EA046293B1 - METHOD FOR PRODUCING BROMODOMAIN INHIBITOR - Google Patents

Description

Cross reference to related application

This application claims priority under 35 U.S.C. § 119(e) by U.S. Provisional Application 62/702,085, filed July 23, 2018, the entire contents of which are incorporated herein by reference.

Field of technology

The present invention relates to methods for the preparation of pharmaceutical compositions and, in particular, to processes for the synthesis and purification of a bromodomain inhibitor useful for the treatment of cancer.

State of the art

Bromodomain proteins (BRDs) are an important class of histone reader proteins that recognize acetylated lysine residues (KAc) on histone tails and guide transcriptional complexes to turn on genes. Among the eight BRD families, BRD and BET (bromodomain and extra-terminal) proteins were found to be suitable for drug discovery. Chemical inhibition of BET proteins produces a wide range of desirable biological effects, such as antitumor, anti-inflammatory, and male contraceptive properties. In US Patent No. 9,034,900 discloses a series of bromodomain inhibitors with nanomolar affinity for BET proteins. The discovery of these potent, selective and permeable inhibitors of BET bromodomain proteins has stimulated research activities in various therapeutic areas, especially in oncology. Several clinical studies have been initiated for small molecule inhibitors of BET bromodomain proteins in cancer. In particular, the bromodomain inhibitor 4-[2-(cyclopropylmethoxy)5-methylsulfonylphenyl]-2-methylisoquinolin-1-one, disclosed in US Patent No. 9,034,900, is in clinical trial for the treatment of advanced solid tumors and relapsed/refractory non-Hodgkin's lymphoma (NCT03220347).

4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one, referred to herein as Compound 1, has the following structure: o o

1J

O 1.

The synthesis route and purification process for bromodomain inhibitors disclosed in US Patent No. 9,034,900, require multiple purifications of the intermediates and the final compound by silica gel column chromatography or preparative HPLC and thus have an overall modest yield and an impure final product. In order to realize the medical benefits of bromodomain inhibitors for cancer treatment, industry needs a scalable and reliable purification process to produce bromodomain inhibitors. The present invention satisfies this need.

The essence of the invention

The invention described herein relates to an improved process for the production of bromodomain inhibitors on an industrial scale. Another object of the invention is to provide a suitable purification process for obtaining the final product.

The present embodiments relate to processes for the synthesis and purification of the bromodomain inhibitor compound 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin1-one (Compound 1), which includes its crystalline forms, amorphous forms, solvates and hydrates ; as well as pharmaceutical compositions containing this compound.

Certain embodiments of the invention relate to chemical routes for the synthesis of Compound 1 that do not require column chromatography and are amenable to large-scale synthesis. The overall synthetic sequence and intermediates are unchanged from those described in US Patent No. 9,034,900, but many reagents, procedures and isolation techniques are modified and improved for good manufacturing practice (GMP) production of kilograms of Compound 1.

In one embodiment, the invention relates to a process for preparing a compound of formula I, a hydrate, solvate, prodrug or pharmaceutically acceptable salt thereof:

wherein the process involves coupling a compound of formula II with a compound of formula III to produce a compound of formula I;

- 1 046293 and Рх 'q ^z i

R ¹ R ² (II) О(Ш), where:

X represents Cl, Br or I; And

R ¹ and R ² are each independently selected from H, OH, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C5 alkenyl, optionally substituted C1-C5 alkynyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl, optionally substituted 6-10 membered aryl or optionally substituted 4-7 membered cycloalkyl; or R ¹ , R ² and the boron to which they are attached together form an optionally substituted 5-10 membered ring containing carbon and 0 to 5 heteroatoms.

In other aspects of this method (i) X is Br; and/or (ii) R ¹ , R ² and the boron to which they are attached together form an optionally substituted 5-10 membered ring containing carbon and from 0 to 5 heteroatoms selected from O and N. In addition, In another aspect of the methods of the invention, R ¹ , R ² and the boron to which they are attached together form an optionally substituted 5-10 membered ring in which the two ring atoms directly attached to the boron are oxygens. In another aspect of the methods, the optionally substituted 5-10 membered boron containing ring contains from 1 to 3 nitrogen atoms. In addition, the optionally substituted boron-containing ring may be an 8-membered ring.

In another embodiment of the invention, the compound of formula II has formula II-a: c\ _z o ν-ίΧ V QBQ

Vw-^( _R <)p _(n _ _a)> where:

each Q is independently selected from -O-, -NH-, -N(R ⁵ )-, or optionally substituted methylene;

W represents -O-, -NH- or -N(R ⁵ )-;

each ^R4 is independently selected from H, OH, CN, optionally substituted amino, -C(O) ^R5 , ^-COOR5 , -C(O)N( ^R5 )2, ^-SO2R5 , optionally substituted C1-C5 alkyl , optionally substituted C1C5 alkenyl, optionally substituted C1-C5 alkynyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl, optionally substituted 6-10 membered aryl or optionally substituted 4-7 membered cycloalkyl;

each R ⁵ is independently selected from H, optionally substituted C1-C5 alkyl, optionally substituted C1-C5 alkenyl, optionally substituted C1-C5 alkynyl, optionally substituted 410 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl, optionally substituted 6-10 membered -membered aryl or optionally substituted 4-7 membered cycloalkyl; and p represents 0 to 4.

Alternatively, the compound of formula II has the following formula II-b:

Where:

each ^R4 is independently selected from H, OH, CN, optionally substituted amino, -C(O) ^R5 , ^-COOR5 , -C(O)N( ^R5 )2, ^-SO2R5 , optionally substituted C1-C5 alkyl , optionally substituted C1C5 alkenyl, optionally substituted C1-C5 alkynyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl, optionally substituted 6-10 membered aryl or optionally substituted 4-7 membered cycloalkyl;

each R ⁵ is independently selected from H, optionally substituted C1-C5 alkyl, optionally substituted C1-C5 alkenyl, optionally substituted C1-C5 alkynyl, optionally substituted 410 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl, optionally substituted 6-10 membered -membered aryl or optionally substituted 4-7 membered cycloalkyl; and p represents 0 to 4.

In one embodiment of the invention, the compound of formula II is:

- 2 046293

The compound of formula II can be formed by contacting the compound of formula IV with bis(pinacolato)diboron (B ₂ pin ₂ ), a palladium catalyst, and diethanolamine (DEA) (DEA is added after completion of the first reaction), the compound of formula IV having the following structure:

where X' represents Cl, Br or I.

Further, the compound of formula IV can be prepared by monobromination of the compound of formula V:

to obtain the compound of formula VI:

V „A ^Br (VI), and O-alkylation of the compound of formula VI to obtain the compound of formula IV, where X' represents Br. Monobromination may prevail over dibromination of the compound of formula V in a ratio of about 95:5 or more. In another aspect, monobromination may dominate dibromination of a compound of Formula V in a ratio of about 99:1 or more.

In another aspect of the invention, the methods described herein further comprise crystallizing a compound of Formula I from a mixture of formic acid and water. A crystallized compound of Formula I may have an X-ray powder diffraction (XRPD) pattern with the following characteristics:

Table 1

No. Pos. [°20] interatomic distance [A] Rel. Intensity [%] 1 7.807098 11.32447 13.16 2 8.691139 10.17446 15.67 3 8.944468 9.88685 40.82 4 11.47771 7.70979 20.22 5 13.75333 6.43883 19.45 6 15.27651 5.80009 8.04 7 15.69109 5.64776 64.51 8 15.99297 5.54183 66.46 9 16.27756 5.44557 7.77 10 16.89633 5.24752 43.12 AND 17.50072 5.06763 36.25 12 17.96524 4.93763 88.03 13 19.20236 4.62223 11.22 14 19.70334 4.50582 15.85 15 20.50266 4.33193 20.82 16 21.13626 4.20348 38.66 17 21.89583 4.05935 81.05 18 22.10196 4.02195 61.36 19 22.57031 3.93954 13.52 20 22.97552 3.87097 16.48 21 23.32722 3.8134 25.65 22 23.5865 3.77206 13.16 23 24.44054 3.64216 100

- 3 046293

24 25.17524 3.53751 6.64 25 25.60385 3.47925 14.72 26 26.41086 3.37474 9.88 27 27.71849 3.21844 12.35 28 28.72787 3.10761 4.64 29 29.60304 3.0177 3.73 thirty 31.95225 2,801 2.61 31 32.84832 2.72661 5.47 32 33.83981 2.64895 2.15 33 34.39729 2.60729 2.3 34 35.02682 2.56186 3.75 35 35.70021 2.51506 2.55 36 37.16499 2.41923 2.11 37 38.06795 2.3639 8.22 38 38.94192 2.31284 1.09

In one embodiment of the invention, the methods or processes described herein result in a compound of Formula I having a purity of at least about 90%, about 95%, or about 99%.

The described invention relates to compounds of formula I, a hydrate, solvate, prodrug or pharmaceutically acceptable salt thereof prepared by any of the processes described herein.

In one aspect, the invention relates to a process for monobrominating a compound of formula VII, wherein the process comprises monobrominating a compound of formula VII to produce a compound of formula VIII.

Two processes for preparing the compound of formula VIII are described herein: Process 1 (methylene chloride process) is based on the differential solubility of that particular compound. Process 2 (TFA process) is based on solution chemistry; the latter process may provide better control over a wider range of substrates, although both processes provide suitable compounds.

Thus, the methylene chloride procedure may not work for any meta-directing group other than SO ₂ Me (halogens are electron withdrawing groups (EWG)) since this process relies on specific physical properties to control bromination (monobromide crystallizes). However, the MeCN/TFA procedure should be more general to any EWG meta guide. Compounds of formula VII and formula VIII have the following structures:

Where:

^R3 is selected from the group consisting of ^SO2R4 , NO2, CN, _SO3H , CHO, C(O) ^R4 , ^COOR4 , _CO2H , C(O)N( ^R4 )2 and C(O) NH2;

R ⁴ represents H, optionally substituted C|-C8 alkyl, optionally substituted C1-C8 cycloalkyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted 6-10 membered aryl and optionally substituted 5-10 membered heteroaryl; and wherein the compound of formula VIII has a purity of greater than about 99% by weight. In one aspect of this method or process, the compound of formula VIII is washed with water at a temperature between about 18°C and 23°C. In another aspect, the method or process further comprises subjecting the washed compound of formula VIII to drying at a temperature of from about 23°C to about 85°C. In addition, the compound of formula VIII can be washed with acetonitrile (MeCN) before washing with water.

Both the above summary and the following summary of the drawings and detailed description are provided as an example and explanation. They are intended to provide more detailed information but should not be construed as limiting. Other objects, advantages and new features will be readily apparent to those skilled in the art from the following detailed description.

Brief description of drawings

In fig. 1 shows a process for the large-scale synthesis of intermediate 5 from a commercially available compound.

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In fig. 2 shows a process for the large-scale synthesis of intermediate 6 from intermediate 5.

In fig. 3 shows the process for the large-scale synthesis process of cross-matching partner 2 from intermediate 6.

In fig. 4A and 4B show a process for the large-scale synthesis of intermediate 3 from a commercially available compound.

In fig. Figure 5 shows the process for the large-scale synthesis of target compound 1 by the combination reaction of cross-coupling partners 2 and 3.

In fig. Figure 6 shows the process for Large Cleanup Process 1.

In fig. Figure 7 shows solubility curve 1.

In fig. Figure 8 shows the first polymorph interconversion diagram in the purification process for 1.

In fig. Figure 9 shows the second scheme of polymorph interconversion during the purification process for 1.

In fig. 10A and B show a heat map summarizing the performance of the catalyst (FIG. 10A), where high performance liquid chromatography (HPLC) yields for this screening range range from <5% up to ~85%. Larger circles indicate higher yield. Lighter colors indicate higher purity. In fig. 10B shows a heat map with HPLC yields ranging from ~50-95%. Larger dark circles indicate higher yield.

In fig. 11 shows 1H NMR for Compound 1 (CC-90010). Solvent: d6DMSO.

In fig. 12 shows microscopy of Compound 1 (CC-90010) Form I.

In fig. 13 shows the XRPD of Compound 1 (CC-90010) Form I.

In fig. 14 shows XRPD of Form I CC-90010 after milling (preferred orientation).

In fig. 15 shows the DSC of Compound 1 (CC-90010) Form I.

In fig. 16 shows microscopy of Compound 1 (CC-90010) (Metastable) Form 4.

In fig. 17 shows the XRPD of Compound 1 (CC-90010) (Metastable) Form 4.

In fig. 18 shows the DSC of Compound 1 (CC-90010) (Metastable) Form 4.

In fig. 19 shows microscopy of Compound 1 (CC-90010) (Metastable) Form 5.

In fig. 20 shows the XRPD of Compound 1 (CC-90010) (Metastable) Form 5.

In fig. 21 shows the DSC of Compound 1 (CC-90010) (Metastable) Form 5.

In fig. 22 shows the conversion of Compound 4 to Compound 5: Effect of Sulfuric Acid.

In fig. 23 shows the conversion of Compound 5 and Compound 5-a diBr: No H2SO4.

In fig. 24 shows the Reaction Profile of Compound 4 to Compound 5: Batch Addition of NBS, Seeding.

Detailed description

I. Overview

The present application relates to the development of a preferred process or method for the synthesis of Compound 1. In particular, in a preferred embodiment of the invention, the method may involve the synthesis of Compound 1 on a large or multi-kilogram scale. In another preferred embodiment of the invention, the synthesis method does not require preparative chromatography or complex purification procedures. In one aspect, the final synthetic step in the synthesis of Compound 1 involves a cross-coupling reaction between the boronate ester of Compound 2' and the bromide of Compound 3, as shown below.

It is an issue that previous attempts to produce boronate esters, such as Compound 2', have been met with difficulties related to product stability and scalability. In the present disclosure, the inventors describe a solution to this problem using the boronate ester of Compound 2 shown below. Compound 2 was produced on a multi-kilogram scale, in high purity, without the need for cumbersome purification steps, and was successfully coupled with the bromide of Compound 3 to obtain the target Compound 1 in high yield and purity.

II. Synthesis of Compound 1

In one aspect, the invention relates to a process for preparing a compound of formula I, its hydrate,

- 5 046293 solvate, prodrug or pharmaceutically acceptable salt, in which the compound of formula I has the following structure:

The process or method preferably involves reacting a compound of formula II with a compound of formula III to produce a compound of formula I,

Where:

X represents Cl, Br or I; And

R ¹ and R ² are each independently selected from H, OH, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C5 alkenyl, optionally substituted C1-C5 alkynyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl, optionally substituted 6-10 membered aryl or optionally substituted 4-7 membered cycloalkyl; or R ¹ , R ² and the boron to which they are attached together form an optionally substituted 5-10 membered ring containing carbon and 0 to 5 heteroatoms.

In some embodiments, R ¹ , R ² and the boron to which they are attached form an optionally substituted 5-10 membered ring containing carbon and 0 to 5 heteroatoms. In some embodiments, each heteroatom(s) is independently selected from O and N.

In some embodiments, R ¹ , R ² and the boron to which they are attached form an optionally substituted 5-membered ring. In some embodiments, R ¹ , R ² and the boron to which they are attached form an optionally substituted 6-membered ring. In some embodiments, R ¹ , R ² and the boron to which they are attached form an optionally substituted 7-membered ring. In some embodiments, R ¹ , R ² and the boron to which they are attached form an optionally substituted 8-membered ring.

In some embodiments, R ¹ , R ² and the boron to which they are attached form an optionally substituted 9-membered ring. In some embodiments, R ¹ , R ² and the boron to which they are attached form an optionally substituted 5-membered ring.

In some embodiments, R ¹ , R ² and the boron to which they are attached form an optionally substituted 5-10 membered ring containing (i) carbon and no heteroatoms; (ii) carbon and 1 heteroatom; (iii) carbon and 2 heteroatoms; (iv) carbon and 3 heteroatoms; (v) carbon and 4 heteroatoms; or (vi) carbon and 5 heteroatoms.

In some embodiments, each heteroatom(s) is independently selected from O, S, N, or P.

In some embodiments of the invention, the compound of formula II has formula II-a:

Where:

each Q is independently selected from -O-, -NH- or -N(R ⁵ )- or optionally substituted methylene;

W represents -O-, -NH- or -N(R ⁵ )-;

each R ⁴ is independently selected from H, OH, CN, optionally substituted amino, -C(O)R ⁵ , -COOR ⁵ , -C(O)N(R ⁵ ) ₂ , -SO ₂ R ⁵ , optionally substituted C1- C5 alkyl, optionally substituted C1C5 alkenyl, optionally substituted C1-C5 alkynyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl, optionally substituted 6-10 membered aryl or optionally substituted 4-7 membered cycloalkyl;

each R ⁵ is independently selected from H, optionally substituted C1-C5 alkyl, optionally substituted C1-C5 alkenyl, optionally substituted C1-C5 alkynyl, optionally substituted 410 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl, optionally substituted 6-10 membered -membered aryl or optionally substituted 4-7 membered cycloalkyl; and p represents 0 to 4.

In some embodiments, the compound of formula II has formula II-b:

- 6 046293

Where:

each ^R4 is independently selected from H, OH, CN, optionally substituted amino, -C(O) ^R5 , ^-COOR5 , -C(O)N( ^R5 )2, ^-SO2R5 , optionally substituted C1-C5 alkyl , optionally substituted C1C5 alkenyl, optionally substituted C1-C5 alkynyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl, optionally substituted 6-10 membered aryl or optionally substituted 4-7 membered cycloalkyl;

each R ⁵ is independently selected from H, optionally substituted C1-C5 alkyl, optionally substituted C1-C5 alkenyl, optionally substituted C1-C5 alkynyl, optionally substituted 410 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl, optionally substituted 6-10 membered -membered aryl or optionally substituted 4-7 membered cycloalkyl; and p represents 0 to 4.

In some embodiments of the invention, the compound of Formula II is: °h/°

[GT

Η

With reference to FIG. 5, the process may involve charging the reactor with a compound of formula II, a compound of formula III, a base and isopropanol (IPA) at a temperature between about 15°C and about 25°C. For example, the temperature may be about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, or about 25°C.

