Methods for preparing biheteroaryl compounds and crystalline forms thereof

Abstract

[0003] Methods for preparing biheteroaryl compounds, including the biheteroaryl compound 3-(difluoromethoxy)-5-[2-(3,3-difluoropyrrolidin-1-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyridin-2-amine, are provided. Among other advantages, the methods offer the use of relatively non-toxic and inexpensive solvents; reduced usage of expensive noble metal catalysts; reduced reaction temperatures in certain steps; the use of relatively non-toxic oxidizing agents; the use of inexpensive transition metal catalysts; improved process efficiency with reduced costs and waste by reducing the molar ratios of certain reactants; significantly higher reactant concentrations in certain steps; elimination of the need for multiple chromatographic purification steps; elimination of the need for certain extraction steps using organic solvents; and higher yields and improved purity.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 087109, filed October 2, 2020, the entire contents of which are incorporated herein by reference.

[0002] Field of Disclosure The present disclosure relates to methods for preparing substituted biheteroaryl compounds. [Background technology]

[0003] background Neuronal or axonal degeneration plays a central role in the proper development of the nervous system and is a hallmark of many neurodegenerative diseases, including, for example, amyotrophic lateral sclerosis (ALS), glaucoma, Alzheimer's disease and Parkinson's disease, and traumatic injury to the brain and spinal cord. U.S. Patent Application Publication No. 2018 / 0133219, incorporated herein by reference, describes a compound of Formula I The compound JPEG0007805356000001.jpg46170 has been disclosed, which has been demonstrated to be effective in treating neurodegenerative diseases and nervous system injuries, for example, through the inhibition of dual leucine zipper kinase (DLK) in neurons.

[0004] Common problems associated with known methods for preparing biheteroaryl compounds, especially in large quantities, include: toxic and harmful solvents may be used in some of the process steps; multiple solvent types may be used; high precious metal catalyst loadings may be required; relatively high reaction temperatures may be used; toxic and harmful oxidants may be required; high molar ratios of reactants and reagents may be used in some of the reaction steps; low reactant concentrations may be used in some of the process steps with associated throughput penalties; multiple chromatographic purification steps may be used or required, which may require specialized process equipment with associated cost and throughput penalties; solvent extraction steps may be required; solvent removal steps may be required to isolate intermediates and final products as solids; and yields may be low.

[0005] Therefore, there is a need for improved methods for preparing compounds of formula I. Summary of the Invention

[0006] Short description A first aspect of the present disclosure is a compound of formula I JPEG0007805356000002.jpg53170 relates to a method for preparing the compound.

[0007] R 1 , R 2 and R 3 are independently H, F, Cl, Br, I, and C 1-6 Alkyl and C 1-6 haloalkyl.

[0008] X 1 is CR 4 where R 4 -F, -Cl, -Br, -I, -(L 1 ) 0-1 -C 1-6 Alkyl, -(L 1 ) 0-1-C 1-6 Haloalkyl, -(L 1 ) 0-1 -C 1-6 Heteroalkyl, -(L 2 ) 0-1 -C 3-8 Cycloalkyl, -(L 2 ) 0-1 -3 to 7-membered heterocycloalkyl, -(L 2 ) 0-1 -6 to 10-membered aryl, and -(L 2 ) 0-1 L is selected from the group consisting of 5- to 10-membered heteroaryl. 1 -O-, -N(H)-, -S-, -N(C 1-6 L is selected from the group consisting of alkyl)- and ═O. 2 -O-, -N(H)-, -N(C 1-6 Alkyl)-, -S-, =O, C 1-4 Alkylene, C 1-4 Alkenylene, C 1-4 Alkynylene, C 1-4 Alkoxylene, C 1-4 Aminoalkylene, C 1-4 Thioalkylene and C 1-4 heteroalkylene.

[0009] R 4 is the carbon atom and heteroatom, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Haloalkyl, 3-5 membered cycloalkyl, 3-5 membered heterocycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Dialkylamino, C 1-6 R selected from the group consisting of alkylthio, ═O, —NH, —CN, —NO, and —SF R4 It may be substituted with a substituent.

[0010] R 5 and R 6 are independently linear or branched C 1-6 alkyl, or R 5and R 6 together with the oxygen and boron atoms to which they are attached form a 5- to 7-membered heterocyclic ring, and each ring carbon atom is 1-4 It may be substituted with a straight chain alkyl group.

[0011] X 2 is N. A is a 3- to 12-membered N-containing heterocycloalkyl; JPEG0007805356000003.jpg28170.

[0012] A is F, Cl, Br, I, -OH, -CN, -NO2, -SF5, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, -(L A ) 0-1 -3 to 8-membered cycloalkyl, -(L A ) 0-1 -3 to 8-membered heterocycloalkyl, -(L A ) 0-1 -5-6 membered heteroaryl, -(L A ) 0-1 -C6 aryl, -(L A ) 0-1 -NR R1a R R1b , -(L A ) 0-1 -OR R1a , -(L A ) 0-1 -SR R1a , -(L A ) 0-1 -N(R R1a )C(=Y 1 ) OR R1c , -(L A ) 0-1 -OC(=O)N(R R1a )(R R1b ), -(L A ) 0-1 -N(R R1a )C(=O)N(R R1a )(R R1b ), -(L A ) 0-1 -C(=O)N(R R1a)(R R1b ), -(L A ) 0-1 -N(R R1a )C(=O)R R1b , -(L A ) 0-1 -C(=O)OR R1a , -(L A ) 0-1 -OC(=O)R R1a , -(L A ) 0-1 -P(=O)(OR R1a )(OR R1b ), -(L A ) 0-1 -S(O) 1-2 R R1c , -(L A ) 0-1 -S(O) 1-2 N(R R1a )(R R1b ), -(L A ) 0-1 -N(R R1a )S(O) 1-2 N(R R1a )(R R1b ) and -(L A ) 0-1 -N(R R1a )S(O) 1-2 (R R1c 1 to 5 R selected from the group consisting of A It may be substituted with a substituent.

[0013] Y 1 is O or S.

[0014] L A is C 1-4 Alkylene, C 1-4 Heteroalkylene, C 1-4 Alkoxylene, C 1-4 Aminoalkylene, C 1-4 Thioalkylene, C 2-4 Alkenylene and C 2-4 alkynylene.

[0015] R R1a and R R1bare each independently hydrogen, C 1-8 Alkyl, C 1-8 It is selected from the group consisting of haloalkyl, 3- to 8-membered cycloalkyl, phenyl, benzyl, 5- to 6-membered heteroaryl, and 3- to 8-membered heterocycloalkyl.

[0016] R R1c is C 1-8 Alkyl, C 1-8 R is selected from the group consisting of haloalkyl, 3- to 8-membered cycloalkyl, phenyl, benzyl, 5- to 6-membered heteroaryl, and 3- to 7-membered heterocycloalkyl; A In carbon atoms and heteroatoms, F, Cl, Br, I, -NH2, -OH, -CN, -NO2, =O, -SF5, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 (Halo)alkyl-C(=O)-, C 1-4 (Halo)alkyl-S(O) 0-2 -, C 1-4 (Halo)alkyl-N(H)S(O) 0-2 -, C 1-4 (Halo)alkyl-S(O) 0-2 N(H)-, (halo)alkyl-N(H)-S(O) 0-2 N(H)-, C 1-4 (Halo)alkyl-C(=O)N(H)-, C 1-4 (Halo)alkyl-N(H)-C(=O)-, ((halo)alkyl)N-C(=O)-, C 1-4 (Halo)alkyl-OC(=O)N(H)-, C 1-4 (Halo)alkyl-OC(=O)N(H)-, (halo)alkyl-N(H)-C(=O)O-, ((halo)alkyl)N-C(=O)O-, C 1-4 Alkylthio, C 1-4 Alkylamino and C 1-4 R selected from dialkylamino RA It may be substituted with a substituent.

[0017] Cy is a 3- to 12-membered N-containing heterocycloalkyl; JPEG0007805356000004.jpg22170, Cy may contain one or two additional heteroatoms selected from the group consisting of O, S and N.

[0018] Cy is a carbon or heteroatom that can be selected from F, Cl, Br, I, -OH, -CN, -NO2, -SF5, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, -(L Cy ) 0-1 -3 to 8-membered cycloalkyl, -(L Cy ) 0-1 -3 to 8-membered heterocycloalkyl, -(L Cy ) 0-1 -5-6 membered heteroaryl, -(L Cy ) 0-1 -phenyl, -(L Cy ) 0-1 -NR RCa R RCb , -(L Cy ) 0-1 -OR RCa , -(L Cy ) 0-1 -SR RCa , -(L Cy ) 0-1 -N(R RCa )C(=Y 1 ) OR RCc , -(L Cy ) 0-1 -OC(=O)N(R RCa )(R RCb ), -(L Cy ) 0-1 -N(R RCa )C(=O)N(R RCa )(R RCb ), -(L Cy ) 0-1 -C(=O)N(R RCa )(R RCb ), -(L Cy ) 0-1 -N(R RCa )C(=O)R RCb , -(L Cy ) 0-1 -C(=O)OR RCa , -(LCy ) 0-1 -OC(=O)R RCa , -(L Cy ) 0-1 -P(=O)(OR RCa )(OR RCb ), -(L Cy ) 0-1 -S(O) 1-2 R RCc , -(L Cy ) 0-1 -S(O) 1-2 N(R RCa )(R RCb ), -(L Cy ) 0-1 -N(R RCa )S(O) 1-2 N(R RCa )(R RCb ) and -(L Cy ) 0-1 -N(R RCa )S(O) 1-2 (R RCc ) R selected from the group consisting of Cy It may be substituted with a substituent.

[0019] L Cy is C 1-4 Alkylene, C 1-4 Heteroalkylene, C 1-4 Alkoxylene, C 1-4 Aminoalkylene, C 1-4 Thioalkylene, C 2-4 Alkenylene and C 2-4 alkynylene.

[0020] R RCa and R RCb are each independently hydrogen, C 1-8 Alkyl, C 1-8 It is selected from the group consisting of haloalkyl, 3-8 membered cycloalkyl, phenyl, benzyl, 5-6 membered heteroaryl and 3-8 membered heterocycloalkyl.

[0021] R RCc is C 1-8 Alkyl, C 1-8It is selected from the group consisting of haloalkyl, 3- to 8-membered cycloalkyl, phenyl, benzyl, 5- to 6-membered heteroaryl, and 3- to 7-membered heterocycloalkyl.

[0022] R Cy In carbon atoms and heteroatoms, F, Cl, Br, I, -NH2, -OH, -CN, -NO2, =O, -SF5, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 (Halo)alkyl-C(=O)-, C 1-4 (Halo)alkyl-S(O) 0-2 -, C 1-4 (Halo)alkyl-N(H)S(O) 0-2 -, C 1-4 (Halo)alkyl-S(O) 0-2 N(H)-, (halo)alkyl-N(H)-S(O) 0-2 N(H)-, C 1-4 (Halo)alkyl-C(=O)N(H)-, C 1-4 (Halo)alkyl-N(H)-C(=O)-, ((halo)alkyl)N-C(=O)-, C 1-4 (Halo)alkyl-OC(=O)N(H)-, C 1-4 (Halo)alkyl-OC(=O)N(H)-, (halo)alkyl-N(H)-C(=O)O-, ((halo)alkyl)N-C(=O)O-, C 1-4 Alkylthio, C 1-4 Alkylamino and C 1-4 1 to 5 R selected from the group consisting of dialkylamino RCy It may be substituted with a substituent.

[0023] This method involves substituting the methoxysulfonyl group of compound (v) with a 3- to 12-membered amine-containing heterocycloalkyl compound (vi) in a solvent under basic conditions to obtain a compound of formula (I). Contains JPEG0007805356000005.jpg53170.

[0024] The method further includes preparing compound (v) according to one of Schemes (A)-(C).

[0025] In Scheme (A), the sulfone compound (v) is reacted with the sulfone compound (v) according to the following reaction scheme: Prepared according to JPEG0007805356000006.jpg94170.

[0026] Scheme (A) includes step 1 of mixing compound (ix) with a halogenating reagent in a solvent and reacting to form compound (x); step 2 of borylating compound (x) with a borylation reagent to form a solution of compound (iv); and step 3 of forming a solution of compound (iv), compound (iii), a catalyst, a base, and a solvent and reacting to form compound (v).

[0027] In Scheme (B), the sulfone compound (v) is reacted with the sulfone compound (v) according to the following reaction scheme: Prepared according to JPEG0007805356000007.jpg47170.

[0028] Scheme (B) includes step 1, in which compound (ix) is directly borylated with a borylation reagent to form a reaction product mixture containing primarily compound (iv) in solution; and step 2, in which the reaction product mixture from step 1 is mixed with compound (iii), a catalyst, a base, and a solvent and reacted to form compound (v).

[0029] In scheme (C), sulfone compound (v) is prepared by catalytic coupling reaction of sulfone compound (iii) with boronate ester reagent (iv) in the presence of a base and a solvent, according to the following reaction scheme: JPEG0007805356000008.jpg57170 to provide compound (v).

[0030] Scheme (C) further includes scheme (1), scheme (2), or a combination of scheme (1) and scheme (2).

[0031] Scheme (1) illustrates the following reaction scheme, which involves treating an alkylthio compound (i) with at least one oxidizing agent in a solvent to obtain a mixture of sulfone oxide compounds (viii): preparing sulfone compound (iii) according to JPEG0007805356000009.jpg36170; and Displacing the halogen atom from sulfone compound (viii) with an optionally substituted 3- to 12-membered amine-containing heterocycloalkyl compound (vii) in a solvent under basic conditions to form a reaction product mixture containing sulfone compound (iii). Contains JPEG0007805356000010.jpg41170.

[0032] Scheme (2) shows the reaction of a species compound (iva) (wherein X 1 is CO-CHF2, and R 1 and R 2 are H, and the moiety -B(OR 5 )(OR 6 )but Compound (iva) can be prepared according to the following reaction scheme: Prepared according to JPEG0007805356000012.jpg91170.

[0033] In step 1, a reaction mixture is formed containing compound (17), compound (18), a solvent, and a base, and reacted to form a reaction product mixture containing primarily compound (19) in solution.

[0034] In step 2, a reaction mixture containing a solution of compound (19) is hydrogenated in the presence of a catalyst to form a reaction product mixture containing compound (20).

[0035] In step 3, a reaction mixture comprising compound (20), N-bromosuccinamide, and a polar aprotic solvent is reacted to form a reaction product mixture comprising primarily compound (21) in solution.

[0036] In step 4, a reaction mixture is formed comprising compound (21), bis-pin-diborane, and a noble metal catalyst in solution and reacted to form a reaction product mixture comprising compound (iva).

[0037] Another aspect of the present disclosure relates to a method for preparing Compound 1. The method comprises the following steps 1 to 4:

[0038] In the first step, the following scheme Compound (vii) is reacted with compound (i) in the presence of a solvent and an organic base according to JPEG0007805356000013.jpg37170 to form a reaction mixture containing compound (ii).

[0039] The solvent is selected from the group consisting of dimethyl sulfoxide, acetonitrile, and ethanol. The equivalent ratio of the organic base to compound (vii) is about 2.2:1 to about 2.6:1.

[0040] In the second step, the following reaction scheme Compound (ii) is oxidized with hydrogen peroxide in the presence of sodium tungstate dihydrate (Na2WO4·2H2O) according to JPEG0007805356000014.jpg38170 to form a reaction product mixture containing compound (iii).

[0041] Hydrogen peroxide is added to the reaction product mixture from step (1), with an equivalent ratio of hydrogen peroxide to compound (ii) of about 2:1 to about 3.5:1.

[0042] In the third step, the following scheme According to JPEG0007805356000015.jpg74170, Suzuki coupling of compound (iii) with compound (iva) is carried out in the presence of an alkali metal carbonate base, a palladium catalyst, and a solvent to form a reaction product mixture compound (v), and then N-acetylcysteine ​​is added to the reaction product mixture to scavenge the palladium.

[0043] The solvent is tetrahydrofuran and water, and the palladium catalyst is PdCl2(dppf).

[0044] In the fourth step, the following reaction scheme Compound (v) is reacted with compound (vi) in the presence of at least one organic base and a solvent to form a reaction product mixture comprising compound 1 according to JPEG0007805356000016.jpg57170.

[0045] The at least one organic base is selected from the group consisting of 1,1,3,3-tetramethylguanidine and 1,8-diazabicyclo[5.4.0]undec-7-ene. The solvent is selected from the group consisting of toluene, anisole, mesitylene, diethylamine, di-n-propylamine, di-isopropylamine, di-n-butylamine, and combinations thereof.

[0046] Another aspect of the present disclosure relates to a method for preparing Compound 1. The method comprises the following steps 1 to 6:

[0047] In the first step, the following reaction scheme Compound (vii) is reacted with compound (i) in the presence of ethanol and triethylamine according to JPEG0007805356000017.jpg36170 to form compound (ii).

[0048] The equivalent ratio of trimethylamine to compound (vii) is about 2.4:1.

[0049] In the second step, the following reaction scheme Compound (ii) is oxidized with hydrogen peroxide in the presence of sodium tungstate dihydrate (Na2WO4·2H2O) according to JPEG0007805356000018.jpg37170 to form a reaction product mixture containing compound (iii).

[0050] Hydrogen peroxide is added to the reaction product mixture from step (1), with the equivalent ratio of hydrogen peroxide to compound (ii) being about 3:1.

[0051] In the third step, (i) the following scheme According to JPEG0007805356000019.jpg74170, Suzuki coupling of compound (iii) with compound (iva) is carried out in the presence of K2CO3 or Na2CO3, PdCl2(dppf) catalyst and tetrahydrofuran and water solvent to form a reaction product mixture compound (v), followed by (ii) adding N-acetylcysteine ​​to the reaction product mixture to scavenge palladium.

[0052] The equivalent ratio of K2CO3 or Na2CO3 to compound (iii) is about 3:1, and the PdCl2(dppf) content is about 0.5 mol % based on compound (iii).

[0053] In the fourth step, the following reaction scheme Compound (v) is reacted with compound (vi) in the presence of at least one base and a solvent according to JPEG0007805356000020.jpg58170 to form a reaction product mixture comprising compound 1.

[0054] The at least one base is selected from the group consisting of 1,1,3,3-tetramethylguanidine and 1,8-diazabicyclo[5.4.0]undec-7-ene. The solvent is selected from the group consisting of toluene, anisole, mesitylene, diethylamine, di-n-propylamine, di-isopropylamine, di-n-butylamine, and combinations thereof.

[0055] In the fifth step, Compound 1 is isolated from the reaction product mixture of step (4) by the following order of steps: adding an anti-solvent selected from isopropanol and n-propanol to the reaction product mixture; cooling the reaction product mixture to form a slurry containing solid Compound 1; and isolating solid Compound 1 from the reaction product mixture.

[0056] In a sixth step, a supersaturated solution of Compound 1 and methyl isobutyl ketone is formed by the steps of seeding the supersaturated solution with crystalline Compound 1 Form A; cooling the solution to form a slurry containing crystalline Compound 1 Form A; and isolating crystalline Compound 1 Form A from the slurry.

[0057] Another aspect of the present disclosure is a compound of formula (iii): Regarding compound JPEG0007805356000021.jpg48170.

[0058] Another aspect of the present disclosure is Compound I JPEG0007805356000022.jpg53170, The present invention relates to a crystalline form having an X-ray powder diffraction pattern with at least two peaks at positions selected from the group consisting of 7.7±0.3(°2θ), 12.1±0.3(°2θ), 16.2±0.3(°2θ), 16.4±0.3(°2θ), 16.6±0.3(°2θ), 17.1±0.3(°2θ), 18.8±0.3(°2θ), 19.4±0.3(°2θ), 19.8±0.3(°2θ), 20.3±0.3(°2θ), 20.5±0.3(°2θ), 23.3±0.3(°2θ), 24.7±0.3(°2θ), 25.3±0.3(°2θ), and 26.5±0.3(°2θ).

[0059] A further aspect of the present disclosure relates to a pharmaceutical composition comprising a crystalline form of Compound I and at least one excipient.

[0060] A further aspect of the present disclosure relates to a method of preparing a crystalline form of Compound I, comprising dissolving Compound I in a solvent to form a solution, forming a slurry of crystals of Compound I from the solution, and isolating the crystallized Compound I.

[0061] A further aspect of the present disclosure relates to a method of treating a neurodegenerative condition, comprising administering an effective amount of a crystalline form of Compound I. [Brief explanation of the drawings]

[0062] [Figure 1] FIG. 1 shows the XRPD pattern of a representative crystalline form of Compound 1, identified herein as Form A.

[0063] [Figure 2] FIG. 2 shows the XRPD patterns of crystalline Compound 1 Form A (pattern (a)); Compound 1 tableted under a pressure of 900 MPa followed by tablet milling (pattern (b)); Compound 1 tableted under a pressure of 900 MPa followed by tablet milling (pattern (c)); Compound 1 after manual dry milling (pattern (d)); Compound 1 after manual wet milling (pattern (e)); and Compound 1 manually wet milled and then dried (pattern (f)). DETAILED DESCRIPTION OF THE INVENTION

[0064] Detailed Description The present disclosure relates to improved methods for preparing compounds of formula I and related intermediates.

