 kg, 1.63 kg/kg compound l0C(i)) was charged into the first reactor followed by compound lOC(i) (7.3 kg, 93 moles). The temperature of the mixture was adjusted to 25-30 °C and the first reactor was further charged with [l,l’-Bis(diphenylphosphino) ferrocene] palladium (II) chloride (0.505 kg, 0.07 kg/kg compound l0C(i)). Nitrogen was bubbled through the solution for 1-2 hours before the solution was heated to 75-80 °C and stirred for 2 hours.

The first reactor contents were sampled and tested for compound l0C(i) content by HPLC Method-011. Sampling and LC testing was continued (with 30 minute intervals) until the compound l0C(i) content was less than 5.0%.

[0447] The reaction mixture was cooled to 45 °C and the first reactor contents was distilled under reduced pressure in order to reach a volume of 3 L/kg while maintaining the temperature of the reactor below 60 °C. Water was charged (58.4 kg, 8.0 kg/kg compound 2C) into the first reactor followed by methyl tert-butyl ether (54 kg, 7.4 kg/kg compound l0C(i)) and the mixture was stirred for at least 10 minutes. Agitation was stopped and the mixture was allowed to settle for at least 10 minutes. The bottom aqueous layer was removed and transferred to a first vessel and the organic layer was drained to a second vessel. The aqueous phase was charged to the first reactor followed by methyl /-butyl ether (27 kg, 3.7 kg/kg compound l0C(i)) and the mixture was stirred for at least 10 minutes. Agitation was stopped and mixture was allowed to settle for at least 10 minutes. The bottom aqueous layer was removed and transferred to the first vessel and the organic layer was drained to the second vessel. The aqueous phase was charged to the first reactor followed by methyl /-butyl ether (27 kg, 3.7 kg/kg compound l0C(i)) and the mixture was stirred for at least 10 minutes. Agitation was stopped and mixture was allowed to settle for at least 10 minutes. The bottom aqueous layer was removed and transferred to the first vessel.

[0448] The organic phase in the second vessel was charged into the first reactor followed by silica gel (3.65 kg, 0.50 kg/kg compound l0C(i)), and the reactor contents was stirred for at least 2 hours at 25-30 °C. The reactor contents were filtered, and the filtrate was collected in a third vessel. The first reactor was rinsed with methyl /-butyl ether (27 kg, 3.7 kg/kg compound l0C(i)) which was then filtered through the filter cake and collected in the third vessel. The filtrate in the third vessel was charged into a second reactor.

[0449] The contents of the second reactor were distilled under reduced pressure in order to reach a volume of 2 L/kg while maintaining the temperature of the reactor below 50 °C. Heptane (25 kg, 3.42 kg/kg compound l0C(i)) was charged into the second reactor and the contents of the second reactor were distilled under reduced pressure in order to reach a volume of 4 L/kg while maintaining the temperature of the reactor below 50 °C. Charging the second reactor with heptane and distilling the reactor contents as described was repeated two more times. The second reactor was then charged with dichloromethane (14.56 kg, 2.0 kg/kg compound l0C(i)) and the mixture was stirred for at least 2 hours at 25-30 °C. The contents of the second reactor were filtered and the filter cake and reactor was washed with a mixture of dichloromethane (3.24 kg, 0.44 kg/kg compound l0C(i)) and heptane (3.32 kg, 0.45 kg/kg compound l0C(i)). The filter cake was dried under vacuum at 30-40 °C for 14 hours to give crude compound 1(a) (-10 kg). Dichloromethane was charged (26.6 kg, 3.64 kg/kg compound l0C(i)) into an inerted third reactor, followed by the crude compound 1(a) (-10 kg). The reactor contents were heated to 35-45 °C and stirred for at least 2 hours. Heptane was charged (27.36, 3.75 kg/kg compound l0C(i)) into the third reactor over a period of 3 hours. The mixture was cooled to 20-30 °C and this temperature was held for at least 2 hours. The solids were filtered and filter cake was washed with a mixture of dichloromethane (4.44 kg, 0.61 kg/kg compound l0C(i)) and heptane (4.55 kg, 0.62 kg/kg compound l0C(i)). The solids were dried in a vacuum oven at 30-40 °C for at least 14 hours to give compound 1(a) (8.53 kg, 78% yield). The purity of the product was determined to be 98.71 A% using analytical HPLC Method-Ol l.

[0450] Example 1C: Preparation of (2-(trifluoromethyl)pyrimidin-5-yl)boronic acid (Compound 8)

[0451] Example 1C Analytical Methods

[0452] Compound 8 2-(trifluoromethy l)pyrimi din-5 -ylboronic acid was prepared from compounds 8A 5-bromo-2-iodopyrimidine and 8B 5-bromo-2-(trifluoromethyl)pyrimidine as follows:

[0453] In step 1, DMF (149.6 kg, 7 L/kg compound 8A) was charged to an inerted reactor with stirring. Compound 8 A (22.5 kg, 78.98 moles, 1 equivalent) was charged to the reactor followed by Cul (6 kg, 0.4 eq., 2.674 kg/kg compound 8A) and followed by

Me0₂CCF₂S0₂F (21.2 kg, 0.944 kg/kg compound 8A). The reactor contents were stirred at 80- 90 °C for at least 3 hours to form a reaction product mixture comprising compound 8B. The reactor was sampled and tested for compound 8A content by LC with a limit of < 5% compound 8A. Mixing at 80-90 °C was continued until compound 8A content was < 5%. 25 molar NaHCCE (371.3 kg, 16.5 kg/kg compound 8A) was combined with the reaction product mixture and held for 6 hours with stirring at 20-30 °C. MTBE (116.6 kg, 5.18 kg/kg compound 8A) was combined with the reaction product mixture followed by celite filter aids (22.5 kg, 1 kg/kg compound 8A). The reaction product mixture was stirred for 15 minutes at 20-30 °C, filtered, and the filtrate was collected. The filter cake was washed with MTBE (33.3 kg, 1.48 kg/kg compound 8A) and the filtrates were combined.

[0454] The collected filtrate was allowed to settle for at least 10 minutes and the bottom aqueous layer was removed. The aqueous layer was washed twice with MTBE (116.6 kg, 5.18 kg/kg compound 8A), where a phase separation and aqueous layer removal was done after each MTBE wash. The three organic layers were combined and further combined with 5 molar aqueous NaCl (212 kg, 9.42 kg/kg compound 8A) and stirred for at least 10 minutes. The admixture was allowed to settle for at least 10 minutes and the bottom aqueous layer was removed. The organic layer was combined with 5 molar aqueous NaCl (212 kg, 9.42 kg/kg compound 8A) and stirred for at least 10 minutes. The admixture was allowed to settle for at least 10 minutes and the bottom aqueous layer was removed. The organic layer remaining in the reactor was distilled under atmospheric pressure to reduce the volume to a minimum stir volume (about lL/kg compound 8A). The reactor contents were then further distilled under reduced pressure (50-100 mbar) and compound 8B was collected as an 80-90 °C fraction. The yield of compound 8A was 76.6% and the HPLC purity by method MTH-003 was 95.71% by HPLC Method 003 V01.

[0455] In step 2, THF (179.4 kg, 7.12 kg/kg compound 8B) was charged to an inerted reactor followed by compound 8B (25.2 kg, 111 moles) and B(0/-Pr)₃ (31.3 kg, 12.43 kg/kg compound 8B) and cooling to -70 to -80 °C. w-BuLi (39.7 kg, 1.58 kg/kg compound 8B) was charged to the reactor dropwise over 6 hours to form a reaction mixture, followed by agitation for at least 1 hour to form a reaction product mixture comprising compound 8. The reaction product mixture was sampled and tested for compound 8B content by HPLC method 007 V01. Reaction was continued until the compound 8B content was less than 5%.

[0456] Water (7 kg, 0.28 kg/kg compound 8B) as a solution in THF (22.4 kg, 0.88 kg/kg compound 8B) was added to the reaction product mixture with stirring while maintaining the temperature -55 to -65 °C, and the reaction product mixture was held at that temperature for at least 30 minutes with stirring. The reaction product heated to 0 °C over 1-2 hours and then water (376 kg, l3kg/kg compound 8B) was combined with the reaction product mixture while maintaining the temperature under 10 °C and the reaction product mixture was maintained under those conditions for at least 30 minutes. The admixture was allowed to settle for at least 10 minutes and the bottom aqueous layer comprising compound 8 was removed. The aqueous layer was admixed with MTBE (93.2 kg, 3.7 kg/kg compound 8B) and stirred for at least 10 minutes. The admixture was allowed to settle for at least 10 minutes and the bottom aqueous layer comprising compound 8 was removed. The pH of the aqueous layer was adjusted to 1 to 2 at a temperature of less than 25°C with concentrated HC1 (12.35 kg, 0.49 kg/kg compound 8B).

[0457] The pH-adjusted aqueous phase was admixed with MTBE (93.2 kg, 3.7 kg/kg compound 8B) and stirred for at least 10 minutes. The admixture was allowed to settle for at least 10 minutes and the bottom aqueous layer was removed leaving an organic layer comprising compound 8. The aqueous layer was admixed with MTBE (93.2 kg, 3.7 kg/kg compound 8B) and stirred for at least 10 minutes, the admixture was allowed to settle for at least 10 minutes, and the bottom aqueous layer was removed. The aqueous layer was step was repeated and the aqueous layer was discarded. The organic layers were combined in a reactor and distilled under reduced pressure at a temperature of less than 45 °C to reduce the volume to about 3 L/kg compound 8B. l,4-dioxane (130.16 kg, 5.17 kg/kg compound 8B) was charged to the reactor with stirring and the rector contents were distilled under reduced pressure to reduce the volume to about 3 L/kg compound 8B. The reactor contents were cooled to 25 °C to yield a solution of compound 8 in l,4-dioxane (71.3 kg, 82% yield). The assay was determined to be 24.5 w/w % compound 8.

[0458] Example 1D: Preparation of compound 4(a)

[0459] Compound 4(a) (2S,4R,5S)-l-(tert-butoxycarbonyl)-4-fluoro-5- methylpyrrobdine-2-carboxybc acid was prepared according to the method depicted in FIG. 3 and described below.

[0460] Example 1D Analytical Methods

[0461] Example 1D step 1.

[0462] Compound 4B (2S,4S)-l-(tert-butoxycarbonyl)-4-(tert- butyldimethylsilyloxy)pyrrolidine-2-carboxylic acid was prepared from compound 4A (2S,4S)- l-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid as follows: idazole

[0463] Compound 4A (65.2 kg) and imidazole (37.8 kg, 0.580 kg/kg compound 4A) was charged into a glass-lined reactor containing DCM (279 L). Tert-butyldimethylsilyl chloride (46.2 kg, 0.709 kg/kg compound 4A ) was added dropwise into the reaction mixture at 10 to 15 °C in a period of 2.5 to 3 hours. The reaction mixture was stirred at 25 to 30 °C for 5 hours. The reactor contents were sampled and tested for compound 4A content by HPLC Method-OOl. Sampling and testing continued until the compound 4A content was less than 0.1%.

[0464] The reaction mixture was cooled to 10 to l5°C, filtered and washed three times with 15 L of DCM. The phases were allowed to separation and the organic phase was washed twice with 5 w% citric acid (80 kg) and agitated for 20 minutes. The organic phase was then washed twice with brine (80 kg) and agitated for 20 minutes. The organic phase was then dehydrated over anhydrous sodium sulfate (~25 kg), filtered with 100 mesh non-woven filter- cloth, and washed three times with DCM (10L). The fraction was concentrated under vacuum at 40-45 °C. Ethyl acetate (130 kg, 2.0 kg/kg compound 4A) was charged to the reactor and the fraction was concentrated at 45 °C over 5 hours to yield compound 4A in ethyl acetate as a light yellow solution (142.5 kg). HPLC purity by HPLC Method-OOl was 98.6% with 0.6% impurities. The crude product was used for step 2 of Example 1D directly.

[0465] Example 1D step 2.

[0466] Compound 4C (2S,4S)-l-(tert-butoxycarbonyl)-4-(tert-butyldimethylsilyloxy)- 5-oxopynOlidine-2-carboxylic acid was prepared from compound 4B (2S,4S)-l-(tert- butoxycarbonyl)-4-(tert-butyldimethylsilyloxy)pyrrolidine-2-carboxylic acid as follows: Nal0₄, RU0₃

EtOAc, H₂0

Step 2

[0467] Water (650 kg, 19.8 kg/kg compound 4B) and sodium periodate (58.7 kg, 1.79 kg/kg compound 4B) was charged into a stirred reactor. After 10 minutes of stirring, a yellow solution was obtained that was then combined with ethyl acetate reactor (245 kg, 7.47 kg/kg compound 4B). A solution of compound 4B was charged into the reactor (49 kg, 67 w%) in ethyl acetate (16 kg) over 30 minutes. Ruthenium dioxide was charged into the reactor (770 g, 0.0235 kg/kg compound 4B) and the contents of the reactor was purged with nitrogen three times, and stirred at 50-55 °C for 24 hours under nitrogen to form a reaction product mixture. The reactor contents were sampled and tested for compound 4B content and compound 4C content by HPLC Method-001. Sampling and testing continued until the compound 4B content was less than 0.24% and the compound 4C content exceeded 95.0%.

[0468] The reaction product mixture was cooled to room temperature (~25 °C) and filtered through a pad of celite. The resulting filter cake was washed with ethyl acetate (20 kg). Phases were separated, and the aqueous phase was extracted with ethyl acetate (120 kg). The organic phases were combined, cooled to below 10 °C, and slowly added to 10 wt % aqueous sodium bisulfite (120 kg, pH = 7, adjusted with 10 wt % NaOH, 120 kg) to maintain an internal temperature below 10 °C. Phases were separated and the organic phase was extracted with 10 w% aqueous sodium bisulfite (pH = 7, adjusted with 10 wt % NaOH, 80 kg). The organic phase was washed twice with brine (50 kg), dried over anhydrous sodium sulfate (~35 kg), and filtered with 100 mesh non- woven filter-cloth. The resulting filter cake was washed with ethyl acetate (25 kg). The filtrate and the concentrate were combined and were concentrated under vacuum at 40 to 45 °C for 8 hours. Crude compound 4C was obtained as a yellow oil (55 kg).

[0469] Compound 4C was crystallized as follows. Heptane (2 L/kg, 137 kg) was added to 110 kg of crude compound 4C, and the reaction mixture was concentrated to about 1 L/kg at 40 to 45 °C over 6 hours. Heptane (2 L/kg, 137 kg) was added and the reaction mixture was sampled and tested for GC. (GC, EA: 0. l7A%). Heptane (3.75 L/kg, 263 kg) was added to the reaction mixture and cooled to 15 °C with an ice- water bath over a period of 1 hour, causing solid compound 4C to precipitate out from the solution. The mixture was stirred at 15 to 20 °C for 30 minutes, cooled to 5 °C with an ice-water bath over a period of 2 hours, and stirred at 5 to 10 °C for 30 minutes. The reaction mixture was filtered to obtain wet crude compound 4C. The wet crude was dried under vacuum at 25 °C for 6 hours to produce 67.8 kg of compound 4C with 98.1 A% LC purity from 101 kg wet solid. The isolation yield obtained was 64.4% (calculated by LC-assay).

[0470] The mother liquor was concentrated under vacuum at 40 to 45 °C for 6 hours to produce about 90 kg of crude compound 4C as a yellow oil. The crude compound 4C was dissolved into «-heptane (137 kg, 2 L/kg), the mixture was cooled to 5 °C with an ice-water bath over a period of 2 hours and stirred at 0 to 5 °C for 30 minutes. The mixture was filtered to obtain wet crude of compound 4C (about 9 kg with 95.6 C% LC purity). The wet crude was dried under vacuum at 25 °C for 6 hours to produce 6.9 kg of compound 4C with 96.9 A% LC purity from 9 kg wet solid. The isolation yield was 6.5% (calculated by LC-assay).