In some embodiments, the ratio of a compound of formula II to a compound of formula III is between about 1:1 and about 3:1. In some embodiments of the invention, the base is potassium carbonate. The reaction mixture can be stirred to form a slurry followed by charging water for a time of about 10 to about 20 minutes (or any time period between or including these two values, for example, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19 or about 20 minutes) and maintaining the temperature between about 15°C and about 25°C (e.g. about 15, about 16, about 17, about 18, about 20, about 21, about 22, about 23, about 24 or about 25°C). Then the reactor is purged with a 3X vacuum (3 times), followed by loading of the Pd catalyst. In one embodiment of the invention, the Pd catalyst is SPhos Pd(crotyl)Cl having the structure shown below, where Cy is cyclohexyl:

The reactor may be purged with vacuum and then heated to a temperature between about 65°C and 75°C (e.g., about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73 , about 74 or about 75°C) and stir for about 5 hours to about 8 hours (or any period of time between or including these two values, for example, about 5, about 5.25, about 5.5, about 5.75, about 6, about 6.25, about 6.75, about 7, about 7.25, about 7.5, about 7.75 or about 8 hours). The reactor is then charged with trioctylfosine at a temperature of from about 60°C to 70°C (or any temperature between or including these two values, for example, about 60, about 61, about 62, about 63, about 64, about 65, about 66 , about 67, about 68, about 69, or about 70°C) and stir for about 0.5 hour to about 1.5 hour (or any period of time between or including these two values, for example, about 0.5 , about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4 or about 1.5 h). The process further involves cooling the reactor to a temperature between about 18°C and 25°C (or any temperature between or including these two values, for example, about 18, about 19, about 20, about 21, about 22, about 23, about 24 or about 25°C) for a period of time between about 3 hours to about 5 hours (or any period of time between or including these two values, for example, about 3, about 3.25, about 3.5, about 3, 75, about 4, about 4.25, about 4.5, about 4.75 or about 5 hours). The reaction slurry in the reactor is then filtered, washed with IPA and filtered, washed

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IPA/water and filter and rinse with water and filter twice more. The suspension is then washed with ethyl acetate and filtered, then dried at a temperature of not more than about 40°C to obtain crude 1.

In some embodiments of the invention, the process further comprises crystallizing a compound of Formula I from formic acid and water. With reference to FIG. 6, in some embodiments of the invention, crystallization involves charging the first reactor with Compound 1 in formic acid and stirring for about 15 minutes to about 30 minutes (or any time period between or including these two values, for example, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29 or about 30 min) at a temperature between about 20°C and about 30°C (or any temperature between or including these two values, for example about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29 or about 30 °C). The second reactor is charged with formic acid and water, brought to a temperature between about 20°C and about 30°C (or any temperature between or including these two values, for example, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, or about 30°C), seeded with Compound 1 and stirred for about 60 minutes to about 90 minutes (or any time period between or including these two values, e.g. , about 60, about 65, about 70, about 75, about 80, about 85 or about 90 min). For a period of time from about 15 to about 30 minutes (or any period of time between or including these two values, for example, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 24, about 25, about 26, about 27, about 28, about 29, or about 30 minutes), the second reactor is simultaneously charged with the solution from the first reactor and water, maintaining the temperature in the second reactor between about 20°C and about 30°C (or any temperature between or including these two values, for example, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29 or about 30°C). The mixture in the second reactor is stirred and the solids are filtered and washed with a mixture of formic acid and water and then with water only. The solid particles are dried to obtain crystallized 1.

In some embodiments, the crystallized Compound 1 is polymorphic Form 1, characterized by an X-ray powder diffraction (XRPD) pattern according to table. 2:

table 2

No. Pos. [°2 theta] interatomic distance [A] Rel. Pitene. [%] 1 7.807098 11.32447 13.16 2 8.691139 10.17446 15.67 3 8.944468 9.88685 40.82 4 11.47771 7.70979 20.22 5 13.75333 6.43883 19.45 6 15.27651 5.80009 8.04 7 15.69109 5.64776 64.51 8 15.99297 5.54183 66.46 9 16.27756 5.44557 7.77 10 16.89633 5.24752 43.12 AND 17.50072 5.06763 36.25 12 17.96524 4.93763 88.03 13 19.20236 4.62223 11.22 14 19.70334 4.50582 15.85 15 20.50266 4.33193 20.82 16 21.13626 4.20348 38.66 17 21.89583 4.05935 81.05 18 22.10196 4.02195 61.36 19 22.57031 3.93954 13.52 20 22.97552 3.87097 16.48 21 23.32722 3.8134 25.65 22 23.5865 3.77206 13.16

- 8 046293

23 24.44054 3.64216 100 24 25.17524 3.53751 6.64 25 25.60385 3.47925 14.72 26 26.41086 3.37474 9.88 27 27.71849 3.21844 12.35 28 28.72787 3.10761 4.64 29 29.60304 3.0177 3.73 thirty 31.95225 2,801 2.61 31 32.84832 2.72661 5.47 32 33.83981 2.64895 2.15 33 34.39729 2.60729 2.3 34 35.02682 2.56186 3.75 35 35.70021 2.51506 2.55 36 37.16499 2.41923 2.11 37 38.06795 2.3639 8.22 38 38.94192 2.31284 1.09

In some embodiments, the purity of the compound of Formula I is at least about 90%. In some embodiments, the purity of the compound of Formula I is at least about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%. In some embodiments, the purity of the compound of formula I is at least 99%. In some embodiments, the purity of the compound of Formula I is at least 99.5%. In some embodiments, the purity of the compound of Formula I is at least 99.9%.

III. Synthesis of Cross-Matchable Affiliate Compound 2

In some embodiments of the invention, a compound of formula II is formed by reacting a compound of formula IV:

where X' represents Cl, Br or I; with bis(pinacolato)diborone (B ₂ pin ₂ ), palladium catalyst and diethanolamine (DEA). In some embodiments, X' is Br.

In some embodiments of the invention, a compound of formula IV is prepared by monobromination of a compound of formula V:

to obtain the compound of formula VI:

°x/° ^Br (VI), and O-alkylation of the compound of formula VI to obtain the compound of formula IV, where X' represents Br (Compound 6).

In some embodiments of the invention, monobromination versus dibromination of the compound of Formula V occurs in a ratio of about 80:20 or more. In some embodiments, monobromination versus dibromination of the compound of Formula V occurs in a ratio of about 90:10 or more. In some embodiments, monobromination versus dibromination of a compound of Formula V occurs in a ratio of about 95:5 or greater. In some embodiments, monobromination versus dibromination of a compound of Formula V occurs in a ratio of about 95:5 or greater. In some embodiments, monobromination versus dibromination of a compound of Formula V occurs in a ratio of about 99:1 or greater. In another aspect, the invention relates to a process for monobromination of a compound of formula VII:

Ji t (VII), to obtain the compound of formula (VIII):

- 9 046293

vg (VIII), where:

R ³ is selected from the group consisting of SO2R ⁴ , NO2, CN, SO ₃ H, CHO, C(O)R ⁴ , COOR ⁴ , CO2H, C(O)N(R ⁴ )2 and C(O)NH2;

R ⁴ represents H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 cycloalkyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted 6-10 membered aryl and optionally substituted 5-10 membered heteroaryl; and wherein the compound of formula VIII has a purity of greater than about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% by weight . The process or method may include monobromination of a compound of formula VII to produce a compound of formula VIII.

In some embodiments, monobromination involves contacting a compound of Formula VII with N-bromosuccinimide (NBS). In some embodiments, washing the crude compound of Formula VIII with water occurs at a temperature of from about 18°C to about 23°C (or any temperature between or including these two values, for example, about 18, about 19, about 20, about 21, about 22 or about 23°C). In some embodiments, the process further includes subjecting the washed, crude compound of formula VIII to drying at a temperature of from about 23°C to about 85°C (or any value between or including these two temperatures, for example, about 23, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80 or about 85°C). In some embodiments, the crude compound of Formula VIII is washed with acetonitrile (MeCN) before washing with water. In some embodiments, the MeCN wash occurs at a temperature of from about -12°C to about -8°C (or any temperature between or including these two values, for example, about -12, about -11, about -10, about -9 or about -8°C).

The procedure allows for the following changes. Solvents: Alternative solvents may be used. Examples include chlorinated solvents such as chloroform or 1,2dichloroethane, and non-chlorinated solvents such as acetonitrile, tetrahydrofuran or 2methyltetrahydrofuran. Concentration of the reaction mixture: The concentration of the reaction mixture can vary from about 2X vol. up to about 20X vol. (relative to Compound 4). Brominating agents: Additional brominating agents include bromine and 1,3-Dibromo-5,5-dimethylhydantoin. Bromination reagent stoichiometry: Various amounts of bromination reagent can be used, ranging from about 0.8 eq. to about 1.9 eq. Addition of brominating reagent: The brominating reagent can be added all at once, in batches of about 2 to about 20 batches, or continuously. The addition time can vary from about 0 to about 72 hours. Temperature: A reaction temperature of about 0°C to about 40°C can be used. Acids: Various acids may be represented, including benzenesulfonic acid, p-toluenesulfonic acid, triflic acid, hydrobromic acid and trifluoroacetic acid. Isolation: Instead of directly filtering the product and washing it with methylene chloride and water, an organic solvent capable of dissolving Compound 5 could be charged at the end of the reaction, followed by aqueous workup to remove the succinimide and the addition of an antisolvent or solvent change to an appropriate solvent to crystallize Compound 4 Drying: For drying, a temperature range from about 10 to about 60°C can be used. An alternative process has also been developed for Compound 5. This process is advantageous in that it does not use a chlorinated solvent and also provides additional control over the formation of the dibromine impurity of Compound 5-a. See Oberhauser, T. J. Org. Chem 1997, 62, 4504-4506. The process is as follows. Compound 4 (10 g, 58 mmol) and acetonitrile (100 ml) were charged to the reactor and stirred. The charge was cooled to -20°C. Triflic acid (CF ₃ SO ₃ H or TfOH, 5.5 ml, 62 mmol) was loaded while maintaining the charge temperature from -10 to -25°C. Nbromosuccinimide (NBS, 11.4 g, 64 mmol) was charged, stirred at -10 to -25°C for 30 minutes, then heated to 20°C for 3 to 4 hours. Stirring was continued at a temperature of 15°C to 25°C until the reaction was complete. If the conversion plateaued before completion of the reaction, the reaction was cooled to -5 to -15°C and additional NBS was added, the amount based on the unreacted starting material, followed by heating to 15°C to 25°C and reacting to complete completion. Alternatives to the above procedure using MeCN and TfOH are as follows. Brominating agents: Additional brominating agents include bromine and 1,3-dibromo-5,5-dimethylhydantoin. Stoichiometry of Brominating Reagent: Various amounts of brominating reagent can be used, ranging from about 0.8 eq. up to about 2 eq. Drying: For drying, a temperature range from about 10°C to about 60°C can be used.

- 10 046293

In some embodiments, the compound of formula VIII has a purity of greater than about 90% by weight. In some embodiments, the compound of formula VIII has a purity of greater than about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% by weight. In some embodiments, the compound of formula VIII has a purity of greater than about 99% by weight. In some embodiments, the compound of formula VIII has a purity of greater than about 99.9% by weight. With reference to FIG. 1 compound of formula VI (Compound 5) can be prepared from a compound of formula V (Compound 4) by charging a reactor with acetonitrile (MeCN) and Compound 4 at a temperature between about -20°C and about -12°C (or any amount between these two values or including them, for example, about 20, about -19, about -18, about -17, about -16, about -15, about -14, about -13 or about -12°C). The reactor is then charged with acid and MeCN. In some embodiments, the acid is triflic acid (TfOH). N-bromosuccinimide (NBS) is then added to the reactor in portions and the reactor is maintained for about 4 to about 5 hours. The reactor is then heated to a temperature between about -5°C and about 0°C (or any amount between or including these two values). , for example, about -5, about -4, about -3, about -2, about -1 or about 0°C).

The process further involves heating the reactor to a temperature between about 18°C and about 23°C (or any temperature between or including these values, for example, about 18, about 19, about 20, about 21, about 22 or about 23°C) for a period of time from about 1 hour to about 2 hours (or any period of time between or including these two values, for example, about 1, about 1.25, about 1.75 or about 2 hours) and holding for an additional period time between about 3 hours and about 6 hours (or any period of time between or including these values, for example, about 3, about 3.25, about 3.5, about 3.75, about 4, about 4.25, about 4.5, about 4.75, about 5, about 5.25, about 5.5, about 5.75 or about 6 hours). The process further involves heating the reactor to a temperature between about 45°C and about 50°C (or any temperature between or including these values, for example, about 45, about 46, about 47, about 48, about 49 or about 50°C) and distilling waste from the suspension under vacuum. The reactor is then cooled to a temperature between about -12°C and about -8°C (or any temperature between these two values, for example, about -12, about -11, about -10, about -9, about -8°C) for a period of time from about 0.1 hour to about 4 hours (or any period of time between or including these values, for example, about 0.1, about 0.5, about 1, about 1.25, about 1.5 , about 1.75, about 2, about 2.25, about 2.5, about 2.75, about 3, 3.25, about 3.5, about 3.75 or about 4 hours) and keeping the charge at this temperature for at least about 1 hour. The suspension is then filtered and washed with cold MeCN, heated to a temperature between about 18°C and about 23°C (or any temperature between these two values, for example, about 18, about 19, about 20, about 21, about 22 or about 23 ° C), filter and wash with water. The residue is then dried at a temperature between about 23°C and about 85°C (or any temperature between these two values, for example, about or any value between or including these two temperatures, for example, about 23, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80 or about 85°C) to obtain Compound 5.

With reference to FIG. 2 Compound 6 is prepared by loading the reactor at a temperature between about 15°C and about 25°C (or any temperature between these two values, for example, about 15, about 16, about 17, about 18, about 19, about 20, about 21 , about 22, about 23, about 24 or about 25°C) Compound 5, methyl ethyl ketone (MEK) and base. In some embodiments of the invention, the base is potassium carbonate. The reactor is then charged with bromomethylcyclopropane in MEK for a period of time in excess of about 1 hour. The reactor is then heated to a temperature between about 65°C and about 75°C (or any temperature between or including these two values, for example, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75°C) and held for a period of time between about 7 and about 13 hours (or any period of time between these two values or including them, for example, about 7, about 8, about 9, about 10, about 11, about 12, about or 13 hours). The reactor is then charged with water, stirred and the aqueous layer is removed, followed by repeating this step of loading with water, mixing and removing the aqueous layer two more times.

The reactor is then cooled to a temperature between about 40 and about 50°C (or any temperature between or including these two values, for example, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47 , about 48, about 49 or about 50°C). The suspension is distilled under vacuum to remove the distillate waste, loaded with MEK, distilled under vacuum to remove the distillate waste, loaded with heptane and distilled under vacuum to remove the distillate waste again. The reactor is then seeded with Compound 6, charged with heptane and distilled under vacuum to remove the waste that is distilled off. The reactor is then cooled to a temperature between about 15°C and about 25°C (or any temperature between these two values, for example, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24 or about 25°C) for

- 11 046293 time period from about 1 to about 2 hours (or any time period between or including these values, for example, about 1, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2 hours), and held for about 2 to about 2.5 hours (or any period of time between these values or including them, for example, about 2, about 2.1, about 2.2, about 2.3, about 2.4 or about 2.5 hours). The mixture is then filtered and washed with heptane and MEK and dried at a temperature between about 30°C and about 50°C (or any temperature between or including these values, for example, about 30, about 35, about 40, about 45, about 50° C) to obtain Compound 6.

With reference to FIG. 3, finally, Compound 6 is converted into cross-matching partner Compound 2 as follows. In the first reactor at a temperature between about 15°C to about 25°C (or any temperature within these two values, for example, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22 , about 23, about 24, or about 25°C) load Compound 6, bis(pinacolato)diboron (B ₂ Pin ₂ ), and cesium acetate into THF. The first reactor is purged with vacuum, then loaded with Pd catalyst and purged again. In some embodiments, the Pd catalyst is bis(triphenylphosphine) palladium(P) dichloride or Pd(PPh ₃ ) ₂ Cl ₂ . The first reactor is then heated to a temperature between about 55°C and about 65°C (or any temperature between or including these values, for example, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 62, about 64, or about 65°C), held for about 6 to about 10 hours (or any period of time between or including these values, e.g., about 6, about 7, about 8, about 9 or about 10 hours), cool to a temperature between about 15°C and about 25°C (or any temperature between these two values, for example, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24 or about 25°C) and loaded with silica gel and activated carbon. In some embodiments, the activated carbon is escrob C-941. Other suitable compounds may also be used in this aspect of the method.

The reaction mixture is then stirred for from about 30 minutes to 24 hours, and optionally from about 60 minutes to about 75 minutes (or any period of time between or including these, e.g., about 30 minutes, about 40 minutes, about 50 minutes, about 60 min, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 14 o'clock, about 15 o'clock, about 16 o'clock, about 17 o'clock, about 18 o'clock, about 19 o'clock, about 20 o'clock, about 21 o'clock, about 22 o'clock, about 23 o'clock or about 24 o'clock) and filter and wash with tetrahydrofuran ( THF). The solid is removed and the filtrate is charged to a second reactor at a temperature between about 15°C and about 25°C (or any temperature between these two values, for example, about 15, about 16, about 17, about 18, about 19, about 20 , about 21, about 22, about 23, about 24 or about 25°C). The second reactor is charged with a solution of diethanolamine (DEA) in THF and stirred for a period of time between about 1 minute and about 10 minutes (or any time period between or including these values, for example, about 1, about 2, about 3, about 4 , about 5, about 6, about 7, about 8, about 9, or about 10 minutes), then seeded with Compound 2. A second portion of DEA in THF is added over a period of about 1 hour to about 2 hours, and the reactor is stirred for another about 2 hours to about 5 hours (or any period of time between or including these values, for example, about 2, about 3, about 4 or about 5 hours). The suspension is filtered and washed with THF, then dried at a temperature between about 30°C and about 50°C (or any temperature between or including these values, for example, about 30, about 35, about 40, about 45, about 50°C) to obtain Compound 2.