[0065] Compared to prior art methods, the disclosed methods utilize solvents that are relatively non-toxic, relatively inexpensive, and relatively benign in terms of industrial hygiene, process safety, and environmental impact. In some embodiments, persistent alcohol solvents such as methanol and ethanol are used. Thus, these embodiments provide improved safety and significant cost savings.

[0066] The disclosed process significantly reduces the use of expensive noble metal catalysts in certain process steps compared to prior art processes, thereby resulting in significant cost savings.

[0067] The disclosed method further uses relatively non-toxic oxidants in combination with inexpensive transition metal catalysts to reduce safety risks and costs.

[0068] The disclosed methods further allow for a reduction in the molar ratio of certain reactants, thereby improving process efficiency while reducing costs and waste.

[0069] Furthermore, the disclosed methods allow for significantly higher reactant concentrations in certain steps compared to prior art methods, thereby resulting in significant improvements in process equipment efficiency and process throughput, and associated cost savings.

[0070] Additionally, the disclosed method eliminates the need for multiple chromatographic purification steps compared to prior art methods, which require specialized and expensive process equipment, increase the number of required chemical operators, reduce throughput, and increase costs.

[0071] The disclosed method further eliminates the need for specific extraction steps using organic solvents and eliminates the need for multiple solvent removal steps. This improvement significantly reduces costs by reducing energy consumption, eliminating solvent handling and distillation steps, and consequently avoiding the associated required process equipment and operation, material handling requirements, and industrial hygiene and environmental risks.

[0072] Among the above improvements, the disclosed method also provides higher yields and purity compared to prior art methods.

[0073] Thus, the discovery of the disclosed methods detailed herein represents a significant advance in the art.

[0074] Further aspects are within the scope of this disclosure.

[0075] A first such additional embodiment is Compound I: This relates to a method for preparing JPEG0007805356000023.jpg55170.

[0076] R 1 , R2 and R 3 are independently H, F, Cl, Br, I, and C 1-6 Alkyl and C 1-6 haloalkyl.

[0077] X 1 is CR 4 where R 4 -F, -Cl, -Br, -I, -(L 1 ) 0-1 -C 1-6 Alkyl, -(L 1 ) 0-1 -C 1-6 Haloalkyl, -(L 1 ) 0-1 -C 1-6 Heteroalkyl, -(L 2 ) 0-1 -C 3-8 Cycloalkyl, -(L 2 ) 0-1 -3 to 7-membered heterocycloalkyl, -(L 2 ) 0-1 -6 to 10-membered aryl, and -(L 2 ) 0-1 L is selected from the group consisting of 5- to 10-membered heteroaryl. 1 -O-, -N(H)-, -S-, -N(C 1-6 L is selected from the group consisting of alkyl)- and ═O. 2 -O-, -N(H)-, -N(C 1-6 Alkyl)-, -S-, =O, C 1-4 Alkylene, C 1-4 Alkenylene, C 1-4 Alkynylene, C 1-4 Alkoxylene, C 1-4 Aminoalkylene, C 1-4 Thioalkylene and C 1-4 heteroalkylene.

[0078] R 4 is the carbon atom and heteroatom, F, Cl, Br, I, C 1-6 Alkyl, C 1-6Haloalkyl, 3-5 membered cycloalkyl, 3-5 membered heterocycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Dialkylamino, C 1-6 R selected from the group consisting of alkylthio, ═O, —NH, —CN, —NO, and —SF R4 It may be substituted with a substituent.

[0079] X 2 is N.

[0080] A is a 3- to 12-membered N-containing heterocycloalkyl; The file is JPEG0007805356000024.jpg22170. A is F, Cl, Br, I, -OH, -CN, -NO2, -SF5, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, (L A ) 0-1 -3 to 8-membered cycloalkyl, -(L A ) 0-1 -3 to 8-membered heterocycloalkyl, -(L A ) 0-1 -5-6 membered heteroaryl, -(L A ) 0-1 -C6 aryl, -(L A ) 0-1 -NR R1a R R1b , -(L A ) 0-1 -OR R1a , -(L A ) 0-1 -SR R1a , -(L A ) 0-1 -N(R R1a )C(=Y 1 ) OR R1c , -(L A ) 0-1 -OC(=O)N(R R1a )(R R1b ), -(L A ) 0-1 -N(R R1a )C(=O)N(R R1a)(R R1b ), -(L A ) 0-1 -C(=O)N(R R1a )(R R1b ), -(L A ) 0-1 -N(R R1a )C(=O)R R1b , -(L A ) 0-1 -C(=O)OR R1a , -(L A ) 0-1 -OC(=O)R R1a , -(L A ) 0-1 -P(=O)(OR R1a )(OR R1b ), -(L A ) 0-1 S(O) 1-2 R R1c , -(L A ) 0-1 -S(O) 1-2 N(R R1a )(R R1b ), -(L A ) 0-1 -N(R R1a )S(O) 1-2 N(R R1a )(R R1b ) and -(L A ) 0-1 -N(R R1a )S(O) 1-2 (R R1c 1 to 5 R selected from the group consisting of A It may be substituted with a substituent.

[0081] Y 1 is O or S.

[0082] L A is C 1-4 Alkylene, C 1-4 Heteroalkylene, C 1-4 Alkoxylene, C 1-4 Aminoalkylene, C 1-4 Thioalkylene, C 2-4 Alkenylene and C 2-4 alkynylene.

[0083] R R1a and R R1b are each independently hydrogen, C 1-8 Alkyl, C 1-8 It is selected from the group consisting of haloalkyl, 3- to 8-membered cycloalkyl, phenyl, benzyl, 5- to 6-membered heteroaryl, and 3- to 8-membered heterocycloalkyl.

[0084] R R1c is C 1-8 Alkyl, C 1-8 R is selected from the group consisting of haloalkyl, 3- to 8-membered cycloalkyl, phenyl, benzyl, 5- to 6-membered heteroaryl, and 3- to 7-membered heterocycloalkyl; A In carbon atoms and heteroatoms, F, Cl, Br, I, -NH2, -OH, -CN, -NO2, =O, -SF5, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 (Halo)alkyl-C(=O)-, C 1-4 (Halo)alkyl-S(O) 0-2 -, C 1-4 (Halo)alkyl-N(H)S(O) 0-2 -, C 1-4 (Halo)alkyl-S(O) 0-2 N(H)-, (halo)alkyl-N(H)-S(O) 0-2 N(H)-, C 1-4 (Halo)alkyl-C(=O)N(H)-, C 1-4 (Halo)alkyl-N(H)-C(=O)-, ((halo)alkyl)N-C(=O)-, C 1-4 (Halo)alkyl-OC(=O)N(H)-, C 1-4 (Halo)alkyl-OC(=O)N(H)-, (halo)alkyl-N(H)-C(=O)O-, ((halo)alkyl)N-C(=O)O-, C 1-4 Alkylthio, C 1-4 Alkylamino and C 1-4 R selected from dialkylamino RA It may be substituted with a substituent.

[0085] Cy is a 3- to 12-membered N-containing heterocycloalkyl; JPEG0007805356000025.jpg22170. Cy may contain one or two additional heteroatoms selected from the group consisting of O, S, and N. Cy may contain, at the carbon atom or heteroatom, F, Cl, Br, I, —OH, —CN, —NO2, —SF5, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, -(L Cy ) 0-1 -3-8 membered cycloalkyl, -(L Cy ) 0-1 -3-8-membered heterocycloalkyl, -(L Cy ) 0-1 -5-6 membered heteroaryl, -(L Cy ) 0-1 -phenyl, -(L Cy ) 0-1 -NR RCa R RCb , -(L Cy ) 0-1 -OR RCa , -(L Cy ) 0-1 -SR RCa , -(L Cy ) 0-1 -N(R RCa )C(=Y 1 ) OR RCc , -(L Cy ) 0-1 -OC(=O)N(R RCa )(R RCb ), -(L Cy ) 0-1 -N(R RCa )C(=O)N(R RCa )(R RCb ), -(L Cy ) 0-1 -C(=O)N(R RCa )(R RCb ), -(L Cy ) 0-1 -N(R RCa )C(=O)R RCb , -(L Cy ) 0-1 -C(=O)ORRCa , -(L Cy ) 0-1 -OC(=O)R RCa , -(L Cy ) 0-1 -P(=O)(OR RCa )(OR RCb ), -(L Cy ) 0-1 -S(O) 1-2 R RCc , -(L Cy ) 0-1 -S(O) 1-2 N(R RCa )(R RCb ), -(L Cy ) 0-1 -N(R RCa )S(O) 1-2 N(R RCa )(R RCb ) and -(L Cy ) 0-1 -N(R RCa )S(O) 1-2 (R RCc ) R selected from the group consisting of Cy It may be substituted with a substituent.

[0086] L Cy is C 1-4 Alkylene, C 1-4 Heteroalkylene, C 1-4 Alkoxylene, C 1-4 Aminoalkylene, C 1-4 Thioalkylene, C 2-4 Alkenylene and C 2-4 alkynylene.

[0087] R RCa and R RCb are each independently hydrogen, C 1-8 Alkyl, C 1-8 It is selected from the group consisting of haloalkyl, 3-8 membered cycloalkyl, phenyl, benzyl, 5-6 membered heteroaryl and 3-8 membered heterocycloalkyl.

[0088] R RCc is C 1-8 Alkyl, C 1-8It is selected from the group consisting of haloalkyl, 3- to 8-membered cycloalkyl, phenyl, benzyl, 5- to 6-membered heteroaryl, and 3- to 7-membered heterocycloalkyl.

[0089] R Cy In carbon atoms and heteroatoms, F, Cl, Br, I, -NH2, -OH, -CN, -NO2, =O, -SF5, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 (Halo)alkyl-C(=O)-, C 1-4 (Halo)alkyl-S(O) 0-2 -, C 1-4 (Halo)alkyl-N(H)S(O) 0-2 -, C 1-4 (Halo)alkyl-S(O) 0-2 N(H)-, (halo)alkyl-N(H)-S(O) 0-2 N(H)-, C 1-4 (Halo)alkyl-C(=O)N(H)-, C 1-4 (Halo)alkyl-N(H)-C(=O)-, ((halo)alkyl)N-C(=O)-, C 1-4 (Halo)alkyl-OC(=O)N(H)-, C 1-4 (Halo)alkyl-OC(=O)N(H)-, (halo)alkyl-N(H)-C(=O)O-, ((halo)alkyl)N-C(=O)O-, C 1-4 Alkylthio, C 1-4 Alkylamino and C 1-4 1 to 5 R selected from the group consisting of dialkylamino RCy It may be substituted with a substituent.

[0090] The method comprises catalytically coupling a sulfone compound (iii) and a boronate reagent (iv) in the presence of a base and a solvent to give the following: providing compound (v) as in JPEG0007805356000026.jpg57170.

[0091] R 5 and R 6are independently linear or branched C 1-6 alkyl, or R 5 and R 6 together with the oxygen and boron atoms to which they are attached form a 5- to 7-membered heterocyclic ring, and each ring carbon atom is 1-4 It may be substituted with a straight chain alkyl group.

[0092] The yield of compound (v) based on compound (iii) is at least 60%.

[0093] The method comprises substituting the methoxysulfonyl group of compound (v) with a 3- to 12-membered amine-containing heterocycloalkyl compound (vi) in a solvent under basic conditions to obtain the following: JPEG0007805356000027.jpg53170.

[0094] The compound of formula (I) is isolated as a solid. The yield of the compound of formula (I) based on compound (v) is at least 60%.

[0095] A second such further aspect of the present disclosure relates to a compound of formula (I) obtainable by the method of the first aspect of the present disclosure.

[0096] A third such further aspect of the present disclosure relates to a method for preparing sulfone compound (iii), said third optional aspect comprising: treating the alkylthio compound (i) with at least one oxidizing agent in a solvent to provide the sulfone oxide compound (viii); In a solvent under basic conditions, the halogen atom from sulfone compound (viii) is substituted with an optionally substituted 3- to 12-membered amine-containing heterocycloalkyl compound (vii) to give sulfone compound (iii) as follows: JPEG0007805356000029.jpg40170(R 3 are H, F, Cl, Br, I, and C1-6 Alkyl and C 1-6 haloalkyl) This includes forming the

[0097] A fourth such further aspect of the present disclosure is a compound of formula (Ia): JPEG0007805356000030.jpg44170 relates to the use of the method according to the third aspect of the present disclosure for preparing the compound.

[0098] In the fourth aspect, R 1 , R 2 and R 3 are independently H, F, Cl, Br, I, and C 1-6 Alkyl and C 1-6 haloalkyl.

[0099] X 1 is CR 4 where R 4 -F, -Cl, -Br, -I, -(L 1 ) 0-1 -C 1-6 Alkyl, -(L 1 ) 0-1 -C 1-6 Haloalkyl, -(L 1 ) 0-1 -C 1-6 Heteroalkyl, -(L 2 ) 0-1 -C 3-8 Cycloalkyl, -(L 2 ) 0-1 -3 to 7-membered heterocycloalkyl, -(L 2 ) 0-1 -6 to 10-membered aryl, and -(L 2 ) 0-1 - selected from the group consisting of 5- to 10-membered heteroaryl.

[0100] X 2 is N.

[0101] L 1 -O-, -N(H)-, -S-, -N(C 1-6is selected from the group consisting of alkyl)- and ═O.

[0102] L 2 -O-, -N(H)-, -N(C 1-6 Alkyl)-, -S-, =O, C 1-4 Alkylene, C 1-4 Alkenylene, C 1-4 Alkynylene, C 1-4 Alkoxylene, C 1-4 Aminoalkylene, C 1-4 Thioalkylene and C 1-4 heteroalkylene.

[0103] R 4 is the carbon atom and heteroatom, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Haloalkyl, 3-5 membered cycloalkyl, 3-5 membered heterocycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Dialkylamino, C 1-6 R selected from the group consisting of alkylthio, ═O, —NH, —CN, —NO, and —SF R4 It may be substituted with a substituent.

[0104] JPEG0007805356000031.jpg21170 is an optionally substituted 3- to 12-membered N-containing heterocycloalkyl.

[0105] A is an optionally substituted 3- to 12-membered N-containing heterocycloalkyl;

[0106] The file is JPEG0007805356000032.jpg24170.

[0107] A fifth such further aspect of the present disclosure is directed to the following reaction scheme: JPEG0007805356000033.jpg94170 relates to a method for preparing a boronate compound (iva).

[0108] The method of the fifth embodiment includes steps A to D.

[0109] Step A: forming a reaction mixture comprising compound (17), compound (18), a solvent, and a base, and reacting to form a reaction product mixture comprising primarily compound (19) in solution.

[0110] Step B, hydrogenating a reaction mixture containing a solution of compound (19) in the presence of a catalyst to form a reaction product mixture containing compound (20).

[0111] Step C, reacting a reaction mixture comprising compound (20), N-bromosuccinamide, and a polar aprotic solvent to form a reaction product mixture comprising primarily compound (21) in solution.

[0112] Step D. forming a reaction mixture comprising compound (21) in solution, bis-pyne-diborane, and a noble metal catalyst, and reacting to form a reaction product mixture comprising compound (iva);

[0113] A sixth such further aspect of the present disclosure is a compound of formula (Ib): JPEG0007805356000034.jpg38170 relates to the use of the method according to the fifth aspect of the present disclosure for preparing the compound.

[0114] In the sixth aspect, R 3 are H, F, Cl, Br, I, and C 1-6 Alkyl and C 1-6 haloalkyl.

[0115] X 2 is N.

[0116] Cy and A each independently represent an optionally substituted 3- to 12-membered N-containing heterocyclyl. JPEG0007805356000035.jpg22170.

[0117] A seventh such further aspect of the present disclosure is a compound represented by the following reaction scheme: JPEG0007805356000036.jpg93170 relates to a process for preparing sulfone compound (v).

[0118] In the seventh aspect, R 1 , R 2 and R 3 are independently H, F, Cl, Br, I, and C 1-6 Alkyl and C 1-6 haloalkyl.

[0119] X 1 is CR 4 where R 4 -F, -Cl, -Br, -I, -(L 1 ) 0-1 -C 1-6 Alkyl, -(L 1 ) 0-1 -C 1-6 Haloalkyl, -(L 1 ) 0-1 -C 1-6 Heteroalkyl, -(L 2 ) 0-1 -C 3-8 Cycloalkyl, -(L 2 ) 0-1 -3 to 7-membered heterocycloalkyl, -(L 2 ) 0-1 -6 to 10-membered aryl, and -(L 2 ) 0-1 - selected from the group consisting of 5- to 10-membered heteroaryl.

[0120] L 1 -O-, -N(H)-, -S-, -N(C 1-6 is selected from the group consisting of alkyl)- and ═O.

[0121] L 2 -O-, -N(H)-, -N(C 1-6 Alkyl)-, -S-, =O, C 1-4 Alkylene, C 1-4 Alkenylene, C 1-4Alkynylene, C 1-4 Alkoxylene, C 1-4 Aminoalkylene, C 1-4 Thioalkylene and C 1-4 heteroalkylene.

[0122] R 4 is the carbon atom and heteroatom, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Haloalkyl, 3-5 membered cycloalkyl, 3-5 membered heterocycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Dialkylamino, C 1-6 R selected from the group consisting of alkylthio, ═O, —NH, —CN, —NO, and —SF R4 It may be substituted with a substituent.

[0123] JPEG0007805356000037.jpg21170 is an optionally substituted 3- to 12-membered N-containing heterocycloalkyl.

[0124] R 5 and R 6 are independently linear or branched C 1-6 alkyl, or R 5 and R 6 together with the oxygen and boron atoms to which they are attached form a 5- to 7-membered heterocyclic ring, and each ring carbon atom is 1-4 It may be substituted with a straight chain alkyl group.

[0125] The seventh embodiment includes steps A to C.

[0126] In step A, compound (ix) is mixed with a halogenating reagent in a solvent and reacted to form compound (x).

[0127] In step B, compound (x) is borylated with a borylation reagent to form a solution of compound (iv).

[0128] In step C, a solution of compound (iv), compound (iii), a catalyst, a base and a solvent is formed and reacted to form compound (v).

[0129] An eighth further aspect of the present disclosure is a compound represented by the following reaction scheme: JPEG0007805356000038.jpg46170 relates to a method for preparing sulfone compound (V).

[0130] In the eighth aspect, R 1 , R 2 and R 3 are independently H, F, Cl, Br, I, and C 1-6 Alkyl and C 1-6 haloalkyl.

[0131] X 1 is CR 4 where R 4 -F, -Cl, -Br, -I, -(L 1 ) 0-1 -C 1-6 Alkyl, -(L 1 ) 0-1 -C 1-6 Haloalkyl, -(L 1 ) 0-1 -C 1-6 Heteroalkyl, -(L 2 ) 0-1 -C 3-8 Cycloalkyl, -(L 2 ) 0-1 -3 to 7-membered heterocycloalkyl, -(L 2 ) 0-1 -6 to 10-membered aryl, and -(L 2 ) 0-1 - selected from the group consisting of 5- to 10-membered heteroaryl.

[0132] L 1 -O-, -N(H)-, -S-, -N(C 1-6 is selected from the group consisting of alkyl)- and ═O.

[0133] L 2 -O-, -N(H)-, -N(C 1-6 Alkyl)-, -S-, =O, C 1-4 Alkylene, C 1-4 Alkenylene, C 1-4 Alkynylene, C 1-4 Alkoxylene, C 1-4 Aminoalkylene, C 1-4 Thioalkylene and C 1-4 heteroalkylene.

[0134] R 4 is the carbon atom and heteroatom, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Haloalkyl, 3-5 membered cycloalkyl, 3-5 membered heterocycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Dialkylamino, C 1-6 R selected from the group consisting of alkylthio, ═O, —NH, —CN, —NO, and —SF R4 It may be substituted with a substituent.

[0135] JPEG0007805356000039.jpg22170 is an optionally substituted 3- to 12-membered N-containing heterocycloalkyl.

[0136] R 5 and R 6 are independently linear or branched C 1-6 alkyl, or R 5 and R 6 together with the oxygen and boron atoms to which they are attached form a 5- to 7-membered heterocyclic ring, and each ring carbon atom is 1-4 It may be substituted with a straight chain alkyl group.

[0137] The method of the eighth embodiment comprises steps A and B.

[0138] In Step A, compound (ix) is directly borylated with a borylation reagent to form a reaction product mixture containing primarily compound (iv) in solution.

[0139] In step B, the reaction product mixture from step A is mixed with compound (iii), a catalyst, a base and a solvent and reacted to form compound (v).

[0140] A further ninth aspect of the present disclosure is a compound of formula (I): JPEG0007805356000040.jpg47170 relates to the use of the process of the eighth method for preparing the compound.

[0141] In the ninth aspect, R 1 , R 2 and R 3 are independently H, F, Cl, Br, I, and C 1-6 Alkyl and C 1-6 haloalkyl.

[0142] X 1 is CR 4 where R 4 -F, -Cl, -Br, -I, -(L 1 ) 0-1 -C 1-6 Alkyl, -(L 1 ) 0-1 -C 1-6 Haloalkyl, -(L 1 ) 0-1 -C 1-6 Heteroalkyl, -(L 2 ) 0-1 -C 3-8 Cycloalkyl, -(L 2 ) 0-1 -3 to 7-membered heterocycloalkyl, -(L 2 ) 0-1 -6 to 10-membered aryl, and -(L 2 ) 0-1 - selected from the group consisting of 5- to 10-membered heteroaryl.