[0471] The second mother liquor was concentrated under vacuum at 40 to 45 °C and poured onto silica (20 kg, 200 to 300 mesh, 2.5 kg/kg). The silica was washed with a solution of petroleum ether and ethyl acetate (10/1, v/v, 100 L) and the filtrate was collected and concentrated under vacuum at 45 °C to dryness. Heptane was added (3 L/kg) to the compound 4C crude oil and the mixture was cooled from room temperature to 15 °C with an ice- water bath over a period of 1 hour, leading to the formation of a precipitate. The mixture was stirred 15 to 20 °C for 30 minutes, cooled to 5 °C with an ice- water bath over a period of 2 hours, and stirred at 5 to 10 °C for 30 minutes. The reaction mixture was filtered to obtain wet crude compound 4C. The wet crude was dried under vacuum at 25 °C for 6 hours to produce 3.3 kg of compound 4C with 95.3 A% LC purity. The isolation yield was 64.4% (calculated by LC-assay). The total of compound 4C obtained was 78 kg in 77.4% isolation yield (calculated by LC-assay).

[0472] Example 1D step 3

[0473] Compound 4D (2S,4S)-l-(tert-butoxycarbonyl)-4-(tert-butyldimethylsilyloxy)- 5-methylenepyrrolidine-2-carboxylic acid was prepared from compound 4C (2S,4S)-l-(tert- butoxycarbonyl)-4-(tert-butyldimethylsilyloxy)-5-oxopynOlidine-2-carboxylic acid as follows:

Step 3 [0474] Dimethyl titanocene (289 kg, 8.9 wt.% in toluene, 1.28 kg/kg compound 4C), titanocene dichloride (0.803 kg, 0.040 kg/kg compound 4C), and 20.1 kg of compound 4C were charged into a reactor to produce a red-colored mixture. The reactor was purged with nitrogen 5 times, and the reaction mixture was subsequently stirred for 8 hours while the internal temperature was held at 75 to 80 °C. A sample of the reaction mixture was removed, diluted with acetonitrile, and analyzed by HPLC using Method-OOl. The method showed 90.6% of compound 4D was generated and 0.34% of compound 4C remained.

[0475] The reaction mixture was cooled to 25 °C and concentrated under vacuum at 45 °C to dryness over a period of 14 hours to produce about 60 kg of crude solid. Heptane was added (114 kg) to the above residue under stirring for 1 hour at 5 tolO °C. The mixture was filtered and the cake was washed with heptane (about 50 kg). The filtrate and the concentrate were combined under vacuum at 45 °C to dryness over a period of 7 hours to produce about 30 kg of crude solid. Heptane was added (28.4 kg) under stirring for 1 hour at 5 to 10 °C. The mixture was filtered and the cake was washed with heptane (about 10 kg) to produce a solution of compound 4D with heptane (62 kg). Silica (14 kg, 60 to 100 mesh) was added to the above solution over a period of 30 minutes while the solution was stirred at a temperature of 25 to 30 °C. The solution was poured to the silica (35 g, 200 to 300 mesh) under vacuum (petroleum ether/ethyl acetate = 20/1). The filtrate and concentrate were combined under vacuum at 45 °C to dryness. 17.1 kg of compound 4D was obtained with 92.8 A % LC purity and a yield of 85.5%.

[0476] Example 1D step 4.

[0477] Compound 4E (2S,4S,5S)-l-(tert-butoxycarbonyl)-4-(tert- butyldimethylsilyloxy)-5-methylpyrrolidine-2-carboxylic acid was prepared from compound 4D (2S,4S)-l-(tert-butoxycarbonyl)-4-(tert-butyldimethylsilyloxy)-5-methylenepyrrolidine-2- carboxylic acid as follows:

p

[0478] Compound 4D (17.1 kg, 46.1 mol), methanol (136 kg, 7.68 kg/kg compound 4D), and activated carbon (1.7 kg, 0.1 kg/kg compound 4D) were charged into a reactor and stirred at 25 to 30 °C for 1 hour. The reaction mixture was then filtered and charged with activated carbon (1.7 kg). The resulting cake was twice washed with methanol (10 L).

Approximately 20 kg of filtrate was collected. The filtrate was stirred at 25 to 30 °C for 1 hour, filtered (-220 L), and combined with wet palladium on carbon (5 wt %, 4.25 kg). The cake was twice washed with methanol (10 L) and approximately 30 kg of filtrate was collected. The reactor containing this solution was purged with hydrogen gas three times, and the solution was stirred at 25 to 30 °C for 18 hours under a hydrogen atmosphere (P = 1 atm). The reactor contents were sampled and tested for compound 4E content by HPLC Method-OOl and showed that compound 4E was present as 95.3 A %.

[0479] The mixture was filtered and washed with methanol (about 25 L). The filtrate and the wash solution were combined and concentrated under vacuum at 45 °C to about 15 L. The concentrate was charged with activated carbon (0.3 kg, 0.18 kg/ kg compound 4D) and this mixture was stirred at 25-30 °C for 1 hour, filtered (about 15 L), and charged with wet palladium on carbon (5 wt %, 0.556 kg). The reactor containing this solution was purged with hydrogen gas three times, and the solution was stirred at 25 to 30 °C for 18 hours under a hydrogen atmosphere (P = 1 atm). The reactor contents were sampled and tested for compound 4E content by HPLC Method-OOl and showed that compound 4E was present as 95.3 A %.

[0480] The mixture was filtered and washed with methanol (about 5 L), and concentrated under vacuum at 45 °C to dryness. 14.4 kg of compound 4E was obtained (yield = 84%) with a purity of 97.3 A %.

[0481] Example 1D step 5.

[0482] Compound 4F (2S,4S,5S)-l-(tert-butoxycarbonyl)-4-hydroxy-5- methylpynOlidine-2-carboxylic acid was prepared from compound 4E (2S,4S,5S)-l-(tert- butoxycarbonyl)-4-(tert-butyldimethylsilyloxy)-5-methylpyrrolidine-2-carboxylic acid as follows:

[0483] Compound 4E (30.3 kg, 81.11 mol) and tetrahydrofuran (135 kg, 4.46 kg/kg compound 4E) were charged into a reactor and stirred for 10 minutes. The mixture was cooled to 20 to 25 °C before tetrabutylammonium fluoride trihydrate (25.6 kg, 0.845 kg/kg compound 4E) was added to form a reaction mixture. The reactor was purged three times with nitrogen then stirred at 20 to 30 °C for 1 hour to form a reaction product mixture comprising compound 4F. The reactor contents were sampled and tested for compound 4F content by HPLC Method- 001 and showed that compound 4F was present at 83.6 A%.

[0484] The reaction product mixture was cooled to 10 °C, mixed with pre-cooled water (130 kg, 4.29 kg/kg compound 4E, about 10 °C), and stirred for 10 minutes. The organic phase of the mixture was extracted three times with ethyl acetate (108 kg, 81 kg, and 54 kg). The extracted organic phases were combined and twice washed with brine (120 kg, 20 wt %). The mixture was dried with anhydrous sodium sulfate (50 kg). The solid was collected by filtration and washed twice with ethyl acetate (25 kg). The filtrate was concentrated under vacuum at 50 °C. HPLC analysis showed the ethyl acetate was present at 0.6 A%. Petroleum ether (40 kg, 1.3 kg/kg compound 4E) and water (90 kg, 3.0 kg/kg compound 4E) was added to the residue and stirred violently for 30 minutes at 5 to 15 °C. Solid was collected by filtration and washed twice with pre-cooled water (28 kg). 27.1 kg of wet product was obtained. The wet product was dissolved in DCM (143 kg, 4.72 kg/kg compound 4E), and the mixture was washed with brine (54 kg, 20 w%). The phases were separated and the organic phase was dried with anhydrous sodium sulfate (21 kg) followed by stirring for 10 minutes. Anhydrous magnesium sulfate (10.8 kg) was added and the mixture was stirred for 30 minutes, filtered, and twice washed with DCM (20 kg). The mixture was concentrated under vacuum at 45 to 55 °C. 20.3 kg of compound 4F was obtained with 97.8 A % LC purity in 96.6% uncorrected yield.

[0485] Example 1D step 6.

[0486] Compound 4G (2S,4S,5S)-l-(tert-butoxycarbonyl)-4-fluoro-5- methylpynOlidine-2-carboxylic acid was prepared from compound 4F (2S,4S,5S)-l-(tert- butoxycarbonyl)-4-(tert-butyldimethylsilyloxy)-5-methylpyrrolidine-2-carboxylic acid as follows:

[0487] Compound 4F (20.3 kg, 78.29 mol), THF (110 kg, 5.4 kg/kg compound 4F), and TEA (19.8 kg, 0.975 kg/kg compound 4F) was charged into a reactor. The mixture was cooled to 10 °C with an ice bath, and the reactor was then purged with nitrogen three times. Triethylamine trihydrofluoride (10.1 kg, 0.498 kg/kg compound 4F) was added dropwise at 10 to 20 °C, followed by perfluoro-l-butanesulfonyl fluoride addition (52.06 kg, 2.56 kg/kg compound 4F) which was also added dropwise at 10 to 20 °C. The reaction mixture was stirred at 10 to 30 °C for 12 hours. A sample was removed from the reaction mixture and diluted with acetonitrile for analysis. Analysis by HPLC Method-OOl showed compound 4G was present as 40.6 A% and that 0.53 A% of compound 4F remained.

[0488] The mixture was cooled to 10 °C. Aqueous potassium permanganate (150 kg, 3.22 wt %) was added dropwise at 10 to 20 °C to purge any elimination products. The reaction mixture was stirred at 10 to 20 °C for 1 hour. A sample was removed from the reaction mixture was removed and diluted with acetonitrile for analysis. Analysis by HPLC Method-OOl showed compound 4G was present at 50.3 A % and that no elimination products remained.

[0489] Sodium bicarbonate (10.15 kg, 0.5 kg/kg compound 4F, pH = 7 to 8) was added portionwise at 5 to 10 °C and stirred for 10 minutes. Toluene (18 kg, 0.89 kg/kg compound 4F) was added, and the mixture was stirred for 5 minutes and filtered over celite (13 kg, 0.64 kg/kg compound 4F). The collected cake was then washed twice with 30 kg of toluene, and then with 20 kg of toluene. The organic phase was separated and extracted three times with toluene (87 kg, 4.3 kg/kg compound 4F). The organic phases were combined, washed with 20 wt % brine (165 kg, 8.1 kg/kg compound 4F), and dried over anhydrous sodium sulfate (41.2 kg, 2.03 kg/kg compound 4F). The mixture was then washed twice with toluene (20 kg) and concentrated under vacuum at 60 °C. LC analysis showed that 60 A % toluene remained.

[0490] Petroleum ether (65 kg, 3.2 kg/kg compound 4F) and silica gel (20 kg, 200-300 mesh) were added to the residue and stirred for 10 minutes. The mixture was filtered on silica gel (40 kg, 200-300 mesh) and eluted with a solution of ethyl acetate and petroleum ether (1 : 10, 1.7 L). The mixture was concentrated under vacuum at 45°C. 13.1 kg of compound 4G was obtained with 90.2 A % LC purity in 63.7% uncorrected yield.

[0491] Example 1D step 7.

[0492] Compound 4(a) (2S,4R,5S)-l-(tert-butoxycarbonyl)-4-fluoro-5- methylpynOlidine-2-carboxylic acid was prepared from compound 4G (2S,4S,5S)-l-(tert- butoxycarbonyl)-4-fluoro-5-methylpynOlidine-2-carboxylic acid as follows:

4G 4(a)

[0493] Compound 4G (13 kg, 49.75 mol), methanol (83 kg, 6.4 kg/kg compound 4G), and THF (92.5 kg, 7.1 kg/kg compound 4G) were charged into a reactor. The mixture was cooled to l0°C with an ice bath. Lithium hydroxide (2.7 kg, 0.27 kg/kg compound 4G) in water (105 kg, 8.1 kg/kg compound 4G) was added dropwise to the reaction mixture. The mixture was gradually warmed to 25 to 30 °C over a period of 1 hour and stirred at temperature for 12 hours to form a reaction product mixture comprising compound 4(a). A sample was removed from the reaction mixture and diluted with acetonitrile for analysis. Analysis by HPLC Method- 002 showed compound 4(a) was present as 84.5 A %, and that 1.45 A % of compound 4G remained.

[0494] The mixture was concentrated under vacuum at 45 °C and the residue (about 120 kg) was cooled to 20 °C, washed twice with 80 kg of DCM and once with 47 kg of DCM. The organic phase was collected. The aqueous phase was cooled to 10 °C, pH adjusted to 2 to 3 with 1M HC1 (about 65 kg, 0-10 °C) added dropwise to the reaction mixture over a period of approximately 2.5 hours. White precipitate formed in the reaction mixture. The reaction mixture continued stirring for 30 minutes at 0 to 10 °C, was filtered, and the collected solids were washed twice with cool water (18 kg). The solids were then dried under vacuum at 60 °C for 7 hours to yield 10.1 kg of crude product compound 4(a) (yield = 82.1%) with an LC purity of 99.6 A %.

[0495] Example 2: Preparation of Crystalline Forms

[0496] Example 2 -A: Polymorph screening [0497] Compound 1(a) starting material was characterized by X-ray powder diffraction (XRPD) (see FIG. 6), thermo-gravimetric analysis (TGA) and differential scanning calorimetry (DSC) (see FIG. 7), proton nuclear magnetic resonance (1H NMR) (see FIG. 8) and dynamic vapor sorption (DVS) (see FIG. 9). Characterization results reveal that the starting material is a slightly hygroscopic hydrate, assigned as Type A.

[0498] Using Type A as starting material, a polymorph screening was performed, through methods of vapor diffusion, anti-solvent addition, slurry conversion, slow evaporation and slow cooling. From screening and follow-up investigation, a total of 14 crystal forms were discovered, including anhydrate Type E, hydrate Type A, 10 solvate forms, and two transient forms (Type A0 and B converted into Type A at ambient conditions). Characterization results of the 14 crystal forms are summarized in Table 1 below, and an inter-conversion diagram is illustrated in FIG. 5. Amorphous formation was observed after Type A was magnetically stirred in water.

[0499] Table 1 : Characterization results of crystal forms

[0500] Hydrate Type A and anhydrate Type E were selected to be scaled up for further evaluation. Type A and E were each suspended in water at room temperature (RT, ~25 °C) and 50 °C using magnetic stirring and shaking, respectively. For both Type A and E, magnetic stirring resulted in significant amorphous formation, whereas no crystallinity decrease was observed through shaking, suggesting its mechanical stability issue. Kinetic solubility of Type A and E was measured in HPLC water, pH 6.5 phosphate buffer and 0.01 N HC1 at 37 °C. Solubility samples were taken at the endpoints of 1, 2, 4 and 24 hrs, with cakes for XRPD test and supernatants for HPLC and pH analysis. The results showed that no form change occurred for both forms, and Type A exhibited overall higher solubility than Type E in all the three aqueous media, suggesting that potentially Type E is thermodynamically more stable than Type A at 37 °C.

[0501] Scale-up and jet-milling feasibility of Type E was further investigated. Pure Type E was obtained after a mixture of Type A and E was magnetically stirred in DCM/n- heptane (v/v, 1:3) at RT, indicating that Type E could be isolated directly. Through anti-solvent crystallization in DCM/n-heptane at RT in presence of seed, Type E was successfully prepared at 3-g scale and fully characterized by XRPD, TGA, DSC, polarized light microscopy (PLM), particle size distribution (PSD) and gas chromatography (GC) as indicated in more detail in the examples that follow. Long needle-like crystals were observed, and both solvent residuals were below 50 ppm. After jet milling on 2.86 g of Type E, limited sample (< 50 mg) was collected, and characterized by XRPD, DSC, PLM and PSD. No significant amorphous was detected for the jet milled product.

[0502] Example 2-B: Polymorph Screening

[0503] Analytical methods for polymorph studies.

[0504] X-ray powder diffraction (XRPD)

[0505] For XRPD analysis, PANalytical and Bruker X-ray powder diffractometers were used. The XRPD parameters used are listed below wherein measurement temperature was 25°C.