The following modifications of the above reaction, synthesis 6 of 5, can also be used. Solvent: Various solvents can be used, for example, acetone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, acetonitrile or 2-methyltetrahydrofuran. Reaction volume: Reaction volumes from 3 to 30 volumes relative to 3 can be used. Base: Various inorganic bases can be used, such as cesium carbonate or phosphate bases (sodium, potassium or cesium). In addition, organic bases such as trimethylamine or diisopropyldiimide can be used. Base Particle Size: Various potassium carbonate particle sizes from 325 mesh can be used. Reaction Temperature: A lower temperature such as 50°C can be used. A higher temperature such as 100°C can be used. Any temperature above the boiling point of the solvent can be used in a pressure vessel. Isolation: Various ratios of MEK and n-heptane solvents can be used. Varying amounts of residual water may be left. Various amounts of seeds can be used, from 0 to 50%. Seeding may occur later in the process and/or at a lower temperature. Unseeded crystallization can be used. A different release temperature from 0°C to 50°C can be used. A different wash may be used, for example a different ratio of MEK to n-heptane. An antisolvent other than n-heptane may be used, such as hexane, pentane, or methyl t-butyl ether. Alternatively, the mixture can be solvent exchanged to a solvent where Compound 3 has a solubility of less than 100 mg/ml, and isolated from this system. Drying: For drying, a temperature range of 10 to 60°C can be used. Synthesis reaction 2 from 6 can be modified

- 12 046293 is laid out as follows. Solvent: Various solvents other than THF can be used, such as 1,4-dioxane or 2-methyltetrahydrofuran. Reaction Volume: The reaction volume can vary from 4 to 50 volumes relative to Compound 2. Catalyst and Base: Various palladium catalysts and bases can be used for borylation. Examples can be found in Chow, Wing Kin, et al, RSC Adv., 2013, 3, 12518-12539. Borylation reaction temperature: Reaction temperatures ranging from room temperature (20°C) to solvent reflux can be used. Carbon/Silica Treatment: Treatment can be carried out without silica gel. This process can be performed without carbon processing. Carbon sources other than Ecosorb C-941 may be used. Various amounts of silica can be used, from 0.01X to 1X weight equivalents. Various amounts of Ecosorb C-941 can be used, from 0.01X to 1X weight equivalents. Crystallization: A different diethanolamine addition rate may be used. Various amounts of diethanolamine can be used, from 1.0 to 3.0 molar equivalents. A different sludge wash with more or less THF can be used. You can use different amounts of seeds from 0.0001X wt. up to 50X wt. Alternatively, the process can be seedless. Drying: For drying, a temperature range from 10°C to 60°C can be used.

IV. Synthesis of Cross-Matchable Affiliate Compound 3

Cross-coupling partner Compound 3 is prepared from commercially available Compound 8 as shown below.

Vg

L 9 J 3

With reference to FIG. 4A, Compound 8 is placed in the first reactor in MeCN at a temperature between about 15°C and about 25°C (or any temperature within these two values, for example, about 15, about 16, about 17, about 18, about 19, about 20 , about 21, about 22, about 23, about 24 or about 25°C). The base, in some embodiments of the invention, cesium carbonate, is then added to the first portion of the reaction mixture, and the first reaction mixture is then heated to a temperature between about 32°C and about 36°C (or any temperature between or including these values, for example, about 32, about 33, about 34, about 35 or about 36°C). MeI (methyl iodide) in MeCN is then added to the first reaction mixture over a period of about 1 hour to 2 hours (or any time period between or including these, e.g., about 1, about 1.25, about 1.5, about 1.75 or about 2 hours). The first reactor is then heated to a temperature between about 35°C and about 42°C (or any temperature between and including these values, for example, about 35, about 36, about 37, about 38, about 39, about 40, about 41, or about 42°C) and stir for about 10 to about 14 hours (or any period of time between and including these values, for example, about 10, about 10.5, about 11, about 11.5, about 12, about 12.5, about 13, about 13.5 or about 14 hours). The first reactor is then cooled to a temperature between about 15°C and about 25°C (or any temperature between these two values, for example, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22 , about 23, about 24 or about 25°C), filter and wash with MeCN and the solids are removed and the filtrate is charged to a second reactor at a temperature between about 15°C and about 25°C (or any temperature within these two values, for example, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24 or about 25°C). The mixture in the second reactor is concentrated at atmospheric pressure at a temperature of about 80°C. The second reactor is then cooled to a temperature between about 15°C and about 25°C (or any temperature between these two values, for example, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22 , about 23, about 24 or about 25°C) and filter and wash with MeCN. The solids are removed and the filtrate is charged to a third reactor. The third reactor is then heated to a temperature between about 45°C and about 55°C (or any temperature between or including these values, for example, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54 or about 55°C). NBS in MeCN is then added to the third reactor, maintaining the third reactor at a temperature between about 45°C and about 55°C (or any temperature between or including these values, for example, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54 or about 55°C). The third reaction mixture is stirred for about 3 hours to about 4 hours (or any period of time between these values, for example, about 3, about 3.25, about 3.5, about 3.75 or about 4 hours), maintaining the temperature , then add NBS to MeCN and pure MeCN again for a period of time from about 15 minutes to about 25 minutes (or any period of time between these two values, for example, about 15, about 16, about 17, about 18, about 19, about 20 , about 21, about 22, about 23, about 24 or about 25 min).

Now, with reference to FIG. 4B, the third reaction mixture is stirred for about 3 hours to about 4 hours (or any time period in between and including these, e.g., about 3, about 3.25, about 3.5, about 3.75, or about 4 hours) and then add activated carbon. The third reactor then

- 13 046293 heated to a temperature between about 55°C and about 60°C (or any temperature between and including these values, for example, about 55, about 56, about 57, about 58, about 59 or about 60°C), filter and wash with MeCN at the same temperature as the third reactor. The solids are removed and the filtrate is charged to a fourth reactor at a temperature between about 45°C and about 55°C (or any temperature between and including these values, for example, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 52, about 54 or about 55°C). The mixture in the fourth reactor is then concentrated under vacuum at a temperature between about 45°C and about 55°C (or any temperature between these values and the inclusion of these values, for example, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 52, about 54 or about 55°C), then seeded with Compound 3, stirred at a temperature between about 30°C and 40°C (or any temperature between and including these values, e.g. about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, or about 40°C) for about 60 to 120 minutes (or any period of time between these values and including them, for example, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 105, about 110, about 115 or about 120 min). The fourth reactor is then cooled to a temperature between about 15°C and 20°C for about 1 hour to about 2 hours (or any period of time between and including these values, for example, about 1, about 1.25, about 1. 5, about 1.75 or about 2 hours). The fourth reactor is then charged with water for about 90 minutes to about 3 hours while maintaining the temperature, and stirred for another period of time from about 30 minutes to about 90 minutes (or any time period in between and including these, e.g. about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85 or about 90 min). The suspension was then filtered and washed with MeCN in water (optionally heptane), and the solids were dried at a temperature between about 30°C and 50°C (or any temperature between and including these values, for example, about 30, about 35, about 40, about 45 or about 50° C.) to obtain Compound 3. The first method for the synthesis of Compound 3 (Process A in the Examples) can be carried out using alternative reagents and conditions as follows. Solvents: Alternative solvents may be used. Examples include chlorinated solvents such as methylene chloride, chloroform or 1,2-dichloroethane, and non-chlorinated solvents such as tetrahydrofuran or 2-methyltetrahydrofuran. Reaction concentration: Reaction concentration can vary from about 2X vol. up to about 40X vol. (relative to Compound 9). Brominating agents: Additional brominating agents include bromine and 1,3Dibromo-5,5-dimethylhydantoin. Bromination reagent stoichiometry: Various amounts of bromination reagent can be used, ranging from about 0.8 eq. up to about 2 eq. Crystallization: Various amounts of water can be used, including from 5 volumes to 50 volumes. Crystallization can occur without adding seeds. Various water addition and final retention times can be used. Various flushing procedures can be used. Drying: For drying, a temperature range from about 10°C to about 60°C can be used.

The second process (Process B in the examples) for the synthesis of Compound 3 can be modified as follows. Solvents: Alternative solvents may be used. Examples include chlorinated solvents such as methylene chloride, chloroform or 1,2-dichloroethane, and non-chlorinated solvents such as tetrahydrofuran or 2-methyltetrahydrofuran. Reaction concentration: Reaction concentration can vary from 2X vol. up to 40X rpm (relative to Compound 8). Alkylating Reagent: Alternative methylating reagents such as dimethyl sulfate can be used. Alkylating Reactant Stoichiometry: From about 1 to about 10 molar equivalents of methyl iodide can be used. Base: Various inorganic bases such as potassium carbonate or phosphate bases (sodium, potassium or cesium) can be used. Brominating agents: Additional brominating agents include bromine and 1,3-dibromo-5,5-dimethylhydantoin. Bromination reagent stoichiometry: Various amounts of bromination reagent can be used, ranging from about 0.8 eq. up to about 2 eq. Crystallization: Various amounts of water can be used, including from 5 volumes to 50 volumes. Seeding levels from about 0.0001% to about 50% can be used. Crystallization can occur without adding seeds. Various water addition and final retention times can be used. Various flushing procedures can be used. Drying: For drying, a temperature range of about 10 to about 60°C can be used.

V. Reaction of combination of Compounds 2 and 3 to obtain Compound 1

In one embodiment, the invention relates to a method for preparing the compound Compound 1, its hydrate, solvate, prodrug or pharmaceutically acceptable salt:

- 14 046293

° (i), where the process involves the reaction of coupling a compound of formula II with a compound of formula III to produce a compound of formula I;

Where:

X represents Cl, Br or I; And

R ¹ and R ² are each independently selected from H, OH, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C5 alkenyl, optionally substituted C1-C5 alkynyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl, optionally substituted 6-10 membered aryl or optionally substituted 4-7 membered cycloalkyl; or R ¹ , R ² and the boron to which they are attached together form an optionally substituted 5-10 membered ring containing carbon and 0 to 5 heteroatoms.

In other aspects of this method (i) X is Br; and/or (ii) R ¹ , R ² and the boron to which they are attached together form an optionally substituted 5-10 membered ring containing carbon and from 0 to 5 heteroatoms selected from O and N. In addition, In another aspect of the methods of the invention, R ¹ , R ² and the boron to which they are attached together form an optionally substituted 5-10 membered ring in which the two ring atoms directly attached to the boron are oxygens. In another aspect of the methods, the optionally substituted 5-10 membered boron containing ring contains from 1 to 3 nitrogen atoms. In addition, the optionally substituted boron-containing ring may be an 8-membered ring.

Scheme 10: Synthesis of Compound 1

2 1 ⁰

Acetonitrile (1.6 L) was loaded into a mixture of Compound 2 (156.7 g, 460 mmol), Compound 3 (100 g, 420 mmol) and tribasic potassium phosphate (223 g, 1.05 mol). Stirring was started and water (400 ml) was added to the mixture. The system was evacuated with nitrogen three times and Pd(PPh ₃ ) ₂ Cl ₂ (2.9 g, 4 mmol) was charged and the system was evacuated with nitrogen three times. The batch was heated to a temperature of from about 65 to about 75°C (or any temperature between and including these two values), and the contents were stirred for at least about 16 hours until the reaction was complete by HPLC analysis. The mixture was cooled to a temperature of about 60 to about 70° C. (or any temperature between and including these two values), the stirring was stopped and the mixture was allowed to settle. The lower aqueous layer was removed. Water (150 ml) and acetonitrile (700 ml) were charged at a temperature of about 60 to about 70°C (or any temperature between these two values). Ecosorb C-941 (15g) and Celite (10g) were charged to the reaction vessel at a temperature of about 60 to about 70°C (or any temperature between and including these two values). After 1 hour, the mixture was filtered to remove solid particles. The solids were washed twice with 18% water in acetonitrile (500 ml) at a temperature of about 60 to about 70° C. (or any temperature between and including these two values). The filtrates were combined and concentrated at atmospheric pressure to a final volume of 1.5 L. The batch was cooled to a temperature of about 60 to about 65°C (or any temperature between and including these two values) and seeded with Compound 1 (1 g). After 1 hour, water (500 ml) was charged for at least 1 hour at a temperature of from about 60 to about 65°C (or any temperature between and including these two values). The suspension was cooled to a temperature of about 15 to about 25°C (or any temperature between and including these two values) for 4 hours. The product was collected by suction filtration. The wet sediment was washed twice with 45% water in acetonitrile (500 ml). The product was dried under vacuum at a temperature of about 40°C with nitrogen purging. Yield: 139 g 1.

The above procedure for combining Compound 3 and Compound 2 to obtain Compound 1 can be modified by any of the following methods. Reaction Solvents: A variety of reaction solvents other than acetonitrile can be used, including tetrahydrofuran, 2methyltetrahydrofuran, toluene, and isopropanol. Boric ester: Various can be used

- 15 046293 boron esters from Compound 2, including the pinacolate ester of Compound 7 and free boric acid of Compound 2. Examples of boron esters can be found in Lennox et al., Chem. Soc. Rev., 43:412 (2014). Carbon Treatment: Carbon treatments other than Ecosorb C-941 may be used. Various amounts of carbon can be used, from 0.01 to 0.5X by weight. Carbon can be removed. Various amounts of Celite can be used, from 0.01 to 0.5X by weight. Crystallization: Various amounts of water can be used, including from 5 volumes to 50 volumes. Crystallization can occur without adding seeds. Various water addition and final retention times can be used. Various flushing procedures can be used. Drying: For drying, a temperature range of 10 to 60°C can be used. Catalysts: Various combinations of metal and ligand can be used. Examples of metal/ligand combinations can be found in Maluenda, Irene; Navarro, Oscar, Molecules, 2015, 20, 7528. Various catalysts may include: XPhos-3G (cas# 1445085-55-1); cataCXium® A Pd 3G (CAS# 1651823-59-4); PdCl ₂ (DtBPF) (CAS# 95408-45-0); SPhos 3G (Cas# 1445085-82-4); AmPhos 3G (Cas# 1820817-64-8); RSuz 3G (Cas# 1445086-12-3); Pd PEPPSI IPent Cas#1158652-41-5); Pd(PPh ₃ ) ₂ Cl ₂ (Cas# 13965-03-2). Examples of catalyst systems that have been demonstrated to lead to Compound 1 are listed below in Table. 4 when using boron esters 2 or 7 in combination with 3.

Table 4

Catalyst Screening Summary Table

Kosh < |ΟΙΙΊ I About l\ I I at

1' I. I I opn It II Illi III I

111······

..... ;...............~..... pggiwgjg...................... ........................................

ymyy—_Ξ

YAYAYILYTLLM

....... mmVyamzhG”” yiShchDVy.....' feKBE-Efii——. 1ίϊ!β=ΒΪ®!ϊΐϊ£ 8нвьй11ж1_ 6И=Яй£Я___ YirmyVizb '

............;

11¾¾¾¾ ~........~ ;

HB071

HB075

VI. Purification of Compound 1 (CC-90010) by crystallization from formic acid and water

The invention relates to methods for purifying Compound 1 by crystallization from formic acid and water. Methods for preparing three different polymorphs of Compound 1 are also described, including the most stable form, Form 1, and two metastable forms, Form 4 and Form 5. Supporting data (XRPD, DSC, photomicroscopy) for all three forms are provided in the examples below.

The structure of Compound 1 (CC-90010) is shown below:

O

SS-90010

Crystallization is the main technique for isolating active pharmaceutical ingredients. Crystallization should be purifying and should lead to control of the polymorph. This process discussed describes a method for crystallizing the most stable known form of Compound 1 (CC-90010) from formic acid and water. Methods for isolating the two metastable forms are also described.

In particular, methods for purifying Compound 1 (CC-90010) from formic acid and water are described that have never been used before. By varying the solvent composition, addition rate, and drying, different polymorphs can be obtained.

The initial process for isolating the final Compound 1 (CC-90010), Form 1, involves the use of 39 volumes of two ICH Class II solvents, methanol and tetrahydrofuran, as well as a series of distillations that increase the complexity of the process. The process is not seeded, thereby relying on the random formation of solid particles, which does not allow control of polymorphic or physical characteristics.

The four processes are described below. All use only formic acid, ICH class III solvent and water. The two processes for Form 1 (the most stable polymorph) both control the polymorph by seeding with Form 1 and are more volume efficient (14 to 16 X vol). Also describes the formation process of (metastable) Form 4 and the process

- 16 046293 formation of (metastable) Form 5. For all described methods, solvent ratios, temperature, amount of seeds, composition and amount of washing, as well as drying temperature can be changed.

Process 1 (for Form 1): Compound 1 (1.0 X wt.) and formic acid (7.0 X vol.) are charged into Reactor 1. This mixture is stirred and then transferred to Reactor 2 through a post-treatment filter. Formic acid (1.0 X vol.) is loaded into Reactor 1, and then transferred through the same after-treatment filter to Reactor 2. Water (2.2 X by volume) is loaded through a separate after-treatment filter into Reactor 2 for 1 hour. Compound 1 seeds (1 wt.%, Form 1) are charged and the mixture is maintained at a temperature of from about 20°C to about 25°C (or any temperature between and including these two values, for example, about 20, about 21, about 22 , about 23, about 24 or about 25°C). Water (4.8 X vol.) is loaded into reactor 2 through a post-treatment filter in three separate portions (0.25, 0.60 and 3.95 X vol.). Each load is added over 1 hour with 1 hour between loads. After all three loadings, the mixture is kept for at least one hour. A charge temperature of about 20°C to about 25°C (or any temperature between and including these two values, for example, about 20, about 21, about 22, about 23, about 24 or about 25°C) is maintained for all batches .

The charge is filtered, washed twice with formic acid and water from the after-treatment filter (1.5X volume of formic acid + 1.5X by volume of water each), twice with water from the after-treatment filter (3X by volume each) and dried under reduced pressure from about 35° C to about 45°C (or any temperature between and including these two values, for example, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44 or about 45°C).

Process 2 (for Form 1): Compound 1 (CC-90010) (1.0X wt.) is loaded into formic acid (5.0X vol.) in Reactor 1 and stirred at a temperature of 20°C to 30°C (or any temperature between and including these two values, for example, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29 or about 30°C) until dissolved. Reactor 2 is charged with formic acid from the after-treatment filter (2.0 x vol.) and water from the after-treatment filter (1.8 x vol.) and stirred at a temperature of about 20°C to about 30°C (or any temperature between these two values including and including, for example, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29 or about 30°C). Compound 1 (CC-90010) seeds (Form 1, 0.02 to 0.04 X wt.) are charged to Reactor 2 and the resulting slurry is stirred for at least 60 minutes.