[0143] L 1-O-, -N(H)-, -S-, -N(C 1-6 is selected from the group consisting of alkyl)- and ═O.

[0144] L 2 -O-, -N(H)-, -N(C 1-6 Alkyl)-, -S-, =O, C 1-4 Alkylene, C 1-4 Alkenylene, C 1-4 Alkynylene, C 1-4 Alkoxylene, C 1-4 Aminoalkylene, C 1-4 Thioalkylene and C 1-4 heteroalkylene.

[0145] R 4 is the carbon atom and heteroatom, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Haloalkyl, 3-5 membered cycloalkyl, 3-5 membered heterocycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Dialkylamino, C 1-6 R selected from the group consisting of alkylthio, ═O, —NH, —CN, —NO, and —SF R4 It may be substituted with a substituent.

[0146] Cy and A are independently an optionally substituted 3- to 12-membered N-containing heterocycloalkyl The file is JPEG0007805356000041.jpg21170.

[0147] R 5 and R 6 are independently linear or branched C 1-6 alkyl, or R 5 and R 6 together with the oxygen and boron atoms to which they are attached form a 5- to 7-membered heterocyclic ring, and each ring carbon atom is 1-4 It may be substituted with a straight chain alkyl group.

[0148] A further tenth aspect of the present disclosure is compound (24): JPEG0007805356000042.jpg53170, relating to the species of formula (v).

[0149] A further eleventh aspect of the present disclosure is a compound of formula (va): Regarding compound JPEG0007805356000043.jpg54170.

[0150] R 4 -F, -Cl, -Br, -I, -(L 1 ) 0-1 -C 1-6 Alkyl, -(L 1 ) 0-1 -C 1-6 Haloalkyl, -(L 1 ) 0-1 -C 1-6 Heteroalkyl, -(L 2 ) 0-1 -C 3-8 Cycloalkyl, -(L 2 ) 0-1 -3 to 7-membered heterocycloalkyl, and -(L 2 ) 0-1 -6- to 10-membered aryl.

[0151] L 1 -O-, -N(H)-, -S-, -N(C 1-6 is selected from the group consisting of alkyl)- and ═O.

[0152] L 2 -O-, -N(H)-, -N(C 1-6 Alkyl)-, -S-, =O, C 1-4 Alkylene, C 1-4 Alkenylene, C 1-4 Alkynylene, C 1-4 Alkoxylene, C 1-4 Aminoalkylene, C 1-4 Thioalkylene and C 1-4 heteroalkylene.

[0153] R 4 is the carbon atom and heteroatom, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Haloalkyl, 3-5 membered cycloalkyl, 3-5 membered heterocycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Dialkylamino, C 1-6 R selected from the group consisting of alkylthio, ═O, —NH, —CN, —NO, and —SF R4 It may be substituted with a substituent.

[0154] definition

[0155] As used herein, the term "alkyl" by itself or as part of another substituent, unless otherwise indicated, refers to the number of carbon atoms designated (i.e., C 1-8means a straight-chain or branched-chain hydrocarbon radical having 1 to 8 carbons. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl. The term "alkenyl" refers to an unsaturated alkyl radical having one or more double bonds. Similarly, the term "alkynyl" refers to an unsaturated alkyl radical having one or more triple bonds. Examples of such unsaturated alkyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and straight-chain and branched groups, including higher homologs and isomers. The terms "cycloalkyl," "carbocyclic," or "carbocycle" refer to a hydrocarbon ring system having the specified number of total ring atoms (e.g., 3 to 12 ring atoms in a 3- to 12-membered cycloalkyl or C3-12 cycloalkyl) and which is fully saturated or has no more than one double bond between the ring vertices for 3- to 5-membered cycloalkyls, and saturated or has no more than two double bonds between the ring vertices for 6 or more-membered cycloalkyls. Monocyclic or polycyclic rings may be substituted with one or more oxo groups. As used herein, "cycloalkyl," "carbocyclic," or "carbocycle" also refers to polycyclic (including fused and bridged bicyclic, fused and bridged polycyclic, and spirocyclic) hydrocarbon ring systems, such as bicyclo[2.2.1]heptane, pinane, bicyclo[2.2.2]octane, adamantane, norborene, spirocyclic C 5-12 Alkanes, etc. As used herein, the terms "alkenyl," "alkynyl," "cycloalkyl," "carbocycle," and "carbocyclic" are meant to include mono- and polyhalogenated variants thereof.

[0156] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise indicated, a stable straight- or branched-chain hydrocarbon of the specified number of carbon atoms and one to three heteroatoms selected from the group consisting of O, N, Si, and S, where the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The heteroatoms O, N, and S may be placed at any interior position of the heteroalkyl group. The heteroatom Si may be placed at any position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule. A "heteroalkyl" may contain up to three units of unsaturation and may include mono- and polyhalogenated variants, or combinations thereof. Examples include -CH2-CH2-O-CH3, -CH2-CH2-O-CF3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, and -CH=C=N(CH3)-CH3. Up to two heteroatoms may be consecutive, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3.

[0157] The terms "heterocycloalkyl," "heterocyclic," or "heterocycle" refer to a saturated or partially unsaturated ring system radical having the indicated number of total ring atoms and containing 1 to 5 heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized as a ring atom (e.g., a 3- to 12-membered heterocycloalkyl having 3 to 12 ring atoms and containing at least one heteroatom, which is defined as C 2-11(It may also be referred to as heterocycloalkyl). Unless otherwise specified, a "heterocycloalkyl," "heterocyclic," or "heterocycle" ring system may be a monocyclic or a fused, bridged, or spirocyclic polycyclic (including fused bicyclic, bridged bicyclic, or spirocyclic) ring system. The monocyclic or polycyclic ring may be substituted with one or more oxo groups. A "heterocycloalkyl," "heterocyclic," or "heterocycle" group may be attached to the remainder of the molecule through one or more ring carbons or heteroatoms. Non-limiting examples of "heterocycloalkyl", "heterocyclic" or "heterocyclic" rings include pyrrolidine, piperidine, N-methylpiperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide ... Examples include pyrroline-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, tropane, 2-azaspiro[3.3]heptane, (1R,5S)-3-azabicyclo[3.2.1]octane, (1s,4s)-2-azabicyclo[2.2.2]octane, (1R,4R)-2-oxa-5-azabicyclo[2.2.2]octane, and the like. "Heterocycloalkyl," "heterocyclic," or "heterocycle" can include mono- and polyhalogenated variants thereof. "Cyclic ether" refers to a heterocycle containing one or more oxygen ring atoms, and examples include tetrahydrofuran, methyl-tetrahydrofuran, 1,4-dioxane, and dioxolane.

[0158] The term "alkylene" by itself or as part of another substituent means a divalent radical derived from an alkane, as exemplified by -CH2CH2CH2CH2-, which may also be branched. Typically, an alkyl (or alkylene) group has from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention. "Alkenylene" and "alkynylene" refer to unsaturated forms of "alkylene" having double or triple bonds, respectively. "Alkylene," "alkenylene," and "alkynylene" are also meant to include mono- and polyhalogenated variants.

[0159] The term "heteroalkylene" by itself or as part of another substituent means a saturated, unsaturated, or polyunsaturated divalent radical derived from heteroalkyl, as exemplified by -CH-CH-S-CH-CH-, -CH-S-CH-CH-NH-CH-, -CH-CH=C(H)CH-O-CH-, and -S-CH-C≡C-. The term "heteroalkylene" is also meant to include mono- and polyhalogenated variants.

[0160] The terms "alkoxylene" and "aminoalkylene" and "thioalkylene," by themselves or as part of another substituent, mean a saturated, unsaturated, or polyunsaturated divalent radical derived from alkoxy, alkylamino, and alkylthio, as exemplified by -OCHCH-, -O-CH-CH=CH-, -N(H)CHC(H)(CH)CH-, and -S-CH-C≡C-, respectively. The terms "alkoxylene" and "aminoalkylene" and "thioalkylene" are meant to include mono- and polyhalogenated variants.

[0161] The terms "alkoxy," "alkylamino," and "alkylthio" are used in their conventional sense to refer to those alkyl groups appended to the remainder of the molecule via an oxygen atom ("oxy"), an amino group ("amino"), or a thio group, and further include mono- and polyhalogenated variants thereof. Additionally, for dialkylamino groups, the alkyl portions may be the same or different.

[0162] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl. For example, "C 1-4 The term "haloalkyl" is meant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, difluoromethyl, and the like. As used herein, the term "(halo)alkyl" may include halogenated alkyls. Thus, the term "(halo)alkyl" includes both alkyl and haloalkyl (e.g., monohaloalkyl and polyhaloalkyl).

[0163] The term "aryl," unless otherwise specified, refers to a polyunsaturated, typically aromatic hydrocarbon ring, which may be monocyclic or polycyclic (up to three rings) that are fused together. The term "heteroaryl" refers to an aryl ring containing 1 to 5 heteroatoms selected from N, O, and S, where the nitrogen and sulfur atoms may be oxidized and the nitrogen atom may be quaternized. A heteroaryl group may be attached to the remainder of the molecule through a heteroatom. Non-limiting examples of aryl groups include phenyl, naphthyl, and biphenyl, while non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, and isoindolyl. , indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl, and the like. Optional substituents for each of the above noted aryl and heteroaryl ring systems may be selected from the group of acceptable substituents further described below.

[0164] In some embodiments, the above terms (e.g., "alkyl," "aryl," and "heteroaryl") include both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

[0165] As used herein, "alkylaromatic" refers to an aryl group substituted with one or more alkyl groups. Examples include toluene, ethylbenzene, p-xylene, m-xylene, and mesitylene.

[0166] As used herein, "haloaromatic" refers to an aryl group substituted with one or more halo groups. Examples include toluene, ethylbenzene, p-xylene, m-xylene, and mesitylene.

[0167] Substituents for alkyl radicals (including those groups often referred to as alkylene, alkenyl, alkynyl, heteroalkyl, and cycloalkyl) include, but are not limited to, -halogen, =O, -OR', -NR'R'', -SR', -SiR'R''R''', -OC(O)R', -C(O)R', -COR', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'''C(O)NR' R'', -NR''C(O)2R', -NHC(NH2)=NH, -NRC(NH2)=NH, -NHC(NH2)=NR', -NR'''C(NR'R'')=N-CN, -NR'''C(NR'R'')= NOR', -NHC(NH2)=NR', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NR'S(O)2R'', -NR'''S(O)2NR'R'', -CN, -NO2, -(CH2) 1-4 -OR', -(CH2) 1-4 -NR'R'', -(CH2) 1-4 -SR', -(CH2) 1-4 -SiR'R''R''', -(CH2) 1-4 -OC(O)R', -(CH2) 1-4 -C(O)R', -(CH2) 1-4 -CO2R', -(CH2) 1-4 CONR'R'' can be a number ranging from 0 to (2m'+1), where m' is the total number of carbon atoms in such radical. R', R'' and R''' can each independently be, for example, hydrogen, unsubstituted C, in particular. 1-6 Alkyl, unsubstituted heteroalkyl, unsubstituted aryl, aryl substituted with 1 to 3 halogens, unsubstituted C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Thioalkoxy group, or unsubstituted aryl-C 1-4It refers to groups including alkyl groups, unsubstituted heteroaryls, and substituted heteroaryls. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring. For example, -NR'R" is meant to include 1-pyrrolidinyl and 4-morpholinyl. Other substituents for alkyl groups, including heteroalkyl, alkylene, include, for example, =O, =NR', =N-OR', =N-CN, and =NH, where R' includes the above substituents. When a substituent on an alkyl radical (including groups often referred to as alkylene, alkenyl, alkynyl, heteroalkyl, and cycloalkyl) is an alkylene, alkenylene, or alkynylene linker (e.g., for alkylene, -(CH2) 1-4 When containing -NR'R''), alkylene linkers also include halo variants. For example, the linker "-(CH) when used as part of a substituent group" is 1-4 "-" is meant to include difluoromethylene, 1,2-difluoroethylene, and the like.

[0168] Similarly, substituents on the aryl and heteroaryl groups are varied and typically include, but are not limited to, -halogen, -OR', -OC(O)R', -NR'R'', -SR', -R', -CN, -NO2, -C02R', -CONR'R'', -C(O)R, -OC(O)NR'R'', -NR''C(O)R', -NR''C(O)2R', -NR'C(O)NR''R''', -NHC(NH2)=NH, -NR'C(NH2)=NH, -NHC(NH2)=NR', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NR'S(O)2R'', -N3, perfluoro-C 1-4 Alkoxy and perfluoro-C 1-4 Alkyl, -(CH2) 1-4 -OR', -(CH2) 1-4 -NR'R'', -(CH2) 1-4 -SR', -(CH2) 1-4 -SiR'R''R''', -(CH2) 1-4 -OC(O)R', -(CH2) 1-4 -C(O)R', -(CH2) 1-4-CO2R', -(CH2) 1-4 R', R'' and R'' are independently selected from the group consisting of hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl)-C 1-4 Alkyl and unsubstituted aryloxy-C 1-4 Other suitable substituents include each of the above aryl substituents attached by an alkylene tether of 1 to 4 carbon atoms. When the aryl or heteroaryl group substituent is an alkylene, alkenylene, alkynylene linker (e.g., in the case of alkylene, -(CH2) 1-4 When containing -NR'R''), alkylene linkers also include halo variants. For example, the linker "-(CH) when used as part of a substituent group" is 1-4 "-" is meant to include difluoromethylene, 1,2-difluoroethylene, and the like.

[0169] The term "heteroatom," as used herein, is meant to include oxygen (O), nitrogen (N), sulfur (S), and silicon (Si).

[0170] As used herein, the term "C-linked" means that the group it describes is attached to the remainder of the molecule through a ring carbon atom.

[0171] As used herein, the term "N-linked" means that the group it describes is attached to the remainder of the molecule through a ring nitrogen atom.

[0172] Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers, positional isomers, and individual isomers (e.g., resolved optical isomers) are all intended to be encompassed within the scope of the present invention.

[0173] As used herein, the term "chiral" refers to a molecule that has the property of not being superimposable on its mirror image partner, while the term "achiral" refers to a molecule that is superimposable on its mirror image partner.

[0174] As used herein, the term "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0175] As used herein, a bond that crosses a bond in a chemical structure fragment JPEG0007805356000044.jpg7170 shows the point of attachment of the bond that the wavy bond crosses in the chemical structure fragment to the rest of the molecule or structural formula.

[0176] As used herein, the term "reaction mixture" refers to a mixture of reactants. As used herein, the term "reaction product mixture" refers to a mixture of reaction products formed from the reaction mixture.

[0177] As used herein, the group within the brackets (e.g., X d ) followed by a subscript integer range (e.g., (X d ) 0-2 ) means that the group can have the number of occurrences specified by the integer range. For example, (X d ) 0-1 is the group X d means that there can be zero or one occurrence of

[0178] "Diastereomer" refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers can separate under high-resolution analytical procedures such as electrophoresis and chromatography.

[0179] "Enantiomers" refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.

[0180] As used herein, "positional isomer" refers to molecules with the same molecular formula but with different bonding patterns that vary in the location of functional groups or other substituents relative to the parent structure. Examples include: p-xylene and m-xylene; and pentan-1-ol, pentan-2-ol, and pentan-3-ol.

[0181] Stereochemical definitions and conventions used herein generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., New York, 1994. The compounds of the present invention may contain asymmetric or chiral centers and therefore may exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention, including, but not limited to, diastereomers, enantiomers, and atropisomers, and mixtures thereof, e.g., racemic mixtures, are intended to form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing optically active compounds, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its one or more chiral centers. The prefixes d and l, or (+) and (-), are used to indicate the sign of rotation of plane-polarized light by a compound; (-) or l means the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A specific stereoisomer is also referred to as an enantiomer, and a mixture of such isomers is sometimes called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

[0182] As used herein, the term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions via reorganization of some of the bonding electrons.

[0183] In the structures depicted herein, when the stereochemistry of any particular chiral atom is not specified, all stereoisomers are contemplated and included as compounds of the present invention. When stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, that stereoisomer is so specified and defined. Unless otherwise indicated, when a solid wedge or dashed line is used, relative stereochemistry is intended.

[0184] As used herein, "polymorph" or "polymorphism" refers to the ability of a substance to exist in two or more crystalline forms, and different crystalline forms of a particular substance are called "polymorphs." Generally, polymorphism can be influenced by the ability of a substance's molecules to change their conformation or form different inter- or intramolecular interactions, particularly hydrogen bonds, which is thought to be reflected in different atomic arrangements within the crystal lattice of different polymorphs. Different polymorphs of a substance may have different energies of the crystal lattice, and therefore, in the solid state, they may exhibit different physical properties, such as morphology, density, melting point, color, stability, solubility, dissolution rate, etc., which may affect properties such as, but not limited to, the stability, dissolution rate, and / or bioavailability of a given polymorph, as well as its suitability for use as a medicine and pharmaceutical composition.

[0185] As used herein, "morphology" refers to the external shape and present faces of a crystal, regardless of its internal structure. Crystals can exhibit various morphologies based on various conditions, such as growth rate, agitation, and the presence of impurities.

[0186] As used herein, "solvate" refers to any form of a compound that is non-covalently bound to another molecule (such as a polar solvent). Such solvates are typically crystalline solids with a substantially fixed molar ratio of solute and solvent. Representative solvents include water, methanol, ethyl acetate, acetic acid, ethanolamine, n-heptane, N,N-dimethylacetamide, anisole, ethanol (EtOH), toluene, 2-propanol, 1-butanol, 2-methyltetrahydrofuran (2-Me-THF), tetrahydrofuran (THF), isobutyl alcohol, and dimethyl sulfoxide (DMSO). The term "hydrate" refers to a complex in which the solvent molecule is water.

[0187] As used herein, the term "seed" may be used as a noun to describe one or more crystals of a crystalline compound of Formula I (e.g., polymorph Form A of the compound of Formula I). ​​The term "seed" may also be used as a verb to describe the act of introducing one or more crystals of said crystalline compound of Formula I into an environment (including, but not limited to, for example, a solution, mixture, suspension, or dispersion), thereby resulting in the formation of more crystals of the crystalline compound of Formula I.

[0188] As used herein, the term "protecting group" refers to a substituent commonly used to block or protect a particular functional group on a compound. For example, an "amino-protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality of the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ), and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a "hydroxy-protecting group" refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable protecting groups include acetyl and silyl. A "carboxy-protecting group" refers to a substituent of a carboxy group that blocks or protects the carboxy functionality. Common carboxy-protecting groups include phenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, nitroethyl, and the like. For a general description of protecting groups and their uses, see P. G. M. Buts and T. W. Greene, Greene's Protective Groups in Organic Synthesis, 4th ed., Wiley-Interscience, New York, 2006.

[0189] As used herein, the term "salts" is intended to include salts of active compounds prepared with relatively non-toxic acids or bases (e.g., pharmaceutically acceptable salts), depending on the specific substituents found on the compounds described herein. When a compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, etc. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc., cyclic amines, naturally occurring amines, etc. When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, phosphoric acid, monohydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like. Also included are salts of amino acids such as arginate, and salts of organic acids such as glucuronic acid or galactunolonic acid (see, e.g., Berge, SM et al., Pharmaceutical Salts, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain compounds of the present invention contain both basic and acidic functional groups that allow the compounds to be converted into either base or acid addition salts.

[0190] As used herein, the terms "predominantly" and "substantially" refer to greater than 50%, at least 75%, at least 90%, at least 95%, or at least 99% on a population %, w / w%, w / v%, v / v%, or molar % basis.

[0191] The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise these salts are equivalent to the parent form of the compound for purposes of this invention.

[0192] Certain compounds of the present invention can exist in solvated forms, including hydrated forms, as well as unsolvated forms. Generally, solvated forms are equivalent to unsolvated forms and are intended to be included within the scope of the present invention. Certain compounds of the present invention can exist in multiple crystalline or amorphous forms. Generally, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

[0193] As used herein, the term "organic base" refers to an organic compound containing one or more nitrogen atoms and acting as a base. One example of an organic base is a tertiary amine, such as a trialkylamine, where the alkyl groups are the same or different and can be linear or branched, such as diethylamine, diisopropylethylamine (DIPEA), triethylamine (TEA), di-n-butylamine, and tri-n-butylamine. Another example of an organic base is a cyclic amine, such as quinuclidine, 2,2,6,6-tetramethylpiperidine (TMP), pempidine (PMP), 1,4-diazabicyclo[2.2.2]octane (DABCO), and N-methyl-morpholine (NMM). Cyclic amines can also be classified as secondary or tertiary amines. Other examples of organic bases include amidine and guanidine bases, such as 1,1,3,3-tetramethylguanidine (TMG), 7-methyl-1,5,7 triazabicyclo(4.4.0)dec-5-ene (MTBD), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,5,7-triazabicyclo(4.4.0)dec-5-ene (TBD), and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN).

[0194] As used herein, the term "inorganic base" refers to a base that contains an inorganic component. Examples of inorganic bases include, but are not limited to, alkali metal hydroxides, ammonium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate, and sodium bicarbonate.