[0506] Thermo-gravimetric analysis (TGA) and differential scanning calorimetry

(DSC)

[0507] TGA data was collected using a TA Q500/Q5000 TGA from TA Instruments. DSC and mDSC were performed using a TA Q200/Q2000 DSC from TA Instruments. Detailed parameters used are listed below.

[0508] Proton nuclear magnetic resonance (1H NMR)

[0509] ' H NMR data was collected on Bruker 400M NMR Spectrometer using DMSO- d6. [0510] Dynamic vapor sorption (DV S)

DVS was measured via a SMS (Surface Measurement Systems) DVS Intrinsic instrument. DVS test parameters are listed below.

[0511] High Pressure Liquid Chromatography (HPLC)

[0512] Agilent 1100 HPLC was utilized and detailed chromatographic conditions for solubility measurement are listed below.

[0513] Particle Size Distribution (PSD)

[0514] PSD data was collected using Laser Diffraction Particle Size S-3500, and the parameters are listed below.

[0515] Gas Chromatography (GC)

[0516] Solvent residual was measured using Agilent 7820A GC System with Agilent 7697 A Headspace. Detailed parameters used are listed below.

[0517] Example 2-B(l ) - Anti-solvent addition experiments

[0518] The solubility of compound 1(a) Type A was estimated in 22 solvents at RT. Approximate 2 mg solids were added into a 3-mL glass vial. Solvents in Table 2 were then added into the vials step by step in sequence of 50, 50, 200 and 700 pL until the solids were dissolved or a total volume of 1 mL was reached. Results summarized in Table 2 were used to guide the solvent selection in polymorph screening.

[0519] Table 2: Summary of solubility experiments

[0520] A total of 16 anti-solvent addition experiments were carried out. For each experiment, about 15 mg of compound 1(a) Type A was weighed into a 20 mL glass vial, followed by the addition of 0.3-1.0 mL corresponding solvent. The mixture was then magnetically stirred at the speed of 500 RPM to get a clear solution at RT. Subsequently, the relative anti-solvent was added to the solution to induce precipitation or until the total amount of anti-solvent reached 10.0 mL. The clear solutions were transferred to slurry at 5 °C. If no precipitation occurred, the solution was then transferred to slow evaporation at RT. The solids were isolated for XRPD analysis. Results summarized in Table 3 showed that Type B, C, D, F,

H and K were generated.

[0521] Table 3: Summary of anti-solvent addition experiments

*: Solid was obtained via stirring at 5 °C.

**: Solid was obtained via slow evaporation at RT.

[0522] Example 2-B(2) - Solid vapor diffusion experiments

[0523] Solid vapor diffusion experiments were conducted using 11 solvents. For each experiment, about 10 mg of compound 1(a) Type A was weighed into a 3 mL vial, which was placed into a 20 mL vial with 4 mL of corresponding solvent. The 20 mL vial was sealed with a cap and kept at RT for 12 days to allow the solvent vapor to interact with the solid sample. The isolated solids were tested by XRPD. The results summarized in Table 4 and indicate that Type A, B and F were obtained. [0524] Table 4: Summary of solid vapor diffusion experiments

[0525] Example 2B-(3) - Slow evaporation experiments

[0526] Slow evaporation experiments were performed under 12 conditions. For each experiment, around 15 mg of compound 1(a) Type A was weighed into a 3 mL glass vial, followed by the addition of corresponding solvent or solvent mixture to get a clear solution. Subsequently, the vial was covered with parafilm with 3~4 pinholes, and kept at RT to allow the solution to evaporate slowly. The isolated solids were tested by XRPD. As summarized in Table 5, Type A, E, F and H were generated

[0527] Table 5: Summary of slow evaporation experiments

[0528] Example 2-B(4) - Slurry conversion at room temperature experiments

[0529] Slurry conversion experiments were conducted at RT in different solvent systems. For each experiment, about 20 mg of compound 1(a) Type A was suspended in 0.3 mL corresponding solvent in a 1.5 mL glass vial. After the suspension was magnetically stirred for 9 days at RT, the remaining solids were isolated for XRPD analysis. Results summarized in Table 6 showed that Type A, F, G, H and J were obtained

[0530] Table 6: Summary of slurry conversion experiments

[0531] Example 2-B(5) - Slurry conversion at 50°C experiments

[0532] Slurry conversion experiments were conducted at 50 °C in different solvent systems. For each experiment, about 20 mg of compound 1(a) Type A was suspended in 0.3 mL corresponding solvent in a 1.5 mL glass vial. After the suspension was magnetically stirred for 9 days at 50 °C, the remaining solids were isolated for XRPD analysis. Results summarized in Table 7 indicate that Type D, F, G, H and I were produced [0533] Table 7: Summary of slurry conversion at 50 °C experiments

[0534] Example 2-B(6) - Liquid vapor diffusion

[0535] Fourteen liquid vapor diffusion experiments were conducted. For each experiment, about 15 mg of compound 1(a) Type A was dissolved in 0.5-1.0 mL of corresponding solvent to obtain a clear solution in a 3 mL vial. Subsequently, the solution was placed into a 20 mL vial with 4 mL of relative anti-solvent. The 20 mL vial was sealed with a cap and kept at RT, allowing sufficient time for solvent vapor to interact with the solution.

Solids were isolated for XRPD analysis. Results summarized in Table 8 show that Type B, D, E and H were obtained.

[0536] Table 8: Summary of liquid vapor diffusion experiments

[0537] Example 2-B(7) - Slow Cooling

[0538] Slow cooling experiments were conducted in 14 solvent systems. For each experiment, about 20 mg of compound 1(a) Type A was suspended in 1.0 mL of corresponding solvent in a 3-mL glass vial at RT. The suspension was transferred to slurry at 50 °C on a magnetic stirrer with the speed of 500 RPM. The sample was equilibrated at 50 °C for 2 hrs and filtered using a 0.45 pm Nylon membrane. Subsequently, the filtrate was slowly cooled down from 50 °C to 5 °C at a rate of 0.1 °C/min. The sample was stored at 5 °C before XRPD analysis. The results summarized in Table 9 indicate that Type G and H were obtained.

[0539] Table 9: Summary of slow cooling experiments

[0540] Example 2-C: Co-Crystal Screening

[0541] According to approximate solubility data of freebase, four solvent systems were used in the screening. For each solvent of acetone, THF and EtOAc, freebase stock solutions with a concentration of 30 mg/mL were prepared separately. In each experiment, 0.5 mL stock solution and corresponding acid were mixed with a molar charge ratio of 1 :1, and stirred at RT overnight. For conditions with IPA/H20 (19: 1, v/v), the solvent was added to a mixture of freebase solid and acid with a molar charge ratio of 1: 1, and the suspensions obtained were stirred at RT overnight. Heating-cooling (65 °C to 5 °C) was applied to suspensions obtained before the solids were centrifuged and vacuum dried at RT. For samples without any solid, clear solutions were transferred to 5 °C and stirred for 2.5 days. If solids were still not obtained, 1.0 mL H20 was added to acetone clear solutions and heating-cooling (65 °C to 5 °C) was applied to emulsions obtained; 1.0 mL n-heptane was added to THF/EtOAc solutions and then transferred to 5 °C. Eventually, clear solutions obtained after anti-solvent addition were transferred to evaporation at RT.

[0542] As summarized in Table 10, a total of three crystalline hits were isolated and their characterization data are summarized in Table 11.

[0543] Table 10: Summary of co-crystal screening

N/A: No or limited amount of solid observed.

*: Limited diffraction peaks were observed.

[0544] Table 11 : Data summary of co-crystals

N/A: No or limited amount of solid observed.

*: No significant signal was detected in 'H NMR. Limited diffraction peaks were observed.

[0545] Example 2-D: Compound 1(a) prepared by the prior art process of WO 2016/128529

[0546] Compound 1(a) was prepared by the process disclosed in WO 2016/128529 and was characterized by XRPD and found to be amorphous. See FIGS. 59 and 61. TGA and DSC results for said compound are also shown in FIG. 62. HPLC results for said compound are shown in FIG. 63.

[0547] Example 2-E: Compound 1(a) Hydrate Type A

[0548] Compound 1(a) starting material was characterized by XRPD, TGA, DSC, 1H NMR and DVS. The XRPD result of FIG. 6 indicated the starting material was crystalline Type A. TGA and DSC data are shown in FIG. 7. A weight loss of 3.3% up to l30°C was observed in TGA, and DSC result showed a relatively broad endothermic peak at 98.0 °C (onset temperature). Further XRPD results showed no form change after Type A was heated to 80 °C, cooled to 30 °C under protection of nitrogen, and then exposed to air. In addition, no process solvent MeOH was detected by 'H NMR as shown in FIG. 8, indicating that Type A is a hydrate.

[0549] To further identify Type A and investigate its dehydration behavior, DSC at open condition was conducted to test if the relatively broad endothermic peak observed in FIG.

7 was caused by overlap of dehydration peak and melting peak, and variable temperature XRPD (VT-XRPD) was performed to observe the dehydrated form of Type A. The uncapped DSC result of another Type A batch showed an endotherm at 56.4 °C (peak temperature) due to dehydration before melting at 101.6 °C (peak temperature). With the dehydration temperature known, VT-XRPD was performed with temperature increased to 80 °C and back to 30 °C under protection of nitrogen. A distinctive XRPD was observed after dehydration of Type A at 70 °C, and this new form is assigned as Type AO. After exposure to ambient conditions for ~30 mins, Type AO converted into Type A. Therefore, Type AO is deemed to be a transient anhydrate that can be observed with protection from moisture.

[0550] To evaluate the hygroscopicity and physical stability of Type A under different humidity, DVS data was collected at 25 °C after the sample was equilibrated at ambient humidity 70%RH. As shown in FIG. 9, water absorption went up slowly with relative humidity higher than 10% RH and a water uptake of 0.3% was observed up to 80%RH, suggesting the Type A sample is slightly hygroscopic. Dehydration occurred at 0%RH, indicating that critical water activity at 25 °C is between 0%RH and l0%RH for Type A and A0.

[0551] Example 2-F: Compound 1(a) Anhydrate Type E

[0552] Compound 1(a) Type E was obtained via slow evaporation in DCM/n-heptane (v/v, 1: 1) at RT. The XRPD pattern is shown in FIG. 10, and TGA/DSC curves are displayed in FIG. 11. The results indicated that Type E was crystalline with a weight loss of 1.7% before 140 °C in TGA and a sharp melting endotherm at 147.0 °C in DSC (onset temperature). No significant solvent signal was detected by 1H NMR as shown in FIG. 12, indicating that Type E is an anhydrate.

[0553] Compound 1(a) Type E was re-prepared to lOO-mg scale via slow evaporation in DCM/n-heptane (v/v, 1:2) at RT, and needle-like crystals were observed. To evaluate the hygroscopicity of Type E, DVS data was collected at 25 °C after the sample was pre equilibrated at 0%RH to remove unbounded water. The DVS result shown in FIG. 13 showed a water uptake of 0.3% at 25°C/80%RH, suggesting Type E sample is slightly hygroscopic.

XRPD results showed no form change after DVS test as shown in FIG. 71.

[0554] Example 2-G: Evaluation of Type A and Type E

[0555] Based on the form identification results, Type A and E were selected and re prepared for further evaluation, including mechanical stability investigation, critical water activity determination and kinetic solubility measurement. [0556] Type A was re-prepared as follows.

[0557] Compound 1(a) hydrate Type A was re-prepared to 1 g via drying Type B cake (prepared from amorphous compound 1(a)) at 60 °C for evaluation. 1.0 g of amorphous compound 1(a) solids were weighed into a 20 mL glass vial. 8 mL MeOH was added to the vial with mechanical stirring at RT overnight to form a suspension. The suspension was sampled for XPRD and the resulting pattern corresponded to Type B. The suspension was evaporated at RT to induce additional precipitation. After solvent removal, the solids were dried at 60 °C overnight. XRPD results are shown in FIG. 20 and indicate that Type A was prepared. As per the TGA and DSC results shown in FIG. 21, a weight loss of 2.1% up to 80 °C and a broad endotherm at 98.1 °C was observed.

[0558] Type E was re-prepared as follows.

[0559] Compound 1(a) Type E was prepared to 1 g via anti-solvent addition in DCM/«- heptane at RT, followed by evaporation to dryness. 1.0 g of amorphous compound 1(a) solids were weighed into a 20 mL glass vial. 4 mL DCM was added and stirred at RT to yield a clear solution. 4 mL «-heptane was added to the solution followed by addition of about 1 mg compound 1(a) Type E seed crystals. The solution turned cloudy immediately. Stirring was continued for 6 hours. The suspension was evaporated at RT to induce further crystallization. After solvent removal, the solids were dried at 60 °C overnight. XRPD results shown in FIG. 22 showed Type E was successfully re-prepared. As per TGA and DSC data shown in FIG. 23, a weight loss of 0.4% up to 145 °C and a sharp melting endotherm at 145.9 °C (onset temperature) were observed.

[0560] Magnetic stirring on re-prepared Type A and E resulted in amorphous formation in water, whereas no crystallinity decrease was observed via shaking, suggesting mechanical stability issue. Kinetic solubility results in three aqueous media (HPLC water, pH 6.5 phosphate buffer and 0.01N HC1) showed that Type A exhibited overall higher solubility than Type E up to 24 hrs at 37 °C, revealing that potentially Type E is thermodynamically more stable than Type A at 37 °C.

[0561] Example 2-G(l): Mechanical force stability in water

[0562] Hydrate Type A was prone to convert into amorphous after magnetic stirring in water at RT and 50 °C for nine days. 'H NMR results showed no evident chemical degradation for the slurry sample at RT. To investigate the cause of amorphous formation, Type A and E were suspended in water at RT and 50 °C using magnetic stirring and shaking, respectively. The results are summarized in Table 12 (where“Exp” refers to experiment,“S. Form” refers to starting form,“Loading” refers to solid loading (mg/mL),“Method” refers to the slurry method, “Temp.” refers to temperature in °C,“Time” refers to sampling time in days, and“Solid form” refers to the solid form obtained after slurring. As the XRPD results showed, amorphous was obtained at RT and an amorphous halo was observed at 50°C after Type E was magnetically stirred in water for seven days. Type A and a mixture of Type A and E were shaken in water at RT for three days. XRPD results showed no significant crystallinity decrease, indicating that the mechanical milling effect of magnetic stirring contributed to the amorphous formation in water.

[0563] Table 12: Summary of Type A and Type E slurry experiments

[0564] Example 2-G(2): Critical Water Activity

[0565] To determine the critical water activity between Type A and E, slurry conversion was attempted in three solvent-water systems at RT via shaking method, including acetone, ACN and DMSO, in which no solvation was observed from polymorph screening.

[0566] In detail, ~40 mg of solids were shaken in 1 mL of solvent mixture at a speed of 500 RPM. Results are summarized in Table 13. Both Type A and E converted into oil in acetone/H20 (v/v, 1 :2) and ACN/H20 (v/v, 1 :2) after shaking at RT, whereas a new DMSO solvate Type M was observed in DMSO/H20 (v/v, 1:2). [0567] Table 13: Summary of Type A and Type E water activity experiments

[0568] Example 2-G(3): Kinetic Solubility

[0569] To compare in-vitro dissolution between Type A and E, kinetic solubility was measured at 37 °C in water (HPLC grade), pH 6.5 phosphate buffer and 0.01N HC1 at the endpoints of 1, 2, 4 and 24 hrs. Suspensions were mixed in 4-mL plastic vials and rolled (25 RPM) at 37 °C in an incubator, with an initial solid loading of 5 mg/mL. At the endpoints of 1, 2, 4 and 24 hours, suspensions were separated via centrifugation at a high speed of 14000 RPM. Solids were characterized by XRPD, and supernatants were analyzed by HPLC and pH tests.

No form change was observed for Type A and E in all the three media up to 24 hrs. Results are summarized in Table 14 (where“Phos.” Refers to phosphate,“S” refers to solubility in pg/mL, “pH” refers to final pH, and“FC” refers to form change). Type A exhibited overall higher solubility than Type E in all the three aqueous media, suggesting Type E is possibly

thermodynamically more stable than Type A at 37 °C.