Compound 1 (CC-90010)/formic acid solution in Reactor 1 and water (4.4X vol.) are then simultaneously loaded through post-treatment filters into the seed bed suspension in Reactor 2 for a period of 6 to 10 hours (or any period of time between these two values, for example about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5 or about 10 h) while maintaining a temperature of about 20°C to about 30°C (or any temperature between and including these two values, for example, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29 or about 30°C). After addition, formic acid (1X vol.) is charged into Reactor 1. The formic acid wash in Reactor 1 and water (0.9X vol.) are simultaneously charged through post-treatment filters into the charge in Reactor 2 for at least about 15 minutes while maintaining a temperature of about 20°C to about 30°C (or any temperature between and including these two values, for example, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29 or about 30°C).

Process for Form 4: Compound 1 (CC-90010) (1.0 X vol.) is charged into the reaction flask followed by formic acid (8.0 X vol.) and water (2.2 X vol.). A small amount of Form 1 seeds is charged and the mixture is stirred at a temperature of from about 20°C to about 25°C (or any temperature between and including these two values, for example, about 20, about 21, about 22, about 23, about 24 or about 25°C) for about 2 hours or for any suitable period of time. The suspension is filtered, but the wet precipitate is not dried.

Process for Form 5: Compound 1 (CC-90010) (1.0 X vol.) is charged into the reaction flask followed by formic acid (8.0 X vol.) and water (2.2 X vol.). This mixture is stirred at a temperature of about 15°C (or at any suitable temperature) for about 4 hours (or for any suitable period of time). The suspension is filtered, but the wet precipitate is not dried. The charge is filtered, washed twice with formic acid and water from the after-treatment filter (1.5X vol. formic acid + 1.5X vol. water each), twice with water from the after-treatment filter (3X vol. each) and dried under reduced pressure at a temperature of about 35°C to about 45°C (or any temperature between and including these two values, for example, about 35, about 36, about 37, about 38, about 39 or about 40°C).

VI. Definitions

The following definitions are provided to facilitate understanding of certain terms used in this description.

Technical and scientific terms used herein have the meanings generally understood by one of ordinary skill in the art unless otherwise defined. Any

- 17 046293 suitable substances and/or methodologies known to those skilled in the art can be used when performing the methods described herein.

As used herein and in the claims, the singular forms include references to the plural unless the context clearly indicates otherwise. Throughout this specification, unless otherwise indicated, contain, contains, and containing are used inclusively and not exclusively, so that a specified integer or group of integers may include one or more other unspecified integers or groups of integers. The term or is inclusive unless it is modified, as in or... or. Thus, unless the context indicates otherwise, the word or means any one member of a specified list, and also includes any combination of members of that list. Except in the worked examples or where otherwise indicated, all numbers expressing amounts of ingredients or reaction conditions used herein are to be understood as modified in all cases by the term about. The term about will be understandable to people having ordinary skill in the art, and will vary to some extent depending on the context in which it is used. If there are uses of a term that are not clear to people of ordinary skill in the art given the context in which it is used, then about will mean up to plus or minus 10% of the particular term. For example, in some embodiments this will mean plus or minus 5% of a particular term. Specific ranges are presented herein with numerical values preceded by the term about.

The term about is used herein to provide literal support for the exact number it precedes, as well as a number that closely or approximately corresponds to the number preceded by the term. In determining whether a number is close or approximate to a specifically cited number, a close or approximate unquoted number may be a number that, in the context in which it is presented, provides a substantial equivalent to the specific quoted number.

The headings are for convenience only and should not be construed as limiting the invention in any way. 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. The terminology used herein is intended only to describe specific embodiments of the invention and is not intended to limit the scope of the present invention, which is defined solely by the claims. To make the present disclosure clearer, definitions for specific terms are first provided. Additional definitions are provided in the detailed description.

The bromodomain inhibitor compound described herein (ie, Compound 1) is a bromodomain 4 (BRD4) inhibitor. In preliminary in vitro studies, BRD4 inhibition was observed, in addition to other cancer-associated inhibitory activity, in several different cell lines (Raji, human Burkitt's lymphoma cells; HL-60, human proleukemia cells; and NCI-H460, human non-small cell lung cancer cells) . See US Patent No. 9,034,900.

In the context of the present embodiments of the invention, 4-[2-(cyclopropylmethoxy)-5methylsulfonylphenyl]-2-methylisoquinolin-1-one or Compound 1 and the like includes their crystalline forms, amorphous forms, solvates, hydrates and pharmaceutically acceptable salts, unless the context specifics are indicated (e.g. Form 1); as well as pharmaceutical compositions containing this compound. Unless otherwise indicated, the structures depicted herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms or unnaturally occurring proportions of atomic isotopes in one or more of the atoms composing such compounds.

All numerical designations, eg pH, temperature, time, concentration and molecular weight, including ranges, are approximations that change (+) or (-) in increments of 1, 5 or 10%. It should be understood, although not always directly, that all numerical designations are preceded by the term about. It should also be understood, although not always expressly, that the reagents described herein are examples only and that their equivalents are known in the art.

FIO means for information only.

HPLC stands for High Performance Liquid Chromatography.

IPC stands for in process control.

NMR stands for Nuclear Magnetic Resonance.

NMT means nothing more.

As used herein, C _mn such as C1. ₁₂ , C1-8 or C1. ₆ , when used before a group, refers to that group containing m to n carbon atoms.

Optionally substituted refers to a group selected from that group and a substituted form of that group. Substituents may include any of the groups defined below. In one embodiment of the invention, the substituents are selected from C1-C10 or C1- _C6 alkyl substituted with C1-C10 or C1

- 18 046293

C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, C3-C8 cycloalkyl, C2-C10 heterocyclyl, C ₁ -C ₁₀ heteroaryl, substituted C2-C6 alkenyl, substituted C2-C6 alkynyl, substituted C6- C10 aryl, substituted _C3 -C8 cycloalkyl, substituted C2-C10 heterocyclyl, substituted C1-C10 heteroaryl, halo, nitro, cyano, -CO2H or their C1-C6 alkyl ester.

Alkyl refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and preferably from 1 to 6 carbon atoms. This term includes, for example, linear and branched hydrocarbyl groups such as methyl ( _CH3 -), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl (( _CH3 ) _2CH- ), n-butyl ( CH ₃ CH ₂ CH ₂ CH ₂ -), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), tert-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2 -) and neopentyl ((CH3)3CH2-).

Alkenyl refers to monovalent straight or branched hydrocarbyl groups having 2 to 10 carbon atoms and preferably 2 to 6 carbon atoms or preferably 2 to 4 carbon atoms and having at least 1 and preferably 1 to 2 vinyl unsaturation sites (> C=C<).

Examples of such groups include, for example, vinyl, allyl and but-3-en-1 yl. This term includes cis and trans isomers or mixtures of these isomers.

Alkynyl refers to straight or branched monovalent hydrocarbyl groups having from 2 to 10 carbon atoms and preferably from 2 to 6 carbon atoms or preferably from 2 to 3 carbon atoms and having at least 1 and preferably 1 to 2 acetylene (-C) sites =C-) unsaturation. Examples of such alkynyl groups include acetylenyl (-C=CH) and propargyl (-CH ₂ C=CH).

Substituted alkyl refers to an alkyl group having 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl , aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester amino ester, (carboxyl ester) oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halogen, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclyl, substituted heterocyclyl, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO ₃ H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio and substituted alkylthio, where said substituents teliers are like that as defined herein.

Heteroalkyl refers to an alkyl group in which one or more carbon atoms have been replaced by -O-, -S-, SO2, P-containing moieties as provided herein, -NRQ-,

where RQ represents H or C1-C6 alkyl. Substituted heteroalkyl refers to a heteroalkyl group having 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl , aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester amino ester, (carboxyl ester) oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halogen, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclyl, substituted heterocyclyl, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio and substituted alkylthio, where the indicated substituents are as defined in this document.

Substituted alkenyl refers to alkenyl groups having 1 to 3 substituents and preferably 1 to 2 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino , aminocarbonyloxy, aminosulfonyl, aminosulfo

- 19 046293 niloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl , cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halogen, hydroxy, heteroaryl, substitution substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclyl, substituted heterocyclyl, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO ₃ H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio and substituted alkylthio, wherein said substituents are as defined herein and provided that any hydroxyl or thiol substitution is not attached to a vinyl (unsaturated) carbon atom. Heteroalkenyl refers to an alkenyl group in which one or more carbon atoms have been replaced by -O-, -S-, SO2, P-containing moieties as provided herein, -NRQ-,

where RQ represents H or C1-C6 alkyl. Substituted heteroalkenyl refers to a heteroalkenyl group having 1 to 5, preferably 1 to 3, and more preferably 1 to 2 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, ( carboxyl ester) amino, (carboxyl ester )oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substitution pure guanidino, halogen, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy , substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclyl, substituted heterocyclyl, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio and substituted alkylthio, where indicated vigilantes are like defined herein.

Substituted alkynyl refers to alkynyl groups having 1 to 3 substituents and preferably 1 to 2 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino , aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halogen, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclyl, substituted heterocyclyl, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO ₃ H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio and substituted alkylthio, wherein said substituents are as defined herein, and provided that any hydroxyl or thiol substitution is not attached to an acetylene carbon atom.

Heteroalkynyl refers to an alkynyl group in which one or more carbon atoms are replaced by -O-, -S-, SO2, P-containing moieties as provided herein, NRQ-,

where RQ represents H or C1-C6 alkyl. Substituted heteroalkynyl refers to a heteroalkynyl group having 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl , aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonyl

- 20 046293 but, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy , substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halogen, hydroxy, heteroaryl, substituted heteroaryl, hetero aryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclyl, substituted heterocyclyl, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO ₃ H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio and substituted alkylthio, wherein said substituents are as defined herein.

Alkylene refers to divalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms, preferably having from 1 to 6 and more preferably from 1 to 3 carbon atoms, which are either straight chain or branched. This term is illustrated by such groups as methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), isopropylene (-CH2CH(CH3)- or -CH(CH3)CH2-), butylene ( -CH2CH2CH2CH2-), isobutylene (-CH2CH(CH3)CH ₂ -), sec-butylene (-CH ₂ CH ₂ (CH ₃ -)CH-) and the like. Likewise, alkenylene and alkynylene refer to an alkylene moiety containing the corresponding 1 or 2 carbon-carbon double bonds or carbon-carbon triple bond.

Substituted alkylene refers to an alkylene group having from 1 to 3 hydrogens substituted with substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl , aryloxy, substituted aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl, carboxyl ester, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and oxo, wherein said substituents are defined herein. In some embodiments, the alkylene has 1 to 2 of the above groups or has 1 to 3 carbon atoms replaced by -O-, -S-, or NRQ- moieties, where RQ is H or C1-C6 alkyl. It should be noted that when an oxo group replaces an alkylene, the 2 hydrogens attached to the same carbon of the alkylene group are replaced by =O. Substituted alkenylene and substituted alkynylene refer to alkenylene and substituted alkynylene moieties substituted with substituents as described for substituted alkylene.

Alkynylene refers to straight or branched divalent hydrocarbyl groups having from 2 to 10 carbon atoms and preferably from 2 to 6 carbon atoms or preferably from 2 to 3 carbon atoms and having at least 1 and preferably 1 to 2 acetylene (-C) units =C-) unsaturation. Examples of such alkynylene groups include C=C- and CH ₂ C=C-.

Substituted alkynylene refers to alkynylene groups having 1 to 3 substituents and preferably 1 to 2 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino , aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halogen, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclyl, substituted heterocyclyl, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO ₃ H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio and substituted alkylthio, wherein said substituents are as defined herein, and provided that any hydroxyl or thiol substitution is not associated with an acetylene carbon atom.

Heteroalkylene refers to an alkylene group in which one or more carbon atoms have been replaced by -O-, -S-, SO2, P-containing moieties as provided herein, -NRQ-,

where RQ represents H or C1-C6 alkyl. Substituted heteroalkylene refers to heteroalkynylene groups having 1 to 3 substituents, and preferably 1 to 2 substituents selected from those disclosed for substituted alkylene.

Heteroalkenylene refers to an alkenylene group in which one or more carbon atoms

- 21 046293 replaced by fragments -O-, -S-, SO2, P-containing fragment, as provided herein, -NRQ-,

where RQ represents H or C1-C6 alkyl. Substituted heteroalkenylene refers to heteroalkynylene groups having from 1 to 3 substituents and preferably from 1 to 2 substituents selected from the substituents disclosed for substituted alkenylene.

Heteroalkynylene refers to an alkynylene group in which one or more carbon atoms are replaced by -O-, -S-, SO2, P-containing moieties as provided herein, -nr ^q -,

where R ^q represents H or C1-C6 alkyl. Substituted heteroalkynylene refers to heteroalkynylene groups having 1 to 3 substituents, and preferably 1 to 2 substituents selected from those disclosed for substituted alkynylene.

Alkoxy refers to the O alkyl group, where alkyl is defined herein. Alkoxy includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy and n-pentoxy.

Substituted alkoxy refers to the group O (substituted alkyl), where substituted alkyl is defined herein.

Acyl belongs to the groups H-C(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C( O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(O)-, substituted cycloalkenyl-C(O)-, aryl-C (O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocyclic-C(O)- and substituted heterocyclic-C(O)-, where alkyl , substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. Acyl includes an acetyl group CH3C(O)-.

Acylamino belongs to the groups -KI ⁴⁷ C(O)alkyl, -NR ⁴⁷ C(O)substituted alkyl, -NR ⁴⁷ C(O) cycloalkyl, -NR ⁴⁷ C(O)substituted cycloalkyl, -NR ⁴⁷ C(O)cycloalkenyl , -NR ⁴⁷ C(O)substituted cycloalkenyl, -NR ⁴⁷ C(O ⁾ alkenyl, -NR ⁴⁷ C(O)substituted alkenyl, -NR 47 C(O)alkynyl, -NR ⁴⁷ C(O)substituted alkynyl, - No. ⁴⁷ C(O)aryl, -NR ⁴⁷ C(O)substituted aryl, -NR ⁴⁷ C(O)heteroaryl, -NR ⁴⁷ C(O)substituted heteroaryl, NR ⁴⁷ C(O)heterocyclic and NR ⁴⁷ C(O )substituted heterocyclic, where R ⁴⁷ represents hydrogen or alkyl and where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

Acyloxy belongs to the groups alkyl-C(O)O-, substituted alkyl-C(O)O-, alkenyl-C(O)O-, substituted alkenyl-C(O)O-, alkynyl-C(O)O- , substituted alkynyl-C(O)O-, aryl-C(O)O-, substituted aryl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, cycloalkenyl -C(O)O-, substituted cycloalkenyl-C(O)O-, heteroaryl-C(O)O-, substituted heteroaryl-C(O)O-, heterocyclic-C(O)O, and substituted heterocyclic-C(O) )O-, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocycle are as defined in this document.

Amino belongs to the NH2 group.

Substituted amino refers to the group -NR ⁴⁸ R ⁴⁹ , where R ⁴⁸ and R ⁴⁹ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl , cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, SO ₂ -alkyl, ^O ₂ -substituted alkyl, ^O ₂ -alkenyl, ^O ₂ -substituted alkenyl, ^O ₂ -cycloalkyl, ^O ₂ -substituted cycloalkyl, ^O ₂ -cycloalkenyl, ^O ₂ -substituted cycloalkenyl, ^O ₂ -aryl, ^O 2 -substituted aryl, ^ _{O 2 -heteroaryl} , ^O ₂ -substituted heteroaryl, -8O ₂ heterocyclic and ^O ₂ -substituted heterocyclic, and where R ⁴⁸ and R ⁴⁹ are optionally combined with a nitrogen attached thereto to form a heterocyclic or substituted heterocyclic group, provided that R ⁴⁸ and R ⁴⁹ are both not hydrogen, and where alkyl, substituted alkyl , al

- 22 046293 kenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. When R ⁴⁸ is hydrogen and R ⁴⁹ is alkyl, the substituted amino group is sometimes referred to herein as alkylamino. When R ⁴⁸ and R ⁴⁹ are alkyl, the substituted amino group is sometimes referred to herein as dialkylamino. When referring to a mono-amino group, it means that either ^R48 or ^R49 is hydrogen, but not both. When we talk about a disubstituted amino group, it means that neither ^R48 nor ^R49 is hydrogen.

Aminocarbonyl refers to the group -C(O)NR ⁵⁰ R ⁵¹ , where R ⁵⁰ and R ⁵¹ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl , substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and where R ⁵⁰ and R ⁵¹ are optionally joined together with a nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and where alkyl, substituted alkyl , alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

Aminothiocarbonyl refers to the group -C(S)NR ⁵⁰ R ⁵¹ , where R ⁵⁰ and R ⁵¹ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl , substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and where R ⁵⁰ and R ⁵¹ are optionally joined together with a nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and where alkyl, substituted alkyl , alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

Aminocarbonylamino refers to the group -NR ⁴⁷ C(O)NR ⁵⁰ R ⁵¹ , where R ⁴⁷ represents hydrogen or alkyl, and R ⁵⁰ and R ⁵¹ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and wherein R ⁵⁰ and R ⁵¹ are optionally combined with a nitrogen bonded thereto to form a heterocyclic or a substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are such as defined herein. Aminothiocarbonylamino refers to the group -NR ⁴⁷ C(S)NR ⁵⁰ R ⁵¹ , where R ⁴⁷ represents hydrogen or alkyl, and R ⁵⁰ and R ⁵¹ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and wherein R ⁵⁰ and R ⁵¹ are optionally combined with a nitrogen bonded thereto to form a heterocyclic or a substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are such as defined herein.

Aminocarbonyloxy refers to the group -OC(O)NR ⁵⁰ R ⁵¹ , where R ⁵⁰ and R ⁵¹ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl , substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and where R ⁵⁰ and R ⁵¹ are optionally joined together with a nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and where alkyl, substituted alkyl , alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

Aminosulfonyl refers to the group -SO ₂ NR ⁵⁰ R ⁵¹ , where R ⁵⁰ and R ⁵¹ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalke

- 23 046293 nyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and where R ⁵⁰ and R ⁵¹ are optionally combined with a nitrogen associated therewith to form a heterocyclic or substituted heterocyclic group, and where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

Aminosulfonyloxy refers to the group -O-SO ₂ NR ⁵⁰ R ⁵¹ , where R ⁵⁰ and R ⁵¹ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl , substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and where R ⁵⁰ and R ⁵¹ are optionally joined together with a nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and where alkyl, substituted alkyl , alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

Aminosulfonylamino refers to the group -NR ⁴⁷ SO ₂ NR ⁵⁰ R ⁵¹ , where R ⁴⁷ represents hydrogen or alkyl, and R ⁵⁰ and R ⁵¹ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and wherein R ⁵⁰ and R ⁵¹ are optionally combined together with a nitrogen bonded thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined in this document.