[0195] As used herein, the term "strong base" refers to a base that completely or nearly completely dissociates in water.

[0196] As used herein, the term "polar aprotic solvent" refers to any polar solvent that does not have proton-donating ability. Examples include, but are not limited to, 2-methyltetrahydrofuran, tetrahydrofuran, ethyl acetate, propyl acetate (e.g., isopropyl acetate, iPrOAc), acetone, dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile (CHCN), N,N-dimethylacetamide, N-methylpyrrolidone (NMP), hexamethylphosphoramide, and propylene carbonate.

[0197] As used herein, the term "polar protic solvent" refers to any polar solvent that has proton-donating capability. Examples include, but are not limited to, water, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, formic acid, nitromethane, and acetic acid.

[0198] As used herein, the term "polar organic solvent" refers to both polar aprotic solvents and polar protic solvents, excluding water.

[0199] As used herein, the term "nonpolar solvent" refers to a solvent that contains bonds between atoms of similar electronegativity, such as carbon and hydrogen, such that the charge on the molecule is evenly distributed. Nonpolar solvents are characterized by having a low dielectric constant. Examples include, but are not limited to, pentane (e.g., n-pentane), hexane (e.g., n-hexane), heptane (e.g., n-heptane), cyclopentane, methyl tert-butyl ether, diethyl ether, toluene, benzene, 1,4-dioxane, carbon tetrachloride, chloroform, and dichloromethane (DCM). In some embodiments, nonpolar solvents have a dielectric constant of less than 2, and examples include, but are not limited to, n-pentane, n-hexane, and n-heptane. Compared to other nonpolar solvents, DCM exhibits some polarity at the bond level (i.e., between carbon and chlorine), but only slight polarity at the molecular level due to polarity symmetry-based compensation.

[0200] As used herein, the term "solvent" refers to any of polar aprotic solvents, polar protic solvents, and non-polar solvents.

[0201] As used herein, the term "anti-solvent" refers to a solvent in which the referenced compound is poorly soluble and which induces precipitation or crystallization of said compound from solution.

[0202] As used herein, unless otherwise indicated, the term "percent yield" refers to the yield on a molar basis of the indicated reaction, calculated from the actual yield to the theoretical yield based on a non-stoichiometric excess of reactants. For example, if 1.0 mole of compound A is reacted with 1.1 molar equivalents of compound B to form 0.9 moles of compound C, the percent yield (based on compound A) is (0.9) / (1.0) x 100 = 90%.

[0203] As used herein, the term "purity," unless otherwise specified, refers to the amount of a compound in a sample compared to the total amount of compound in the sample. In some embodiments, purity can be measured by high-pressure liquid chromatography (HPLC) analysis, where the area percent of the product represents the purity.

[0204] As used herein, the term "area percent" or "area %" with respect to purity refers to the area percent of a compound's peak in a chromatogram (such as an HPLC chromatogram) as a percentage of the total area of ​​all peaks.

[0205] It should be readily understood that where applicant has defined an embodiment or portion thereof with open-ended terms such as "comprising," the description (unless otherwise expressly stated) should be construed as also describing such embodiment(s) using the terms "consisting essentially of" or "consisting of."

[0206] The transitional phrase "consisting essentially of" is used to define a composition or method that includes materials, steps, features, components, or elements in addition to those literally disclosed, but these additional materials, steps, features, components, or elements do not materially affect the basic and novel characteristics of the claim.

[0207] As used herein, the terms "comprises," "comprising," "includes," "including," "has," "having," "contains," "containing," "characterized by," or any variation thereof, are intended to cover a non-exclusive inclusion, subject to any limitations expressly stated. For example, a composition, mixture, process, or method that includes a list of elements is not necessarily limited to only those elements and may include other elements not expressly listed or inherent in such composition, mixture, process, or method.

[0208] As used herein, the indefinite articles "a" and "an" preceding an element or component of the disclosure are intended to be non-limiting regarding the number of instances (i.e., occurrences) of the element or component. Thus, "a" or "an" should be read to include one or at least one, and the singular form of an element or component also includes the plural, unless the number is clearly intended to be singular. Synthesis method

[0209] The methods of the disclosure comprise reacting a compound of Formula I: JPEG0007805356000045.jpg47170 relates to the preparation of the compound.

[0210] R 1 , R 2 and R 3 are independently H, F, Cl, Br, I, and C 1-6 Alkyl and C 1-6 haloalkyl.

[0211] X 1 is CR 4 where R 4 -F, -Cl, -Br, -I, -(L 1 ) 0-1 -C 1-6 Alkyl, -(L1 ) 0-1 -C 1-6 Haloalkyl, -(L 1 ) 0-1 -C 1-6 Heteroalkyl, -(L 2 ) 0-1 -C 3-8 Cycloalkyl, -(L 2 ) 0-1 -3 to 7-membered heterocycloalkyl, -(L 2 ) 0-1 -6 to 10-membered aryl, and -(L 2 ) 0-1 - selected from the group consisting of 5- to 10-membered heteroaryl.

[0212] L 1 -O-, -N(H)-, -S-, -N(C 1-6 is selected from the group consisting of alkyl)- and ═O.

[0213] L 2 -O-, -N(H)-, -N(C 1-6 Alkyl)-, -S-, =O, C 1-4 Alkylene, C 1-4 Alkenylene, C 1-4 Alkynylene, C 1-4 Alkoxylene, C 1-4 Aminoalkylene, C 1-4 Thioalkylene and C 1-4 heteroalkylene.

[0214] R 4 is the carbon atom and heteroatom, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Haloalkyl, 3-5 membered cycloalkyl, 3-5 membered heterocycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 1-6 Dialkylamino, C 1-6 R selected from the group consisting of alkylthio, ═O, —NH, —CN, —NO, and —SF R4 It may be substituted with a substituent.

[0215] X 2 is N.

[0216] A has the following structure: JPEG0007805356000046.jpg27170 is a 3- to 12-membered, 5- to 9-membered, 6- to 8-membered, or 7-membered N-containing heterocycloalkyl.

[0217] A is F, Cl, Br, I, -OH, -CN, -NO2, -SF5, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, -(L A ) 0-1 -3 to 8-membered cycloalkyl, -(L A ) 0-1 -3 to 8-membered heterocycloalkyl, -(L A ) 0-1 -5-6 membered heteroaryl, -(L A ) 0-1 -C6 aryl, -(L A ) 0-1 -NR R1a R R1b , -(L A ) 0-1 -OR R1a , -(L A ) 0-1 -SR R1a , -(L A ) 0-1 -N(R R1a )C(=Y 1 ) OR R1c , -(L A ) 0-1 -OC(=O)N(R R1a )(R R1b ), -(L A ) 0-1 -N(R R1a )C(=O)N(R R1a )(R R1b ), -(L A ) 0-1 -C(=O)N(R R1a )(R R1b ), -(L A ) 0-1 -N(R R1a )C(=O)R R1b , -(LA ) 0-1 -C(=O)OR R1a , -(L A ) 0-1 -OC(=O)R R1a , -(L A ) 0-1 -P(=O)(OR R1a )(OR R1b ), -(L A ) 0-1 -S(O) 1-2 R R1c , -(L A ) 0-1 -S(O) 1-2 N(R R1a )(R R1b ), -(L A ) 0-1 -N(R R1a )S(O) 1-2 N(R R1a )(R R1b ) and -(L A ) 0-1 -N(R R1a )S(O) 1-2 (R R1c 1 to 5 R selected from the group consisting of A It may be substituted with a substituent.

[0218] Y 1 is O or S.

[0219] L A is C 1-4 Alkylene, C 1-4 Heteroalkylene, C 1-4 Alkoxylene, C 1-4 Aminoalkylene, C 1-4 Thioalkylene, C 2-4 Alkenylene and C 2-4 alkynylene.

[0220] R R1a and R R1b are each independently hydrogen, C 1-8 Alkyl, C 1-8It is selected from the group consisting of haloalkyl, 3- to 8-membered cycloalkyl, phenyl, benzyl, 5- to 6-membered heteroaryl, and 3- to 8-membered heterocycloalkyl.

[0221] R R1c is C 1-8 Alkyl, C 1-8 R is selected from the group consisting of haloalkyl, 3- to 8-membered cycloalkyl, phenyl, benzyl, 5- to 6-membered heteroaryl, and 3- to 7-membered heterocycloalkyl; A In carbon atoms and heteroatoms, F, Cl, Br, I, -NH2, -OH, -CN, -NO2, =O, -SF5, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 (Halo)alkyl-C(=O)-, C 1-4 (Halo)alkyl-S(O) 0-2 -, C 1-4 (Halo)alkyl-N(H)S(O) 0-2 -, C 1-4 (Halo)alkyl-S(O) 0-2 N(H)-, (halo)alkyl-N(H)-S(O) 0-2 N(H)-, C 1-4 (Halo)alkyl-C(=O)N(H)-, C 1-4 (Halo)alkyl-N(H)-C(=O)-, ((halo)alkyl)N-C(=O)-, C 1-4 (Halo)alkyl-OC(=O)N(H)-, C 1-4 (Halo)alkyl-OC(=O)N(H)-, (halo)alkyl-N(H)-C(=O)O-, ((halo)alkyl)N-C(=O)O-, C 1-4 Alkylthio, C 1-4 Alkylamino and C 1-4 R selected from dialkylamino RA It may be substituted with a substituent.

[0222] Cy has the following structure: JPEG0007805356000047.jpg20170 is a 3- to 12-membered, 4- to 7-membered, 5-membered, or 6-membered N-containing heterocycloalkyl.

[0223] Cy may contain one or two additional heteroatoms selected from the group consisting of O, S and N.

[0224] Cy is a carbon or heteroatom that can be selected from F, Cl, Br, I, -OH, -CN, -NO2, -SF5, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Heteroalkyl, -(L Cy ) 0-1 -3 to 8-membered cycloalkyl, -(L Cy ) 0-1 -3 to 8-membered heterocycloalkyl, -(L Cy ) 0-1 -5-6 membered heteroaryl, -(L Cy ) 0-1 -phenyl, -(L Cy ) 0-1 -NR RCa R RCb , -(L Cy ) 0-1 -OR RCa , -(L Cy ) 0-1 -SR RCa , -(L Cy ) 0-1 -N(R RCa )C(=Y 1 ) OR RCc , -(L Cy ) 0-1 -OC(=O)N(R RCa )(R RCb ), -(L Cy ) 0-1 -N(R RCa )C(=O)N(R RCa )(R RCb ), -(L Cy ) 0-1 -C(=O)N(R RCa )(R RCb ), -(L Cy ) 0-1 -N(R RCa )C(=O)R RCb , -(L Cy ) 0-1 -C(=O)OR RCa , -(L Cy )0-1 -OC(=O)R RCa , -(L Cy ) 0-1 -P(=O)(OR RCa )(OR RCb ), -(L Cy ) 0-1 -S(O) 1-2 R RCc , -(L Cy ) 0-1 -S(O) 1-2 N(R RCa )(R RCb ), -(L Cy ) 0-1 -N(R RCa )S(O) 1-2 N(R RCa )(R RCb ) and -(L Cy ) 0-1 -N(R RCa )S(O) 1-2 (R RCc ) R selected from the group consisting of Cy It may be substituted with a substituent.

[0225] L Cy is C 1-4 Alkylene, C 1-4 Heteroalkylene, C 1-4 Alkoxylene, C 1-4 Aminoalkylene, C 1-4 Thioalkylene, C 2-4 Alkenylene and C 2-4 alkynylene.

[0226] R RCa and R RCb are each independently hydrogen, C 1-8 Alkyl, C 1-8 It is selected from the group consisting of haloalkyl, 3-8 membered cycloalkyl, phenyl, benzyl, 5-6 membered heteroaryl and 3-8 membered heterocycloalkyl.

[0227] R RCc is C 1-8 Alkyl, C 1-8It is selected from the group consisting of haloalkyl, 3- to 8-membered cycloalkyl, phenyl, benzyl, 5- to 6-membered heteroaryl, and 3- to 7-membered heterocycloalkyl.

[0228] R Cy In carbon atoms and heteroatoms, F, Cl, Br, I, -NH2, -OH, -CN, -NO2, =O, -SF5, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 (Halo)alkyl-C(=O)-, C 1-4 (Halo)alkyl-S(O) 0-2 -, C 1-4 (Halo)alkyl-N(H)S(O) 0-2 -, C 1-4 (Halo)alkyl-S(O) 0-2 N(H)-, (halo)alkyl-N(H)-S(O) 0-2 N(H)-, C 1-4 (Halo)alkyl-C(=O)N(H)-, C 1-4 (Halo)alkyl-N(H)-C(=O)-, ((halo)alkyl)N-C(=O)-, C 1-4 (Halo)alkyl-OC(=O)N(H)-, C 1-4 (Halo)alkyl-OC(=O)N(H)-, (halo)alkyl-N(H)-C(=O)O-, ((halo)alkyl)N-C(=O)O-, C 1-4 Alkylthio, C 1-4 Alkylamino and C 1-4 1 to 5 R selected from the group consisting of dialkylamino RCy It may be substituted with a substituent.

[0229] In some embodiments, L 1 is -O-.

[0230] In some embodiments, R 4 is -(L 1 ) 0-1 -C 1-6 In some embodiments, R 4is selected from methoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, methyl, monofluoromethyl, difluoromethyl, and trifluoromethyl. In some such embodiments, R 4 is monofluoromethoxy, difluoromethoxy, or trifluoromethoxy. In one embodiment, R 4 is difluoromethoxy.

[0231] In some embodiments, R 1 , R 2 and R 3 are hydrogen atoms.

[0232] In some embodiments, A is selected from the group consisting of F, Cl, Br, I, CN, CH3O-, CH3, cyclopropylmethyl, CF3, and butyl. A In some embodiments, A is substituted with F. In some particular embodiments, A is Selected from JPEG0007805356000048.jpg24170.

[0233] In one aspect, A is JPEG0007805356000049.jpg17170.

[0234] In some embodiments, Cy is Selected from JPEG0007805356000050.jpg27170.

[0235] In one embodiment, C y is as follows JPEG0007805356000051.jpg19170.

[0236] In some embodiments, R 1 , R 2 and R 3 are H and X, respectively. 1 is CR4 where R 4 is -(L 1 ) 0-1 -C 1-6 haloalkyl, and L 1 is -O- and ;X 2 is N; A is 1 to 5 R A an optionally substituted 3- to 12-membered N-containing heterocycloalkyl, wherein each R A is F; and Cy is a 3-12 membered N-containing heterocycloalkyl.

[0237] In some embodiments, R 1 , R 2 and R 3 are H and X, respectively. 1 is CR 4 where R 4 is selected from monofluoromethoxy, difluoromethoxy, and trifluoromethoxy; A is a 4-7 membered N-containing heterocycloalkyl substituted with 1-3 F atoms; and Cy is a 5-9 membered N-containing heterocycloalkyl further comprising an oxygen heteroatom.

[0238] In some embodiments, R 1 , R 2 and R 3 are H and X, respectively. 1 is CR 4 where R 4 is -(L 1 ) 0-1 -C 1-6 haloalkyl, and L 1 is -O- and ;X 2 is N; A is 0 to 5 R A substituted 3- to 12-membered heterocycloalkyl, where each R A is F; and Cy is a 3- to 12-membered heterocycloalkyl.

[0239] In some embodiments, R 4 is difluoromethoxy.

[0240] In some embodiments, A is pyrrolidine.

[0241] In embodiments, the compound of formula I is JPEG0007805356000052.jpg62170 (in the formula, R 4 Ha-(L 1 ) 0-1 -C 1-6 haloalkyl, and L 1 is -O-;R A is F; and Cy is a 3- to 12-membered heterocycloalkyl. It has the following structure.

[0242] In some embodiments, A is one or two R A is replaced by .

[0243] In some embodiments, A is two R A is replaced by .

[0244] In embodiments, A is difluoropyrrolidine.

[0245] In embodiments, Cy is 2-oxa-5-azabicyclo[2.2.1]heptane.

[0246] In embodiments, Cy is (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane.

[0247] In embodiments, Cy is JPEG0007805356000053.jpg25170.

[0248] In embodiments, the compound of formula I is JPEG0007805356000054.jpg64170 (in the formula, R 4 Ha-(L 1 ) 0-1 -C 1-6 haloalkyl, and L 1 is -O-;X 2is N; A is 0 to 5 R A 3- to 12-membered heterocycloalkyl substituted with a substituent, wherein each R A is F) It has the following structure.

[0249] In some embodiments, A is pyrrolidine and Cy is 2-oxa-5-azabicyclo[2.2.1]heptane.

[0250] In some embodiments, R 4 is difluoromethoxy, A is pyrrolidine, and Cy is 2-oxa-5-azabicyclo[2.2.1]heptane.

[0251] In embodiments, the methods of the disclosure relate to the preparation of 3-(difluoromethoxy)-5-[2-(3,3-difluoropyrrolidin-1-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyridin-2-amine, or a pharmaceutically acceptable salt thereof.

[0252] In embodiments, the methods of the present disclosure include: JPEG0007805356000055.jpg60170 or a pharmaceutically acceptable salt thereof.

[0253] In embodiments, the methods of the present disclosure include: JPEG0007805356000056.jpg61170 or a pharmaceutically acceptable salt thereof.

[0254] In one embodiment, the compound of formula I is Compound 1, where Compound 1 is a species of Compound I: JPEG0007805356000057.jpg51170 or 5-(6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(3,3-difluoropyrrolidin-1-yl)pyrimidin-4-yl)-3-(difluoromethoxy)pyridin-2-amine, or 3-(Difluoromethoxy)-5-[2-(3,3-difluoropyrrolidin-1-yl)-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyridin-2-amine (Compound 1).

[0255] The method of the present disclosure can be carried out by the following scheme: JPEG0007805356000058.jpg56170, carrying out a catalytic coupling reaction between sulfone compound (iii) and boronate reagent (iv) in the presence of a base and a solvent to provide compound (v).

[0256] R 5 and R 6 are each independently a linear or branched C 1-6 alkyl, or R 5 and R 6 together with the oxygen and boron atoms to which they are attached form a 5- to 7-membered heterocyclic ring, where each ring carbon atom is bonded to one or two C 1-4 It may be substituted with a straight chain alkyl group.

[0257] The method of the present disclosure can be carried out by the following scheme: and further comprising displacing the methoxysulfonyl group of compound (v) under basic conditions in a solvent containing a 3- to 12-membered amine-containing heterocycloalkyl compound (vi) according to JPEG0007805356000059.jpg53170 to provide a compound of Formula I. Preparation of compound (v) from compounds (iii) and (iv) JPEG0007805356000060.jpg57170

[0258] The reaction mixture is formed from a solvent, compound (iii), a stoichiometric excess of compound (iv), a base, and a catalyst. In some embodiments, the reaction mixture is a suspension. The reaction mixture is heated to a reaction temperature with mixing and maintained at the reaction temperature with mixing for a time sufficient to achieve a desired conversion, thereby forming a reaction product mixture containing compound (v) in solution. An in-process test for the proportion of unreacted compound (iii) can be performed to assess the degree of conversion.

[0259] In some embodiments, the concentration of compound (iii) in the reaction mixture can suitably be about 10 g / L, about 25 g / L, about 50 g / L, about 75 g / L, about 100 g / L, about 125 g / L, about 150 g / L, about 175 g / L, or about 200 g / L, and any range constructed therein, e.g., from about 10 g / L to about 200 g / L, from about 25 g / L to about 150 g / L, or from about 50 g / L to about 100 g / L. On a moles / liter basis, the concentration may suitably be about 0.05 moles / L, about 0.1 moles / L, about 0.15 moles / L, about 0.2 moles / L, about 0.25 moles / L, about 0.3 moles / L, about 0.35 moles / L, about 0.4 moles / L, about 0.45 moles / L, or about 0.5 moles / L, and any range therein, for example, about 0.05 moles / L to about 0.5 moles / L, about 0.1 moles / L to about 0.4 moles / L, or about 0.15 moles / L to about 0.3 moles / L.

[0260] In some embodiments, the equivalent ratio of compound (iii) to compound (iv) is 1:1.01, about 1:1.05, about 1:1.1, about 1:1.15, about 1:1.2, about 1:1.25, about 1:1.3, about 1:1.35, about 1:1.4, about 1:1.45, or 1:1.49, and any range constructed therefrom, for example, about 1:1.01 to 1:1.49, about 1:1.05 to about 1:1.4, about 1:1.1 to about 1:1.3, or about 1:1.15.

[0261] In some embodiments, the ratio of equivalents of compound (iii) to base can be about 1:1.5, about 1:2, about 1:2.5, about 1:3, about 1:3.5, about 1:4, about 1:4.5, about 1:5 or more, and any range built therein, such as about 1:1.5 to about 1:5, about 1:2 to about 1:4, or about 1:2.5 to about 1:3.5.

[0262] In some embodiments, the equivalent ratio of compound (iii) to catalyst can be about 50:1, about 100:1, about 150:1, about 200:1, about 250:1, or about 300:1, and any range derived therefrom, such as about 50:1 to about 300:1 or about 150:1 to about 250:1. Alternatively, the palladium catalyst content based on compound (iii) can be about 2 mol%, about 1 mol%, about 0.75 mol%, about 0.5 mol%, about 0.25 mol%, and any range derived therefrom, such as about 2 mol% to about 0.25 mol%, about 1 mol% to about 0.25 mol%, or about 0.75 mol% to about 0.25 mol%.