[0570] Table 14:

[0571] Example 2-H: Scale-up and jet milling feasibility of Type E

[0572] Example 2-H(l): Slurry competition experiment of hydrate Type A and anhydrate Type E in DC /«-heptane

[0573] A slurry competition experiment of hydrate Type A and anhydrate E was performed. A saturated solution of compound 1(a) Type A in DC /«-heptane (1 :3 v/v) was prepared at RT with stirring for 30 minutes. About 5 mg each of compound 1(a) Type A and Type E were placed into an HPLC vial. The Type A solution was filtered through a PTFE filter into the vial to form a mixture and the contents were stirred magnetically at RT. After equilibration overnight, the mixture was centrifuged and samples for XRPD analysis. The XRPD results are depicted in FIG. 14.

[0574] Example 2-H(2): Anti-solvent crystallization in DCM/«-heptane

[0575] Compound 1(a) anhydrate Type E was scaled up to a 3 g scale as follows. 2.89 g of amorphous compound 1(a) solids were placed in a 100 mL reactor and combined with 10 mL DCM with stirring to obtain a clear solution «-heptane was added in 3 mL increments until cloudiness was observed after 9 mL of «-heptane had been added. 0.40 g of compound 1(a) Type E seed crystals were added with stirring and aged for 1 hour. 21 mL «-heptane was added over 4 hours with a syringe pump, and stirring was continued overnight. The crystals were isolated by filtration and dried in a vacuum oven at 50 °C overnight. 3.01 g dry solids at a yield of about 93.3% was obtained. The initial compound 1(a) concentration was about 280 mg/mL; the seed load was 14%; the seeding point occurred at DCM/«-heptane 10:9 v/v; the final DCM/«-heptane ratio was 1:3 v/v; the mother liquor concentration was 3.1 mg/mL; needle-like crystal morphology was observed; the crystal form was Type E; and the melting point was 147.5 °C; the residual solvent was <32 ppm DCM and 19.4 ppm «-heptane. Particle size distribution data (PSD) is show in Table 15 below.

[0576] Table 15: Compound 1(a) Type E particle size distribution

[0577] XRPD result shown in FIG. 15 indicated that Type E was obtained. As per TGA and DSC data in FIG. 16, a weight loss of 0.8% before 145 °C and a sharp endothermic peak at 147.5 °C (onset temperature) were observed. The PSD data showed a bimodal distribution of particle size, and the second maxima was assigned to small agglomerates, as it decreased after ultrasonic treatment.

[0578] Example 2-H(3): Jet milling investigation

[0579] Jet milling was performed on 2.86 g of compound 1(a) Type E, to investigate any possible mechanical effect. In the study, 2.86 g of Type E was milled at 0.7 mPa and a feed rate of 2 kg/h. The PSD characterization data (with no ultrasonic treatment) is summarized in Table 16. The PSD characterization data (with ultrasonic treatment) is summarized in Table 17

[0580] Table 16: Jet milling data (no ultrasonic treatment)

[0581] Table 16: Jet milling data (no ultrasonic treatment)

[0582] As the XRPD result showed in FIG. 17, no form change or significant amorphous halo was observed for the jet milled product. DSC result FIG. 18 showed a widened endotherm at 140.8 °C (onset temperature). The milled product consisted of small particles, small agglomerates and a few long needles. PSD data summarized in Table 16 showed irregular distribution of particle size, and the decreased maxima (> 10 pm) after ultrasonic treatment was assigned to small agglomerates. [0583] Example 2-1: Compound 1(a) Type AO

[0584] Type AO was obtained by dehydration of Type A under protection of nitrogen, and the XRPD pattern is shown in FIG. 24. Type AO is believed to be a transient form as it converted into Type A after exposure to ambient conditions.

[0585] Example 2-J: Compound 1(a) Type B

[0586] Type B may be obtained by MeOH-mediated crystallization or solid phase transition. As shown in FIG. 19, the representative XRPD pattern of Type B was collected in transmission mode, which was obtained via interaction of Type A solids with MeOH vapor.

The rapid form conversion from Type B to A was observed after air drying within 10 minutes. Considering the solvate formation with multiple alcohols, Type B is speculated to be a transient MeOH solvate.

[0587] Example 2-K: Compound 1(a) Type C

[0588] Type C could be reproducibly obtained via adding H₂0 into DMAc solution.

The XRPD result in FIG. 25 showed that Type C possessed high crystallinity. TGA and DSC results in FIG. 26 showed a considerable weight loss of 12.3% before 200 °C and a sharp endotherm at 100.4 °C (onset temperature) before decomposition. As the 'H NMR result showed in FIG. 27, 0.90 equivalent of DMAc to compound 1(a) (11.4%) was detected, consistent with TGA weight loss. Furthermore, XRPD results showed that Type C converted into amorphous after being heated to 105 °C and cooled to 30 °C under protection of nitrogen and exposed to air. Therefore, Type C is believed to be a DMAc solvate.

[0589] Example 2-L: Compound 1(a) Type D

[0590] Type D was obtained via anisole-mediated crystallization. Type D was obtained via interaction of anisole solution with «-heptane vapor, and its XRPD is shown in FIG. 28.

TGA and DSC results in FIG. 29 showed a considerable weight loss of 20.7% before 200 °C and a sharp endotherm at 94.9 °C (onset temperature). As the 'H NMR result showed in FIG. 30, 0.84 equivalent of anisole to compound 1(a) (13.0%) and no significant amount of n-heptane were detected. Furthermore, several characteristic peaks of Type E were observed after Type D was heated to 100 °C, cooled to 30 °C under protection of nitrogen and exposed to air, as shown by XRPD in FIG. 31. Therefore, Type D is believed to be an anisole solvate.

[0591] Example 2-M: Compound 1(a) Type F [0592] Type F could be obtained by EtOH-mediated crystallization or solid phase transition. Type F was obtained via slow evaporation of EtOH solution at RT, and its XRPD is shown in FIG. 32. TGA and DSC results in FIG. 33 showed a weight loss of 8.3% before 200 °C and a sharp endotherm at 100.3 °C followed by a small endotherm at 136.4 °C (onset temperature). As the 'H NMR result showed in FIG. 34, 0.88 equivalent of EtOH to compound 1(a) (6.2%) was detected. Furthermore, several characteristic peaks of Type E were observed after Type F was heated to 105 °C, cooled to 30 °C under protection of nitrogen and exposed to air, as shown by XRPD in FIG. 35. Therefore, Type F is believed to be an EtOH solvate.

[0593] Example 2-N: Compound 1(a) Type G

[0594] Type G could be obtained by toluene-mediated crystallization. Type G was obtained via slow cooling of toluene solution from 50 to 5 °C, and its XRPD is shown in FIG. 36. TGA and DSC results in FIG. 37 showed a weight loss of 17.8% before 200 °C and a sharp endotherm at 106.3 °C (onset temperature). 'H NMR result FIG. 38 showed 0.82 equivalent of toluene to compound 1(a) (11.0%) was detected. Furthermore, Type G converted into Type E after being heated to 110 °C, cooled to 30 °C under protection of nitrogen and exposed to air, as shown by XRPD in FIG. 39. Therefore, Type G is believed to be a toluene solvate

[0595] Example 2-0: Compound 1(a) Type H

[0596] Type H could be obtained by IPA-mediated crystallization or phase transition. Type H was obtained via slow evaporation in MTBE/IPA (v/v, 1 : 1) at RT, and its XRPD is shown in FIG. 40. TGA and DSC results in FIG. 41 showed a weight loss of 15.8% before 200 °C and a sharp endotherm at 116.3 °C (onset temperature). 'H NMR result FIG. 42 showed 1.02 equivalent of IP A to compound 1(a) (9.1%) and no significant amount of MTBE were detected. Furthermore, Type H converted into Type E after being heated to 125 °C, cooled to 30 °C under protection of nitrogen and exposed to air, as shown by XRPD in FIG. 43. Therefore, Type H is believed to be an IPA solvate.

[0597] Example 2-P: Compound 1(a) Type I

[0598] Type I was obtained by slurry conversion of Type A in 1 -butanol at 50°C. The XRPD result in FIG. 44 showed that Type I possessed high crystallinity. TGA and DSC results in FIG. 45 showed a weight loss of 13.7% before 200 °C and a sharp endotherm at 90.0 °C (onset temperature). 'H NMR result FIG. 46 showed 1.13 equivalent of 1 -butanol to compound 1(a) (12.1%) was detected. Furthermore, Type I converted into amorphous after being heated to 95 °C, cooled to 30 °C under protection of nitrogen and exposed to air. Therefore, Type I is believed to be a 1 -butanol solvate.

[0599] Example 2-Q: Compound 1(a) Type J

[0600] Type J was obtained via slurry of Type A in MeTHF/n-heptane (v/v, 1:2) at RT. The XRPD result in FIG. 47 showed that Type J possessed high crystallinity. TGA and DSC results in FIG. 48 showed a weight loss of 14.4% before 200 °C and a sharp endotherm at 82.2 °C (onset temperature). 'H NMR result FIG. 49 showed 0.93 equivalent of MeTHF to compound 1(a) (11.6%) and no significant amount of n-heptane were detected. Furthermore, significant amount of amorphous was generated after Type J was heated to 85 °C, cooled to 30 °C under protection of nitrogen and exposed to air. Therefore, Type J is believed to be a MeTHF solvate.

[0601] Example 2-R: Compound 1(a) Type K

[0602] Type K was obtained via slurry of Type A in THF/n-heptane (v/v, 1 :2) at -20 °C. The XRPD result in FIG. 50 showed that Type K possessed high crystallinity. TGA and DSC results in FIG. 51 showed a weight loss of 10.0% before 200 °C and a sharp endotherm at 86.8 °C (onset temperature). 'H NMR result FIG. 52 showed 0.76 equivalent of THF to compound 1(a) (8.3%) was detected. Furthermore, significant amount of amorphous was generated after Type K was heated to 90 °C, cooled to 30 °C under protection of nitrogen and exposed to air. Therefore, Type K is believed to be a THF solvate.

[0603] Example 2-S: Compound 1(a) Type L

[0604] Type L was obtained via slurry of amorphous compound 1(a) in isobutyl alcohol at RT. The XRPD result in FIG. 53 showed that Type L possessed high crystallinity. TGA and DSC results in FIG. 54 showed a considerable weight loss of 11.2% before 200 °C and a sharp endotherm at 106.8 °C (onset temperature). 'H NMR result FIG. 55 showed 0.97 equivalent of isobutyl alcohol to compound 1(a) (10.6%) was detected. Furthermore, Type L converted into amorphous after being heated to 110 °C, cooled to 30 °C under protection of nitrogen and exposed to air. Therefore, Type L is believed to be an isobutyl alcohol solvate.

[0605] Example 2-T: Compound 1(a) Type M

[0606] Type M was obtained via shaking of Type E in DMSO/water (v/v, 1 : 1) at RT. The XRPD result in FIG. 56 showed that Type M possessed high crystallinity. TGA and DSC results in FIG. 57 showed a considerable weight loss of 10.7% before 200 °C and a sharp endotherm at 110.7 °C (onset temperature). By ' H NMR FIG. 58, 0.90 equivalent of DMSO to compound 1(a) (10.4%) was detected, consistent with TGA weight loss. Furthermore, Type M converted into amorphous form after being heated to 115 °C, cooled to 30 °C under protection of nitrogen and exposed to air. Therefore, Type M is believed to be a DMSO solvate.

[0607] Example 2-U: Compound 1(a) Type E scale up from amorphous starting material

[0608] Compound 1(a) Type E was prepared from amorphous compound 1(a) via anti solvent crystallization in DCM/«-heptane at RT with seed. 66.6 g of amorphous compound 1(a) was charged to a 1 L reactor. 220 mL of DCM was added to the reactor with stirring at RT to obtain a clear solution. 125 mL of «-heptane was added followed by the addition of about 5 mg of compound 1(a) Type E seed crystals. The seed crystals slowly dissolved. 5 mL of additional «-heptane was added followed by 2.6 g of compound 1(a) Type E seed crystals. The majority of the seed crystals dissolved and only limited needle-like crystals were observed on the reactor wall during stirring. 530 mL «-heptane was charged over 4 hours with a syringe pump.

Cloudiness was observed after an additional 20 mL «-heptane was added. After aging overnight, the crystallized solids were collected by filtration and washed with «-heptane. The cake was oven dried under vacuum at 50 °C overnight. 62.6 g solids were collected at a yield of about 93.4%.

[0609] Long needle-like crystals were observed. Most of the seed dissolved during stirring, however, good quality attributes of Type E product were still achieved. Therefore, anti solvent crystallization process in DCM/n-heptane is commercially practical with limited seed. XRPD results shown in FIG. 64 show that Type E is obtained from anti-solvent crystallization. As per TGA and DSC data displayed in FIG. 65, a weight loss of 1.2% was observed up to 145 °C in TGA, and DSC result shows a sharp melting endotherm at 147.3 °C (onset temperature). The product was fully characterized by XRPD, TGA, DSC, PLM, HPLC and GC, with results summarized in the Table below.

*: Most of the 2.6 g of seed crystals were dissolved at this point, and evident cloudiness was observed at a solvent ratio of DCM/«-heptane of 22: 15.

**: HPLC purity of starting material is 99.18 area%.

[0610] Example 2-V: Anhydrate compound 1(a) gentisic acid co-crystal Type A

[0611] Compound 1(a) free base (300.1 mg) and gentisic acid (76.1 mg) were combined in a 20 mL glass vial and 6.0 mL EtOAc was then added to form a clear solution. 8.0 mL of «- heptane was charged to the vial followed by about 50 mg of compound 1(a) gentisic acid co crystal Type A seed and a cloudy solution was observed. 5.0 mL «-heptane was added to the vial and a suspension was observed after stirring at RT for 2 hours. The suspension was cooled to 5 °C and stirred for 17 hours to induce additional crystallization. The suspension was filtered and the collected crystals were vacuum dried at RT for 4 hours providing a yield of 66.5%. XRPD results are shown in FIG. 66. Characteristic peaks were at degrees 2-theta at angles of l2.5°±0.2°, l3.0°±0.2°, l4.4°±0.2°, l5.7°±0.2°, l7.5°±0.2°, 2l.7°±0.2°, 25.5°±0.2°, and 26.3°±0.2°. As shown in FIG. 67 and FIG. 70, a weight loss of 2.5% up to 110 °C was observed in TGA and DSC result showed one endothermic peak at 170.8 °C (onset temperature). The stoichiometric ratio was determined to be 1.00 (acid/freebase) and no significant solvent signal was detected by 1H NMR as shown in FIG. 68. Based on the characterization data collected, gentisic acid co-crystal Type A is believed to be an anhydrate.

[0612] Kinetic solubility of gentisic acid co-crystal Type A was measured in water and three bio-relevant media (SGF, FaSSIF, and FeSSIF) at 37 °C, using compound 1(a) freebase Type E as a control. All the solubility samples (initial solid loading of -10 mg/mL) were kept rolling on a rolling incubator at 37 °C with a speed of 25 rpm, and sampled at 1, 2, 4 and 24 hours, respectively. After centrifugation, supernatants were collected for HPLC and pH tests, and wet cakes were collected for XRPD characterization. Compared with freebase Type E, gentisic acid co-crystal Type A showed increased solubility (twice) in FaSSIF/FeSSIF and comparable solubility in SGF/water. Furthermore, no form change was observed after gentisic acid co-crystal Type A or freebase Type E was suspended in water and three bio-media

(SGF/FaSSIF/FeSSIF) for 24 hours.

[0613] Solid-state stability of gentisic acid co-crystal Type A was evaluated under 80 °C (closed)/24 hrs, 25 °C/60%RH/6 days and 40 °C/75%RH/6 days with compound 1(a) freebase Type E as control. Stability samples were characterized by XRPD to check any solid form change and HPLC to check purity change. No solid form change or significant HPLC purity decrease was observed after stability test based on XRPD and HPLC results, indicating that gentisic acid co-crystal Type A and freebase Type E were both physically and chemically stable under tested conditions.