Amidino belongs to the group -C(=NR ⁵² )NR ⁵⁰ R ⁵¹ , where R ⁵⁰ , R ⁵¹ and R ⁵² are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl , substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and wherein ^R50 and ^R51 are optionally joined together with a nitrogen bonded thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

Aryl or Ar refers to a monovalent aromatic carbocyclic group containing from 6 to 14 carbon atoms, having a single ring (e.g. phenyl) or multiple fused rings (e.g. naphthyl or anthryl), where the fused rings may or may not be aromatic ( e.g. 2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-on-7-yl and the like) provided that the point of attachment is on the aromatic carbon atom. Preferred aryl groups are phenyl and naphthyl.

Substituted aryl refers to aryl groups that are substituted with 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy , substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substitute substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cyclo alkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halogen, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclyl, substituted heterocyclyl, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO ₃ H, substituted sulfonyl , substituted with sulfonyloxy , thioacyl, thiol, alkylthio and substituted alkylthio, wherein said substituents are as defined herein.

Arylene refers to a divalent aromatic carbocyclic group containing from 6 to 14 carbon atoms, having a single ring or several fused rings. Substituted arylene refers to an arylene having from 1 to 5, preferably from 1 to 3 or more preferably from

- 24 046293 up to 2 substituents, as defined for aryl groups.

Heteroarylene refers to a divalent aromatic group containing from 1 to 10 carbon atoms and from 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur within the ring. Substituted heteroarylene refers to heteroarylene groups that are substituted with 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of the same group of substituents as defined for substituted aryl.

Aryloxy refers to the group -O-aryl, where aryl is as defined herein, which includes, for example, phenoxy and naphthoxy.

Substituted aryloxy refers to the group -O-(substituted aryl), wherein substituted aryl is as defined herein.

Arylthio refers to the group -S-aryl, where aryl is as defined herein.

Substituted arylthio refers to the group S (substituted aryl), wherein substituted aryl is as defined herein.

Carbonyl belongs to the divalent group -C(O)-, which is equivalent to -C(=O)-.

Carboxyl or carboxy refers to COOH or its salts.

Carboxyl ester or carboxy ester belongs to the group -C(O)(O)-alkyl, -C(O)(O)-substituted alkyl, -C(O)(O)-alkenyl, -C(O)(). O)-substituted alkenyl, -C(O)(O)-substituted alkynyl, -C(O)(O)-substituted alkynyl, -C(O)(O)-aryl, -C(O)(O)- substituted aryl, -C(O)(O)-cycloalkyl, -C(O)(O)-substituted cycloalkyl, -C(O)(O)-cycloalkenyl, -C(O)(O)-substituted cycloalkenyl, -C(O)(O)-heteroaryl, -C(O)(O)-substituted heteroaryl, -C(O)(O)-heterocyclic and -C(O)(O)-substituted heterocyclic, where alkyl, substituted alkyl , alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

(Carboxyl ester)amino belongs to the group -NR ⁴⁷ C(O)(O)^km, -NR ⁴⁷ C(O)(O)substituted alkyl, ^R^C^^^^hm, -NR ⁴⁷ C( 0)(0)-substituted alkenyl, -NR ⁴⁷ C(O)(O)-alkynyl, -NR ⁴⁷ C(0)(0)-substituted alkynyl, -PK ⁴⁷ C(O)(O)-aryl, - No. ⁴⁷ C(O)(O)-substituted aryl, -NR ⁴⁷ C(O)(O)cycloalkyl, -NR ⁴⁷ C(0)(0)-substituted cycloalkyl, -NR ⁴⁷ C(O)(O)- cycloalkenyl, -NR ⁴⁷ C(O)(O)-substituted cycloalkenyl, -NR ⁴⁷ C(O)(O)-heteroaryl, -NR ⁴⁷ C(O)(O)-substituted heteroaryl, -NR ⁴⁷ C(O )(O)heterocyclic and -NR ⁴⁷ C(0)(0)-substituted heterocyclic, where R ⁴⁷ represents alkyl or hydrogen, and where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

(Carboxyl ester)oxy belongs to the group -O-C(O)O-alkyl, -O-C(O)O-substituted alkyl, -O-C(O)O-alkenyl, -O-C(O) O-substituted alkenyl, -O-C(O)O-alkynyl, -O-C(O)(O)-substituted alkynyl, -O-C(O)O-aryl, -O-C(O)O- substituted aryl, -O-C(O)O-cycloalkyl, -O-C(O)O-substituted cycloalkyl, -O-C(O)O-cycloalkenyl, -O-C(O)O-substituted cycloalkenyl, - O-C(O)O-heteroaryl, -OC(O)O-substituted heteroaryl, -O-C(O)O-heterocyclic and -O-C(O)O-substituted heterocyclic, where alkyl, substituted alkyl, alkenyl , substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

Cyano belongs to the CN group.

Cycloalkyl refers to cyclic alkyl groups containing from 3 to 10 carbon atoms, having one or more cyclic rings, including fused, bridged and spiro ring systems. The fused ring may be an aryl ring, as long as the non-aryl portion is connected to the rest of the molecule. Examples of suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclooctyl.

Cycloalkenyl refers to non-aromatic cyclic alkyl groups containing from 3 to 10 carbon atoms, having one or more cyclic rings and having at least one >C=C< ring unsaturation and preferably 1 to 2 >C=C< ring unsaturation sites.

Substituted cycloalkyl and substituted cycloalkenyl refer to a cycloalkyl or cycloalkenyl group having 1 to 5 or preferably 1 to 3 substituents selected from the group consisting of oxo, thioxo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl , carboxyl ester, (carboxyl ester)amino, (carboxyl ester

- 25 046293 ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenylthio, substituted cycloalkenyl, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenyl thio, guanidino, substituted guanidino, halogen, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclyl, substituted heterocyclyl, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio and substitution alkylthio, where the indicated substituents are as defined herein.

Cyclopropano refers to:

Cyclobutano refers to:

Cycloalkyloxy refers to -O-cycloalkyl.

Substituted cycloalkyloxy refers to -O-(substituted cycloalkyl).

Cycloalkylthio refers to -S-cycloalkyl.

Substituted cycloalkylthio refers to ^-(substituted cycloalkyl).

Cycloalkenyloxy refers to -O-cycloalkenyl.

Substituted cycloalkenyloxy refers to -O-(substituted cycloalkenyl).

Cycloalkenylthio refers to -S-cycloalkenyl.

Substituted cycloalkenylthio refers to ^-(substituted cycloalkenyl).

Guanidino belongs to the -NHC(=NH)NH2 group.

Substituted guanidino refers to -NR ⁵³ C(=NR ⁵³ )N(R ⁵³ ) ₂ where each R ⁵³ is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclic and substituted heterocyclic, and two R ⁵³ groups attached to a common guanidino nitrogen atom are optionally combined with the nitrogen attached thereto to form a heterocyclic or substituted heterocyclic group, provided that at least one R ⁵³ is not is hydrogen, and wherein said substituents are as defined herein.

Halo or halogen refers to fluoro, chloro, bromo and iodo.

Hydroxy or hydroxyl refers to the -OH group.

Heteroaryl refers to an aromatic group containing from 1 to 10 carbon atoms and from 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring. Such heteroaryl groups may have a single ring (e.g., pyridinyl or furyl) or multiple fused rings (e.g., indolizinyl or benzothienyl), which fused rings may or may not be aromatic and/or contain a heteroatom, provided the point of attachment is through an atom of an aromatic heteroaryl group. In one embodiment of the invention, the nitrogen and/or sulfur atom(s) of the ring of the heteroaryl group are optionally oxidized to produce N-oxide (N^G), sulfinyl or sulfonyl moieties. Certain non-limiting examples include pyridinyl, pyrrolyl, indolyl, thiophenyl, oxazolyl, tizolyl and furanyl.

Substituted heteroaryl refers to heteroaryl groups that are substituted with 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of the same group of substituents as defined for substituted aryl.

Heteroaryloxy refers to -O-heteroaryl.

Substituted heteroaryloxy belongs to the -O-(substituted heteroaryl) group.

Heteroarylthio belongs to the -S-heteroaryl group.

Substituted heteroarylthio belongs to the group ^- (substituted heteroaryl).

Heterocycle, or heterocyclic, or heterocycloalkyl, or heterocyclyl refers to a saturated or partially saturated, but non-aromatic group having from 1 to 10 ring carbon atoms and from 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen. The heterocycle spans a single ring or multiple fused rings, including fused bridged and spiro-ring systems. In fused ring systems, one or more rings may be cycloalkyl, aryl, or heteroaryl, as long as the point of attachment is through a non-aromatic ring. In one embodiment of the invention, the nitrogen and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to produce N-oxide, sulfinyl or sulfonyl moieties.

Substituted heterocyclic or substituted heterocycloalkyl or substituted hetero

- 26 046293 cyclyl refers to heterocyclyl groups which are substituted with 1 to 5 or preferably 1 to 3 with the same substituents as defined for the substituted cycloalkyl.

Heterocyclyloxy belongs to the -O-heterocyclyl group.

Substituted heterocyclyloxy belongs to the group -O- (substituted heterocyclyl).

Heterocyclylthio belongs to the -S-heterocyclyl group.

Substituted heterocyclylthio belongs to the group ^- (substituted heterocyclyl).

Examples of heterocycles and heteroaryls include, but are not limited to, azetidine, pyrrole, furan, thiophene, imidazole, pyrazole, pyridine, pyrazyl, pyrimidine, pyridazine, indolysine, isoindole, indole, dihydroindole, indazole, purine, quinolysine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4- tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholinyl, thiomorpholinyl (also called thiamorpholinyl), 1,1dioxothiomorpholinyl, piperidinyl, pyrrolidine and tetrahydrofuranyl.

Nitro belongs to the -NO2 group.

Oxo refers to the atom (=O).

Phenylene refers to a divalent aryl ring where the ring contains 6 carbon atoms.

Substituted phenylene refers to phenylenes that are substituted with 1 to 4, preferably 1 to 3, and more preferably 1 to 2 substituents selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthi o, substituted cycloalkenylthio, guanidino , substituted guanidino, halogen, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclyl, substituted heterocyclyl, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO ₃ H, substituted sulfonyl, substituted nogo sulfonyloxy, thioacyl, thiol, alkylthio and substituted alkylthio, wherein said substituents are as defined herein.

Spirocycloalkyl and spiro ring systems refer to divalent cyclic groups containing from 3 to 10 carbon atoms, having a cycloalkyl or heterocycloalkyl ring with a spiro unit (a unit formed by a single atom that is the only common member of the rings), exemplified by the following structure:

Sulfonyl belongs to the divalent group -S(O) ₂ -.

Substituted sulfonyl belongs to the group ^O ₂ -alkyl, -SO ₂ -substituted alkyl, ^O ₂ -alkenyl, -SO ₂ -substituted alkenyl, ^O ₂ -cycloalkyl, ^O ₂ -substituted cycloalkyl, ^O ₂ -cycloalkenyl, -SO2-substituted cycloalkenyl, ^O ₂ -aryl, ^O ₂ -substituted aryl, ^O ₂ -heteroaryl, ^O ₂ -substituted heteroaryl, ^O ₂ -heterocyclic, ^O ₂ -substituted heterocyclic, where alkyl, substituted alkyl, alkenyl , substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. Substituted sulfonyl includes groups such as methyl -SO2-, phenyl -SO2- and 4methylphenyl^O ₂ -.

Substituted sulfonyloxy belongs to the group -OSO ₂ -alkyl, -OSO ₂ -substituted alkyl, -OSO2alkenyl, -OSO ₂ -substituted alkenyl, -OSO ₂ -cycloalkyl, -OSO ₂ -substituted cycloalkyl, -OSO ₂ -hhk.to alkenyl, -OSO ₂ -substituted cycloalkenyl, -OSO^iipn.i. -OSO ₂ -substituted aryl, -OSO ₂ -heteroaryl, -OSO ₂ -substituted heteroaryl, -OSO ₂ -heterocyclic, -OSO ₂ -substituted heterocyclic, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl , substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

Thioacyl belongs to the groups H-C(S)-, alkyl-C^)-, substituted alkyl-C^)-, alkenyl-C^)-, substituted alkenyl-C^)-, alkynyl-C^)-, substituted alkynyl- C^)-, cycloalkyl-C^)-, substituted cycloalkyl-C^)-, cycloalkenyl-C^)-, substituted cycloalkenyl-C^)-, aryl-C(b)-. substituted aryl

- 27 046293

C(S)-, heteroaryl-CiS)-. substituted heteroaryl-CiS)-. heterocyclic-CiS)- and substituted heterocyclic-CiS)-. wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

Thiol belongs to the SH group.

Thiocarbonyl belongs to the divalent group -C(S)-, which is equivalent to -C(=S)-.

Thioxo refers to the (=S) atom.

Alkylthio refers to the group S-alkyl, where alkyl is as defined herein.

Substituted alkylthio refers to the group ^- (substituted alkyl), wherein substituted alkyl is as defined herein.

The substituted ring may be substituted by one or more fusion and/or spiro rings. Such ring fusions include a cycloalkyl fusion, a heterocyclyl fusion, an aryl fusion, and a heteroaryl ring fusion, each of which may be unsubstituted or substituted. Such spiro rings include a cycloalkyl fusion and a heterocyclyl fusion, each of which may be unsubstituted or substituted.

It is clear that the above definitions are not intended to include unacceptable substitution patterns (eg, methyl substituted with 5 fluoro groups). Such unacceptable substitution patterns are well known to those skilled in the art.

It is clear that the above definitions are not intended to include unacceptable substitution patterns (eg, methyl substituted with 5 fluoro groups). Such unacceptable substitution patterns are well known to those skilled in the art.

Pharmaceutically acceptable salt refers to salts of a compound, wherein the salts are suitable for pharmaceutical use and are derived from various organic and inorganic counterions well known in the art and include, when the compound contains acid functionality, by way of example only, sodium, potassium, calcium, magnesium, ammonium and tetraalkylammonium; and when the molecule contains basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate and oxalate (see Stahl and Wermuth, eds., Handbook of Pharmaceutically Acceptable Salts, (2002), Verlag Helvetica Chimica Acta, Zurich, Switzerland) for a discussion of pharmaceutical salts, their selection, preparation and use.

In general, pharmaceutically acceptable salts are those salts that retain substantially one or more of the desired pharmacological activities of the parent compound and that are suitable for administration in vivo. Pharmaceutically acceptable salts include acid addition salts formed with inorganic acids or organic acids. Inorganic acids useful for forming pharmaceutically acceptable acid addition salts include, by way of example and not limitation, hydrohalide acids (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, etc.), sulfuric acid, nitric acid, phosphoric acid etc. Organic acids useful for forming pharmaceutically acceptable acid addition salts include, for example, acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, oxalic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid acid, maleic acid, fumaric acid, tartaric acid, citric acid, palmitic acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandarin acid, alkylsulfonic acids (e.g. methanesulfonic acid, ethanesulfonic acid, 1, 2-ethane disulfonic acid, 2-hydroxyethanosulfonic acid, etc.), arylsulfonic acids (e.g. benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, etc.), glutamic acid acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like.

Pharmaceutically acceptable salts also include those formed when the acidic proton present in the parent compound is either replaced by a metal ion (eg, an alkali metal ion, an alkaline earth metal ion, or an aluminum ion) or an ammonium ion (eg, an ammonium ion derived from organic base such as ethanolamine, diethanolamine, triethanolamine, morpholine, piperidine, dimethylamine, diethylamine, triethylamine and ammonia).

Examples

The disclosed ingredients, compositions, processes and procedures for applying the methods disclosed herein may be as described above. Other embodiments of the invention and uses will be apparent to one skilled in the art in light of the present disclosure. The following examples are provided only as an illustration of various embodiments of the invention and should not be construed as limiting the invention in any way.

Example 1: Synthesis of Compound 1

- 28 046293

The synthesis of compound 1 was carried out according to Scheme 1 below. According to Scheme 1, the synthesis began with bromination of the starting material 4-(methylsulfonyl)phenol 4 to give compound 5. Compound 5 was O-alkylated with (bromomethyl)cyclopropane to give compound 6. The boronate of Compound 2 was then formed by borylation of Compound 6 with a Pd catalyst and bis(pinacolato)diboron to yield transition Compound 7, which was then treated with diethanolamine (DEA) to yield cross-coupling partner Compound 2. Cross-coupling partner Compound 3 was prepared in one pot starting with commercially available Compound 8. Compound 8 was N-methylated and brominated to give Compound 3. Compounds 2 and 3 were cross-coupled (Norio, M. and Suzuki, A., Chem. Rev., 95(7), 2457-2483 (1995)) to give the target compound 1 .

Scheme 1: Synthesis of compound 1

1.1: Bromination 4

Bromination of Compound 4 to produce Compound 5 is not difficult in itself, but settling on monobrominated Compound 5 was not easy. Bis-brominated Compound 5-a (see Scheme 2 below) is a particularly harmful impurity because it combines further to form a difficult-to-purify impurity.

Scheme 2: Bromination of Compound 4

The key to high purity with reasonable yield was to exploit the differences in solubility of the starting material Compound 4 (46 mg/ml at 20°C) and the product Compound 5 (8 mg/ml) in CH ₂ Cl ₂ . These differences in solubility are summarized in Table. 3 below.

Table 3

Compound Solubility _{in CH2С12} , 10°С Solubility in CH2CI2, 20°С Solubility in CH2CI2, 30°С Solubility in CH2CI2, 10% H2SO4, 10°С Solubility in CH2CI2, 10% H2SO4, 20°С Solubility in CH2CI2, 10% H2SO4, 30°С Connection 4 30 mg/ml 46 mg/ml 198 mg/ml 19 mg/ml 51 mg/ml 390 mg/ml Connection 5 6 mg/ml 8 mg/ml 20 mg/ml 5 mg/ml 8 mg/ml 11 mg/ml Compound 5a diBr 5 mg/ml 7 mg/ml 10 mg/ml 5 mg/ml 7 mg/ml 14 mg/ml

This difference in solubility is exploited by carrying out the reaction at high concentration to displace Compound 5 from solution once it is formed, thereby minimizing its ability to further react with the brominating reagent to form Compound 5-a diBr. The reaction mixture is seeded with Compound 5 in order to initiate its crystallization.