[0263] In some embodiments, the reaction temperature can vary depending on the identity and concentration of the solvent, reactants, and reagents. In some embodiments, the reaction temperature can be the reflux temperature of the reaction mixture. In some other embodiments, the reaction temperature can be below the reflux temperature, e.g., about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, or about 80°C, and any range derived therefrom, e.g., about 50°C to about 80°C, about 55°C to about 75°C, or about 55°C to 65°C.

[0264] The reaction time may vary depending on the solvent, the concentration of compounds (iii) and (iv), the base and catalyst, and the reaction temperature. Non-limiting examples of typical reaction times are 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, or 6 hours.

[0265] The reaction may be monitored for completion by suitable in-process testing methods known in the art, such as high pressure liquid chromatography ("HPLC") or infrared spectroscopy.

[0266] Catalysts within the scope of the present disclosure include transition metal catalysts such as palladium, platinum, gold, ruthenium, rhodium, and iridium catalysts. In some embodiments, the coupling reaction catalyst is a palladium catalyst. In some such embodiments, the palladium catalyst is a zero-valent Pd(0) catalyst.

[0267] In some embodiments, the palladium catalyst is [PdCl(X)]2, where X is allyl, cinnamyl, or crotyl; [Pd(X)PR 7 ](wherein, R 7 is alkyl or aryl; [Pd(X)(Y)] (wherein X is allyl, cinnamyl, or crotyl, and Y is cyclopentadienyl or p-cymyl); Pd(dba)2; Pd2(dba)3; Pd(OAc)2; PdZ2 (wherein Z is Cl, Br, or I); Pd2Z2(PR 8 )2 (wherein Z is Cl, Br or I, and R 8 is alkyl or aryl); and PdPd(TFA)2, each catalyst being combined with a phosphine ligand, a base, or a combination thereof.

[0268] In some embodiments, the catalyst is selected from the group consisting of Pd(dppf)Cl, Pd(dppe)Cl, Pd(PCy)Cl, Pd(PPh)Cl, Pd(OAc)(PPh), Pd(PPh), Pd(PPh)Cl, Pd(PCy), Pd(PCy)Cl, and Pd(t-BuP). In some such embodiments, the catalyst is Pd(dppf)Cl.

[0269] The catalyst may be complexed with a solvent. Non-limiting examples of such complexing solvents include dichloromethane, chloroform, and acetonitrile.

[0270] The coupling reaction solvent may suitably be a nonpolar solvent (e.g., methyl tert-butyl ether, diethyl ether, toluene, benzene, 1,4-dioxane, carbon tetrachloride, chloroform, or dichloromethane), a polar aprotic solvent (e.g., tetrahydrofuran, methyl-tetrahydrofuran, ethyl acetate, propyl acetate, acetone, dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, N,N-dimethylacetamide, N-methylpyrrolidone, hexamethylphosphoramide, or propylene carbonate), or a polar protic solvent (e.g., methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, formic acid, nitromethane, and acetic acid). In some embodiments, the solvent may be a combination of a polar organic solvent and water. In some embodiments, the solvent is a cyclic ether, dioxane, toluene, acetonitrile, ethyl acetate, isopropyl acetate, n-propyl acetate, dimethylformamide, dimethyl sulfoxide, or a combination thereof. In some embodiments, the solvent is a cyclic ether. In some embodiments, the solvent is tetrahydrofuran or methyl-tetrahydrofuran, hi some embodiments, the solvent is tetrahydrofuran and water.

[0271] Suitable bases for the coupling reaction include carbonates, phosphates, tertiary amines, cyclic amidines, and guanidines. In some embodiments, the base is a carbonate or an alkali metal carbonate, such as sodium carbonate or potassium carbonate. The molar ratio of base to compound (iii) is about 1.5:1, about 2:1, about 2.5:1, about 3:1, about 3.5:1, about 4:1, about 4.5:1, or about 5:1, and any ranges derived therefrom, such as about 1.5:1 to about 5:1, about 2:1 to about 4:1, or about 2.5:1 to about 3.5:1.

[0272] The coupling reaction may include a step of scavenging the catalyst from the reaction product mixture containing compound (v) by adding at least one metal catalyst scavenger. Non-limiting examples of scavenger include thiols, thioureas, thiocarbamates, and xanthates, or salts thereof. In some such embodiments, the catalyst scavenger is a thiol. In one embodiment, the catalyst scavenger is N-acetylcysteine. The amount of scavenger may vary depending on the catalyst itself and its equivalents. Typically, about 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 equivalents of scavenger per equivalent of catalyst may be used.

[0273] In some embodiments, if compound (v) is dissolved in the reaction product mixture, the method further comprises precipitating compound (v) therefrom by adding at least one anti-solvent to form a slurry or suspension of compound (v). In some such embodiments, the anti-solvent is a non-polar solvent. In some such embodiments, the anti-solvent is n-heptane. The anti-solvent may be added with mixing at the reaction temperature or at a reduced temperature. In some embodiments, the anti-solvent may be added after phase separation of the reaction product mixture. In some embodiments, the anti-solvent may be added to the reaction product mixture without prior phase separation. In some embodiments, seed crystals of compound (v) may be added before the anti-solvent addition. After the anti-solvent addition, the reaction product mixture may be cooled with mixing and aged at a temperature that produces a slurry of compound (v). Cooling may be to a temperature close to room temperature or below, for example, about 20°C, about 15°C, about 10°C, or about 5°C or below. In such embodiments, solid compound (v) may be isolated by methods known in the art, such as filtration and / or centrifugation. The solid compound (v) may be washed after isolation. Washing may be carried out using the reaction solvent, an antisolvent, or a solvent in which compound (v) is poorly soluble. The solid compound (v) may be dried by methods known in the art, for example, under reduced pressure.

[0274] Additional purification steps for compound (v) are within the scope of this disclosure, including, but not limited to, solvent exchange of the reaction product mixture; compound (v) solution washes; extraction; precipitation, isolation and washing; chromatographic purification, such as HPLC, ion exchange, or exclusion; and combinations thereof.

[0275] In some embodiments, the process for preparing compound (v) is carried out in the absence of additional purification steps, as described elsewhere herein, hi some such embodiments, the process for preparing compound (v) is carried out in the absence of a chromatographic purification step, a solvent exchange step, or a combination thereof.

[0276] The yield of compound (v) is at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90%. The purity of compound (v) by HPLC is at least 98 area%, at least 98.5 area%, at least 99 area%, or at least 99.5 area%, for example, 99 area%, 99.1 area%, 99.2 area%, 99.3 area%, 99.4 area%, 99.5 area%, 99.6 area%, or 99.7 area%.

[0277] Among other advantages, compared to prior art methods, the process for preparing compound (v) allows for the replacement of acetonitrile with less toxic and less expensive tetrahydrofuran, allows for reduced catalyst loading, allows for reduced reaction temperatures, allows for the elimination of chromatographic purification steps, and (v) maintains or improves yield and provides high purity. In embodiments, the disclosed method for preparing compound (v) allows for at least a 10-fold reduction in catalyst loading. In embodiments, the disclosed method for preparing compound (v) allows for a reduction in reaction temperature by at least 50°C.

[0278] In some embodiments, compounds (iii), (iv), and (v) have the following structure: JPEG0007805356000061.jpg55170. Preparation of Compounds of Formula I from Compound (v) and Compound (vi) JPEG0007805356000062.jpg52170

[0279] The disclosed method includes forming a reaction mixture from a solvent, compound (v), a stoichiometric excess of compound (vi), and a base. In some embodiments, the reaction mixture is a suspension. In some embodiments, the reaction mixture is an emulsion. The reaction mixture is heated to a reaction temperature with mixing and held at the reaction temperature with mixing for a time sufficient to achieve a desired conversion, thereby forming a reaction product mixture containing a compound of Formula I. In some embodiments, compound I is dissolved in the reaction product mixture. An in-process test for the proportion of unreacted compound (v) can be performed to assess the degree of conversion.

[0280] In some embodiments, the concentration of compound (v) in the reaction mixture can suitably be about 50 g / L, about 100 g / L, about 150 g / L, about 200 g / L, about 250 g / L, about 300 g / L, about 350 g / L, or about 400 g / L, and any range constructed therein, e.g., from about 50 g / L to about 400 g / L, from about 100 g / L to about 350 g / L, or from about 200 g / L to about 300 g / L. On a mole / L basis, the concentration may suitably be about 0.1 mol / L, about 0.25 mol / L, about 0.5 mol / L, about 0.75 mol / L, or about 1 mol / L, and any range built therein, e.g., about 0.1 mol / L to about 1 mol / L, about 0.25 mol / L to about 0.75 mol / L, or about 0.5 mol / L to about 0.75 mol / L.

[0281] In some embodiments, the equivalent ratio of compound (v) to compound (vi) is 1:1.01, about 1:1.1, about 1:1.2, about 1:1.3, about 1:1.4, about 1:1.5, about 1:1.6, about 1:1.7, about 1:1.8, about 1:1.9, about 1:2, about 1:2.1, about 1:2.2, about 1:2.3, or 1:2.4, and any range therein, for example, 1:1.01 to 1:2.4, about 1:1.1 to about 1:2, about 1:1.2 to about 1:1.8, or about 1:1.4 to about 1:1.6.

[0282] In some embodiments, the equivalent ratio of compound (v) to base can be about 1:1.01, about 1:1.1, about 1:1.2, about 1:1.3, about 1:1.4, about 1:1.5, about 1:1.6, about 1:1.7, about 1:1.8, about 1:1.9, about 1:2, about 1:2.1, about 1:2.2, about 1:2.3, or 1:2.4, and any range therein, for example, 1:1.01 to 1:2.4, about 1:1.1 to about 1:2, about 1:1.2 to about 1:1.8, or about 1:1.4 to about 1:1.6.

[0283] In some embodiments, the reaction temperature can vary depending on the identity and concentration of the solvent, reactants, and reagents. In some embodiments, the reaction temperature can be the reflux temperature of the reaction mixture. In some other embodiments, the reaction temperature can be below the reflux temperature. In any of various embodiments, the temperature is suitably about 90°C, about 95°C, about 100°C, about 105°C, about 110°C, about 115°C, about 120°C, about 125°C, about 130°C, about 135°C, about 140°C, about 145°C, about 150°C, and above, as well as any range derived therefrom, such as about 90°C to about 150°C, about 100°C to about 140°C, about 110°C to about 135°C, about 115°C to about 125°C, or about 120°C to about 130°C.

[0284] The reaction time may vary depending on the solvent, the concentration of compound (v) and compound (vi), and the base. Non-limiting examples of typical reaction times are 2 hours, 5 hours, 10 hours, 15 hours, 20 hours, 24 hours, 30 hours, or 36 hours.

[0285] In some embodiments, compound (vi) has the structure: JPEG0007805356000063.jpg20170; Compound (v) has the structure: JPEG0007805356000064.jpg44170, and Compound 1 has the structure: JPEG0007805356000065.jpg45170.

[0286] The reaction rate may be monitored for completion by appropriate in-process testing methods as described elsewhere herein.

[0287] The base for preparing the compound of Formula I can include any suitable base. In some embodiments, the base is selected from carbonates, phosphates, tertiary amines, cyclic amidines, and guanidines. In some such embodiments, the base is a cyclic amidine. In one embodiment, the base is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,1,3,3-tetramethylguanidine (TMG), or 1,5-diazabicyclo[4.3.0]non-5-ene (DBN). In some embodiments, the base is DBU or TMG. In some embodiments, the base is a combination of DBU, TMG, or DBN with at least one of N,N-diisopropylethylamine (iPrEtN), trimethylamine (EtN), 1,4-diazabicyclo[2.2.2]octane (DABCO), or 2,6-lutidine.

[0288] The solvent for preparing Compound I may suitably comprise at least one polar aprotic solvent, at least one nonpolar solvent, at least one solvent base, or a combination thereof. In some embodiments, the solvent is selected from nonpolar solvents such as alkylaromatic or haloaromatic solvents, secondary amines, tertiary amines, and combinations thereof. In some embodiments, the solvent is selected from dimethyl sulfoxide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, acetonitrile, and combinations thereof. In one embodiment, the base can also function as the solvent. In such an embodiment, the base / solvent is a dialkylamine such as diethylamine, di-n-propylamine, di-isopropylamine, di-n-butylamine, or tri-n-butylamine. In such an embodiment, the base / solvent is di-n-butylamine.

[0289] In some embodiments, the solvent is selected from toluene, anisole, and mesitylene. In some such embodiments, the solvent is mesitylene. In some embodiments, the solvent is selected from the group consisting of toluene, anisole, mesitylene, diethylamine, di-n-propylamine, di-isopropylamine, di-n-butylamine, and combinations thereof. In some embodiments, the solvent comprises a combination of (i) toluene, anisole, or mesitylene with (ii) a dialkylamine, such as diethylamine, di-n-propylamine, di-isopropylamine, di-n-butylamine, or tri-n-butylamine. The base is DBU or DBN, or DBU or DBN, in combination with an organic base such as iPrEtN or EtN, and the equivalent ratio of base to (v) is from about 1.9:1 to about 2.8:1, or from about 2.2:1 to about 2.6:1, for example, about 1.9:1, about 2:1, about 2.1:1, about 2.2:1, about 2.3:1, about 2.4:1, about 2.5:1, about 2.6:1, about 2.7:1, or about 2.8:1.

[0290] In some embodiments, the base is also the solvent and is di-n-butylamine or tri-n-butylamine. In some such embodiments, the base / solvent is di-n-butylamine. In such embodiments, an additional base may be used. In such embodiments, the additional base may be DBU or DBN in combination with an organic base such as iPrEtN or EtN, or DBU or DBN, and the equivalent ratio of base to (v) is about 1.3:1 to about 2.1:1, or about 1.5:1 to about 1.9:1, e.g., about 1.3:1, about 1.4:1, about 1.5:1, about 1.6:1, about 1.7:1, about 1.8:1, about 1.9:1, about 2:1, or about 2.1:1.

[0291] In some embodiments, if Compound I is dissolved in the reaction product mixture, the method may further include precipitating Compound I therefrom by adding at least one anti-solvent to form a slurry or suspension of Compound I. In some embodiments, the anti-solvent is selected from water, alcohol, and combinations thereof. In some embodiments, the anti-solvent is an alcohol. In one such embodiment, the anti-solvent is n-propanol or i-propanol. The anti-solvent may be added while mixing at the reaction temperature or at a lower temperature. After the addition of the anti-solvent, the reaction product mixture may be cooled while mixing and aged at a suitable temperature to produce a slurry of the compound of Formula I. For example, cooling may be to about 50°C, about 45°C, about 40°C, about 35°C, about 30°C, or below room temperature, e.g., about 20°C, about 15°C, about 10°C, or about 5°C. In such embodiments, solid Compound I may be isolated by methods known in the art, such as filtration and / or centrifugation. The solid Compound I may be washed after isolation. Washing can be carried out using the reaction solvent, an anti-solvent, or a solvent in which compound (v) is poorly soluble. Solid compound (v) can be dried by methods known in the art, for example, under reduced pressure.

[0292] In some embodiments, Compound I produced by this process is amorphous free base. In some embodiments, Compound I produced by this process is crystalline free base. The crystalline form of the free base of Compound I is identified herein as polymorphic Form A. A representative XRPD pattern of polymorphic Form A is shown in Figure 1. In embodiments, the crystalline polymorph of Compound I can be crystalline polymorphic Form A of Compound I. Crystalline polymorph Form A may have an X-ray powder diffraction pattern that includes two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, or all of the peaks at about 7.7±0.3, 12.1±0.3, 16.2±0.3, 16.4±0.3, 16.6±0.3, 17.1±0.3, 18.8±0.3, 19.4±0.3, 19.8±0.3, 20.3±0.3, 20.5±0.3, 23.3±0.3, 24.7±0.3, 25.3±0.3, and 26.5±0.3 degrees 2θ. In embodiments, the X-ray powder diffraction pattern may include two, three, four, or five peaks at approximately 7.7±0.3, 18.8±0.3, 19.8±0.3, 24.7±0.3, and 26.5±0.3 degrees 2θ. In embodiments, the X-ray powder diffraction pattern comprises peaks at two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, or all of the peaks at about 7.7±0.3, 12.1±0.3, 16.2±0.3, 16.4±0.3, 16.6±0.3, 17.1±0.3, 18.8±0.3, 19.4±0.3, 19.8±0.3, 20.3±0.3, 20.5±0.3, 23.3±0.3, 24.7±0.3, 25.3±0.3, and 26.5±0.3 degrees 2θ. In embodiments, the X-ray powder diffraction pattern of Form A is substantially similar to the XRPD pattern shown in FIG. In embodiments, the X-ray powder diffraction pattern of Form A is substantially similar to at least one of the XRPD patterns shown in FIG.

[0293] Purification of Compound I is within the scope of the present disclosure. For example, but not limited to, purification by solvent exchange of the reaction product mixture; solution washing; extraction; precipitation, isolation and washing; crystallization; chromatographic purification such as HPLC, ion exchange, or exclusion; and combinations thereof are contemplated in the present disclosure.

[0294] In some embodiments, the process for preparing Compound I is carried out without additional chromatographic purification steps, solvent exchange steps, or both. In some embodiments, Compound I can be purified by a crystallization process described herein.

[0295] In embodiments, the yield of Compound I from the disclosed methods is at least 65%, at least 70%, or at least 75%, based on Compound (v). In embodiments, the purity of Compound I from the reaction steps of the present disclosure, as determined by HPLC, is at least 98 area%, at least 98.5 area%, at least 99 area%, or at least 99.5 area%.

[0296] Among other advantages, compared to prior art methods, the process for preparing compound I allows for a reduction in the molar ratio of compound (v) to compound (vi) while maintaining or improving yield and providing high purity. In embodiments, the reduction in the molar ratio of compound (v) to compound (vi) is less than 1:2 (e.g., about 1:1.5).

[0297] Among other advantages, compared to prior art methods, the process for preparing Compound I further allows for increased reactant concentrations while maintaining or improving yield and providing high purity. In some embodiments, the reactant concentration is increased by an order of about three-fold. Among other advantages, compared to prior art methods, a purification step may be eliminated while maintaining or improving yield and providing high purity. Furthermore, the present method allows for the replacement of the prior art NMP solvent, which is a substance of very high concern (SVHC) such that its use in the European Union is subject to authorization under the REACH regulation. Crystallization of Compound I

[0298] Compound I prepared by the methods of the present disclosure is characterized by high purity. However, further purification may be achieved by crystallization of Compound I.

[0299] In any of the various embodiments of the present disclosure, Compound I can be prepared according to the following scheme: Further purification may be achieved by crystallization according to JPEG0007805356000066.jpg51170.

[0300] The disclosed scheme involves dissolving Compound I in a solvent, filtering the resulting solution, seeding and cooling the solution to form crystals, and isolating the crystallized product.

[0301] In the first step, compound I prepared from compound (v) and compound (vi) is referred to as crude compound I. Crude compound I is dissolved in a solvent at a temperature below the boiling point of the solvent to form a solution. The solvent may be a polar aprotic solvent such as a ketone. In embodiments, the solvent is acetone, methyl ethyl ketone (MEK), or methyl isobutyl ketone (MIBK). In embodiments, the solvent is MIBK. The solution has a saturation temperature about 5°C to about 10°C lower than the dissolution temperature. In embodiments, the dissolution temperature is appropriately lower than the boiling point of the solvent, for example, about 5°C, about 10°C, about 15°C, about 20°C, or about 25°C lower than the boiling point of the solvent.

[0302] The solution of Compound I can then be filtered through a polishing filter at a temperature above the saturation temperature. Polishing filters are known in the art and generally have a pore size rating of about 5 μm or less, such as about 4 μm, about 3 μm, about 2 μm, about 1 μm, about 0.5 μm, or about 0.2 μm. Non-limiting examples of such filters include polytetrafluoroethylene (PTFE) membranes, sintered metal, polypropylene, nylon, and glass microfiber filters.

[0303] In some embodiments, activated carbon filtration may be performed before abrasive filtration. Activated carbon filtration is known in the art and involves contacting a liquid mixture with activated carbon particles (e.g., powder), which are characterized by a porous microstructure and a large internal surface area. Certain dissolved substances, such as impurities, are primarily removed from the liquid by adsorption. Activated carbon may be added to the liquid mixture and subsequently filtered, or the liquid mixture may be filtered through an activated carbon bed, or a combination of these techniques may be used. Non-limiting examples of activated carbon include Norit® SXPlus, DARCO® KB, and DARCO® G-60.

[0304] After filtration, the solution of Compound I may be seeded with crystalline Compound I free base, polymorph Form A. In some embodiments, dry seed crystals may be used. In some embodiments, the seed crystals may be slurried in a solvent, such as the same solvent used to dissolve the compound of Formula I, at an appropriate temperature, for example, about room temperature. The solution of Compound I is cooled to below the saturation point, at which point the seed crystal slurry is added. The suspension may be aged at the seed crystal addition temperature.