[0614] To investigate the solid form stability as a function of humidity, DVS isotherm plot data was collected at 25 °C that showed that compound 1(a) gentisic acid co-crystal Type A and compound 1(a) freebase Type E are slightly hygroscopic with no solid form change after DVS test.

[0615] To evaluate its mechanical force stability, compound 1(a) gentisic acid co crystal Type A was suspended in H₂0 and n-heptane with magnetically stirring and with compound 1(a) freebase Type E as control. Amorphous solid was observed by XRPD testing after freebase Type E was magnetically stirred in H₂0 for 6 days at RT, whereas crystalline samples were still observed for each of: (i) freebase Type E magnetically stirred in «-heptane for 6 days; (ii) compound 1(a) gentisic acid co-crystal Type A magnetically stirred in «-heptane; and (iii) compound 1(a) gentisic acid co-crystal Type A magnetically stirred in H₂0 for 6 days. As a result, gentisic acid co-crystal Type A showed better mechanical force stability than freebase Type E in H₂0.

[0616] Example 2-W: Anhydrate compound 1(a) gentisic acid co-crystal Type B

[0617] Anhydrate compound 1(a) gentisic acid co-crystal Type B may be prepared by a method similar to the method for preparing compound 1(a) gentisic acid co-crystal Type A, but wherein EtOAc is replaced with THF. XRPD results are shown in FIG. 69. Characteristic peak data in degrees 2-theta was shown at angles of 6.6°±0.2°, 7.9°±0.2°, 12.2°±0.2°, l2.4°±0.2°, 14.0°±0.2°, 15.1°±0.2°, 16.3°±0.2°, 21.1°±0.2°, 25.3°±0.2°, and 25.6°±0.2°. The TGA/DSC data of Type B is shown in FIG. 72. A weight loss of 8.6% up to 160 °C was observed in TGA and DSC result showed multiple thermal events before melting/decomposition. Stoichiometry was determined to be 0.95 (acid/freebase) and 6.6% THF (a molar ratio of 0.60 to freebase) was detected by 1H NMR as shown in FIG. 73, suggesting Type B was possibly a THF solvate.

[0618] Example 2-X: Hydrate compound 1(a) picolinamide co-crystal Type A

[0619] Compound 1(a) free base (200.9 mg) and picolinamide (40.3 mg) were combined in a 20 mL glass vial and 2.0 mL EtOAc was then added to form a clear solution. 8.0 mL of «-heptane was charged to the vial followed by about 10 mg of compound 1(a) picolinamide co-crystal Type A seed and a cloudy solution was observed. 10.0 mL «-heptane was added to the vial and a suspension was observed after stirring at RT for 28 hours. Fast evaporation was done with stirring at RT for 17 hours to induce further crystallization. The suspension was filtered and the collected crystals were vacuum dried at RT for 6 hours. XRPD results are shown in FIG. 74 and FIG. 78. As shown in FIG. 75 and FIG. 79, a weight loss of 3.5% up to 65 °C was observed in TGA and DSC result showed a broad endothermic peak at 64.6 °C (onset temperature). Stoichiometry was determined to be 1.19 (acid/freebase) and no significant solvent signal was detected by 'H NMR as shown in FIG. 76 and FIG. 80. As shown in FIG. 77, the sample turned to amorphous after being heated to 75 °C. Based on the characterization date collected, picolinamide co-crystal Type A is believed to be a hydrate with the loss of water being concomitant with degradation and melting.

[0620] Example 2-Y : Preparation of crystalline compound 1(a) free base anhydrate Type AL

[0621] Type AL crystalline compound 1(a) free base anhydrate was obtained via slurry of Type E in EtOAc/n-heptane (v/v, 1 :3) for five days at 50 °C. XRPD pattern is shown in FIG. 81 and TGA/DSC curves are displayed in FIG. 82. Type AL exhibited characteristic peaks at 2- theta at angles of 7.6°±0.2°, 8.4°±0.2°, 13.2°±0.2°, 13.8°±0.2°, 14.8°±0.2°, l5.2°±0.2°, l5.6°±0.2°, l5.9°±0.2°, l6.9°±0.2°, l8. l°±0.2°, 20.5°±0.2°, and 2l.3°±0.2°. The results indicated that Type AL was crystalline with a weight loss of 1.1% before 150 °C in TGA and two endothermic peaks at 93.3 and 147.5 °C (onset) in DSC (with closed lid). When DSC testing was performed with an open lid, the endotherm around 93.3 °C disappeared, suggesting the first endotherm may not be caused by strongly bonded water/solvent. As shown in the 'H NMR spectrum FIG. 83, no EtOAc/n-heptane signal was detected. Thus, under one possible theory, it is believed that the first endotherm observed in FIG. 82 may be caused by surface water.

[0622] Type AL converted to anhydrate Type E after being exposed to ambient conditions (23±2 °C, 70% RH) for three days, indicating anhydrate Type E is

thermodynamically more stable than Type AL at RT (23±2 °C). This may explain the fact that when a Type AL sample was heated to 120 °C and cooled to 30 °C under a nitrogen blanket and then exposed to air, anhydrate Type E was observed.

[0623] Example 2-Z: Preparation of crystalline compound 1(a) free base hydrate Type BO

[0624] Compound 1(a) Type E crystals were slurried in MeOH/H₂0 (v/v, 1 : 1) at 60 °C to form a clear solution. After two days solid material was observed. Based on XRPD comparison, the wet solid material obtained was a new crystalline form, designated as Type BN. Type BO was obtained after the solid Type BN was air dried at ambient conditions for about 1.5 hrs. Their XRPD patterns were shown in FIG. 84. Characteristic peaks expressed in degrees 2-theta were at angles of 12.1°±0.2°, 12.4°±0.2°, 13.9°±0.2°, 15.0°±0.2°, 15.4°±0.2°,

17.1°±0.2°, 18.3°±0.2°, 21.5°±0.2°, 22.1°±0.2°, 24.4°±0.2°, 25.1°±0.2°, 26.2°±0.2°, and 26.3°±0.2°. The DSC curve of Type BO is shown in FIG. 85. The results indicated that Type BO was crystalline with one overlapped endothermic peak at 84.2 °C (onset), and one exothermic peak at 128.5 °C (onset) followed by one sharp endothermic peak at 148.3 °C (peak). Because amorphous material was obtained after heating Type BO to 120 °C and no MeOH signal was detected by 'H NMR shown in FIG. 86, it is believed that Type BO is a hydrate.

[0625] Example 2-AA: Preparation of crystalline compound 1(a) free base «-heptane solvate Type BP

[0626] Compound 1(a) Type E crystals were slurried in isopropyl acetate/n-heptane at 70 °C and isobutyl acetate/n-heptane at 90 °C, respectively. The resulting solid material was characterized by XRPD and TGA/DSC and designated as Type BP with the results shown in FIG. 87 and FIG. 88. Characteristic peaks expressed in degrees 2-theta were at angles of 8.5°±0.2°, l2.9°±0.2°, l7.6°±0.2°, l8.l°±0.2°, l9.4°±0.2°, 20.8°±0.2°, 2l.2°±0.2°, 22.9°±0.2°, and 24.0°±0.2°. Type BP was crystalline with a weight loss of 3.0% up to 140 °C in TGA and a minor endothermic peak at 122.5 °C before the sharp melting/decomposition signal at 147.3 °C (peak) in DSC. Anhydrate Type E was observed after a Type BP sample was heated to 130 °C and cooled to 30 °C under a nitrogen blanket and exposed to air. As shown in the 'H NMR spectrum in FIG. 89, the stoichiometric ratio of «-heptane:API is 0.16: 1 (2.6 wt %). Combined with the form change after heating, it is believed that Type BP is an «-heptane solvate.

[0627] Example 2-AB: Preparation of crystalline compound 1(a) free base 2-pentanol solvate Type BK

[0628] Compound 1(a) Type E crystals were slurried in 2-pentanol/n-heptane (v/v, 2: 1) at 50°C. The resulting solid material was characterized by XRPD and TGA/DSC and designated as Type BK with the results shown in FIG. 90 and FIG. 91. Characteristic peaks expressed in degrees 2-theta were at angles of l l.9°±0.2°, 13.0°±0.2°, 14.4°±0.2°, 14.7°±0.2°, 16.9°±0.2°, 17.9°±0.2°, 19.3°±0.2°, 21.8°±0.2°, 22.7°±0.2°, 23.9°±0.2°, 24.6°±0.2°, and 26.1°±0.2°. The results indicate that Type BK is crystalline with a weight loss of 11.6% before 120 °C in TGA and one sharp melting endotherm at 71.5 °C in DSC (peak). To further identify Type BK, a heating experiment was done at 89 °C and the result indicated that Type BK converted to amorphous form after heating. In addition, around 0.92 molar equivalence of 2-pentanol (15.5 wt.%) was detected in the sample by 'H NMR shown in FIG. 92. Combined with the form change after heating, it is believed that Type BK is a 2-pentanol solvate.

[0629] Example 2-AC: Preparation of crystalline compound 1(a) free base l-propanol solvate Type AX

[0630] Type AX was obtained via fast evaporation of compound 1(a) in 1- propanol/isopropyl acetate (v/v, 5:4) at RT. The resulting solid material was characterized by XRPD and TGA/DSC and designated as type AX with the results shown in FIG. 93 and FIG.

94. Characteristic peaks expressed in degrees 2-theta were at angles of l l.5°±0.2°, l2.9°±0.2°, l3. l°±0.2°, l7.4°±0.2°, l8.2°±0.2°, 23. l°±0.2°, 23.9°±0.2°, and 25.9°±0.2°. The results indicated that Type AX is crystalline with a weight loss of 11.0% before 150 °C in TGA and endothermic peaks at 113.5 °C and 122.0 °C (peak) before decomposition in DSC. To further identify Type AX, a heating experiment was conducted at 118 °C and the result indicated that Type AX converted to amorphous form after heating. In addition, about 0.94 molar equivalence of l-propanol (11.3 wt %) was detected in the sample by 1H NMR shown in FIG. 95. Combined with the heating experiment result, it is believed that Type AX is a l-propanol solvate. [0631] Example 2-AD: Preparation of crystalline compound 1(a) free base /«.-xylene solvate Type Q

[0632] Type Q was obtained via fast evaporation of compound 1(a) in methyl acetate/m-xylene (v/v, 5:4) at RT. The resulting solid material was characterized by XRPD and TGA/DSC and designated Type Q with the results shown in FIG. 96 and FIG. 97. Characteristic peaks expressed in degrees 2-theta were shown at angles of 5.5°±0.2°, 12.5°±0.2°, l5.0°±0.2°, l7.6°±0.2°, 20.2°±0.2°, 22. l°±0.2°, 22.8°±0.2°, and 26.6°±0.2°. The results indicated that Type Q is crystalline with a two-step weight loss of 13.7% before 200 °C in TGA and one endothermic peak at 78.8 °C (peak) before decomposition in DSC. To further identify Type Q, a heating experiment was conducted at 80 °C and the result indicated that Type Q converted to amorphous form after heating. In addition, about 0.73 molar equivalence of /«-xylene (14.9 wt.%) was detected in the sample by 'H NMR shown in FIG. 98. Combined with the heating experiment result, it is believed that Type Q is an /«-xylene solvate.

[0633] Example 2-AE: Preparation of crystalline compound 1(a) free base EGME solvate Type P

[0634] Type P was obtained via fast evaporation of compound 1(a) in EGME/n-heptane (v/v, 1: 1) at RT. The resulting solid material was characterized by XRPD and TGA/DSC and designated Type P with the results showed in FIG. 99 and FIG. 100. Characteristic peaks expressed in degrees 2-theta were shown at angles of 11.9°±0.2°, 12.3°±0.2°, l2.7°±0.2°, l4.0°±0.2°, l7.l°±0.2°, 20.0°±0.2°, 23.9°±0.2°, 24.l°±0.2°, 25.5°±0.2°, 25.8°±0.2°, and 27.2°±0.2°. The results indicated that Type P was crystalline with a weight loss of 13.8% before 150 °C in TGA and two endothermic peaks at 104.7 °C and 142.0 °C (peak) before

decomposition in DSC. To further identify Type P, a heating experiment was conducted at 105 °C and the result indicated that Type P converted to amorphous form after heating. In addition, about 1.03 molar equivalence of EGME (15.1 wt %) was detected in the sample by 'H NMR shown in FIG. 101. Combined with the heating experiment result, it is believed that Type P is an EGME solvate.

[0635] Example 2-AF: Preparation of crystalline compound 1(a) free base sec-butyl alcohol solvate Type AQ

[0636] Type AQ was obtained via fast evaporation of compound 1(a) in sec-butyl alcohol/MTBE (v/v, 5:4) at RT. The resulting solid material was characterized by XRPD and TGA/DSC and designated Type AQ with results shown in FIG. 102 and FIG. 103.

Characteristic peaks expressed in degrees 2-theta were shown at angles of 11.5°±0.2°, l2.7°±0.2°, l2.9°±0.2°, l4. l°±0.2°, l7.4°±0.2°, l7.9°±0.2°, 2l.9°±0.2°, 22.7°±0.2°, 23.l°±0.2°, 23.5°±0.2°, 23.9°±0.2°, 25.5°±0.2°, and 27.6°±0.2°. The results indicated that Type AQ was crystalline with a weight loss of 16.3% before 120 °C in TGA and two endothermic peaks at 99.7 °C and 110.8 °C (peak) before decomposition. To further identify Type AQ, a heating experiment was conducted at l08°C and the result indicated that Type AQ converted to amorphous form after heating. In addition, about 0.92 molar equivalence of .sec-butyl alcohol (13.1 wt.%) was detected in the sample by 'H NMR shown in FIG. 104. Combined with the heating experiment result, it is believed that Type AQ is a sec-butyl alcohol solvate.

[0637] This written description uses examples to disclose the invention, including the best mode, and also to enable any person skilled in the art to practice the invention, including making and using any devices or systems and performing any incorporated methods. The patentable scope of the invention is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements with insubstantial differences from the literal languages of the claims.

Claims

WHAT IS CLAIMED IS:

1. A process for preparing compound 3, the process comprising:

(i) reacting compound 1 with a sulfonating reagent in a solvent to form compound 2

according to step 1, where Y is an arylsulfonyl or alkylsulfonyl group

Compound 1 Compound 2 and

(ii) reacting compound 2 with a nitrogen source in a solvent to form compound 3 according to step 2

p

wherein:

compound 3 is a free base;

the yield of compound 3 based on compound 1 is at least 30%;

R¹ is selected from halo, halo-Ci-4 alkyl-, halo-Ci-4 alkoxy-, and -CN; and

R² is selected from H and cyclopropyl-.

2. The process of claim 1 wherein R¹ is selected from -F, -CF₃, -CHF₂, -OCF₃, -OCHF₂, - OCH₂CF₃, and -CN.

3. The process of claim 2 wherein R¹ is -CF₃.

4. The process of any one of claims 1 to 3 wherein R² is H.

5. The process of any one of claims 1 to 4 wherein the sulfonating reagent: (i) is a sulfonate ester; (ii) is selected from mesylate chloride and tosylate chloride; or (iii) is mesylate chloride.

6. The process of any one of claims 1 to 5 wherein the step 1 reaction further comprises a base.

7. The process of claim 6 wherein the base for step 1 is (i) an amine base, or (ii) an amine base selected from trimethylamine, diisopropylethylamine, tributylamine and octylamine.

8. The process of any one of claims 1 to 7 wherein the solvent for step 1: (i) comprises or is polar aprotic solvent; (ii) is selected from one or more of 2-methyltetrahydrofuran,

tetrahydrofuran, ethyl acetate, propyl acetate, acetone, dimethylformamide, acetonitrile, and dimethyl sulfoxide; (iii) is selected from 2-methyltetrahydrofuran and tetrahydrofuran; or (iv) is 2-methyltetrahydrofuran.