In fig. 22 (Conversion of Compound 4 to Compound 5: Effect of Sulfuric Acid) it can be seen that in the absence of acid the initial reaction to Compound 5 is rapid, however the conversion plateau is about 30% of Compound 5. The major by-product was found

- 29 046293 impurity Compound 5-a diBr (see Fig. 23: Conversion of Compound 5 and Compound 5-a diBr: No H ₂ SO ₄ ). Adding more and more sulfuric acid results in higher conversion to the desired Compound 5.

In fig. 24 (Reaction Profile of Compound 4 to Compound 5: Batch Addition of NBS, Seeding) further monitors the reaction. Batch addition of NBS after the addition of catalytic sulfuric acid minimizes the temperature rise, and the addition of Compound 5 after the initial loading of NBS promotes the reactive crystallization of Compound 5. After approximately 67 hours of reaction, it can be seen that the main product is Compound 5, with only a small fraction (< 5%) di-brominated impurity. In contrast, in a reaction where Compound 4 and all NBS were loaded followed by the addition of 4 volumes of methylene chloride in a rapid exotherm, the major product was found to be the undesired Compound 5-a diBr.

Thus, the reaction was carried out at high concentration in CH ₂ Cl ₂ with portionwise addition of solid NBS (to control both electrophile availability and ectotherm). At the end of the reaction, no more than 5% of the starting material of Compound 4 was typically found in the suspension samples. After filtration, the crude precipitate was washed with cold CH ₂ Cl ₂ and the CH ₂ Cl ₂ washed filter cake contained no more than 0.5% wt. dibrominated Compound 5-a. It also contained large amounts of succinimide, which was undetectable by HPLC.

The following procedure was carried out: Compound 4 (25 g, 145 mmol) was added to the reaction vessel, then CH ₂ Cl ₂ (100 ml) was added and stirred. The mixture was brought to a temperature from 17°C to 23°C. Sulfuric acid (2.7 ml, 51 mmol) was loaded into the mixture at a temperature of 17°C to 23°C. The mixture was stirred at a temperature from 17°C to 23°C for 10-20 minutes. The first portion of Nbromosuccimide (NBS) was loaded (6.5 g, 36.5 mmol) into the mixture while maintaining the temperature from 17°C to 23°C and stirred for at least 30 minutes. A second portion of NBS (6.5 g, 36.5 mmol) was added to the mixture at a temperature of 17°C to 23°C and stirred for at least 30 minutes. The mixture was seeded with Compound 5 (0.02 wt.) and stirred for approx. 30 min at 17°C to 23°C to induce crystallization.

A third portion of NBS (6.5 g, 36.5 mmol) was added to the mixture at a temperature of 17°C to 23°C and stirred for at least 30 minutes. NBS (6.5 g, 36.5 mmol) was charged to the mixture at a temperature of 17°C to 23°C and stirred for at least 30 minutes. Additional CH ₂ Cl ₂ was charged (50 ml) to the batch while maintaining the temperature between 17°C and 23°C to aid in mixing and transfer to filtration. The mixture was stirred at a temperature from 17°C to 23°C until complete according to HPLC analysis (~20-40 hours). The product was collected by suction filtration. The filter cake was washed in a suspension with CH ₂ Cl ₂ (3x50 ml) at a temperature of 17°C to 23°C (target 20°C). The filter cake was washed in suspension with purified water (3.0 vol.) at a temperature of 65°C to 75°C for 2 to 3 hours. The filter cake was then washed in a suspension with purified water (3x1.0 vol., 3x1.0 wt.) at a temperature of 17°C to 23°C. The wet sediment was dried under vacuum under nitrogen at a temperature of 60°C. Yield: 27 g 5 (74% molar) >97% by weight. ^1H NMR (500 MHz, d6-DMSO) 8.01 (1H, d, ⁴ J = 2.1 Hz, RO-Ar meta-H), 7.76 (1H, dd, J = 8.6 and ⁴ J = 2.1 Hz, RO-Ar meta-H), 7.14 (1H, d, J = 8.6 Hz, RO-Ar ortho-H), 3.38 (1H, br s, OH), 3.20 (3H, s, CH ₃ ); MS (ES ^- ) calc. 249/251; found 249/251. Melting point (MP): (DSC) 188°C.

The procedure described above allowed the following modifications. Solvents: Alternative solvents may be used. Examples include chlorinated solvents such as chloroform or 1,2-dichloroethane, and non-chlorinated solvents such as acetonitrile, tetrahydrofuran or 2-methyltetrahydrofuran. Concentration of the reaction mixture: The concentration of the reaction mixture can vary from about 2X vol. up to about 20X vol. (relative to Compound 4). Brominating agents: Additional brominating agents include bromine and 1,3-dibromo-5,5-dimethylhydantoin. Bromination reagent stoichiometry: Various amounts of bromination reagent can be used, ranging from about 0.8 eq. to about 1.9 eq. Addition of brominating reagent: The brominating reagent can be added all at once, in batches of about 2 to about 20 batches, or continuously. The addition time can vary from about 0 to about 72 hours. Temperature: A reaction temperature of about 0°C to about 40°C can be used. Acids: Various acids may be represented, including benzenesulfonic acid, p-toluenesulfonic acid, triflic acid, hydrobromic acid and trifluoroacetic acid. Isolation: Instead of directly filtering the product and washing it with methylene chloride and water, an organic solvent capable of dissolving Compound 5 could be charged at the end of the reaction, followed by aqueous workup to remove the succinimide and the addition of an antisolvent or solvent change to an appropriate solvent to crystallize Compound 4 Drying: For drying, a temperature range of about 10 to about 60°C can be used. An alternative process has also been developed for Compound 5. This process is advantageous in that it does not use a chlorinated solvent and also provides additional control over the formation of the dibromine impurity of Compound 5-a. See Oberhauser, T. J. Org. Chem

- 30 046293

1997, 62, 4504-4506. The process is as follows. Compound 4 (10 g, 58 mmol) and acetonitrile (100 ml) were charged to the reactor and stirred. The mixture was cooled to -20°C. Triflic acid (CF ₃ SO ₃ H or TfOH, 5.5 ml, 62 mmol) was loaded while maintaining the charge temperature from -10 to -25°C. N-bromosuccinimide (NBS, 11.4 g, 64 mmol) was charged, stirred at -10 to -25°C for 30 minutes, then heated to 20°C for 3 to 4 hours. Stirring was continued at a temperature of 15°C to 25°C until the reaction was complete. If the conversion plateaued before completion of the reaction, then the reaction was cooled to -5 to -15°C and additional NBS was added, the amount based on the unreacted starting material, followed by heating to 15°C to 25°C and reaction until complete completion. After completion of the reaction, the mixture was heated to a temperature of 40°C to 50°C and concentrated under reduced pressure to 40 ml. The mixture was cooled to a temperature of -5°C to -15°C, and the resulting solid product particles were filtered. The solids were washed in suspension three times each time with 20 ml of water for at least 15 minutes. The final residue was dried at 50° C. to 60° C. under reduced pressure to obtain 10 g of 5 containing less than 0.1% MeCN, 0.07% water and 0.1% triflic acid (TfOH) by weight.

Alternatives to the above procedure using MeCN and TfOH are as follows. Brominating agents: Additional brominating agents include bromine and 1,3-dibromo5,5-dimethylhydantoin. Stoichiometry of Brominating Reagent: Various amounts of brominating reagent can be used, ranging from about 0.8 eq. up to about 2 eq. Drying: For drying, a temperature range from about 10°C to about 60°C can be used.

Impurity 5-a was obtained and characterized as follows. 10 g of Compound 4 and sulfuric acid (35 mol.%) were dissolved in MeOH (10 vol.). The mixture was stirred at a temperature of 20°C to 25°C for 5-10 minutes, and 2.0 equivalents of NBS was charged in one portion. The resulting yellow mixture was stirred for three days at 20-25°C. The mixture was concentrated under reduced pressure and the resulting solid was suspended in water at a temperature of 95-100°C for 3 hours. After a second overnight suspension in CH ₂ Cl ₂ at room temperature, the mixture was filtered and dried to give white solid 5-a (15.0 g, 78%). ^1H NMR (500 MHz, d ₆ -DMSO), 8.05 (2H, s, ArH), 3.40 (1H, br s, HO-Ar), 3.28 (3H, s, CH3); MS (ES ^- ) calc.. 327/329/331; found 327/329/331; MP (DSC): MP (DSC): 226°С (start 221°С, 102 J/g); lit. 224-226°C.

1.2: O-alkylation of 5 to give 6

Compound 6 was prepared according to Scheme 7 below.

Scheme 7: O-alkylation of 5 to give 6

Compound 5 (100 g, 398 mmol) and methyl ethyl ketone (MEK, 700 ml) were charged to the reaction vessel and stirred. Potassium carbonate (K ₂ CO ₃ , 325 mesh 82.56 g, 597 mmol) was then charged into a stirred reaction vessel at a temperature of 15°C to 25°C. Bromomethylcyclopropane (64.4 ml, 664 mmol) was charged into the reaction vessel for at least 1 hour, maintaining the temperature between 15°C and 25°C. MEK (200 ml) was added to the reactor and the reactor was heated to 65-75°C. The contents of the reaction vessel were stirred at 65 to 75°C for approximately 10 hours until the reaction was complete as determined by HPLC. Water (3.0 vol., 3.0 wt.) was loaded into the vessel, maintaining the temperature from 65 to 75°C. The mixture was stirred at a temperature from 65 to 75°C. The phases were left to separate at 65°C to 75°C and the lower aqueous phase was removed. Water (300 ml) was loaded into the vessel, maintaining the temperature between 65°C and 75°C. The mixture was stirred for at least 10 minutes at a temperature of 65 to 75°C. The phases were separated at a temperature of 65°C to 75°C and the lower aqueous phase was removed. Washing with water was repeated once. The temperature was brought to 40-50°C. The mixture was concentrated to ca. 500 ml at reduced pressure. The mixture was distilled under reduced pressure at temperatures up to 50°C with MEK to a water content of <1.0% w/w. n-Heptane (500 ml) was loaded into the vessel, maintaining the temperature between 40 and 50°C. The mixture was continuously distilled under vacuum with n-heptane (300 ml), maintaining a volume of 1 L in the reaction vessel. Seeds of Compound 6 (0.01 wt.) were added at a temperature of 40 to 50°C. The mixture was continuously distilled under reduced pressure at temperatures up to 50° C. with nheptane (300 ml) while maintaining a volume of 1 L in the reactor. The mixture was cooled to 15-25°C and kept for 2 hours. The product was collected by suction filtration. The filter cake was washed with a solution of 10% MEK in n-heptane (5 vol.) at a temperature of 15 to 25°C. The filter cake was dried under reduced pressure at temperatures up to 40°C in vacuum with a stream of nitrogen to obtain 95 g of 6. 1H NMR (500 MHz, d ₆ -DMSO) 8.07 (1H, d, ⁴ J = 2.2 Hz, ArH) , 7.86 (1H, d, J = 8.7 Hz, meta-ArH), 7.29 (1H, d, J = 8.8 Hz, ortho-ArH), 4.04 (2H, d, J = 6.9 Hz, OCH^CH), 3.21 (3H, s, CH3), 1.31-1.24 (1H, m, OCH), 0.62-0.58

- 31 046293 (2H, m, 2 x CHCHHb), 0.40-0.37 (2H, m, 2 x CHCHaHb); MS (ES+) calc. 305/307; found 305/307; MR: (DSC) 93°C.

The following modifications of the above reaction, synthesis 6 of 5, can also be used. Solvent: Various solvents can be used, for example, acetone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, acetonitrile or 2-methyltetrahydrofuran. Reaction volume: Reaction volumes from 3 to 30 volumes relative to 3 can be used. Base: Various inorganic bases can be used, such as cesium carbonate or phosphate bases (sodium, potassium or cesium). In addition, organic bases such as trimethylamine or diisopropyldiimide can be used. Base Particle Size: Various potassium carbonate particle sizes from 325 mesh can be used. Reaction Temperature: A lower temperature such as 50°C can be used. A higher temperature such as about 100°C can be used. Any temperature above the boiling point of the solvent can be used in a pressure vessel. Isolation: Various ratios of MEK and n-heptane solvents can be used. Varying amounts of residual water may be left. Various amounts of seeds can be used, from 0 to 50%. Seeding may occur later in the process and/or at a lower temperature. Unseeded crystallization can be used. A different release temperature from 0°C to 50°C can be used. A different wash could be used, such as a different ratio of MEK to n-heptane. An antisolvent other than n-heptane may be used, such as hexane, pentane, or methyl tert-butyl ether. Alternatively, the mixture can be solvent exchanged to a solvent where Compound 3 has a solubility of less than 100 mg/ml, and isolated from this system. Drying: For drying, a temperature range of 10 to 60°C can be used.

Compound 10 shown below may also be formed by O-alkylation of unreacted 4 present in product 5, or alternatively from or through palladium-mediated proteodesbromination or proteodesborylation in the downstream chemistry discussed in Example 1.3 below.

O _l „O

Preparation of methylsulfonylphenyl(cyclopropylethyl)ether 10:

Compound 4 (0.86 g, 5.0 mmol) and K ₂ CO ₃ (1.04 g, 7.5 mmol) were suspended in acetone (17 ml, 20 vol). Cyclopropyl methyl bromide (0.73 ml, 7.5 mmol) was added in several small portions over ~1 minute and the reaction mixture was heated to 50°C for 48 hours, then cooled to 25°C. While stirring, water (5.0 mL) was added and the acetone was evaporated on a rotary evaporator to form a fine white solid, which was filtered and returned to the vessel as a wet paste. A mixture of MeOH/water (8 ml) was added in a ratio of 1:1 and heated to 40°C with stirring. After 1 hour, the white solid was filtered off. The residual solid was washed with fresh water, which was also passed through the precipitate, which was then isolated and left to air dry for two days to give a dense white solid 10 (1.00 g, 88%). ^1H NMR (500 MHz, CDCl ₃ ) 7.85 (2H, d, J = 8.8 Hz, RO-Ar ortho-H), 7.00 (2H, d, J = 8.8 Hz, RO-Ar meta-H), 3.87 ( 2H, d, J = 7.0 Hz, OCH2CH), 3.02 (3H, s, CH3), 1.34-1.23 (1H, m, OCH2CH), 0.72-0.60 (2H, m, 2 x CHCHHb), 0.42-0.31 (2H , m, 2 x CHCHaHb).

1.3: Synthesis and Isolation of Compound Affiliate Boric Ester 2

The final step in bond formation prior to Compound 1 is the Suzuki-Miyaura coupling reaction between Compounds 2 and 3, as shown in Scheme 3 below (Norio, M. and Suzuki, A., Chem. Rev., 95(7), 2457-2483 (1995) ). Early studies showed that the boron ester of isoquinolinone Compound 3-a has poor physical properties and solid-phase stability (Kaila, N. et al., J. Med. Chem., 57: 1299-1322 (2014)). The O-alkylphenol pinacolatoboronate, Compound 7, had acceptable stability in the solid phase and could be isolated by crystallization.

Scheme 3: Suzuki-Miyaura coupling reaction between 2 and 3

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However, studies on the stability of the isolation process of Compound 7 have shown that Compound 7 has poor stability in solution, decomposing mainly into the proteodeborylated compound 10, as shown in Scheme 4 below. This was particularly problematic because the isolation process involved exchanging a solvent from 2-MeTHF (2-methyltetrahydrofuran) to iPrOAc (isopropyl acetate), which is not a fast setup operation when scaled up.

Scheme 4: Modification 7

A search was undertaken for a more stable boron ester. Early attempts were aimed at preparing the N-methyliminodiacetic acid (MIDA) boronate Compound 2-a (E. Gilis and M. Burke, Multistep Synthesis of Complex Boronic Acids from Simple MIDA Boronates, J. Am. Chem. Soc, 130(43) : 14084-14085 (2008)), however all attempts resulted in decomposition of the product. The applicant then turned to the relatively little known boronate formed by the addition of diethanolamine to Compound 7 (Bonin et al., Tetrahedron Lett., 52:1132-1135 (2011)). Addition of diethanolamine to a solution of Compound 7 resulted in rapid ester formation and concomitant crystallization of Compound 2.

The discovery of the boron ester of Compound 2 allowed for a simple, rapid, high yield, high purity process involving the following procedure. Tetrahydrofuran (THF, 1500 ml) was charged into a flask containing Compound 6 (100 g, 328 mmol), bis(pinacolato)diboron (90.7 g, 357 mmol) and cesium acetate (CsOAc, 158 g, 822 mmol). The system was purged three times with nitrogen under vacuum. Pd(PPh ₃ ) ₂ Cl ₂ (13.8 g, 20 mmol) was added to the reaction mixture and the system was purged with nitrogen three times under vacuum. Then the reaction mixture was heated to 55-65°C.

The mixture was stirred for approximately 8 hours until the reaction was complete as determined by HPLC. The mixture was cooled to 15-25°C (target 20°C) and silica gel (20 g) and Ecosorb C-941 (20 g) were loaded into it. After 1 hour, the mixture was filtered to remove solids. Residual solids were washed twice, each time with THF (300 ml). The filtrate and washings were combined. In a separate vessel, diethanolamine (34.5 ml, 360 mmol) was dissolved in THF (250 ml). Then a solution of diethanolamine in THF (25 ml) was loaded into the mixture. After 10 minutes, the mixture was seeded with 2 (1 g) and kept for 1 to 2 hours. The remaining solution of diethanolamine in THF was charged to the mixture over at least 2 hours and the suspension was stirred for at least 2 hours. Product 2 was collected by suction filtration. The wet sediment was washed three times with THF (200 ml). The substance was dried under vacuum at 40°C with a nitrogen purge to obtain 94.6 g of 2.