[0305] The seed crystals may be crushed or uncrushed. In some embodiments, the seed crystals may be characterized by a particle size distribution. For example, in some embodiments, the diameter of the particle sphere ("D(v,0.1)") below which 10% of the particles in a sample are smaller by volume is suitably about 0.5 μm, about 1 μm, about 2 μm, about 3 μm, about 4 μm, about 5 μm, about 6 μm, about 7 μm, about 8 μm, about 9 μm, about 10 μm, or greater, and any ranges derived therefrom, such as about 0.5 μm to about 10 μm, about 1 μm to about 8 μm, or about 1 μm to about 5 μm. In some embodiments, the diameter of the particle sphere below which 50% of the particles in a sample are smaller by volume ("D(v,0.5)") is suitably about 2 μm, about 4 μm, about 10 μm, about 15 μm, about 20 μm, about 25 μm, or greater, and any range constructed therefrom, such as about 2 μm to about 25 μm, about 4 μm to about 20 μm, about 4 μm to about 15 μm, or about 4 μm to about 10 μm. In some embodiments, the diameter of the particle sphere below which 90% of the particles in a sample are smaller by volume ("D(v,0.9)") is suitably about 5 μm, about 10 μm, about 15 μm, about 20 μm, about 25 μm, about 30 μm, about 35 μm, about 40 μm, about 45 μm, about 50 μm, about 55 μm, about 60 μm, about 65 μm, about 70 μm, about 75 μm, about 80 μm, about 85 μm, about 90 μm, about 95 μm, about 100 μm, or more, and any range therein, e.g., about 5 μm to about 100 μm, about 10 μm to about 80 μm, about 10 μm to about 30 μm, or about 60 μm to about 80 μm. In some embodiments, the seed loading is suitably about 0.1 wt%, about 0.25 wt%, about 0.5 wt%, about 0.75 wt%, about 1 wt%, about 1.5 wt%, about 2 wt%, about 2.5 wt%, about 3 wt%, about 3.5 wt%, or about 4 wt%, or greater, and any range derived therefrom, such as about 0.1 wt% to about 4 wt%, about 1 wt% to about 3 wt%, or about 1.5 wt% to about 2.5 wt%. In some embodiments, seed crystal size, size range, and loading outside the values ​​and ranges exemplified above are possible to provide crystallized Compound I in the desired size range.

[0306] The suspension may then be cooled to the final crystallization temperature while stirring. The final temperature is generally below 20°C, e.g., about 15°C, about 10°C, about 5°C, about 0°C, about -5°C, about -10°C, about -15°C, or even lower. The cooling rate may suitably be about 5°K / hour, about 7.5°K / hour, about 10°K / hour, about 12.5°K / hour, about 15°K / hour, about 17.5°K / hour, about 20°K / hour, or even higher. The aging time at the final temperature may suitably be 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, or more.

[0307] The crystallized solid Compound I can be isolated by methods known in the art, such as filtration and / or centrifugation. The solid Compound I can be washed after isolation. Washing can be performed using a cold dissolution solvent or a solvent that is considered non-reactive with the compound of Formula I. In some embodiments, the non-reactive solvent is, for example, an alcohol, such as i-propanol, ethanol, or methanol. Successive washes can be performed using the dissolution solvent and alcohol. The solid Compound I can be dried by methods known in the art, for example, under reduced pressure.

[0308] In some embodiments, the crystallized compound I can be milled using any suitable milling process, such as an impact mill, hammer mill, air mill, or jet mill, to achieve a suitable particle size. In some embodiments, the crystallized compound I is subjected to impact milling to achieve a D(v,0.1) particle size of about 2 μm, about 4 μm, about 6 μm, about 8 μm, about 10 μm, about 12 μm, about 14 μm, about 16 μm, about 18 μm, about 20 μm, about 25 μm, about 30 μm, or greater, and any ranges building therefrom, such as about 2 μm to about 30 μm, about 2 μm to about 20 μm, or about 4 μm to about 14 μm. In such embodiments, crystalline Compound I is subjected to impact milling to achieve a D(v,0.5) particle size of about 5 μm, about 10 μm, about 15 μm, about 20 μm, about 25 μm, about 30 μm, about 35 μm, about 40 μm, about 45 μm, about 50 μm, about 55 μm, about 60 μm, about 65 μm, about 70 μm, or greater, and any range derivable therefrom, e.g., about 5 μm to about 70 μm, about 10 μm to about 60 μm, about 10 μm to about 30 μm, about 10 μm to about 20 μm, about 30 μm to about 70 μm, or about 40 μm to about 60 μm. In such embodiments, crystalline Compound I is subjected to impact milling to achieve a D(v,0.9) particle size of about 30 μm, about 40 μm, about 50 μm, about 60 μm, about 70 μm, about 80 μm, about 90 μm, about 100 μm, about 110 μm, about 120 μm, about 130 μm, about 140 μm, about 150 μm, about 160 μm, about 170 μm, about 180 μm, about 190 μm, about 200 μm, or greater, and any ranges derived therefrom, e.g., about 30 μm to about 200 μm, about 40 μm to about 150 μm, about 40 μm to about 100 μm, about 40 μm to about 80 μm, or about 100 μm to about 160 μm. In some embodiments, the particle size range of Compound I can be outside the values ​​and ranges exemplified above.

[0309] The crystallized Compound I can be analytically characterized. For example, in some embodiments, the water content by Karl Fischer can be less than 0.1% by weight; the heavy metal content by, for example, inductively coupled plasma mass spectrometry ("ICP-MS") can be less than 20 ppm; the sum of all organic impurities by HPLC can be less than 0.1% by area or less than 0.05% by area; and the purity by HPLC can be at least 98% by area, at least 98.5% by area, at least 99% by area, at least 99.5% by area, at least 99.8% by area, 99.9% by area, or 100% by area. The yield of Compound I in the crystallization process is at least 80%, at least 85%, or at least 90%.

[0310] Crystalline Compound I is a free base. In some embodiments, the crystal can be characterized as having a needle-like / rod-like morphology. In some embodiments, the crystal can be characterized as having a prism-like morphology. In some embodiments, the crystal is polymorph A.

[0311] In some such embodiments, Compound I is the species 5-(6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(3,3-difluoropyrrolidin-1-yl)pyrimidin-4-yl)-3-(difluoromethoxy)pyridin-2-amine of the following structure: It is named JPEG0007805356000067.jpg50170.

[0312] In one embodiment, the dissolution solvent is MIBK. The solubility of the free base of Compound I in MIBK is about 8.2 wt% at about 90°C, about 5.2 wt% at 80°C, about 4 wt% at 70°C, about 3 wt% at 60°C, about 2 wt% at 50°C, about 1.4 wt% at 40°C, about 1 wt% at 30°C, about 0.9 wt% at 20°C, about 0.6 wt% at 10°C, about 0.4 wt% at 0°C, and about 0.2 wt% at -10°C. In some embodiments, a 6.5 wt% to 7.5 wt% solution of the free base of Compound I in MIBK is formed at 90°C. After filtration at about 90°C and seed crystals are added to form a slurry, the solution is cooled to about 75°C and optionally held (aged) at that temperature for a period of about 0.5 to about 2 hours. The slurry may then be cooled, for example, to about -10°C and aged at that temperature for a period of time, such as about 2 to about 10 hours. The solid crystalline Compound I may be isolated and washed with chilled MIBK (e.g., about 0°C to about 10°C) followed by chilled alcohol, such as ethanol (e.g., about 0°C to about 10°C). The crystalline Compound I may be dried under reduced pressure (e.g., about 20 mbar or less) at a temperature of about 40°C to about 70°C (e.g., 60°C) until a constant weight is achieved.

[0313] Preparation of sulfone compound (iii) In some embodiments, the methods of the present disclosure further comprise the preparation of sulfone compound (iii).

[0314] In one such embodiment, sulfone compound (iii) can be prepared according to the first process scheme.

[0315] In the first step of the first method scheme, According to JPEG0007805356000068.jpg41170, the halogen atom is substituted from the dihalothiopyrimidine compound (i) using a 3- to 12-membered amine-containing heterocycloalkyl compound (vii) under basic conditions in a solvent to obtain an alkylthio compound (ii).

[0316] In the second step of the first method scheme, According to JPEG0007805356000069.jpg37170, the alkylthio compound (ii) is treated with at least one oxidizing agent in a solvent to give the sulfone oxide compound (iii).

[0317] In some embodiments, the solvent for the step of preparing alkylthio compound (ii) is suitably a polar organic solvent. In some embodiments, the solvent for the reaction is selected from dimethyl sulfoxide, dimethylformamide, N,N-dimethylacetylamide, N-methyl-2-pyrrolidone, acetonitrile, methanol, ethanol, n-propanol, i-propanol, n-butanol, cyclohexanol, tetrahydrofuran, 2-Me-tetrahydrofuran, ethyl acetate, n-propyl acetate, i-propyl acetate, and mixtures thereof. In some such embodiments, the solvent is an alcohol. In some such embodiments, the solvent is selected from dimethyl sulfoxide, acetonitrile, methanol, and ethanol. In some embodiments, the solvent is methanol or ethanol. In some embodiments, the solvent is ethanol.

[0318] In some embodiments, the base is selected from carbonates, bicarbonates, phosphates, tertiary amines, and cyclic amidines. In some such embodiments, the base is a tertiary amine. In some such embodiments, the base is iPrEtN or EtN. In some such embodiments, the base is EtN. In some embodiments, the ratio of equivalents of base to compound (vii) is about 1.5:1, about 2:1, about 2.1:1, about 2.2:1, about 2.3:1, about 2.4:1, about 2.5:1, about 2.6:1, about 2.7:1, about 2.8:1, about 2.9:1, about 3:1, about 3.5:1, or about 4:1, and any range therein, such as about 1.5:1 to about 4:1, about 1.5:1 to about 3:1, about 2:1 to about 3:1, or about 2.2:1 to about 2.6:1.

[0319] In some embodiments, the concentration of compound (i) in the reaction mixture can suitably be about 25 g / L, about 50 g / L, about 75 g / L, about 100 g / L, about 125 g / L, about 150 g / L, about 175 g / L, or about 200 g / L, and any range built therein, e.g., from about 25 g / L to about 200 g / L, from about 50 g / L to about 175 g / L, or from about 75 g / L to about 125 g / L. On a moles / liter basis, the concentration may suitably be about 0.1 mol / L, about 0.15 mol / L, about 0.2 mol / L, about 0.25 mol / L, about 0.3 mol / L, about 0.35 mol / L, about 0.4 mol / L, about 0.45 mol / L, about 0.5 mol / L, about 0.55 mol / L, about 0.6 mol / L, about 0.65 mol / L, about 0.7 mol / L, about 0.75 mol / L, about 0.8 mol / L, about 0.85 mol / L, about 0.9 mol / L, about 0.95 mol / L, or about 1 mol / L, and any range therein, such as about 0.1 mol / L to about 1 mol / L, about 0.2 mol / L to about 0.75 mol / L, or about 0.4 mol / L to about 0.75 mol / L.

[0320] The molar ratio of compound (i) to compound (vii) is suitably about 1:1.01, about 1:1.05, about 1:1.1, about 1:1.11, about 1:1.12, about 1:1.13, about 1:1.14, about 1:1.15, about 1:1.2, about 1:1.25, about 1:1.3, about 1:1.35, about 1:1.4, about 1:1.45, or about 1:1.5, and any range therein, for example, 1:1.01 to 1:1.5, 1:05 to 1:1.3, or 1:10 to 1:1.14. The molar ratio of compound (i) to base is suitably about 1:1.5, about 1:2, about 1:2.1, about 1:2.2, about 1:2.3, about 1:2.4, about 1:2.5, about 1:2.6, about 1:2.7, about 1:2.8, about 1:2.9 or about 1:3, and any range therein, for example, from about 1:1.5 to about 1:3, from about 1:2 to about 1:2.8 or from about 1:2.2 to about 1:2.6.

[0321] The reaction temperature is suitably about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 60°C, about 65°C, about 70°C, or about 75°C, and any range derived therefrom, such as about 10°C to about 75°C, about 20°C to about 70°C, about 25°C to about 60°C, about 25°C to about 50°C, or about 30°C to about 40°C. The base may be added over a period of about 0.5 to about 4 hours. The reaction mixture may be aged at the reaction temperature for a period of time, preferably to complete the reaction and form a reaction product mixture containing compound (ii).

[0322] In some embodiments, compound (ii) precipitates from solution in the reaction product mixture upon its formation. In some such embodiments, water may be added to the cooled reaction product mixture to dissolve the water-soluble salt. The precipitated compound (ii) may be isolated by drying or centrifugation and optionally washed. In some embodiments, compound (ii) may be washed with cold alcohol (e.g., methanol or ethanol), cold water, or a combination thereof. The isolated compound (ii) may be dried.

[0323] In some embodiments, the process for preparing compound (ii) is carried out without additional purification steps as described elsewhere herein. In some such embodiments, the process for preparing compound (ii) is carried out without a chromatographic purification step, a solvent exchange step, or a combination thereof. Advantageously, the present method for preparing compound (ii) may be suitably carried out in an alcoholic solvent such as ethanol, thereby allowing for the removal of certain solvents identified as SVHCs, such as DMF, used in prior art methods.

[0324] The yield of compound (ii) based on compound (i) is at least 80%, at least 85%, at least 90%, or at least 94%. The purity of compound (ii) by HPLC is at least 98 area%, at least 98.5 area%, at least 99 area%, at least 99.5 area%, or at least 99.9 area%.

[0325] Among other advantages, compared to prior art methods, the first step of the first method scheme for preparing compound (ii) allows for the replacement of a toxic solvent (e.g., dimethylformamide) with a less toxic solvent, and allows for the elimination of a chromatography step, while maintaining or improving yield and providing high purity.

[0326] In the second step for preparing compound (iii) according to the first method scheme, in some embodiments, the solvent is suitably a polar organic solvent. In some embodiments, the solvent can be a combination of a polar organic solvent and water. In some embodiments, the solvent is selected from dimethyl sulfoxide, dimethylformamide, N,N-dimethylacetylamide, N-methyl-2-pyrrolidone, acetonitrile, methanol, ethanol, n-propanol, i-propanol, n-butanol, cyclohexanol, hexane, toluene, tetrahydrofuran, 2-Me-tetrahydrofuran, ethyl acetate, n-propyl acetate, i-propyl acetate, and mixtures thereof. In some such embodiments, the solvent is an alcohol. In some such embodiments, the solvent is methanol or ethanol, optionally further combined with water. When present in combination with water, the volume ratio of organic solvent to water is suitably about 10:1, 5:1, about 4:1, about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, or about 1: 10. In some particular embodiments, the ratio of water to ethanol is about 5:1, about 2:1, about 1:1, about 1:2, or about 1:5.

[0327] The concentration of compound (ii) in the reaction mixture is suitably about 10 g / L, about 25 g / L, about 50 g / L, about 75 g / L, about 100 g / L, or about 125 g / L, and any range built therein, for example, from about 10 g / L to about 125 g / L, from about 25 g / L to about 100 g / L, or from about 50 g / L to about 75 g / L. On a moles / liter basis, the concentration may suitably be about 0.05 moles / L, about 0.1 moles / L, about 0.15 moles / L, about 0.2 moles / L, about 0.25 moles / L, about 0.3 moles / L, about 0.35 moles / L, about 0.4 moles / L, about 0.45 moles / L, or about 0.5 moles / L, and any range therein, for example, about 0.05 moles / L to about 0.5 moles / L, about 0.1 moles / L to about 0.4 moles / L, or about 0.2 moles / L to about 0.3 moles / L.

[0328] The at least one oxidizing agent may be selected from peracids or salts thereof, peroxides, peroxysulfuric acid or salts thereof, hypochlorides, tungstates, molybdates, and combinations thereof. In some embodiments, the oxidizing agent may be a tungstate, such as sodium tungstate dihydrate. In some embodiments, the oxidizing agent is a peroxide, such as hydrogen peroxide. In some embodiments, the oxidizing agent is a combination of a tungstate and a peroxide, for example, sodium tungstate dihydrate and hydrogen peroxide. Metal-based oxidizing agents (catalysts) (e.g., tungstates or molybdates) may be considered oxidation catalysts. In the case of a metal-based oxidizing agent, the content may be suitably about 0.25 mol%, about 0.5 mol%, about 0.75 mol%, about 1 mol%, about 1.25 mol%, about 1.5 mol%, about 1.75 mol%, about 2 mol%, about 2.5 mol%, about 3 mol%, about 3.5 mol%, about 4 mol%, about 4.5 mol%, about 5 mol%, about 5.5 mol%, about 6 mol%, about 6.5 mol%, about 7 mol%, or about 7.5 mol%, and any range consisting thereof, for example, about 0.25 mol% to about 7.5 mol%, about 0.25 mol% to about 5 mol%, about 0.25 mol% to about 2 mol%, about 0.5 mol% to about 1.5 mol%, or about 0.75 mol% to about 1.25 mol%, on a molar basis based on the content of compound (ii). For other oxidizing agents (e.g., peroxides), the ratio of equivalents of compound (ii) to oxidizing agent is suitably about 1:1.5, about 1:2, about 1:2.1, about 1:2.2, about 1:2.3, about 1:2.4, about 1:2.5, about 1:2.6, about 1:2.7, about 1:2.8, about 1:2.9, or about 1:3, and any range therein, such as about 1:1.5 to about 1:3, about 1:2 to about 1:2.8, or about 1:2.2 to about 1:2.6.

[0329] The reaction temperature is suitably about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, or about 90°C, and any range built therein, for example, about 30°C to about 90°C, about 40°C to about 80°C, about 50°C to about 70°C, or about 55°C to about 65°C. In ethanol and water embodiments, the reaction temperature typically does not exceed 65°C.

[0330] In some embodiments, compound (ii) is mixed with a solvent and a metal-based oxidizing agent (catalyst) with stirring to form a suspension. The suspension is heated to a reaction temperature, and another oxidizing agent (e.g., a peroxide) is added over a period of time, such as about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, or about 8 hours, at the reaction temperature. The reaction mixture may be aged for a period of time at the reaction temperature, preferably to complete the reaction and form a reaction product mixture containing compound (ii).

[0331] In some embodiments, the oxidizing agent in the reaction product mixture containing compound (iii) can be quenched. In some such embodiments, the quencher is sulfite, hydrogen sulfite, or thiosulfate. In one embodiment, the quencher is sodium bisulfite. In some embodiments, the molar ratio of compound (iii) to quencher is suitably about 1.2:1, about 1.1:1, about 1:1.1, or about 1:1.2.

[0332] In some embodiments, compound (iii) precipitates from solution in the reaction product mixture upon formation. The precipitated compound (iii) may be isolated by drying or centrifugation and optionally washed. In some embodiments, compound (iii) may be washed with cold water. The isolated compound (iii) may be dried.

[0333] In some embodiments, the process for preparing compound (iii) is carried out without an additional purification step. In some such embodiments, the process for preparing compound (iii) is carried out without a chromatographic purification step, a solvent exchange step, or a combination thereof.

[0334] The yield of sulfone compound (iii) based on compound (ii) is at least 80%, at least 85%, at least 90%, or at least 94%. The purity of sulfone compound (iii) by HPLC is at least 98 area%, at least 98.5 area%, at least 99 area%, at least 99.5 area%, or at least 99.9 area%.

[0335] Among other advantages, compared to prior art processes, the second step of the first process scheme for preparing compound (iii) allows for the replacement of a toxic solvent (e.g., dichloromethane) with a less toxic solvent that is ecologically more benign; allows for the replacement of a toxic oxidizing agent (e.g., meta-chloroperbenzoic acid) with a safer, less toxic oxidizing agent that can be used in solvent systems that include water; avoids the production of toxic by-products such as chlorobenzoic acid; allows for an increase in reactant concentration; and allows for the elimination of a solvent stripping step while maintaining or improving yield and providing high purity.

[0336] In some embodiments, compounds (i), (vii), (ii), and (iii) are selected from the following: The image is as follows: JPEG0007805356000070.jpg38170.

[0337] In another such embodiment, sulfone compound (iii) can be prepared according to a second process scheme.

[0338] In the first step of the second method scheme, the following scheme is used: According to JPEG0007805356000071.jpg37170, alkylthio compound (i) is treated with at least one oxidizing agent in a solvent to give a mixture of sulfone oxide compounds (viii).

[0339] In the second step of the second method scheme, the following scheme is used: According to JPEG0007805356000072.jpg40170, the halogen atom from sulfone compound (viii) is replaced with 3- to 12-membered amine-containing heterocycloalkyl compound (vii) under basic conditions in a solvent to form a mixture of sulfone compound (iii) and regioisomeric compound (iiia).

[0340] In some embodiments, the solvent for forming compounds (viii), (iii), and (iiia) is a polar solvent. In some such embodiments, the solvent is selected from dimethyl sulfoxide, dimethylformamide, N,N-dimethylacetylamide, N-methyl-2-pyrrolidone, acetonitrile, methanol, ethanol, n-propanol, i-propanol, n-butanol, cyclohexanol, tetrahydrofuran, 2-Me-tetrahydrofuran, ethyl acetate, n-propyl acetate, i-propyl acetate, and mixtures thereof. In some embodiments, the solvent is an alcohol. In some embodiments, the solvent is methanol or ethanol.