9. The process of any one of claims 1 to 8 wherein the nitrogen source for step 2 is ammonia or an ammonium salt.

10. The process of any one of claims 1 to 9 wherein the solvent for step 2: (i) comprises or is a polar organic solvent; (ii) is selected from one or more of methanol, ethanol, 1 -propanol, 2- propanol, 1 -butanol, formic acid, acetic acid, 2-methyltetrahydrofuran, tetrahydrofuran, ethyl acetate, propyl acetate, acetone, dimethylformamide, acetonitrile, and dimethyl sulfoxide; (iii) is selected from one or more of methanol, ethanol, 1 -propanol and 2-propanol; or (iv) is methanol.

11. The process of any one of claims 1 to 10 further comprising a purification step wherein compound 3 is purified by :

(i) solvent exchange from the step 2 solvent to a non-polar solvent having a dielectric

constant of greater than 2 to form a first solution of compound 3 in the non-polar solvent;

(ii) precipitation of solid compound 3 from the first solution by addition of an acid followed by isolation of solid compound 3 and optional washing of isolated solid compound 3;

(iii) dissolution of compound 3 in a non-polar solvent having a dielectric constant of greater than 2 by addition of a base to form a second solution of compound 3 in the non-polar solvent;

(iv) precipitation of solid compound 3 free base from the second solution by addition of an anti-solvent, or concentration by non-polar solvent removal, or a combination thereof; and

(v) isolation of purified compound 3 as a free base.

12. The process of claim 11 wherein the non-polar solvent having a dielectric constant of greater than 2: (i) is selected from one or more of methyl tert-butyl ether, diethyl ether, toluene, l,4-dioxane and chloroform; (ii) is selected from one or both of methyl tert-butyl ether and diethyl ether; or (iii) is methyl tert-butyl ether.

13. The process of claim 11 or 12 wherein the acid for precipitating compound 3: (i) is an organic acid; (ii) is a carboxylic acid; (iii) is selected from one or more of formic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, butanedioic acid, and adipic acid; or (iv) is oxalic acid.

14. The process of any one of claims 11 to 13 wherein the anti-solvent: (i) has a dielectric constant of less than 2; (ii) is selected from one or more of «-pentane, «-hexane, «-heptane and cyclopentane; or (iii) is «-heptane.

15. The process of any one of claims 1 to 14 wherein the yield of compound 3 based on compound 1 is at least 40%, at least 50%, at least 60%, at least 70%, or at least 80%.

16. The process of claim any one of claims 1 to 15 further comprising forming compound 6 from compound 3 by a process comprising:

(i) reacting compound 3, compound 4, and a coupling reagent in a solvent to form

compound 5 according to step 3

wherein

each asterisk denotes a chiral center, and

PG denotes an amine protecting group; and

(ii) reacting compound 5 and an acidic deprotecting reagent in a solvent to form compound 6 according to step 4 below

wherein

R³ is Ci alkyl- and R⁴ is selected from H and -F, or

R³ and R⁴ together with the ring atoms to which they are attached form a three- membered carbocyclic ring.

17. The process of claim 16 wherein R³ is -CH₃ and R⁴ is -F.

18. The process of claim 16 or 17 wherein the step 3 reaction further comprises a base and the amine protecting group: (i) is selected from acetyl trifluoroacetyl, t-butoxy carbonyl, benzyloxy carbonyl and 9-fluorenylmethyleneoxy carbonyl; or (ii) is t-butoxy carbonyl.

19. The process of claim 18 wherein the base for step 3: (i) is an organic base; (ii) is a tertiary amine base; (iii) is selected from N-methyl-morpholine, diisopropylethylamine and triethylamine; or (iv) is N-methyl-morpholine.

20. The process of any one of claims 16 to 19 wherein the coupling reagent: (i) is selected from propane phosphonic acid anhydride; l-[Bis(dimethylamino)methylene]-lH-l,2,3- triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; 2-(lH-benzotriazol-l-yl)-l, 1,3,3- tetramethyluronium hexafluorophosphate; N,N'-dicyclohexylcarbodiimide; benzotriazol-l- yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; benzotriazol-l-yl- oxytripyrrolidinophosphonium hexafluorophosphate; 1.1 '-carbonyldiimidazole: l-ethyl-3-(3- dimethylaminopropyl)carbodiimide and hydroxybenzotriazole; and l-ethyl-3-(3- dimethylaminopropyl)carbodiimide and 4-dimethylaminopyridine; or (ii) is propane phosphonic acid anhydride.

21. The process of any one of claims 16 to 20 wherein the solvent for step 3: (i) comprises or is a polar aprotic solvent; (ii) is selected from is selected from one or more of -2- methyltetrahydrofuran, tetrahydrofuran, ethyl acetate, propyl acetate, acetone,

dimethylformamide, acetonitrile, and dimethyl sulfoxide; or (iii) is selected from one or both of ethyl acetate and propyl acetate.

22. The process of claim 21 wherein step 3 further comprises:

(i) a solvent exchange from the polar aprotic solvent to a polar protic solvent; and

(ii) precipitation of solid compound 5 by addition of an anti-solvent.

23. The process of claim 22 wherein the polar protic solvent: (i) is selected from one or more of methanol, ethanol, 1 -propanol, 2-propanol, 1 -butanol, formic acid and acetic acid; (ii) is selected from one or more of methanol, ethanol, 1 -propanol and 2-propanol; or (iii) is ethanol.

24. The process of any one of claims 16 to 23 wherein the acidic deprotecting reagent is: (i) an organic acid or an inorganic acid; (ii) an acyl halide or a mineral acid; (iii) an acyl chloride selected from acetyl chloride, formyl chloride, propionyl chloride and butyryl chloride or a mineral acid selected from hydrochloric acid and sulfuric acid; or (iv) is acetyl chloride.

25. The process of any one of claims 16 to 24 wherein the solvent for step 4: (i) comprises or is a polar protic solvent; (ii) is selected from one or more of methanol, ethanol, 1 -propanol, 2- propanol, 1 -butanol, formic acid and acetic acid; (iii) is selected from one or more of methanol, ethanol, 1 -propanol and 2-propanol; or (iv) is 1 -propanol.

26. The process of any one of claims 16 to 25 wherein compound 6 is in solution and step 4 further comprises forming a slurry of solid compound 6 by the addition of an anti-solvent, wherein the anti-solvent: (i) has a dielectric constant of less than 2; (ii) is selected from one or more of «-pentane, «-hexane, «-heptane and cyclopentane; or (iii) is «-heptane.

27. The process of any one of claims 16 to 26 further comprising forming crystalline compound I, or a solvate or co-crystal thereof, from compound 6, by a process comprising:

(i) reacting compound 6, compound 7, and a base in a solvent system to form compound (I) according to the step 5 below

■ c d

Compound 6 Step 5

Compound (I)

wherein:

R⁵ is halo;

Xi and X₂ are each C, or one of Xi and X₂ is N and the other is C; and

n is 1 or 2.

28. The process of claim 27 further comprising:

(i) forming a solution of compound (I) by solvent exchange transfer of compound (I) from the solvent system into an organic solvent selected from

(a) a non-polar solvent having a dielectric constant of greater than 2,

(b) a polar aprotic solvent, or

(c) a polar protic solvent; and

(ii) contacting the solution of compound (I) with an anti-solvent to form a slurry of a solvate of crystalline compound (I) with the non-polar solvent having a dielectric constant of greater than 2, polar aprotic solvent or polar protic solvent.

29. The process of claim 27 or claim 28 wherein the anti-solvent has a dielectric constant of less than 2, or is selected from «-pentane, «-hexane and «-heptane, or is «-heptane.

30. The process of any one of claims 27 to 29 wherein the base: (i) is an aqueous solution of an inorganic base; (ii) is selected from an aqueous solution of alkali metal hydroxide, ammonium hydroxide, potassium carbonate and, sodium carbonate; or (iii) is an aqueous solution of potassium carbonate or sodium carbonate.

31. The process of any one of claims 27 to 30 wherein the solvent system for step 5: (i) comprises or is a non-polar solvent having a dielectric constant of greater than 2; (ii) is selected from one or more of methyl tert-butyl ether, diethyl ether, 1 ,4-dioxane and chloroform; (iii) is selected from methyl tert-butyl ether and diethyl ether; or (iv) is methyl tert-butyl ether.

32. The process of any one of claims 28 to 31 wherein the organic solvent for the solvent exchange and forming a solution of compound (I) is selected from:

(i) N,N-dimethylacetamide, and crystalline compound (I) N,N-dimethylacetamide solvate Type C is formed;

(ii) anisole, and crystalline compound (I) anisole solvate Type D is formed;

(iii) ethanol, and crystalline compound (I) ethanol solvate Type F is formed;

(iv) toluene, and crystalline compound (I) toluene solvate Type G is formed;

(v) 2-propanol, and crystalline compound (I) 2-propanol solvate Type H is formed;

(vi) 1 -butanol, and crystalline compound (I) 1 -butanol solvate Type I is formed;

(vii) 2-methyltetrahydrofuran, and crystalline compound (I) 2-methyltetrahydrofuran solvate Type J is formed;

(viii) tetrahydrofuran, and crystalline compound (I) tetrahydrofuran solvate Type K is formed;

(ix) isobutyl alcohol, and crystalline compound (I) isobutyl alcohol solvate Type L is formed; and

(x) dimethyl sulfoxide, and crystalline compound (I) dimethyl sulfoxide solvate Type M is formed.

33. The process of any one of claims 28 to 32 wherein the organic solvent for the solvent exchange and forming a solution of compound (I) is ethanol.

34. The process of any one of claims 28 to 33 further comprising: (i) dissolving the compound (I) solvate in dichloromethane and (ii) contacting the solution of compound (I) in dichloromethane with an anti-solvent to form a slurry of a solvate of crystalline compound (I) and the anti-solvent,

wherein the anti-solvent: (i) is a non-polar surfactant having a dielectric constant of less than 2; (ii) is selected from n-pentane, «-hexane and «-heptane; or (iii) is «-heptane.

35. The process of claim 34 wherein the organic solvent for the solvent exchange and forming a solution of compound (I) is ethanol, the anti-solvent is «-heptane, and crystalline compound (I) is free base anhydrate Type E.

36. The process of any one of claims 16 to 35 wherein:

(i) compound 4 is of the structure 4(a)

Compound 4(a) ;

(n) compound 5 is of the structure 5(a)

Compound 5(a) ; and

(iii) compound 6 is of the structure 6(a)

Compound 6(a)

37. The process of any one of claims 27 to 36 wherein compound (I) is of the structure 1(a):

B_,

38. A process for preparing crystalline compound I, or a solvate or co-crystal thereof, the process comprising:

(i) reacting compound 6 acid salt, compound 7, and a base in a solvent system to form compound I as follows

Compound (I)

wherein,

R¹ is selected from halo, halo-Ci-4 alkyl-, halo-Ci-4 alkoxy-, and -CN,

R² is selected from H and -cyclopropyl,

R³ is Ci-4 alkyl- and R⁴ is selected from H and -F, or R³ and R⁴ together with the ring atoms to which they are attached form a three-membered carbocyclic ring,

R⁵ is halo,

Xi and X₂ are each C, or one of Xi and X₂ is N and the other is C,

n is 1 or 2, and

each asterisk represents a chiral center;

(ii) forming a solution of compound (I) by solvent exchange transfer of compound (I) from the solvent system of reaction step (i) into an organic solvent selected from

(a) a non-polar solvent having a dielectric constant of greater than 2,

(b) a polar aprotic solvent, or

(c) a polar protic solvent; and

(iii) contacting the solution of compound (I) with an anti-solvent to form a slurry of crystalline compound (I).

39. The process of claim 38 wherein crystalline compound (I) is a solvate with the non-polar solvent having a dielectric constant of greater than 2, polar aprotic solvent or polar protic solvent.

40. The process of claim 38 or claim 39 wherein R¹ is selected from -F, -CF₃, -CHF₂, -OCF₃, -OCHF₂, -OCH₂CF₃, and -CN.

41. The process of claim 40 wherein R¹ is -CF₃.

42. The process of any one of claims 38 to 41 wherein R² is H.

43. The process of any one of claims 38 to 42 wherein R³ is -CH₃ and R⁴ is -F.

44. The process of claim any one of claims 38 to 43 wherein R⁵ is -F, Xi and X₂ are each C, and n is 1.

45. The process of any one of claims 38 to 44 wherein the anti-solvent has a dielectric constant of less than 2, or is selected from «-pentane, «-hexane and «-heptane, or is «-heptane.

46. The process of any one of claims 38 to 45 wherein the base: (i) is an aqueous solution of an inorganic base; (ii) is selected from an aqueous solution of alkali metal hydroxide, ammonium hydroxide, potassium carbonate and, sodium carbonate; or (iii) is an aqueous solution of potassium carbonate or sodium carbonate.

47. The process of any one of claims 38 to 40 wherein the solvent system for forming compound (I): (i) comprises or is a non-polar solvent has a dielectric constant of greater than 2;

(ii) is selected from one or more of methyl tert-butyl ether, diethyl ether, l,4-dioxane and chloroform; (iii) is selected from methyl tert-butyl ether and diethyl ether; or (iv) is methyl tert- butyl ether.

48. The process of any one of claims 38 to 47 wherein the organic solvent for the solvent exchange and forming a solution of compound (I) is selected from:

(ii) anisole, and crystalline compound (I) anisole solvate Type D is formed;

(iii) ethanol, and crystalline compound (I) ethanol solvate Type F is formed;

(iv) toluene, and crystalline compound (I) toluene solvate Type G is formed;

(viii) tetrahydrofuran, and crystalline compound (I) tetrahydrofuran solvate Type K is formed; (ix) isobutyl alcohol, and crystalline compound (I) isobutyl alcohol solvate Type L is formed; and

49. The process of any one of claims 38 to 48 wherein the organic solvent for the solvent exchange and forming a solution of compound (I) is ethanol.

50. The process of any one of claims 38 to 49 further comprising: (i) dissolving the compound (I) or a solvate thereof in dichloromethane and (ii) contacting the solution of compound (I) in dichloromethane with an anti-solvent to form a slurry of a solvate of crystalline compound (I) and the anti-solvent,

51. The process of claim 50 wherein the organic solvent for the solvent exchange and forming a solution of compound (I) is ethanol, the anti-solvent is «-heptane, and crystalline compound (I) is free base anhydrate Type E.

52. The process of claim any one of claims 38 to 51 further comprising forming compound 6, the process comprising:

compound 5 according to the following step

wherein

PG denotes an amine protecting group; and

(ii) reacting compound 5 and an acidic deprotecting reagent in a solvent to form compound 6 according to the following step

53. The process of claim 52 wherein the reaction for forming compound 5 further comprises a base and the amine protecting group: (i) is selected from acetyl trifluoroacetyl, t- butoxy carbonyl, benzyloxy carbonyl and 9-fluorenylmethyleneoxy carbonyl; or (ii) is t- butoxy carbonyl.

54. The process of claim 53 wherein the base: (i) is an organic base; (ii) is a tertiary amine base, (iii) is selected from N-methyl-morpholine, diisopropylethylamine and triethylamine; or (iv) is N-methyl-morpholine.

55. The process of any one of claims 52 to 54 wherein the coupling reagent: (i) is selected from propane phosphonic acid anhydride; l-[Bis(dimethylamino)methylene]-lH-l,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate; 2-(lH-benzotriazol-l-yl)-l, 1,3,3- tetramethyluronium hexafluorophosphate; N,N'-dicyclohexylcarbodiimide; benzotriazol-l- yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; benzotriazol-l-yl- oxytripyrrolidinophosphonium hexafluorophosphate; l,r-carbonyldiimidazole; l-ethyl-3-(3- dimethylaminopropyl)carbodiimide and hydroxybenzotriazole; and l-ethyl-3-(3- dimethylaminopropyl)carbodiimide and 4-dimethylaminopyridine; or (ii) is propane phosphonic acid anhydride.

56. The process of any one of claims 52 to 55 wherein the solvent for forming compound 5: (i) is a polar aprotic solvent; (ii) is selected from is selected from one or more of 2- methyltetrahydrofuran, tetrahydrofuran, ethyl acetate, propyl acetate, acetone,

57. The process of claim 56 wherein the step for forming compound 5 further comprises:

(i) a solvent exchange from the polar aprotic solvent to a polar protic solvent, and

(ii) precipitation of solid compound 5 by addition of an anti-solvent.