The reaction for the synthesis of Compound 2 from Compound 6 described above can be modified as follows. Solvent: Various solvents other than THF can be used, such as 1,4-dioxane or 2-methyltetrahydrofuran. Reaction Volume: The reaction volume can vary from 4 to 50 volumes relative to Compound 2. Catalyst and Base: Various palladium catalysts and bases can be used for borylation. Examples can be found in Chow et al., RSC Adv., 3: 12518-12539 (2013). Borylation reaction temperature: Mozh

- 33 046293 but use a reaction temperature from room temperature (20°C) to solvent reflux. Carbon/Silica Treatment: Treatment can be carried out without silica gel. This process can be performed without carbon processing. Carbon sources other than Ecosorb C-941 may be used. Various amounts of silica can be used, from 0.01X to 1X weight equivalents. Various amounts of Ecosorb C-941 can be used, from 0.01X to 1X weight equivalents. Crystallization: A different diethanolamine addition rate may be used. Various amounts of diethanolamine can be used, from 1.0 to 3.0 molar equivalents. A different sludge wash with more or less THF can be used. You can use different amounts of seeds from 0.0001X wt. up to 50X wt. Alternatively, the process can be seedless. Drying: For drying, a temperature range from 10°C to 60°C can be used.

The subsequent Suzuki-Miyaura coupling reaction between Compounds 2 and 3 also proceeded well, providing over 20 kg of crude compound 1 with an average molar yield of 80% and an LCAP of 99.7%.

1.4: Synthesis of Compatible Partner 3

Cross-coupling partner 3 was prepared by two different processes corresponding to Schemes 8 and 9 shown below.

Scheme 8: Process A to get 3

According to Process A, Compound 9 (100 g, 628 mmol) was dissolved in acetonitrile (450 ml) at room temperature. In a separate vessel, N-bromosuccinimide (NBS, 112 g, 628 mmol) was suspended in acetonitrile (1 L). Compound 9 in acetonitrile was loaded into the NBS suspension for at least 45 minutes. The contents of the reaction vessel were heated to 45°C - 55°C and the mixture was stirred until the reaction was completed as determined by HPLC analysis. The mixture was cooled to 35°C-45°C and dissolution was ensured. Norit SX plus carbon (10 g) was loaded into the mixture and the reaction mixture was brought to a temperature of 55°C to 60°C. The mixture was stirred at 55°C to 60°C for about 1 hour and filtered at 55°C to 60°C to remove solid particles. The solids were washed with acetonitrile (500 ml) at 55°C to 60°C. The volume of the combined filtrate was reduced to 900 ml by distilling off acetonitrile under reduced pressure. The mixture with Compound 3 (1 g) was stirred at a temperature of from 35°C to 45°C for at least 60 minutes. The contents of the reaction vessel were cooled to a temperature of from 15°C to 25°C for at least 1 hour. Water (2000 ml) was charged into the reaction vessel for at least 90 minutes and the suspension was kept for at least 60 minutes. The product was collected by suction filtration. The precipitate was washed with a pre-mixed 5% solution of acetonitrile in water (300 ml). The wet sediment was dried under vacuum at 40°C with nitrogen purging. Yield: 120 g 3.

The above procedure, Process A for this synthesis 3, can be applied with alternative reagents and conditions as follows. Solvents: Alternative solvents may be used. Examples include chlorinated solvents such as methylene chloride, chloroform or 1,2-dichloroethane, and non-chlorinated solvents such as tetrahydrofuran or 2methyltetrahydrofuran. Reaction concentration: Reaction concentration can vary from 2X vol. up to 40X rpm (relative to Compound 9). Brominating agents: Additional brominating agents include bromine and 1,3-dibromo-5,5-dimethylhydantoin. Bromination reagent stoichiometry: Various amounts of bromination reagent can be used, ranging from 0.8 eq. up to 2 eq. Crystallization: Various quantities of water can be used, including from 5 to 50 volumes. Crystallization can occur without adding seeds. Various water addition and final retention times can be used. Various flushing procedures can be used. Drying: For drying, a temperature range from 10°C to 60°C can be used.

Scheme 9: Process B for preparation 3

Vg

According to Process B, Compound 3 can be formed starting from 8 through the unselected compound 9 as follows. The reactor was charged with Compound 8 (80 g, 55 mmol), cesium carbonate (Cs ₂ CO ₃ , 215 g, 66 mmol) and acetonitrile (800 ml). The temperature was set from 15 to 25°C and iodomethane (MeI, 86 g, 0.61 mol) was loaded into the reactor while maintaining the charge temperature below 25°C. The mixture was heated to 40°C and stirred for 10 hours to form Compound 9. The mixture was oh

- 34 046293 cooled to 25°C, filtered into a fresh reactor to remove solids and washed twice with acetonitrile. The combined organic layers were concentrated by atmospheric distillation to about 320 ml.

In a separate reactor, N-bromosuccinimide (NBS, 98.1 g, 0.55 mol) was charged into acetonitrile (800 ml) and stirred. The mixture containing Compound 9 was transferred to the NBS solution while maintaining the temperature of the mixture from 15 to 25°C. The mixture was heated to a temperature of 45 to 55°C and stirred for at least 4 hours to ensure completion of the reaction to Compound 3. Once the reaction was complete, Norit SX Plus activated carbon (8 g) was charged and stirred at a temperature of 45 to 55° C for one hour. The mixture was filtered into a fresh vessel, the Norit SX plus precipitate was washed with 400 ml of acetonitrile at a temperature of 45 to 55°C. The acetonitrile layers were combined, cooled to 35 to 45°C and distilled under reduced pressure to 720 ml. The mixture was brought to a temperature of 40°C, loaded with Compound 3 seeds (0.8 g), stirred for one hour, cooled to a temperature of 15 to 25°C for at least an hour, then loaded with water (1600 ml) for at least two hours. The mixture was stirred for another one to two hours, filtered, and the precipitate was washed with a pre-mixed 5% solution of acetonitrile in water (240 ml). The wet sediment was dried under vacuum at 40°C with nitrogen purging. Yield: 52 g 3. Process B for the synthesis of Compound 3 described above can be modified as follows. Solvents: Alternative solvents may be used. Examples include chlorinated solvents such as methylene chloride, chloroform or 1,2-dichloroethane, and non-chlorinated solvents such as tetrahydrofuran or 2-methyltetrahydrofuran. Reaction concentration: Reaction concentration can vary from 2X vol. up to 40X rpm (relative to Compound 8). Alkylating Reagent: Alternative methylating reagents such as dimethyl sulfate can be used. Alkylating Reagent Stoichiometry: 1 to 10 molar equivalents of methyl iodide may be used. Base: Various inorganic bases such as potassium carbonate or phosphate bases (sodium, potassium or cesium) can be used. Brominating agents: Additional brominating agents include bromine and 1,3-dibromo-5,5-dimethylhydantoin. Bromination reagent stoichiometry: Various amounts of bromination reagent can be used, ranging from 0.8 eq. up to 2 eq. Crystallization: Various quantities of water can be used, including from 5 to 50 volumes. Priming levels from 0.0001% to 50% can be used. Crystallization can also occur without adding seeds. Various water addition and final retention times can be used. Various flushing procedures can be used. Drying: For drying, a temperature range of 10 to 60°C can be used.

1.5: Cross-coupling reaction of 2 and 3 to obtain Target Compound 1 is synthesized by Suzuki cross-coupling reaction of 3 and 2 according to Scheme 10 and as described below.

Scheme 10: Synthesis 1

2 1°

Acetonitrile (1.6 L) was loaded into a mixture of Compound 2 (156.7 g, 460 mmol), Compound 3 (100 g, 420 mmol) and tribasic potassium phosphate (223 g, 1.05 mol). Stirring was started and water (400 ml) was added to the mixture. The system was evacuated with nitrogen three times and Pd(PPh ₃ ) ₂ Cl ₂ (2.9 g, 4 mmol) was charged and the system was evacuated with nitrogen three times. The mixture was heated to a temperature of 65 to 75°C and the contents were stirred for at least 16 hours until the reaction was complete as determined by HPLC. The mixture was cooled to a temperature of 60 to 70°C, stirring was stopped and the mixture was allowed to settle. The lower aqueous layer was removed. Water (150 ml) and acetonitrile (700 ml) were loaded at a temperature of 60 to 70°C. Ecosorb C-941 (15 g) and Celite (10 g) were loaded into the reaction vessel at a temperature of 60 to 70°C. After 1 hour, the mixture was filtered to remove solid particles. The solids were washed twice each time with 18% water in acetonitrile (500 ml) at a temperature of 60 to 70°C. The filtrates were combined and concentrated at atmospheric pressure to a final volume of 1.5 L. The mixture was cooled to a temperature of 60 to 65°C and seeded with Compound 1 (1 g). After 1 hour, water (500 ml) was charged for at least 1 hour at a temperature of 60 to 65°C. The suspension was cooled to a temperature of 15 to 25°C for 4 hours. The product was collected by suction filtration. The wet sediment was washed twice with 45% water in acetonitrile (500 ml). The product was dried under vacuum at 40°C with nitrogen purging. Yield: 139 g 1.

The above procedure for combining Compound 3 and Compound 2 to obtain Compound 1 can be modified by any of the following methods. Reaction solvents: Various reaction solvents other than acetonitrile can be used, including tetrahydrofuran, 2

- 35 046293 methyltetrahydrofuran, toluene and isopropanol. Boron ester: Boron esters other than Compound 2 may be used, including the pinacolate ester of Compound 7 and free boric acid of Compound 2. Examples of boron esters can be found in Lennox, Alister, JJ, Lloyd-Jones, Guy C. Chem. Soc. Rev., 2014, 43, 412. Carbon Treatments: Carbon treatments other than Ecosorb C-941 may be used. Various amounts of carbon can be used, from 0.01 to 0.5X by weight. Carbon can be eliminated. Various amounts of Celite can be used, from 0.01 to 0.5X by weight. Crystallization: Various quantities of water can be used, including from 5 to 50 volumes. Crystallization can occur without adding seeds. Various water addition and final retention times can be used. Various flushing procedures can be used. Drying: For drying, a temperature range of 10 to 60°C can be used. Catalysts: Various combinations of metal and ligand can be used. Examples of metal/ligand combinations can be found in Maluenda, Irene; Navarro, Oscar, Molecules, 2015, 20, 7528. Various catalysts can be used, including: XPhos-3G (cas# 1445085-55-1); cataCXium® A Pd 3G (CAS# 1651823-594); PdCl ₂ (DtBPF) (CAS# 95408-45-0); SPhos 3G (Cas# 1445085-82-4); AmPhos 3G (Cas# 1820817-64-8); RSu ₃ 3G (Cas# 1445086-12-3); Pd PEPPSI IPent Cas#1158652-41-5); Pd(PPh ₃ ) ₂ Cl ₂ (Cas# 13965-03-2). Examples of catalyst systems that have been demonstrated to lead to Compound 1 are listed below in Table. 4 when using boron esters 2 or 7 in combination with 3.

Table 4

Catalyst Screening Summary Table

HB071;

THF.XPtes 3G

ThF.CatatXum A 3G T_HF_PdCI2[otSPF) _ ” TWJ>Phos3G______

ThF_AFhos3G THF_PCy3 3G

THF.Pd PE»PSI I Pen: THF_Pd|PFh3)2CI2 2-MeTHF_XPbos 3G 2-MeTHF_CataCXium 2-MeTHF_PdCI2jDtBP 2-MeTHF_SPhos3G 2-MeTHF_APhos3<^ 2-MeTHF_PCv3 3S ~ 2-MeTHF_Pd PEPPSI II 2-Me THFJd(PPh3)2C MeCN .XPhosBG _ MsCNJataCXium A 3 MeCNJ>da2(ptB=FI MeCN.SPhosJG ~ MeCN.APhos 3G

MeCNJC _V 3_3G_ _ VeCH_Pd PEPPSI IPer

With food 3

HB075

Connection 3

MeCN,Pd(PPHl2a2

1.6: Crystallization 1

For the final isolation of Compound 1, filtration with additional purification is required. To do this, the charge must be completely dissolved. Unfortunately, Compound 1 has low solubility in almost all Class 3 and general Class 2 solvents (e.g. THF, MeCN) of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) (ICH Harmonized Guideline Impurities: Guideline for Residual Solvents Q3C(R6) October 20, 2016). Reasonable solubility was obtained in a warm MeCN-water mixture, but this is not an optimal system (heated filtration required, MeCN has a residual solvent limit of only 410 ppm). Additional solvents with reasonable solubility (>50 mg/mL) include N-methyl-2-pyrrolidone (NMP) and dimethylacetamide (DMAc); but developing isolations from these solvents required large volumes and raised issues of residual solvent limit (530 ppm or less for NMT and 1090 ppm or less for DMAc).

Formic acid is one of the ICH Class 3 solvents in which Compound 1 is highly soluble, having a solubility of more than 250 mg/ml at 20°C. The solubility curve of Compound 1 in formic acid-water is quite steep (see Fig. 7), which allows the process to be carried out efficiently in bulk.

Initial attempts to recrystallize crude Compound 1 involved dissolving in formic acid, post-filtering and loading post-filter water to about 20% supersaturation and then seeding with the thermodynamically most stable form (Form 1), then slowly adding water to the final solvent ratio, filtering, washing and drying. The applicant discovered that during the initial loading of water, if the charge was self-seeded, it would form a thick slurry. X-ray diffraction (XRD), differential scanning calorimetry (DSC) and photomicroscopy showed that a metastable form was obtained. After seeding with Form 1, the batch is converted to the desired form (Form 1) before adding the remaining water. This process worked well during several laboratory runs, consistently achieving the desired form and purity with a yield of about 85%.

Unfortunately, when scaling, the batch did not transform into Form 1 after seeding. Additional water was charged and the batch began to transform into the desired form (Form 1 mixture

- 36 046293 and metastable form by X-ray powder diffraction (XRPD)). When additional water was added, XRPD showed only the metastable form. After several hours without any change, Applicant continued loading water to the final solvent ratio, during which time the batch eventually converted to Form 1. This process is summarized in FIG. 8. Subsequently, upon more careful analysis of plant and laboratory samples, it was found that when scaled up, a new metastable form was formed with a similar but different XRPD pattern. This form (metastable B) can be reproduced in the laboratory, but only if the charge has a high ratio of formic acid to water and is seeded with Form 1. Without Form 1 seeds, metastable A is the kinetic form. Both metastable forms convert to Form 1 with additional water and/or drying, leading Applicant to believe that the metastable forms are solvates of formic acid. These findings are summarized in FIG. 9.

While there is a small risk that you will not be able to control the final shape, there is also a risk of creating a difficult-to-mix slurry, which can lead to production problems. Therefore, the crystallization procedure was modified to maintain a constant ratio of formic acid to water. This was accomplished by loading 2.4X wt. formic acid and 1.75X wt. water (final solvent composition) into a crystallizer with 0.03X wt. seeding Form 1 and simultaneously adding Compound 1 to 6.1X wt. formic acid and 4.4X wt. water. The charge was lightly filtered and washed with formic acid/water, then with water and dried under reduced pressure to obtain 8.9 kg of Compound 1 (92% yield) with 99.85% LCAP and formic acid N.D.

Example 2: Typical High Throughput Experimental Reaction

The following procedure is a typical high throughput experimental reaction.

An overview of the reaction is shown below in Scheme 5:

Scheme 5: Reaction conditions tested for cross-coupling reaction of compound 2 and 3

Pd catalysts were dosed into a 24-well reactor vessel as solutions (100 μL of a 0.01 M solution in tetrahydrofuran (THF) or dichloroethane (DCE) depending on the solubility of the ligand). The plates of these ligands are usually dosed before the reaction, the solvent is removed by vacuum in an evaporation centrifuge, and the plates are stored in a glove box. The catalysts selected for the coupling reaction are the following: XPhos, SPhos, CataCXium A, APhos, P(Cy) ₃ , PEPPSIIPent. For the first five ligands, they were initially selected as Buchwald Pd G2/G3 precatalysts. A stock solution of Compound 3 (10 µmol) and Compound 2 (12 µmol) dissolved in the following solvents: dimethylformamide (DMF), tetrahydrofuran (THF), butanol (n-BuOH) and toluene was then added to the plates. The base was then added as a stock solution (30 μmol) in 20 μl of water.

A heat map summarizing the catalyst characteristics is shown in FIG. 10A and 10B. High performance liquid chromatography (HPLC) provides a range of <5% up to ~85% for this screening range. Larger circles indicate higher yield. Lighter circles indicate higher purity.

A similarly designed base and solvent screen also indicates that a number of alcohol solvents (methanol, ethanol, propanol, 2-butanol, 2-propanol, and tert-amyl alcohol) are also viable in this coupling chemistry. Bases such as potassium phosphate, potassium carbonate, potassium acetate and potassium hydroxide have been successful in achieving the combination. In fig. 10B shows a heat map with HPLC yields ranging from ~50-95%. Larger dark circles indicate higher yield.

This microscreening chemistry was scaled up to a laboratory process. To a 250 mL 3-neck flask equipped with overhead stirring, nitrogen inlet, and thermocouple, Compound 3 (1.0 eq., 4.00 g), Compound 2 (1.2 eq., 1.71 x wt.) was added. , potassium carbonate (3.0 eq., 1.74 x wt.). The reactor was inerted three times, and then degassed 2-propanol (24 x vol.) was added and then degassed

- 37 046293 bath water (6 x vol.). Then stirring was started at 300 rpm. The reaction mixture was then stirred and protected with nitrogen for 1 hour. Then the catalyst (0.01 eq., 0.028 x wt.) was added and stirring was continued (300 rpm) and the reactor was heated to a temperature Tj = 65°C. After 2 hours with complete conversion confirmed analytically, trioctylphosphine (0.1 eq, 0.16 x wt) was dosed and the reaction mixture was allowed to slowly cool to room temperature over several hours. The reaction mixture was then filtered, washed with 2-propanol (4 x v/v), 2-propanol:water (4:1, 4 x v/v) and then with water (4 x v/v). Note: If dimer 2 is present in the precipitate, an additional wash (4 x vol) with ethyl acetate (EtOAc) can be added to purge. The precipitate was then transferred to a vacuum oven to dry overnight at 40°C, -40 cmHg. Art. under a stream of nitrogen. After transfer to the bottle, 6.03 g of 1 was isolated, analysis 98.6%, overall yield 91%.