[0341] The at least one oxidizing agent for forming compound (viii) is as described elsewhere herein for preparing compound (iii) from compound (ii). The content of the metal-based oxidizing agent (catalyst) based on compound (i) is generally the same as the content based on compound (ii) described elsewhere herein. The equivalent ratio of other oxidizing agents (e.g., peroxides) based on compound (i) is generally the same as the equivalent ratio based on compound (ii) described elsewhere herein.

[0342] The concentrations and conditions of the oxidation reaction for preparing compound (viii), such as temperature, reagent addition scheme, reaction time, and reaction quench, are generally comparable to the reaction concentrations and conditions for preparing compound (iii) from compound (ii) described elsewhere herein.

[0343] The isolation and subsequent processing of compound (viii) is generally equivalent to the isolation and processing steps for preparing compound (iii) from compound (ii).

[0344] In some embodiments, the process for preparing compound (viii) is carried out without an additional purification step, hi some such embodiments, the process for preparing compound (viii) is carried out without a chromatographic purification step, a solvent exchange step, or a combination thereof.

[0345] The yield of sulfone compound (viii) is at least 50%, at least 55%, at least 60%, at least 65%, or at least 70%. The purity of sulfone compound (viii) by HPLC is at least 98 area%, at least 98.5 area%, at least 99 area%, at least 99.5 area%, or at least 99.8 area%.

[0346] In another such embodiment, sulfone compound (iii) can be prepared according to a third process scheme as follows: It can be prepared according to JPEG0007805356000073.jpg42170.

[0347] In some embodiments, the solvent for forming compounds (xi) and (iii) is a polar solvent. In some such embodiments, the solvent is selected from dimethyl sulfoxide, dimethylformamide, N,N-dimethylacetylamide, N-methyl-2-pyrrolidone, acetonitrile, methanol, ethanol, n-propanol, i-propanol, n-butanol, cyclohexanol, tetrahydrofuran, 2-Me-tetrahydrofuran, ethyl acetate, n-propyl acetate, i-propyl acetate, water, and mixtures thereof. In some embodiments, the solvent is alcohol and water. In some embodiments, the solvent is methanol or ethanol and water, or methanol-water. The concentration of compound (ii) in the solvent is suitably about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, about 10% by weight, about 11% by weight, or about 12% by weight, or any range derived therefrom, such as about 5% by weight to about 12% by weight, or about 5% by weight to about 10% by weight.

[0348] Metal-based oxidizing agents (catalysts) (eg, tungstates or molybdates) may be considered oxidation catalysts. In the case of a metal-based oxidizing agent, the content can be suitably about 0.25 mol%, about 0.5 mol%, about 0.75 mol%, about 1 mol%, about 1.25 mol%, about 1.5 mol%, about 1.75 mol%, about 2 mol%, about 2.5 mol%, about 3 mol%, about 3.5 mol%, about 4 mol%, about 4.5 mol%, about 5 mol%, about 5.5 mol%, about 6 mol%, about 6.5 mol%, about 7 mol%, or about 7.5 mol%, and any range therein, such as about 0.25 mol% to about 7.5 mol%, about 0.25 mol% to about 5 mol%, about 0.25 mol% to about 2 mol%, about 0.5 mol% to about 1.5 mol%, or about 0.75 mol% to about 1.25 mol%, based on the molar content of compound (ii). In some embodiments, the oxidation catalyst is Na2WO4·2H2O. In some such embodiments, Na2WO4·2H2O is in methanol and water. In such embodiments, the molar ratio of compound (ii) to catalyst can be about 0.005:1, about 0.01:1, about 0.02:1, about 0.03:1, about 0.04:1, or about 0.05:1, and any range constructed therein, e.g., from about 0.005:1 to about 0.05:1, from about 0.005:1 to about 0.02:1.

[0349] In some embodiments, the molar ratio of HO to compound (ii) is about 1.5:1, about 2:1, about 2.2:1, about 2.4:1, about 2.6:1, about 2.8:1, about 3:1, about 3.2:1, about 3.4:1, about 3.6:1, about 3.8:1, or about 4:1, and any ranges derived therefrom, such as about 2:1 to about 4:1, about 2:1 to about 3:1, about 2.4:1 to about 3.4:1, or about 2.6:1 to about 3.2:1. In some embodiments, HO may be added to the reaction over a period of about 2 hours to about 10 hours, about 3 hours to about 8 hours, or about 4 hours to about 6 hours. In some embodiments, HO may be added in two or more additions over the course of the reaction, or may be added continuously. In some embodiments, about 1.5, about 2, or about 2.5 equivalents of HO are added within the first 3 hours of the reaction. In any of various embodiments, the addition of HO can be controlled to maintain HO accumulation in the reactor at less than 10%, less than 5%, or less than 3%. In some such embodiments, the reaction temperature is suitably about 50°C, about 55°C, about 60°C, about 65°C, or about 70°C, and any range building therefrom, e.g., about 50°C to about 70°C, or about 55°C to about 65°C. In any of various embodiments, the reaction can be aged for about 5 hours, about 10 hours, or about 15 hours. In any of various embodiments, the final residual sulfoxide intermediate is less than 1%, e.g., about 0.5%, about 0.4%, or about 0.3%.

[0350] In some particular embodiments, compound (ii) is compound 11, disclosed elsewhere herein, and compound (iii) is compound 16, disclosed elsewhere herein and reproduced below. JPEG0007805356000074.jpg39170

[0351] Among other advantages, compared to prior art methods, the first step of the second process scheme for preparing compound (vii) allows for the use of relatively non-toxic, relatively environmentally friendly, and sustainable solvents, allows for the use of relatively non-toxic, relatively environmentally friendly oxidizing agents, and allows for high reactant concentrations while maintaining or improving yields and providing high purity.

[0352] The second step, reacting compounds (vii) and (viii) to form compound (iii) and its regioisomer compound (iiia), generally corresponds to the reaction of reacting compounds (i) and (vii) to form compound (ii), as described elsewhere herein. More specifically, the base, the molar ratio of compound (viii) to compound (vii), the molar ratio of compound (viii) to base, the concentration of compound (viii) in the reaction mixture, the reaction temperature, and the base addition scheme generally correspond to the reaction conditions for the preparation of compound (ii) described elsewhere herein.

[0353] In some embodiments, compound (iii) and regioisomer (iiia) precipitate from solution in the reaction product mixture upon formation. The molar ratio of compound (iii) to compound (iiia) is about 3:1 to about 20:1, about 5:1 to about 15:1, or about 10:1. Based on experimental evidence to date, regioisomer (iiia) is believed to have significantly higher solubility in the solvent mixture compared to sulfone compound (iii). Therefore, compound (iiia) can be effectively separated from compound (iii) during the isolation and washing steps. Accordingly, in some such embodiments, water can be added to the cooled reaction product mixture to dissolve water-soluble salts and a disproportionate amount of regioisomer (iiia) relative to compound (iii). The molar ratio of solid compound (iii) to solid compound (iiia) in the slurry is at least 50:1, at least 75:1, at least 90:1, or at least 95:1. The precipitated compound (iii) can be isolated by drying or centrifugation and optionally washed. In some embodiments, compound (iii) may be washed with cold water. The isolated compound (iii) may be dried.

[0354] The reaction of compound (vii) and compound (viii) provides a yield of compound (iii) of at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, or at least 75%, based on compound (viii). The purity of compound (iii) produced by the reaction as determined by HPLC is at least 97 area%, at least 97.5 area%, at least 98 area%, at least 98.5 area%, at least 99 area%, or at least 99.5 area%.

[0355] In some embodiments, the process for preparing compound (iii) from compounds (vii) and (viii) is carried out without an additional purification step. In some such embodiments, the process for preparing compound (iii) is carried out without a chromatographic purification step, a solvent exchange step, or a combination thereof.

[0356] Among other advantages, compared to prior art methods, the first step of the process scheme for preparing compound (iii) from compounds (vii) and (viii) allows for the use of relatively non-toxic, relatively environmentally friendly, and sustainable solvents, avoiding the need for a purification step while maintaining yield and purity.

[0357] The first and second reaction schemes for preparing compound (iii) are represented by the formula (Ia): JPEG0007805356000075.jpg44170(R 1 , R 2 , R 3 , X 1 , X 2 , A and JPEG0007805356000076.jpg22170(C y ) are as defined elsewhere herein) The compound may be suitable for use in preparing a compound of formula (I).

[0358] In some embodiments, compounds (i), (viii), (vii), (iii), and (iiia) are: As shown in JPEG0007805356000077.jpg36170.

[0359] Preparation of Compound (iv) Species In some embodiments of the present disclosure, methods are provided for preparing compound (iva). The methods generally comprise steps A to D of the scheme detailed below: Proceed according to JPEG0007805356000078.jpg94170.

[0360] In Step A, a reaction mixture is formed comprising 2-nitropyridin-3-ol (Compound (17)), sodium 2-chloro-2,2-difluoroacetate (Compound (18)), a solvent, and a base, and reacted to form a reaction product mixture comprising 3-(difluoromethoxy)-2-nitropyridine (Compound (19)) in solution.

[0361] The solvent for Step A is preferably a polar organic solvent or a polar aprotic solvent. An example of a suitable solvent is dimethylformamide (DMF). The base is preferably a strong base or a strong inorganic base. An example of a suitable base is an aqueous carbonate solution such as sodium carbonate or potassium carbonate. The reaction temperature may vary depending on the identity of the solvent. In the case of DMF, the reaction temperature may be above 50°C, for example, about 75°C, about 90°C, about 100°C, or about 110°C.

[0362] The reaction product mixture of Step A may be washed with a polar organic solvent or a polar aprotic solvent. An example of a suitable solvent is ethyl acetate. The polar aprotic solvent may optionally contain water. The reaction product mixture containing compound 19 in solution may optionally be washed with a brine solution. The reaction product mixture may be concentrated prior to Step B.

[0363] In Step B, the reaction mixture containing the solution of compound (19) is hydrogenated in the presence of a catalyst to form a reaction product mixture containing 3-(difluoromethoxy)pyridin-2-amine (compound (20)). The solvent in Step B can be a polar organic solvent or a polar aprotic solvent. An example of a suitable solvent is ethanol. The catalyst can suitably be a noble metal catalyst described herein. An example of a catalyst is palladium on carbon. The reaction temperature can vary depending on the identity of the solvent. In the case of ethanol, the reaction temperature can be greater than 25°C, for example, about 30°C, about 35°C, about 40°C, about 45°C, about 50°C, or even higher.

[0364] The reaction product mixture of step B can optionally be filtered through diatomaceous earth. A solvent exchange of the reaction product mixture to a polar organic solvent, such as a polar aprotic solvent, can also be performed. One example of a suitable solvent is methyl tert-butyl ether (MTBE). Solid compound (20) can optionally be formed in the reaction product mixture by the addition of an anti-solvent, such as a non-polar solvent. One example of a suitable anti-solvent is n-heptane. In such embodiments, solid compound (20) can be isolated and washed by filtration or centrifugation.

[0365] In Step C, a reaction mixture comprising compound (20), N-bromosuccinamide (NBS), and a polar aprotic solvent is reacted to form a reaction product mixture comprising 5-bromo-3-(difluoromethoxy)pyridin-2-amine (compound (21)). In some embodiments, the solvent is acetonitrile (ACN). The reaction mixture is reacted at a temperature below 20° C., for example, about 15° C., about 10° C., about 5° C., about 0° C., or less, to form a reaction product mixture comprising compound (21).

[0366] The reaction product mixture of step C may be washed with an aqueous acid and a solvent. The acid may suitably be a weak acid such as sodium bisulfite. The solvent may be a polar organic solvent, a non-polar solvent, or a combination thereof. In some embodiments, the washing solvent is a mixture of n-heptane and ethyl acetate. The reaction mixture of step C may be further washed with a brine solution and filtered with diatomaceous earth or the like. The resulting reaction product mixture containing compound (21) in solution may be concentrated in an aromatic solvent such as toluene.

[0367] In Step D, a reaction mixture is formed containing Compound (21), bis-pyne-diborane, and a noble metal catalyst in solution, which are reacted to form a reaction product mixture containing 3-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (Compound (iva)) in solution. The catalyst may suitably be a noble metal catalyst described elsewhere herein. An example of a catalyst is PdCl2(dppf) with a triphenylphosphine ligand. The solvent may suitably be the same solvent used in Step C, such as toluene. The reaction mixture may also contain potassium acetate or sodium acetate. The reaction mixture is reacted at a temperature of about 50°C, about 60°C, about 70°C, about 80°C, about 90°C, about 100°C, or about 110°C.

[0368] The reaction product mixture of step D containing compound (iva) in solution may be filtered through diatomaceous earth, and a slurry of compound (iva) may be formed by the addition of an anti-solvent. A suitable anti-solvent is a non-polar solvent such as n-heptane. The solid compound (iva) may be isolated by filtration or centrifugation, washed, and dried.

[0369] Alternatively, instead of isolating it as a solid, a solution of compound (iva) may be used as a reagent in subsequent reaction steps.

[0370] In some alternatives, step D may further comprise an additional purification step. For example, after filtration, the reaction product mixture containing compound (iva) in solution may be solvent-exchanged to a polar organic solvent. Examples of suitable solvents include TBME or MIBK. Then, aqueous maleic acid and a polar protic organic solvent may be added and aged for a suitable period of time at a temperature below 20°C, e.g., 10°C, to form a slurry of the maleate salt of compound (iva). Examples of polar aprotic solvents include alcohols such as ethanol or methanol. The maleate salt of compound (iva) may be isolated by filtration or centrifugation and washed with a nonpolar solvent (e.g., n-heptane). The isolated maleate salt of compound (iva) may then be dissolved in a solvent (e.g., toluene) and treated with a weak base (e.g., aqueous sodium bicarbonate) to form the free base of compound (iva). A slurry of compound (iva) may be formed by adding an anti-solvent (e.g., n-heptane) and cooling to below 10°C (e.g., -10°C). Compound (23) can be isolated by filtration or centrifugation, washed and dried.

[0371] In some embodiments, the reaction scheme for preparing compound (iva) is represented by formula (Ib): JPEG0007805356000079.jpg38170(R 3 , X 2 , Cy and A are as defined elsewhere herein. can be used to prepare compounds of formula (I).

[0372] In some embodiments of the present disclosure, compound (v) can be prepared according to the first scheme below: It can be prepared according to JPEG0007805356000080.jpg92170.

[0373] R 1 , R 2 , R 3 , R 5 , R 6 , X 1 and halo are as defined elsewhere herein. JPEG0007805356000081.jpg21170 corresponds to Cy as defined elsewhere herein. In step A, compound (ix) may be combined with a halogenating reagent in a solvent to form compound (x). Halogenating reagents are known in the art. Compound (x) may be isolated. In step B, compound (x) is borylated with a borylation reagent described herein to form a solution of compound (iv). Brylation reagents are known in the art. The borylation solvent and catalyst are as described herein. In step C, a reaction mixture is formed comprising a solution of compound (iv), compound (iii), a catalyst, a base, and a solvent. Compound (iii), a catalyst, a base, and a solvent are as described herein. Compounds (iii) and (iv) are reacted as described herein to form compound (v).

[0374] In some embodiments, steps B and C may be carried out in a one-pot manner.

[0375] In some embodiments, R 1 , R 2 and R 3 are H and X respectively. 1 is CR 4 where R 4 is -O-CHF2; halo is Br and the halogenating reagent is N-bromosuccinamide; borylation reagent is bis-pyrrolidone; R 5 and R 6 together form -C(CH3)2-C(CH3)2-.

[0376] In some embodiments, the first method scheme for preparing compound (v) comprises reacting compound (Ia) JPEG0007805356000082.jpg44170(R 1 , R 2 , R 3 , X 1 , A and JPEG0007805356000083.jpg21170(C y ) are as defined elsewhere herein) can be used to prepare

[0377] In some particular embodiments of the present disclosure, compound (va) is: It can be prepared according to the first scheme as follows: JPEG0007805356000084.jpg100170.

[0378] In some such embodiments, R 3 is H.

[0379] In some embodiments of the present disclosure, compound (v) can be prepared according to the following second scheme: It can be prepared according to JPEG0007805356000085.jpg53170.

[0380] R 1 , R 2 , R 3 , X 1 , R 5 , R 6 and borylation reagent is as defined elsewhere herein. JPEG0007805356000086.jpg22170 corresponds to Cy as defined elsewhere herein. A second alternative scheme relates to a method for preparing compound (v) by steps A and B. In step A, compound (ix) is directly borylated with a borylation reagent to form a solution of compound (iv). The borylation solvent is as described herein. The borylation catalyst may suitably be an iridium catalyst. In step B, a reaction mixture is formed comprising a solution of compound (iva), compound (iii), a catalyst, a base, and a solvent. Compound (iii), a catalyst, a base, and a solvent are as described herein. Compounds (iii) and (iv) are reacted as described herein to form compound (v).

[0381] In some embodiments, steps A and B may be carried out in a one-pot manner.

[0382] In some embodiments, R 1 and R2 are H and X respectively. 1 is CR 4 where R 4 is -O-CHF2; the borylation reagent is bis-pyrrolidone; R 5 and R 6 together form -C(CH3)2-C(CH3)2-.

[0383] In some embodiments, a second method scheme for preparing compound (v) comprises reacting compound (I): JPEG0007805356000087.jpg51170(R 1 , R 2 , R 3 , X 1 , Cy and A are as defined elsewhere herein. can be used to prepare

[0384] In some particular embodiments of the present disclosure, compound (va) can be prepared according to the second scheme as follows:

[0385] In some embodiments of the present disclosure, compound (va) is prepared according to the following second scheme: It can be prepared according to JPEG0007805356000088.jpg55170 In some such embodiments, R 3 is H.

[0386] In one particular embodiment of the present disclosure, compound 1 can be prepared by a four-step method as follows.

[0387] In the first step, as described elsewhere herein, According to JPEG0007805356000089.jpg36170, compound (vii) is reacted with compound (i) in the presence of a solvent and an organic base to form a reaction mixture containing compound (ii).

[0388] In some embodiments, the solvent is selected from the group consisting of dimethyl sulfoxide, acetonitrile, and ethanol. The equivalent ratio of the organic base to compound (vii) is about 2.2:1 to about 2.6:1, or about 2.4:1. In some such embodiments, the organic base is triethanolamine. In some such embodiments, the solvent is ethanol, and the reaction temperature is about 30°C to about 40°C.

[0389] In a second step, as described elsewhere herein, Compound (ii) is oxidized with hydrogen peroxide in the presence of sodium tungstate (Na2WO4) according to JPEG0007805356000090.jpg37170 to form a reaction product mixture containing compound (iii).

[0390] In some embodiments, hydrogen peroxide is added to the reaction product mixture from step (1), wherein the equivalent ratio of hydrogen peroxide to compound (ii) is about 2:1 to about 3.5:1, or about 3:1. In some embodiments, the hydrogen peroxide is added over a period of about 4 hours to about 6 hours. In some embodiments, about 2 equivalents of hydrogen peroxide are added during a first portion of the reaction, and the remaining hydrogen peroxide is added during a second portion of the reaction.

[0391] In some embodiments, the reaction temperature is from about 55°C to about 65°C.

[0392] In some embodiments, the sodium tungstate is a dihydrate. In some embodiments, the Na2WO4 is Na2WO4·2H2O in methanol and water.

[0393] In the third step, Suzuki coupling of compound (iii) with compound (iva) is carried out in the presence of an alkali metal carbonate base, a palladium catalyst, and a solvent, as described elsewhere herein, to form a reaction product mixture, compound (v). N-acetylcysteine ​​is added to the reaction product mixture to scavenge the palladium. The third step reaction can be carried out according to the following scheme: Proceed according to JPEG0007805356000091.jpg75170.

[0394] In some embodiments, the solvent is tetrahydrofuran and water. In some embodiments, the palladium catalyst content is about 0.5 mol% based on compound (iii). In some embodiments, the palladium catalyst is PdCl2(dppf). In some embodiments, the equivalent ratio of alkali metal carbonate base to compound (iii) is about 3:1, and the alkali metal carbonate base is KCO3 or NaCO3. In some embodiments, the reaction temperature is about 55°C to about 65°C.

[0395] In some embodiments, compound (v) is isolated from the reaction product mixture by the following order of steps: adding seed crystals to the reaction product mixture to form a mixture; adding n-heptane to the mixture; cooling the mixture to form a slurry comprising solid compound (v); and isolating solid compound (v) from the slurry.

[0396] In the fourth step, as described elsewhere herein, Compound (v) is reacted with compound (vi) in the presence of at least one base and a solvent to form a reaction product mixture comprising compound 1 according to JPEG0007805356000092.jpg58170.

[0397] In some embodiments, the at least one base is selected from the group consisting of 1,1,3,3-tetramethylguanidine and 1,8-diazabicyclo[5.4.0]undec-7-ene. In some embodiments, the solvent is selected from the group consisting of toluene, anisole, mesitylene, diethylamine, di-n-propylamine, di-isopropylamine, di-n-butylamine, and combinations thereof. In one such embodiment, the solvent is di-n-butylamine. In some embodiments, the at least one organic base further comprises a second base selected from the group consisting of 2,6-lutidine, di-isopropylethylamine, and 1,4-diazabicyclo[2.2.2]octane. In some embodiments, the reaction temperature is from about 115°C to about 125°C.