58. The process of claim 57 wherein the polar protic solvent in the step for forming compound 5: (i) is selected from one or more of methanol, ethanol, 1 -propanol, 2-propanol, 1- butanol, formic acid and acetic acid; (ii) is selected from one or more of methanol, ethanol, 1- propanol and 2-propanol; or (iii) is ethanol.

59. The process of any one of claims 52 to 58 wherein the acidic deprotecting reagent is: (i) an organic acid or an inorganic acid; (ii) an acyl halide or a mineral acid; (iii) an acyl chloride selected from acetyl chloride, formyl chloride, propionyl chloride and butyryl chloride or a mineral acid selected from hydrochloric acid and sulfuric acid; or (iv) is acetyl chloride.

60. The process of any one of claims 52 to 59 wherein the solvent for deprotecting compound 5: (i) comprises or is a polar protic solvent; (ii) is selected from one or more of methanol, ethanol, 1 -propanol, 2-propanol, 1 -butanol, formic acid and acetic acid; (iii) is selected from one or more of methanol, ethanol, i-propanol and 2-propanol; or (iv) is 1- propanol.

61. The process of any one of claims 52 to 60 wherein compound 6 is in solution and the process further comprises forming a slurry of solid compound 6 by the addition of an anti solvent, wherein the anti-solvent: (i) has a dielectric constant of less than 2; (ii) is selected from one or more of «-pentane, «-hexane, «-heptane and cyclopentane; or (iii) is «-heptane.

62. The process of any one of claims 52 to 61 further comprising forming compound 3, the process comprising:

(i) reacting compound 1, and a sulfonating reagent in a solvent to form compound 2 according to step 2 below where Y is an arylsulfonyl or alkylsulfonylgroup

Compound 1 Compound 2

; and

(ii) reacting compound 2 and a nitrogen source in a solvent to form compound 3 according to the step below wherein compound 3 is a free base

R²

p

63. The process of claim 62 wherein the sulfonating reagent: (i) is a sulfonate ester; (ii) is selected from mesylate chloride and tosylate chloride; or (iii) is mesylate chloride.

64. The process of claim 62 or claim 63 wherein the mixture for forming compound 2 further comprises a base.

65. The process of claim 64 wherein the base is an amine base, or an amine base selected from trimethylamine, diisopropylethylamine, tributylamine and octylamine.

66. The process of any one of claims 62 to 65 wherein the solvent for the reaction for forming compound 2: (i) is a polar aprotic solvent; (ii) is selected from one or more of 2- methyltetrahydrofuran, tetrahydrofuran, ethyl acetate, propyl acetate, acetone,

dimethylformamide, acetonitrile, and dimethyl sulfoxide; (iii) is selected from 2- methyltetrahydrofuran, tetrahydrofuran; or (iv) is 2-methyltetrahydrofuran.

67. The process of any one of claims 62 to 66 wherein the nitrogen source for the reaction for forming compound 3 is ammonia or an ammonium salt.

68. The process of any one of claims 62 to 67 wherein the solvent for the reaction for forming compound 3: (i) comprises or is a polar organic solvent; (ii) is selected from one or more of methanol, ethanol, 1 -propanol, 2-propanol, 1 -butanol, formic acid, acetic acid, 2- methyltetrahydrofuran, tetrahydrofuran, ethyl acetate, propyl acetate, acetone, dimethylformamide, acetonitrile, and dimethyl sulfoxide; (iii) is selected from one or more of methanol, ethanol, 1 -propanol and 2-propanol; or (iv) is methanol.

69. The process of any one of claims 62 to 68 further comprising a purification step wherein compound 3 is purified by the following order of steps:

(i) solvent exchange from the solvent for the reaction for forming compound 3 to a non polar solvent having a dielectric constant of greater than 2 to form a first solution of compound 3 in the non-polar solvent;

(ii) precipitation of solid compound 3 from solution by addition of an acid followed by

isolation of solid compound 3 and optional washing of isolated solid compound 3;

(iv) precipitation of solid compound 3 free base from the second solution by addition of an anti-solvent, concentration by non-polar solvent removal, or a combination thereof; and

(v) isolation of purified compound 3 free base.

70. The process of claim 69 wherein the non-polar solvent having a dielectric constant of greater than 2: (i) is selected from one or more of methyl tert-butyl ether, diethyl ether, toluene, l,4-dioxane and chloroform; (ii) is selected from one or both of methyl tert-butyl ether and diethyl ether; or (iii) is methyl tert-butyl ether.

71. The process of claim 69 or claim 70 wherein the acid for precipitation compound 3 is: (i) an organic acid; (ii) is a carboxylic acid; (iii) is selected from one or more of formic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, butanedioic acid, and adipic acid; or (iv) is oxalic acid.

72. The process of any one of claims 69 to 71 wherein the anti-solvent: (i) has a dielectric constant of less than 2; (ii) is selected from one or more of «-pentane, «-hexane, «-heptane and cyclopentane; or (iii) is «-heptane.

73. The process of any one of claims 62 to 72 wherein the yield of compound 3 based on compound 1 is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80%.

74. The process of any one of claims 52 to 73 wherein: (i) compound 4 is of the structure 4(a)

; and ^ComP°und 4(a)

(ii) compound 5 is of the structure 5(a)

Compound 5(a)

75. The process of any one of claims 38 to 74 wherein:

(i) compound 6 is of the structure 6(a)

(11) compound (I) is of the structure 1(a):

Compound 1(a)

76. A crystalline (2_<S',4i?,5_<S')-4-fluoro-l-(4-fluorophenylsulfonyl)-5-methyl- V-((5- (trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridine-4-yl)methyl)pyrrolidine-2- carboxamide compound.

77. The compound of claim 76, wherein the compound is free base anhydrate polymorph Type E exhibiting an XRPD pattern having at least three, at least four or at least five, characteristic peaks expressed in degrees 2-theta at angles of 7.5°±0.2°, 8.2°±0.2°, l2.6°±0.2°, 13.1°±0.2°, 13.4°±0.2°, 14.7°±0.2°, 15.1°±0.2°, 15.5°±0.2°, 16.1°±0.2°, 16.6°±0.2°, l8.2°±0.2°, l8.9°±0.2°, l9.9°±0.2°, 20.4°±0.2°, 2l.0°±0.2°, 2l.5°±0.2°, 2l.8°±0.2°, 22.4°±0.2°, 22.7°±0.2°,

24.3°±0.2°, 25.0°±0.2°, 25.4°±0.2°, and 28.4°±0.2°.

78. The compound of claim 76 or claim 77, wherein the compound is free base anhydrate polymorph Type E having a powder X-ray diffraction pattern in accordance with FIG. 10.

79. The compound of any one of claims 76 to 78, wherein the compound is free base anhydrate polymorph Type E having a thermo-gravimetric analysis curve and/or a differential scanning calorimetry curve in accordance with FIG. 11.

80. The compound of claim 76, wherein the compound is free base hydrate polymorph Type A exhibiting an XRPD pattern having at least three, at least four or at least five, characteristic peaks expressed in degrees 2-theta at angles of 7.2°±0.2°, 12.2°±0.2°, 14.0°±0.2°, l4.2°±0.2°, l5.5°±0.2°, l5.8°±0.2°, l7.0°±0.2°, l7.2°±0.2°, l8.4°±0.2°, 2l.3°±0.2°, 2l.6°±0.2°, 22.2°±0.2°, 23.4°±0.2°, 24.4°±0.2°, and 25.2°±0.2°.

81. The compound of claim 76 or claim 80, wherein the compound is free base hydrate polymorph Type A having a powder X-ray diffraction pattern in accordance with FIG. 6.

82. The compound of any one of claims 76, 80 or 81, wherein the compound is free base hydrate polymorph Type A having a thermo-gravimetric analysis curve and/or a differential scanning calorimetry curve in accordance with FIG. 7.

83. The compound of claim 76, wherein the compound is free base dimethylacetamide solvate polymorph Type C exhibiting an XRPD pattern having at least three, at least four or at least five, characteristic peaks expressed in degrees 2-theta at angles of l0.8°±0.2°, l2. l°±0.2°, 12.3°±0.2°, 13.6°±0.2°, 13.8°±0.2°, 14.9°±0.2°, 16.0°±0.2°, 16.2°±0.2°, 17.1°±0.2°, l8.2°±0.2°, 2l.2°±0.2°, 2l.5°±0.2°, 22.4°±0.2°, 2l.2°±0.2°, 23.5°±0.2°, 24.2°±0.2°, 25.2°±0.2°, 27.2°±0.2°.

84. The compound of claim 76 or claim 83, wherein the compound is free base

dimethylacetamide solvate polymorph Type C having a powder X-ray diffraction pattern in accordance with FIG. 25.

85. The compound of any one of claims 76, 83 or 84, wherein the compound is free base dimethylacetamide solvate polymorph Type C having a thermo-gravimetric analysis curve and/or a differential scanning calorimetry curve in accordance with FIG. 26.

86. The compound of claim 76, wherein the compound is free base anisole solvate polymorph Type D exhibiting an XRPD pattern having at least three, at least four or at least five, characteristic peaks expressed in degrees 2-theta at angles of 5.7°±0.2°, l2.8°±0.2°, 15.4°±0.2°, 17.1°±0.2°, l8. l°±0.2° and 20.8°±0.2°.

87. The compound of claim 76 or claim 86, wherein the compound is free base anisole solvate polymorph Type D having a powder X-ray diffraction pattern in accordance with FIG. 28.

88. The compound of any one of claims 76, 86 or 87, wherein the compound is free base anisole solvate polymorph Type D having a thermo-gravimetric analysis curve and/or a differential scanning calorimetry curve in accordance with FIG. 29.

89. The compound of claim 76, wherein the compound is free base ethyl alcohol solvate polymorph Type F exhibiting an XRPD pattern having at least three, at least four or at least five, characteristic peaks expressed in degrees 2-theta at angles of 11.7°±0.2°, l2.9°±0.2°, l3.3°±0.2°, l7.4°±0.2°, l8.5°±0.2°, l9.4°±0.2°, 23.5°±0.2°, 24.3°±0.2° and 25.9°±0.2°.

90. The compound of claim 76 or claim 89, wherein the compound is free base ethyl alcohol solvate polymorph Type F having a powder X-ray diffraction pattern in accordance with FIG.

32.

91. The compound of any one of claims 76, 89 or 90, wherein the compound is free base ethyl alcohol solvate polymorph Type F having a thermo-gravimetric analysis curve and/or a differential scanning calorimetry curve in accordance with FIG. 33.

92. The compound of claim 76, wherein the compound is free base toluene solvate polymorph Type G exhibiting an XRPD pattern having at least three, at least four or at least five, characteristic peaks expressed in degrees 2-theta at angles of 13.8°±0.2°, l6.7°±0.2°, l7.6°±0.2°, l7.8°±0.2°, l8.8°±0.2°, 22.5°±0.2° and 25.1 °±0.2°.

93. The compound of claim 76 or claim 92, wherein the compound is free base toluene solvate polymorph Type G having a powder X-ray diffraction pattern in accordance with FIG.

36.

94. The compound of any one of claims 76, 92 or 93, wherein the compound is free base toluene solvate polymorph Type G having a thermo-gravimetric analysis curve and/or a differential scanning calorimetry curve in accordance with FIG. 37.

95. The compound of claim 76, wherein the compound is free base isopropyl alcohol solvate polymorph Type H exhibiting an XRPD pattern having at least three, at least four or at least five, characteristic peaks expressed in degrees 2-theta at angles of 11.5°±0.2°, l2.8°±0.2°, l3. l°±0.2°, l7.5°±0.2°, l8.2°±0.2°, 22.3°±0.2°, 23.2°±0.2° and 24.0°±0.2°.

96. The compound of claim 76 or claim 95, wherein the compound is free base isopropyl alcohol solvate polymorph Type H having a powder X-ray diffraction pattern in accordance with FIG. 40.

97. The compound of any one of claims 76, 95 or 96, wherein the compound is free base isopropyl alcohol solvate polymorph Type H having a thermo-gravimetric analysis curve and/or a differential scanning calorimetry curve in accordance with FIG. 41.

98. The compound of claim 76, wherein the compound is free base l-butyl alcohol solvate polymorph Type I exhibiting an XRPD pattern having at least three, at least four or at least five, characteristic peaks expressed in degrees 2-theta at angles of 12.0°±0.2°, l2.4°±0.2°,

12.6°±0.2°, 13.3°±0.2°, 14.0°±0.2°, 15.1°±0.2°, 17.2°±0.2°, 17.9°±0.2°, 18.3°±0.2°, l9.7°±0.2°, l9.9°±0.2°, 23.l°±0.2°, 24.3°±0.2°, 25.4°±0.2°, 25.9°±0.2° and 27.3°±0.2°.

99. The compound of claim 76 or claim 98, wherein the compound is free base l-butyl alcohol solvate polymorph Type I having a powder X-ray diffraction pattern in accordance with FIG. 44.

100. The compound of any one of claims 76, 98 or 99, wherein the compound is free base 1- butyl alcohol solvate polymorph Type I having a thermo-gravimetric analysis curve and/or a differential scanning calorimetry curve in accordance with FIG. 45.

101. The compound of claim 76, wherein the compound is free base 2-methyl tetrahydrofuran solvate polymorph Type J exhibiting an XRPD pattern having at least three, at least four or at least five, characteristic peaks expressed in degrees 2-theta at angles of 11.8°±0.2°, 13. l°±0.2°,

14.5°±0.2°, 16.8°±0.2°, 18.4°±0.2°, 19.4°±0.2°, 20.7°±0.2°, 21.8°±0.2°, 24.3°±0.2° and 26.4°±0.2°.

102. The compound of claim 76 or claim 101, wherein the compound is free base 2-methyl tetrahydrofuran solvate polymorph Type J having a powder X-ray diffraction pattern in accordance with FIG. 47.

103. The compound of any one of claims 76, 101 or 102, wherein the compound is free base 2-methyl tetrahydrofuran solvate polymorph Type J having a thermo-gravimetric analysis curve and/or a differential scanning calorimetry curve in accordance with FIG. 48.

104. The compound of claim 76, wherein the compound is free base tetrahydrofuran solvate polymorph Type K exhibiting an XRPD pattern having at least three, at least four or at least five, characteristic peaks expressed in degrees 2-theta at angles of 11.0°±0.2°, l2.0°±0.2°, 12.4°±0.2°, 12.6°±0.2°, 13.3°±0.2°, 13.5°±0.2°, 14.1°±0.2°, 14.7°±0.2° , l7.2°±0.2°, l8.5°±0.2°, l9.5°±0.2°, 20.9°±0.2°, 2l.4°±0.2°, 2l.6°±0.2°, 22.0°±0.2°, 22.2°±0.2°, 22.9°±0.2°,

24.8°±0.2°, 27.l°±0.2°, 27.4°±0.2° and 28.3°±0.2°.

105. The compound of claim 76 or claim 104, wherein the compound is free base

tetrahydrofuran solvate polymorph Type K having a powder X-ray diffraction pattern in accordance with FIG. 50.

106. The compound of any one of claims 76, 104 or 105, wherein the compound is free base tetrahydrofuran solvate polymorph Type K having a thermo-gravimetric analysis curve and/or a differential scanning calorimetry curve in accordance with FIG. 51.

107. The compound of claim 76, wherein the compound is free base isobutyl alcohol solvate polymorph Type L exhibiting an XRPD pattern having at least three, at least four or at least five, characteristic peaks expressed in degrees 2-theta at angles of 11.6°±0.2°, l2.8°±0.2°, l3. l°±0.2°, l4.2°±0.2°, l7.5°±0.2°, l8. l°±0.2°, 22.8°±0.2°, 23. l°±0.2°, 24.0°±0.2° and 25.3°±0.2°.

108. The compound of claim 76 or claim 107, wherein the compound is free base isobutyl alcohol solvate polymorph Type L having a powder X-ray diffraction pattern in accordance with FIG. 53.