Scheme 6: Alternative Reagents and Solvents for Cross-Coupling

Based on the previously outlined results, it was expected that various monodentate (PPh ₃ [triphenylphosphine], PBu ₃ [tributylphosphine], etc.) and bidentate phosphines (dppf [1,1'-bis(diphenylphosphino) ferrocene], BINAP [2, 2'-bis(diphenylphosphino)-1,1'-binaphthyl], Xantphos [4,5-bis(diphenylphosphino)-9,9dimethylxanthene], dppe [1,2-bis(diphenylphosphino)ethane], etc.) , ligated with any number of Pd sources (Pd halides, Pd(II) precatalysts, Pd(O) sources) can be intelligently used to arrive at the raw material of Compound 1. A range of organic solvents ranging from non-polar (heptane, benzene), protic (alcohols), polar aprotic (dimethyl sulfoxide, dimethylformamide, dimethylacetamide, acetonitrile), as well as various esters and ketones (acetone, 2-butanone, ethyl acetate), should also serve as effective solvents for this reaction. Finally, inorganic bases of varying strengths (phosphates, carbonates, acetates, etc.) are viable as stoichiometric base additives, along with organic options such as triethylamine, 1,8-diazabicyclo(5.4.0)undec-7-ene, and others over a wide pKa range.

Example 3: Typical Process of Compound 5

The purpose of this example was to describe a typical process for preparing Compound 5.

Vg % _Z O °* LE

Ar Me MeΗ

II Ί f ₃ c-so ₃ h ----------------* II Ί

MeCN bliss \/

90010-V Vg 90010-D

F.W. 172.20

- 38 046293

Table 5

The basis S.M. May. MM 172.02 G 10.00 Mole 0.058

Reagent Purity MM Mol. Eq. m Raft ness Weight About. Moli X Mass. X About. M/L g/ml G ml 90010-B;4 97% (1476360-1) 172.02 1.00 10.00 - 0.058 1.00 - N.B.S. Reagent (12808-5) 177.98 1.10 11.38 - 0.064 1.14 - Triflovaya acid Reagent Plus (149313-6) 150.08 1.07 1.70 9.34 5.5 0.062 0.93 0.55 MeCN reagent (75-058) 41.05 33.00 0.79 78.75 100.2 1.918 7.87 10.02 90010-D;5 (2095143-3) 251.10 1.00 14.60 - 0.058 1.46 - water reagent (773218-5) 18.00 29.00 1.00 30.35 30.3 1.686 3.03 3.03

Charge 4 (10 g, 58 mmol) and acetonitrile (100 ml) into the reaction vessel and start the stirrer. The charge temperature is adjusted from -18°C to -22°C (target -20°C). Load triflic acid (5.5 ml, 62 mmol) into the mixture, maintaining the temperature from -10°C to -25°C (target -20°C). The mixture is stirred at a temperature from -10°C to -25°C (target -20°C) for 10-20 minutes. Charge NBS (11.38 g, 64 mmol) into the batch at -10°C to -25°C (target -20°C) and stir for ca. 30 minutes at temperatures from -10°C to -25°C (target -20°C). Heat the mixture to 20°C for 3-4 hours (the reaction will occur at an internal temperature of 5°C to 15°C). Stir the mixture at a temperature of 15°C to 25°C (target 20°C) for approximately 1 hour and take a sample to judge completion of the reaction. If Compound 4 relative to Compound 5 is more than 5%: cool the bath to -5°C to -15°C (target -10°C) (cool below 0°C to ensure selectivity). Load NBS into the charge according to the following formula: Weight of NBS = (% Compound 4 x 10 g). Heat the mixture to 20°C for 1-2 hours. Stir the mixture at 15°C to 25°C (target 20°C) for approximately 1 hour and check for complete reaction. Move to the next line.

If Compound 4 relative to Compound 5 is less than 5%: heat the mixture to a temperature of 40°C to 50°C (target 48°C). Concentrate the mixture under reduced pressure to a final volume of ~40 ml. Cool the mixture to a temperature of -15°C to -5°C (target -10°C) and stir for approx. 1 hour. Filter the mixture by filtration with suction. The filter cake was washed in a suspension of purified water (3x20 ml) at a temperature of 15°C to 25°C (target 20°C) for 10 to 15 minutes for each wash. A sample of the filter cake is removed for analysis by ¹ H NMR. Continue washing the cake until the residual succimide drops below 1.0 mol.% relative to 5. Dry the filter cake at temperatures up to 60°C under vacuum and purging with nitrogen. Analyze 5 by HPLC analysis (97% w/w to 99% w/w). Expected yield: 60-85% of theoretical (90-110% w/w).

Example 4: Purification of Compound 1 (CC-90010) by crystallization from formic acid and water.

This example describes a method for purifying Compound 1 by crystallization from formic acid and water. Methods for preparing three different polymorphs of Compound 1, including the most stable form, Form 1, are also described in detail. FIG. 11 shows 1H NMR of Compound 1 (CC-90010). Solvent: d6DMSO; a in fig. 12 shows microscopy of Compound 1 (CC-90010) Form I. FIG. 13 shows the XRPD of Compound 1 (CC-90010) Form I with peak information detailed in Table. 6:

- 39 046293

Table 6

Pos. interatomic Rel. No. [°2Th.J distance Intensity [A] [%] 1 7.848639 11.26463 28.08 2 8.786152 10.06464 8.34 3 9.029003 9.79448 22.96 4 15.3269 5.78113 2.61 5 15.7163 5.63876 54.48 6 16.33764 5.42569 12.05 7 16.96594 5.22614 1.71 8 17.56643 5.04883 35.98 9 18.04998 4.91464 100 10 19.22664 4.61645 4.27 AND 19.77337 4.49002 2.3 12 20.54306 4.3235 6.21 13 21.22113 4.18686 4.48 14 21.87546 4.06308 3.19 15 22.13877 4.01535 2.89 16 22.97622 3.87085 0.46 17 23.35649 3.80869 2.35 18 23.65442 3.76139 16.68 19 24.08656 3.69487 1.33 20 24.47663 3.63687 14.86 21 25.2578 3.52613 8.13 22 25.65436 3.47252 0.89 23 26.45718 3.36894 9.48 24 27.16849 3.28233 0.45 25 27.74005 3.21599 1.05 26 29.58503 3.0195 1.03 27 31.96313 2.80007 1.19 28 32.88567 2.7236 0.86 29 33.84791 2.64834 0.31 thirty 34.38817 2.6058 1.64 31 34.47198 2.60181 1.58 32 36.42635 2.46658 0.63 33 37.21594 2.41604 0.33 34 37.82887 2.37829 1.25 35 38.99599 2.30976 0.47

In fig. Figure 14 shows the XRPD of Form 1 CC-90010 after milling (preferred orientation), and the peak information is detailed in Table 1. 7:

Table 7

interatomic Rel. Pos. distance Intensity No. [°2Th.J [A] [%] 1 7.807098 11.32447 13.16 2 8.691139 10.17446 15.67 3 8.944468 9.88685 40.82 4 11.47771 7.70979 20.22 5 13.75333 6.43883 19.45 6 15.27651 5.80009 8.04 7 15.69109 5.64776 64.51 8 15.99297 5.54183 66.46 9 16.27756 5.44557 7.77 10 16.89633 5.24752 43.12 AND 17.50072 5.06763 36.25

- 40 046293

12 17.96524 4.93763 88.03 13 19.20236 4.62223 11.22 14 19.70334 4.50582 15.85 15 20.50266 4.33193 20.82 16 21.13626 4.20348 38.66 17 21.89583 4.05935 81.05 18 22.10196 4.02195 61.36 19 22.57031 3.93954 13.52 20 22.97552 3.87097 16.48 21 23.32722 3.8134 25.65 22 23.5865 3.77206 13.16 23 24.44054 3.64216 100 24 25.17524 3.53751 6.64 25 25.60385 3.47925 14.72 26 26.41086 3.37474 9.88 27 27.71849 3.21844 12.35 28 28.72787 3.10761 4.64 29 29.60304 3.0177 3.73 thirty 31.95225 2,801 2.61 31 32.84832 2.72661 5.47 32 33.83981 2.64895 2.15 33 34.39729 2.60729 2.3 34 35.02682 2.56186 3.75 35 35.70021 2.51506 2.55 36 37.16499 2.41923 2.11 37 38.06795 2.3639 8.22 38 38.94192 2.31284 1.09

In fig. 15 shows the DSC of Compound 1 (CC-90010) Form 1, FIG. 16 shows a microscopy of Compound 1 (CC-90010) (Metastable) Form 4, and FIG. Figure 17 shows the XRPD of Compound 1 (CC90010) (Metastable) Form 4 with peak information detailed in Table. 8:

- 41 046293

Table 8

Pos. interatomic distance Rel. Intensity No. [°2Th.J [A] [%] 1 6.087217 14.51968 26.56 2 7.793917 11.34359 6.74 3 8.509974 10.39065 97.04 4 8.579043 10.30715 100 5 8.99054 9.83629 8.89 6 12.32699 7.18047 18.46 7 13.73797 6.44599 41.07 8 13.86551 6.38698 56.23 9 15.65508 5.66067 23.89 10 16.16462 5.48337 4.25 AND 16.76656 5.28784 11.47 12 17.20469 5.15416 24.93 13 18.03321 4.91918 49.12 14 18.48628 4.79963 66.84 15 19.79159 4.48593 3.67 16 20.13855 4.40942 6.96 17 20.6493 4.30149 28.13 18 21.24317 4.18256 6.96 19 21.98468 4.04314 12.38 20 23.25331 3.82535 19.7 21 24.89191 3.57713 55.35 22 25.35439 3.51292 7.79 23 27.82135 3.20677 7.29 24 28.34437 3.14878 6.75 25 28.91448 3.08798 2.93 26 29.28762 3.04948 4.24 27 29.70119 3.00547 4.04 28 29.99281 2.97937 3.01 29 30.96875 2.88767 3.71 thirty 31.91952 2.80379 6.16 31 33.16705 2.70113 1.59 32 34.47872 2.60132 1.7 33 35.53605 2.52631 3.93 34 37.5243 2.39689 3.42

In fig. 18 shows the DSC of Compound 1 (CC-90010) (Metastable) Form 4, FIG. 19 shows a microscopy of Compound 1 (CC-90010) (Metastable) Form 5, and FIG. 20 shows the XRPD of Compound 1 (CC-90010) (Metastable) Form 5 with peak information detailed in Table. 9:

- 42 046293

Table 9

interatomic Rel. Pos. distance Intensity No. [°2Th.J [A] [%] 1 5.367535 16.46476 4.56 2 6.912349 12.7882 4.54 3 7.587297 11.65204 78.31 4 7.661662 11.53911 79.95 5 10.75874 8.22335 33.83 6 13.58771 6.51693 16.5 7 13.90358 6.36958 14.71 8 14.22759 6.22525 9.12 9 15.31164 5.78686 26.1 10 16.16874 5.48198 12.65 eleven 17.94544 4.94304 6.77 12 18.54401 4.78481 5.79 13 19.70901 4.50454 100 14 21.02144 4.22618 12.21 15 21.66252 4.10254 5.43 16 21.86711 4.06125 6.05 17 22.40511 3.96821 26.72 18 23.06447 3.85305 34.38 19 23.1363 3.84443 32.67 20 23.48621 3.78794 5.07 21 24.42764 3.64405 2.3 22 24.97185 3.56585 10.07 23 25.25386 3.52667 5.05 24 25.99026 3.42556 3.48 25 26.28902 3.39011 7.62 26 26.54997 3.35738 5.01 27 27.47343 3.24659 3.48 28 27.94074 3.19334 3.05 29 28.74656 3.10563 3.5 thirty 29.32182 3,046 4.68 31 30.00715 2.97798 4.29 32 30.34702 2.9454 3.12 33 31.00177 2.88467 4.25 34 32.14843 2.78435 1.16 35 34.31352 2.61346 3.45 36 35.3472 2.53937 4.58 37 36.70614 2.44842 1.27 38 38.60992 2.33196 0.71

In fig. 21 shows the DSC of Compound 1 (CC-90010) (Metastable) Form 5.

The four processes are described below. All use only formic acid, an ICH class III solvent, and water. The two processes for Form 1 (the most stable polymorph) both control the polymorph by seeding with Form 1 and are more volume efficient (14 to 16 X vol). Also described is the process for forming (metastable) Form 4 and the process for forming (metastable) Form 5. For all of the methods described, solvent ratios can be changed, temperatures can be changed, seed amounts can be changed, compositions can be changed, and wash amounts can be changed. and the drying temperature can also be changed.

Process 1 (for Form 1): Compound 1 (1.0 X wt.) and formic acid (7.0 X vol.) are charged into Reactor 1. This mixture is stirred and then transferred to Reactor 2 through a post-treatment filter. Formic acid (1.0 X vol.) is loaded into Reactor 1, and then transferred through the same after-treatment filter to Reactor 2. Water (2.2 X by volume) is loaded through a separate after-treatment filter into Reactor 2 for 1 hour. Compound 1 seeds (1% wt., Form 1) are loaded and the mixture is maintained at a temperature of from about 20°C to about 25°C. Water (4.8 X vol.) is loaded into reactor 2 through a post-treatment filter in three separate loads (0.25, 0.60 and 3.95 X vol.). Each load is added over 1 hour with 1 hour between loads. After all three loadings, the mixture is kept for at least one hour. For

- 43 046293 all loadings the temperature of the charge is maintained from about 20°C to about 25°C.

The charge is filtered, washed twice with formic acid and water (1.5X vol. formic acid + 1.5X vol. water each time) from the after-treatment filter, twice with water (3X vol.) from the after-treatment filter and dried under reduced pressure at a temperature from about 35°C to about 45°C.

Process 2 (for Form 1): Compound 1 (CC-90010) (1.0X wt.) is loaded into formic acid (5.0X vol.) in Reactor 1 and stirred at a temperature of 20°C to 30°C until dissolved . Formic acid (2.0X vol.) from the post-purification filter and water (1.8X vol.) from the post-purification filter are loaded into Reactor 2 and stirred at a temperature of 20°C to 30°C. Compound 1 (CC-90010) seeds (Form 1, 0.02 to 0.04 X wt.) are charged to Reactor 2 and the resulting slurry is stirred for at least 60 minutes. Compound 1 (CC-90010)/formic acid solution in Reactor 1 and water (4.4X vol.) are then simultaneously loaded through post-treatment filters into the seed bed suspension in Reactor 2 for a period of 6 to 10 hours while maintaining the temperature at about 20 °C to about 30°C. After addition, formic acid (1X vol.) is charged into Reactor 1. The formic acid wash in Reactor 1 and water (0.9X vol.) are simultaneously charged through post-treatment filters into the charge in Reactor 2 for at least 15 minutes while maintaining the temperature from about 20°C to about 30°C.

Process for obtaining Form 4: Compound 1 (CC-90010) (1.0 X wt.) is loaded into the reaction flask, followed by formic acid (8.0 X vol.) and water (2.2 X vol.). A small amount of Form 1 seeds is charged and the mixture is stirred at a temperature of about 20°C to about 25°C for 2 hours. The suspension is filtered, but the wet precipitate is not dried.

Process for obtaining Form 5: Compound 1 (CC-90010) (1.0 X wt.) is loaded into the reaction flask, followed by formic acid (8.0 X vol.) and water (2.2 X vol.). This mixture is stirred at a temperature of about 15°C for about 4 hours. The suspension is filtered, but the wet precipitate is not dried. The charge is filtered, washed twice with formic acid and water (1.5X vol. formic acid + 1.5X vol. water each time) from the after-treatment filter, twice with water (3X vol.) from the after-treatment filter and dried under reduced pressure at a temperature from about 35°C to about 45°C.

Although certain embodiments of the invention have been illustrated and described, it should be understood that changes and modifications may be made thereto in accordance with the average skill of one skilled in the art without departing from the technology in its broader aspects as defined in the following claims.

The present disclosure should not be limited to the specific embodiments of the invention described in this application. Many modifications and variations may be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and compositions within the scope of the disclosure in addition to those listed herein will be apparent to those skilled in the art from the above descriptions. Such changes and variations shall come within the scope of the appended claims. This disclosure is to be limited only by the terms of the appended claims and to the full extent of the equivalents to which such claims are made. It should be understood that this disclosure is not limited to specific methods, reagents, compound compositions or biological systems, which, of course, may vary. It should also be understood that the terminology used herein is intended only to describe specific embodiments of the invention and is not intended to be limiting. Moreover, to the extent that features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will understand that the disclosure is also described in terms of any individual member or subset of members of the Markush group.

As one skilled in the art will appreciate, for any and all purposes, especially in terms of providing a written description, all ranges disclosed herein also include any and all possible sub-ranges and combinations thereof. Any of the ranges listed can be easily recognized as being sufficiently descriptive to allow the same range to be broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. By way of non-limiting example, each range discussed herein can be easily broken down into a lower third, a middle third, and an upper third, etc. As will also be appreciated by one skilled in the art, all words such as up to, at least more than, less than, and the like include the number that is indicated and refer to ranges that can subsequently be broken down into subranges , as discussed above. Finally, as one skilled in the art will appreciate, the range includes each individual term.

All publications, patent applications, issued patents and other documents referred to herein are incorporated herein by reference as if each individual publication, patent application, issued patent or other document were specifically and individually designated for inclusion by reference in its entirety. volume. Definitions contained in the text incorporated by reference are excluded to the extent that they conflict with the definitions contained in this disclosure.

Claims (7)

CLAIM 1. Method for preparing a compound of formula I: wherein the method comprises reacting a compound of formula II-a with a compound of formula III to produce a compound of formula I; where X represents Cl, Br or I. 2. The method according to claim 1, wherein X is Br. 3. The method of claim 1, wherein the compound of formula II-a is formed by contacting the compound of formula IV with bis(pinacolato)diboron (B ₂ pin ₂ ), a palladium catalyst and diethanolamine (DEA), wherein the compound of formula IV has the following structure: where X' represents Cl, Br or I. 4. The method according to claim 3, in which the compound of formula IV is obtained by monobromination of the compound of formula V: to obtain the compound of formula VI: and O-alkylation of a compound of formula VI to obtain a compound of formula IV, wherein X' is Br. 5. The method of claim 4, wherein the monobromination to dibromination of the compound of formula V occurs in a ratio of about 95:5 or more. 6. The method of claim 4, wherein the monobromination to dibromination of the compound of formula V occurs in a ratio of about 99:1 or more. 7. Method according to any one of paragraphs. 1-6, further comprising crystallizing a compound of formula I from a mixture of formic acid and water.