109. The compound of any one of claims 76, 107 or 108, wherein the compound is free base isobutyl alcohol solvate polymorph Type L having a thermo-gravimetric analysis curve and/or a differential scanning calorimetry curve in accordance with FIG. 54.

110. The compound of claim 76, wherein the compound is free base dimethyl sulfoxide solvate polymorph Type M exhibiting an XRPD pattern having at least three, at least four or at least five, characteristic peaks expressed in degrees 2-theta at angles of 12.1°±0.2°, l3.4°±0.2°, l4.7°±0.2°, l8.4°±0.2°, 20.9°±0.2°, 2l.5°±0.2°, 24.9°±0.2°, 26.8°±0.2° and 27.6°±0.2°.

111. The compound of claim 76 or claim 110, wherein the compound is free base dimethyl sulfoxide solvate polymorph Type M having a powder X-ray diffraction pattern in accordance with FIG. 56.

112. The compound of any one of claims 76, 110 or 111, wherein the compound is free base dimethyl sulfoxide solvate polymorph Type M having a thermo-gravimetric analysis curve and/or a differential scanning calorimetry curve in accordance with FIG. 57.

113. The compound of claim 76, wherein the compound is an anhydrate gentisic acid co crystal polymorph Type A exhibiting an XRPD pattern having at least three, at least four or at least five, characteristic peaks expressed in degrees 2-theta at angles of 12.5°±0.2°, l3.0°±0.2°, l4.4°±0.2°, l5.7°±0.2°, l7.5°±0.2°, 2l.7°±0.2°, 25.5°±0.2°, and 26.3°±0.2°.

114. The compound of claim 76 or claim 113, wherein the compound is an anhydrate gentisic acid co-crystal polymorph Type A having a powder X-ray diffraction pattern in accordance with FIG. 66.

115. The compound of any one of claims 76, 113 or 114, wherein the compound is an anhydrate gentisic acid co-crystal polymorph Type A having a thermo-gravimetric analysis curve and/or a differential scanning calorimetry curve in accordance with FIG. 67.

116. The compound of claim 76, wherein the compound is an anhydrate gentisic acid co crystal polymorph Type B exhibiting an XRPD pattern having at least three, at least four or at least five, characteristic peaks expressed in degrees 2-theta at angles of degrees 2-theta at angles of 6.6°±0.2°, 7.9°±0.2°, l2.2°±0.2°, l2.4°±0.2°, l4.0°±0.2°, l5. l°±0.2°, l6.3°±0.2°, 2l.l°±0.2°, 25.3°±0.2°, and 25.6°±0.2°.

117. The compound of claim 76 or claim 116, wherein the compound is an anhydrate gentisic acid co-crystal polymorph Type B having a powder X-ray diffraction pattern in accordance with FIG. 69.

118. The compound of claim 76, wherein the compound is a hydrate picolinamide co-crystal polymorph Type A exhibiting an XRPD pattern having at least three, at least four or at least five, characteristic peaks expressed in degrees 2-theta at angles of degrees 2-theta at angles of l2. l°±0.2°, l2.4°±0.2°, l4.5°±0.2°, l5.8°±0.2°, l8.l°±0.2°, l9. l°±0.2°, 22.0°±0.2°, 24.5°±0.2°, 25.6°±0.2°, and 26.6°±0.2°,

119. The compound of claim 76 or claim 118, wherein the compound is a hydrate

picolinamide co-crystal polymorph Type A having a powder X-ray diffraction pattern in accordance with FIG. 78.

120. The compound of any one of claims 76, 118 or 119, wherein the compound is a hydrate picolinamide co-crystal polymorph Type A having a thermo-gravimetric analysis curve and/or a differential scanning calorimetry curve in accordance with FIG. 79.

121. The compound of claim 76, wherein the compound is a free base anhydrate polymorph Type AL exhibiting an XRPD pattern having at least three, at least four or at least five, characteristic peaks expressed in degrees 2-theta at angles of 7.6°±0.2°, 8.4°±0.2°, l3.2°±0.2°, 13.8°±0.2°, 14.8°±0.2°, 15.2°±0.2°, 15.6°±0.2°, 15.9°±0.2°, 16.9°±0.2°, 18.1°±0.2°, 20.5°±0.2°, and 2l.3°±0.2°.

122. The compound of claim 76 or claim 121, wherein the compound is a free base anhydrate polymorph Type AL having a powder X-ray diffraction pattern in accordance with FIG. 81.

123. The compound of any one of claims 76, 121 or 122, wherein the compound is a free base anhydrate polymorph Type AL having a thermo-gravimetric analysis curve and/or a differential scanning calorimetry curve in accordance with FIG. 82.

124. The compound of claim 76, wherein the compound is a free base hydrate polymorph Type BO exhibiting an XRPD pattern having at least three, at least four or at least five, characteristic peaks expressed in degrees 2-theta at angles of 12.1°±0.2°, l2.4°±0.2°, l3.9°±0.2°, l5.0°±0.2°, l5.4°±0.2°, l7. l°±0.2°, l8.3°±0.2°, 2l.5°±0.2°, 22. l°±0.2°, 24.4°±0.2°, 25.l°±0.2°, 26.2°±0.2°, and 26.3°±0.2°.

125. The compound of claim 76 or claim 124, wherein the compound is a free base hydrate polymorph Type BO having a powder X-ray diffraction pattern in accordance with FIG. 84.

126. The compound of any one of claims 76, 124 or 125, wherein the compound is a free base hydrate polymorph Type BO having a thermo-gravimetric analysis curve and/or a differential scanning calorimetry curve in accordance with FIG. 85.

127. The compound of claim 76, wherein the compound is a free base «-heptane solvate polymorph Type BP exhibiting an XRPD pattern having at least three, at least four or at least five, characteristic peaks expressed in degrees 2-theta at angles of 8.5°±0.2°, l2.9°±0.2°, l7.6°±0.2°, l8.l°±0.2°, l9.4°±0.2°, 20.8°±0.2°, 2l.2°±0.2°, 22.9°±0.2°, and 24.0°±0.2°.

128. The compound of claim 76 or claim 127, wherein the compound is a free base «-heptane solvate polymorph Type BP having a powder X-ray diffraction pattern in accordance with FIG. 87.

129. The compound of any one of claims 76, 127 or 128, wherein the compound is a free base «-heptane solvate polymorph Type BP having a thermo-gravimetric analysis curve and/or a differential scanning calorimetry curve in accordance with FIG. 88.

130. The compound of claim 76, wherein the compound is a free base 2-pentanol solvate polymorph Type BK exhibiting an XRPD pattern having at least three, at least four or at least five, characteristic peaks expressed in degrees 2-theta at angles of 11.9°±0.2°, l3.0°±0.2°, l4.4°±0.2°, l4.7°±0.2°, l6.9°±0.2°, l7.9°±0.2°, l9.3°±0.2°, 2l.8°±0.2°, 22.7°±0.2°, 23.9°±0.2°, 24.6°±0.2°, and 26. l°±0.2°.

131. The compound of claim 76 or claim 130, wherein the compound is a free base 2- pentanol solvate polymorph Type BK having a powder X-ray diffraction pattern in accordance with FIG. 90.

132. The compound of any one of claims 76, 130 or 131, wherein the compound is a free base 2-pentanol solvate polymorph Type BK having a thermo-gravimetric analysis curve and/or a differential scanning calorimetry curve in accordance with FIG. 91.

133. The compound of claim 76, wherein the compound is a free base «-pentanol solvate polymorph Type AX exhibiting an XRPD pattern having at least three, at least four or at least five, characteristic peaks expressed in degrees 2-theta at angles of 11.5°±0.2°, l2.9°±0.2°, l3. l°±0.2°, l7.4°±0.2°, l8.2°±0.2°, 23. l°±0.2°, 23.9°±0.2°, and 25.9°±0.2°.

134. The compound of claim 76 or claim 133, wherein the compound is a free base n- pentanol solvate polymorph Type AX having a powder X-ray diffraction pattern in accordance with FIG. 93.

135. The compound of any one of claims 76, 133 or 134, wherein the compound is a free base rt-pentanol solvate polymorph Type AX having a thermo-gravimetric analysis curve and/or a differential scanning calorimetry curve in accordance with FIG. 94.

136. The compound of claim 76, wherein the compound is a free base /«.-xylene solvate polymorph Type Q exhibiting an XRPD pattern having at least three, at least four or at least five, characteristic peaks expressed in degrees 2-theta at angles of 5.5°±0.2°, l2.5°±0.2°, l5.0°±0.2°, l7.6°±0.2°, 20.2°±0.2°, 22. l°±0.2°, 22.8°±0.2°, and 26.6°±0.2°.

137. The compound of claim 76 or claim 136, wherein the compound is a free base m-xylene solvate polymorph Type Q having a powder X-ray diffraction pattern in accordance with FIG. 96.

138. The compound of any one of claims 76, 136 or 137, wherein the compound is a free base /«.-xylene solvate polymorph Type Q having a thermo-gravimetric analysis curve and/or a differential scanning calorimetry curve in accordance with FIG. 97.

139. The compound of claim 76, wherein the compound is a free base 2-methoxy ethanol solvate polymorph Type P exhibiting an XRPD pattern having at least three, at least four or at least five, characteristic peaks expressed in degrees 2-theta at angles of 11.9°±0.2°, l2.3°±0.2°, l2.7°±0.2°, l4.0°±0.2°, l7. l°±0.2°, 20.0°±0.2°, 23.9°±0.2°, 24. l°±0.2°, 25.5°±0.2°, 25.8°±0.2°, and 27.2°±0.2°.

140. The compound of claim 76 or claim 139, wherein the compound is a free base 2- methoxy ethanol solvate polymorph Type P having a powder X-ray diffraction pattern in accordance with FIG. 99.

141. The compound of any one of claims 76, 139 or 140, wherein the compound is a free base 2-methoxy ethanol solvate polymorph Type P having a thermo-gravimetric analysis curve and/or a differential scanning calorimetry curve in accordance with FIG. 100.

142. The compound of claim 76, wherein the compound is a free base sec-butyl alcohol solvate polymorph Type AQ exhibiting an XRPD pattern having at least three, at least four or at least five, characteristic peaks expressed in degrees 2-theta at angles of 11.5°±0.2°, l2.7°±0.2°,

12.9°±0.2°, 14.1°±0.2°, 17.4°±0.2°, 17.9°±0.2°, 21.9°±0.2°, 22.7°±0.2°, 23.1°±0.2°, 23.5°±0.2°, 23.9°±0.2°, 25.5°±0.2°, and 27.6°±0.2°

143. The compound of claim 76 or claim 142, wherein the compound is a free base seobutyl alcohol solvate polymorph Type AQ having a powder X-ray diffraction pattern in accordance with FIG. 102.

144. The compound of any one of claims 76, 142 or 143, wherein the compound is a free base sec-butyl alcohol solvate polymorph Type AQ having a thermo-gravimetric analysis curve and/or a differential scanning calorimetry curve in accordance with FIG. 103.

145. A pharmaceutical composition comprising the compound of any one of claims 76 to 144 and at least one pharmaceutically acceptable excipient, diluent and/or carrier.

146. A compound (2_<S',4i?,5»S)-4-fluoro-l-(4-fluorophenylsulfonyl)-5-methyl-/V-((5- (trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridine-4-yl)methyl)pyrrohdine-2- carboxamide in free base anhydrate crystalline Type E form characterized by X-ray powder diffraction peaks containing three, four or five peaks selected from7.5°±0.2°, 8.2°±0.2°, 12.6°±0.2°, 13.1°±0.2°, 13.4°±0.2°, 14.7°±0.2°, 15.1°±0.2°, 15.5°±0.2°, 16.1°±0.2°, l6.6°±0.2°, l8.2°±0.2°, l8.9°±0.2°, l9.9°±0.2°, 20.4°±0.2°, 2l.0°±0.2°, 2l.5°±0.2°, 2l.8°±0.2°, 22.4°±0.2°, 22.7°±0.2°, 24.3°±0.2°, 25.0°±0.2°, 25.4°±0.2°, and 28.4°±0.2°.

147. The compound of claim 146 characterized by a powder X-ray diffraction pattern according to FIG. 10.

148. The compound of claim 146 or claim 147 characterized by a thermo-gravimetric analysis curve and/or a differential scanning calorimetry curve in accordance with FIG. 11.

149. A pharmaceutical composition comprising the compound of any one of claims 146 to 148 and at least one pharmaceutically acceptable excipient, diluent and/or carrier.

150. A method of preparing (2_<S',4i?,5_<S')-4-fluoro-l-(4-fluorophenylsulfonyl)-5-methyl- V-((5- (trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridine-4-yl)methyl)pyrrohdine-2- carboxamide in free base anhydrate crystalline Type E, comprising:

(1) mixing (2_<S',4i?,5_<S)-4-fluoro-l-(4-fluorophenylsulfonyl)-5-methyl-/V-((5- (trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridine-4-yl)methyl)pyrrohdine-

2-carboxamide free base starting material with dichloromethane to form a solution having a (2ri',4i?,5ri -4-fluoro-l-(4-fluorophenylsulfonyl)-5-methyl- V-((5- (trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridine-4-yl)methyl)pyrrolidine- 2-carboxamide concentration of at least 50 mg/mL;

(2) combining the solution of (2_<S',4i?,5_<S')-4-fluoro-l-(4-fluorophenylsulfonyl)-5-methyl-/V- ((5-(trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridine-4- yl)methyl)pyrrolidine-2-carboxamide with a non-polar anti-solvent having a dielectric constant of less than 2 to a total volume ratio of dichloromethane to anti-solvent of from about 1 : 1.5 to about 1 : 10 to form a slurry comprising free base anhydrate crystalline Type E (25',4i?,55)-4-fluoro-l -(4-fluorophenylsulfonyl)-5-methyl-/V-((5- (trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridine-4-yl)methyl)pyrrolidine- 2-carboxamide; and

(3) isolating the free base anhydrate crystalline Type E (25',4i?,55)-4-fluoro-l-(4- fluoropheny lsul Tony l)-5-methyl-iV-((5-(trinuoromethyl)-2-(2-(tririuoromethyl)pyri midin- 5-yl)pyridine-4-yl)methyl)pyrrolidine-2-carboxamide from the slurry.

151. The process of 150 wherein the anti-solvent is «-heptane.

152. The process of claim 150 or claim 151 wherein mixing step (1) and combining step (2) are done at from about 15 °C to about 35 °C.

153. The process of any one of claims 150 to 152 wherein the volume ratio of

dichloromethane to anti-solvent is from about 1 :2 to about 1 :4, or about 1 :3.

154. The process of any one of claims 150 to 153 wherein step (2) further comprises adding seed crystals of free base anhydrate crystalline Type E (25'.4/ri55')-4-fluoro- 1 -(4-

P uorophenylsul Tony l)-5-methyl-iV-((5-(trinuoromethyl)-2-(2-(tri fluoromethyl)pyri midin-5- yl)pyridine-4-yl)methyl)pyrrolidine-2-carboxamide seed crystals to the combined solution of (2_<S',4i?,5_<S)-4-fluoro-l-(4-fluorophenylsulfonyl)-5-methyl-/V-((5-(trifluoromethyl)-2-(2- (trifluoromethyl)pyrimidin-5-yl)pyridine-4-yl)methyl)pyrrolidine-2-carboxamide.

155. The process of any one of claims 150 to 154 wherein the starting material is amorphous solid (2_<S',4i?,5_<S')-4-fluoro-l-(4-fluorophenylsulfonyl)-5-methyl-/V-((5-(trifluoromethyl)-2-(2- (trifluoromethyl)pyrimidin-5-yl)pyridine-4-yl)methyl)pyrrolidine-2-carboxamide free base.

156. The process of any one of claims 150 to 155 wherein the starting material is Type F (2_<S',4i?,5_<S)-4-fluoro-l-(4-fluorophenylsulfonyl)-5-methyl-/V-((5-(trifluoromethyl)-2-(2- (trifluoromethyl)pyrimidin-5-yl)pyridine-4-yl)methyl)pyrrolidine-2-carboxamide free base.