[0398] In some optional embodiments, Compound 1 can be isolated from the reaction product mixture by the following sequence of steps, as described elsewhere herein: adding an anti-solvent to the reaction product mixture; cooling to form a slurry comprising solid Compound 1; and isolating solid Compound 1. In some such embodiments, the anti-solvent is selected from the group consisting of isopropanol and n-propanol. In some embodiments, Compound 1 can be processed as described elsewhere herein as follows: forming a supersaturated solution of Compound 1 and methyl isobutyl ketone; seeding the supersaturated solution with crystalline Compound 1 Form A; cooling the solution to form a slurry comprising crystalline Compound 1 Form A; and isolating crystalline Compound 1 Form A.

[0399] In some embodiments, Compound 1 Form A has an X-ray powder diffraction pattern with at least two peaks at a location selected from the group consisting of 7.7±0.3 (°2θ), 12.1±0.3 (°2θ), 16.2±0.3 (°2θ), 16.4±0.3 (°2θ), 16.6±0.3 (°2θ), 17.1±0.3 (°2θ), 18.8±0.3 (°2θ), 19.4±0.3 (°2θ), 19.8±0.3 (°2θ), 20.3±0.3 (°2θ), 20.5±0.3 (°2θ), 23.3±0.3 (°2θ), 24.7±0.3 (°2θ), 25.3±0.3 (°2θ), and 26.5±0.3 (°2θ).

[0400] Pharmaceutical Compositions and Administration

[0401] The present disclosure also provides compositions and medicaments comprising Form A of Compound I. The compositions of the present disclosure can be used to inhibit DLK activity in a patient (e.g., a human).

[0402] As used herein, the term "composition" is intended to encompass not only a product containing the specified ingredients in the specified amounts, but also any product that results directly or indirectly from combining the specified ingredients in the specified amounts. "Pharmaceutically acceptable" means that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0403] In one embodiment, the disclosure provides a pharmaceutical composition (or medicament) comprising Form A of Compound I (or a stereoisomer, geometric isomer, tautomer, solvate, metabolite, isotope, pharmaceutically acceptable salt, or prodrug thereof) and a pharmaceutically acceptable carrier, diluent, or excipient. In another embodiment, the disclosure provides preparing a composition (or medicament) comprising a compound of the disclosure. In another embodiment, the disclosure provides administering Form A of Compound I and a composition comprising Form A of Compound I to a patient (e.g., a human patient) in need thereof.

[0404] The composition is prepared in a manner consistent with medical standards, divided into appropriate amounts, and administered.In this regard, factors to be considered include the specific disorder to be treated, the specific mammal to be treated, the clinical condition of each patient, the cause of the disorder, the delivery site of the drug, the method of administration, the administration schedule, and other factors known to medical professionals.The effective amount of the compound to be administered is governed by such considerations, and is the minimum amount required to inhibit the DLK activity required to prevent or treat undesirable diseases or disorders, such as neurodegeneration, amyloidosis, the formation of neurofibrillary tangles, or undesirable cell proliferation.For example, this amount may be below the amount that is toxic to normal cells or to mammals as a whole.

[0405] In one example, the therapeutically effective amount per dose of parenterally administered Form A of Compound I ranges from about 0.01 to 100 mg / kg, or alternatively, from about 0.1 to 20 mg / kg of patient body weight per day, with a typical initial range of 0.3 to 15 mg / kg / day for the compound used. In certain embodiments, the daily dose is given as a single daily dose, or in divided doses two to six times daily, or in sustained-release form. For a 70 kg adult, the total daily dose is generally about 100 mg to about 1,400 mg. This dosing regimen can be adjusted to provide the optimal therapeutic response. Form A of Compound I can be administered one to four times daily, preferably once or twice daily.

[0406] The compounds of the present disclosure may be administered in any convenient dosage form, such as tablets, powders, capsules, liquids, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain conventional components of pharmaceuticals, such as diluents, carriers, pH adjusters, sweeteners, fillers, and additional active agents.

[0407] Form A of Compound I can be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural, and intranasal, and, if desired for localized treatment, intralesional administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, intracerebral, intraocular, intralesional, or subcutaneous administration.

[0408] Form A of Compound I can be formulated into a pharmaceutical composition according to standard pharmaceutical practice. A typical formulation is prepared by mixing Form A of Compound I with a diluent, carrier, or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel, Howard C. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R. et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C., Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, colorants, sweeteners, fragrances, flavorings, diluents, and other known additives to provide an elegant presentation of Form A of Compound I or to aid in the manufacture of pharmaceutical products (i.e., drugs).

[0409] Suitable carriers, diluents, and additives are well known to those skilled in the art and include materials such as carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents, water, etc. The particular carrier, diluent, or excipient used depends on the means and purpose for which Compound I Form A is to be applied. Solvents are generally selected based on solvents recognized by those skilled in the art as being safe (GRAS) for mammalian administration. Generally, safe solvents are non-toxic aqueous solvents, such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG400, PEG300), etc., and mixtures thereof.

[0410] Acceptable diluents, carriers, additives, and stabilizers are nontoxic to recipients at the dosages and concentrations employed and include buffers and other organic acids, such as phosphate, citric acid, and methionine; antioxidants, including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl, or benzyl alcohol; alkylparabens, such as methyl or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); and low molecular weight (less than about 10 residues) polypeptides. Proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or nonionic surfactants such as TWEEN™, PLURONICS™, or polyethylene glycol (PEG). Form A of Compound I can also be encapsulated in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, such as hydroxymethylcellulose or gelatin-microcapsules and poly-(methyl methacrylate) microcapsules, colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules), or macroemulsions. Such techniques may be found in Remington: The Science and Practice of Pharmacy (2005), 21st ed., Lippincott Williams & Wilkins, Philadelphia, PA.

[0411] Sustained-release preparations can be prepared of Form A of Compound I. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing Form A of Compound I, or an embodiment thereof, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate), or poly(vinyl alcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate (Sidman et al., Biopolymers 22:547, 1983), non-degradable ethylene-vinyl acetate (Langer et al., J. Biomed. Mater. Res. 15:167, 1981), degradable lactic acid-glycolic acid copolymers such as LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid (EP 133,988A). Sustained-release compositions also include liposome-encapsulated compounds that can be prepared by methods known per se (Epstein et al., Proc. Natl. Acad. Sci. USA 82:3688, 1985; Hwang et al., Proc. Natl. Acad. Sci. USA 77:4030, 1980; U.S. Pat. Nos. 4,485,045 and 4,544,545; and EP 102,324A). Typically, the liposomes are small (about 200-800 angstroms), unilamellar, with a lipid content of more than about 30 mol% cholesterol, the ratio selected being adjusted for optimal therapy.

[0412] Formulations include those suitable for the routes of administration detailed herein. Formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations may generally be found in "Remington: The Science and Practice of Pharmacy: Remington the Science and Practice of Pharmacy" (2005), 21st ed., Lippincott Williams & Wilkins (Philadelphia, PA). Such methods include the step of bringing into association the active ingredient with the carrier, which constitutes one or more accessory ingredients.

[0413] In general, formulations are prepared by uniformly and intimately associating the active ingredient with a liquid carrier, diluent, or excipient, or a finely divided solid carrier, diluent, or excipient, or both, and then, if necessary, shaping the product. A typical formulation is prepared by mixing Compound I Form A with a carrier, diluent, or excipient. Formulations can be prepared using conventional dissolution and mixing procedures. For example, bulk Compound I Form A is dissolved in a suitable solvent in the presence of one or more of the above-mentioned excipients. Compound I Form A can be formulated into a pharmaceutical dosage form to provide an easily controllable dosage of the drug and allow patients to comply with the prescribed regimen.

[0414] In one example, Compound I Form A, or any embodiment thereof, can be formulated by mixing it at an appropriate pH and ambient temperature, at the desired purity, with a physiologically acceptable carrier, i.e., a carrier that is non-toxic to recipients at the dosages and concentrations used in galenical dosage forms. The pH of the formulation will depend primarily on the particular application and compound concentration, but is preferably in the range of about 3 to about 8. In one example, Compound I Form A, or any embodiment thereof, is formulated in an acetate buffer at pH 5. In another embodiment, Compound I Form A, or any embodiment thereof, is sterile. The compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation, or as an aqueous solution.

[0415] Formulations of Compound I Form A suitable for oral administration may be prepared as discrete units such as pills, capsules, cachets or tablets, each containing a predetermined amount of Compound I Form A.

[0416] Compressed tablets can be prepared by compressing Compound I Form A in a suitable machine in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersing agent. Molded tablets can be made by molding a mixture of moistened powdered active ingredient and an inert liquid diluent in a suitable machine. The tablets can optionally be coated or scored, and are optionally formulated to provide slow or controlled release of Compound I Form A therefrom.

[0417] Tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, such as gelatin capsules, syrups, or elixirs can be prepared for oral use. Form A of Compound I intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions can contain one or more agents, including sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable preparation. Tablets containing Form A of Compound I in a mixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets are acceptable. These excipients can be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating agents and disintegrating agents such as corn starch or alginic acid, binders such as starch, gelatin, or acacia, and lubricants such as magnesium stearate, stearic acid, or talc. The tablets may be uncoated or they may be coated by known techniques including microencapsulation to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period, for example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

[0418] An example of a suitable oral dosage form is a tablet or capsule containing about 1 mg, 5 mg, 10 mg, 25 mg, 30 mg, 50 mg, 80 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, or 500 mg of Compound I Form A, compounded with about 90-30 mg of anhydrous lactose, about 5-40 mg of croscarmellose sodium, about 5-30 mg of polyvinylpyrrolidone (PVP) K30, and about 1-10 mg of magnesium stearate. The powdered ingredients are first blended and then mixed with a solution of PVP. The resulting composition can be dried, granulated, mixed with magnesium stearate, and compressed into tablets using conventional equipment. In some embodiments, the dosage form is a capsule containing 100 mg of Compound I Form A. In some embodiments, the dosage form is a capsule containing 200 mg of Compound I Form A.

[0419] An exemplary aerosol formulation may be prepared by dissolving, for example, 5-400 mg of Form A of Compound I in a suitable buffer, such as phosphate buffer, and adding, if desired, an isotonicity agent, for example, a salt such as sodium chloride. The solution may be filtered, for example, using a 0.2 micron filter, to remove impurities and contaminants.

[0420] For treatment of the eye or other external tissues, for example, mouth and skin, the formulations are preferably applied as a topical ointment or cream containing, for example, 0.075 to 20% by weight of Compound I Form A. When formulated in an ointment, Compound I Form A may be used with either a paraffinic or a water-miscible ointment base. Alternatively, Compound I Form A may be formulated in a cream with an oil-in-water cream base.

[0421] If desired, the aqueous phase of the cream base may contain a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups, such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol (including PEG 400), and mixtures thereof. Topical formulations may optionally contain a compound that enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogs.

[0422] The oily phase of the emulsion of the present disclosure can be composed of known ingredients in a known manner. The phase can simply contain an emulsifier, but desirably contains a mixture of at least one emulsifier with a fat or oil, or both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. It is also preferred to include both an oil and a fat. Taken together, the emulsifier, with or without a stabilizer, constitutes the so-called emulsifying wax, and the wax, together with the oil and fat, constitutes the so-called emulsifying ointment base that forms the oily dispersed phase of a cream formulation. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present disclosure include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate.

[0423] Aqueous suspensions of Compound I Form A contain the active ingredient in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and acacia gum; dispersing or wetting agents such as naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearates), condensation products of ethylene oxide with long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), and condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweeteners, such as sucrose or saccharin.

[0424] The preparation of Compound I Form A can be in the form of a sterile injectable preparation, for example, a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents as described above. Sterile injectable preparations can also be prepared as sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol, or as lyophilized powders. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils can be conventionally used as solvents or suspending media. For this purpose, any bland fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid can also be used in the preparation of injectables.

[0425] The amount of active ingredient that may be combined with carrier materials to produce a single dosage form will vary depending on the host treated and the particular mode of administration. For example, a sustained-release formulation intended for oral administration to humans may contain about 1 to 1,000 mg or 100 to 500 mg of active ingredient, compounded with an appropriate and convenient amount of carrier material, which may vary from about 5 to about 95% (weight:weight) of the total composition. Pharmaceutical compositions may be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain about 3 to 500 μg of active ingredient per milliliter of solution to result in infusion of a suitable volume at a rate of about 30 mL / hour.

[0426] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

[0427] Formulations suitable for topical administration to the eye also include eye drops, wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations in a concentration of about 0.5 to 20% w / w, for example, about 0.5 to 10% w / w, e.g., about 1.5% w / w.

[0428] Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[0429] Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

[0430] Formulations suitable for pulmonary or nasal administration have, for example, particle sizes in the range of 0.1 to 500 microns (including particle sizes in the range of 0.1 to 500 microns in increments of microns, such as 0.5, 1, 30 microns, 35 microns, etc.), which are administered by rapid inhalation through the nostrils to reach the alveolar sacs, or by inhalation through the mouth. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents, such as compounds previously used to treat the disorders described below.

[0431] The formulations may be packaged in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example, water, for injection immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules, and tablets of the kind described above. Preferred unit dosage formulations are those containing a daily dose or daily unit sub-dose, as herein above recited, of the active ingredient, or an appropriate fraction thereof.

[0432] When the binding target is located in the brain, certain embodiments of the present disclosure result in Form A of Compound I crossing the blood-brain barrier. Certain neurodegenerative diseases are associated with increased permeability of the blood-brain barrier, such that Form A of Compound I can be easily introduced into the brain. When the blood-brain barrier remains intact, there are several art-known approaches for transporting molecules across the blood-brain barrier, including, but not limited to, physical methods, lipid-based methods, and receptor- and channel-based methods.

[0433] Physical methods of transporting Form A of Compound I across the blood-brain barrier include, but are not limited to, bypassing the blood-brain barrier entirely or creating an opening in the blood-brain barrier.

[0434] Methods of circumvention include, but are not limited to, direct injection into the brain (see, e.g., Papanastassiou et al., Gene Therapy 9:398-406, 2002), interstitial injection / convection-enhanced delivery (see, e.g., Bobo et al., Proc. Natl. Acad. Sci. USA 91:2076-2080, 1994), and implantation of a delivery device into the brain (see, e.g., Gill et al., Nature Med. 9:589-595, 2003; and Gliadel Wafers™, Guildford).

[0435] Methods for creating openings in the barrier include, but are not limited to, ultrasound (see, e.g., U.S. Patent Application Publication No. 2002 / 0038086), osmotic pressure (e.g., by administration of hypertonic mannitol (Neuwelt, E.A., "Implications of the Blood-Brain Barrier and Its Manipulation," Vols. 1 and 2, Plenum Press, New York (1989)) and permeabilization with, for example, bradykinin or permeabilizing agent A-7 (see, e.g., U.S. Patent Nos. 5,112,596, 5,268,164, 5,506,206, and 5,686,416).

[0436] Lipid-based methods for transporting Form A of Compound I across the blood-brain barrier include, but are not limited to, encapsulating Form A of Compound I in liposomes linked to antibody-binding fragments that bind to receptors on the vascular endothelium of the blood-brain barrier (see, e.g., U.S. Patent Application Publication No. 2002 / 0025313), and coating Form A of Compound I in low-density lipoprotein particles (see, e.g., U.S. Patent Application Publication No. 2004 / 0204354) or apolipoprotein E (see, e.g., U.S. Patent Application Publication No. 2004 / 0131692).

[0437] Receptor and channel-based methods for transporting Form A of Compound I across the blood-brain barrier include, but are not limited to, increasing the permeability of the blood-brain barrier using glucocorticoid blockers (see, e.g., U.S. Patent Application Publication Nos. 2002 / 0065259, 2003 / 0162695, and 2005 / 0124533); activating potassium channels (see, e.g., U.S. Patent Application Publication No. 2005 / 0089473), inhibiting ABC drug transporters (see, e.g., U.S. Patent Application Publication No. 2003 / 0073713); coating Compound I Form A compounds with transferrin and modulating the activity of one or more transferrin receptors (see, e.g., U.S. Patent Application Publication No. 2003 / 0129186), and cationizing antibodies (see, e.g., U.S. Patent No. 5,004,697).

[0438] For intracerebral use, in certain embodiments, the compound can be administered continuously by infusion into a fluid reservoir in the CNS, although bolus injection is also acceptable. The inhibitor can be administered intracerebroventricularly or otherwise introduced into the CNS or spinal fluid. Administration can be by continuous administration means, such as the use of an indwelling catheter and a pump, or by implantation, for example, intracerebral implantation of a sustained-release vehicle. More specifically, the inhibitor can be injected through a chronically implanted cannula or chronically infused with the aid of an osmotic minipump. Subcutaneous pumps are available to deliver proteins into the ventricles through small tubes. Highly sophisticated pumps can be refilled through the skin, and their delivery rate can be set without surgical intervention. Examples of suitable administration protocols and delivery systems involving continuous intraventricular infusion through a subcutaneous pump device or a completely implanted drug delivery system, used to administer dopamine, dopaminergic agents, and cholinergic agents to patients with Alzheimer's disease and animal models of Parkinson's disease, are described in Harbaugh, J. Neural Transm. Suppl. 24:271, 1987; and DeYebenes et al., Mov. Disord. 2:143, 1987.

[0439] Form A of Compound I used in the present disclosure is formulated and administered in a manner consistent with good medical practice. Factors to consider in this regard include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of drug delivery, the method of administration, the administration schedule, and other factors known to medical professionals. Form A of Compound I is optionally formulated with, but need not be, one or more drugs currently used to prevent or treat the disorder in question. The effective amount of such other drugs depends on the amount of compound of the present disclosure present in the formulation, the type of disorder or treatment, and other factors described above.

[0440] These are generally used in the same dosages and by the same routes of administration as those described herein, or about 1 to 99% of the dosages described herein, or at any dosage and by any route empirically / clinically determined to be appropriate.

[0441] The appropriate dosage of Form A of Compound I (when used alone or in combination with other drugs) for the prevention or treatment of disease depends on the type of disease being treated, the characteristics of the compound, the severity and course of the disease, whether the compound is administered for prophylactic or therapeutic purposes, previous treatments, the patient's medical history and response to the compound, and the discretion of the attending physician. The compound is suitably administered to the patient at one time or over a series of treatments. Depending on the type and severity of the disease, for example, about 1 μg / kg to 15 mg / kg (e.g., 0.1 mg / kg to 10 mg / kg) of the compound may be an initial candidate dose for administration to a patient, whether by one or more separate administrations or by continuous infusion. A typical daily dose may range from about 1 μg / kg to 100 mg / kg or more, depending on the factors mentioned above. For repeated administration over several days or longer, treatment is usually continued until a desired suppression of disease symptoms occurs, depending on the condition. An exemplary dosage of Form A of Compound I would be in the range of about 0.05 mg / kg to about 10 mg / kg. Thus, one or more doses of about 0.5 mg / kg, 2.0 mg / kg, 4.0 mg / kg, or 10 mg / kg (or any combination thereof) may be administered to the patient. Such doses may be administered intermittently, for example, weekly or once every three weeks (e.g., so that the patient receives from about 2 to about 20, or, for example, about 6, doses of antibody). An initial larger dose may be administered, followed by one or more smaller doses. An exemplary dosing regimen involves administering an initial loading dose of about 4 mg / kg, followed by weekly maintenance doses of about 2 mg / kg of the compound. However, other dosing regimens may be useful. The progress of this therapy is easily monitored by conventional techniques and assays.

[0442] Other typical daily doses can range, for example, from about 1 g / kg up to 100 mg / kg or more (e.g., about 1 μg / kg to 1 mg / kg, about 1 μg / kg to about 5 mg / kg, about 1 mg / kg to 10 mg / kg, about 5 mg / kg to about 200 mg / kg, about 50 mg / kg to about 150 mg / kg, about 100 mg / kg to about 500 mg / kg, about 100 mg / kg to about 400 mg / kg, and about 200 mg / kg to about 400 mg / kg), depending on the factors mentioned above. Typically, a clinician will administer the compound until a dose that results in improvement in, or optimally elimination of, one or more symptoms of the treated disease or condition is reached. The progress of this therapy is easily monitored by conventional assays. One or more agents provided herein may be administered together or at different times (e.g., one agent is administered before the administration of the second agent). One or more agents may be administered to a subject using different techniques (e.g., one agent may be administered orally, while a second agent is administered via intramuscular injection or intranasally). One or more agents may be administered such that the one or more agents have a pharmacological effect on the subject simultaneously. Alternatively, one or more agents may be administered such that the pharmacological activity of a first-administered agent ceases before the administration of one or more second-administered agents (e.g., one, two, three, or four second-administered agents).

[0443] Indications and Treatment Methods

[0444] In another aspect, the disclosure provides methods of inhibiting dual leucine zipper kinase (DLK) in an in vitro (e.g., nerve graft in a neural transplant) or in an in vivo setting (e.g., in a patient) by contacting DLK present in the in vitro or in vivo setting with Form A of Compound I. In these methods of the disclosure, inhibition of DLK signaling or expression by Form A of Compound I results in a downstream decrease in JNK phosphorylation (e.g., decreased JNK2 and / or JNK3 phosphorylation), a downstream decrease in JNK activity (e.g., decreased JNK2 and / or JNK3 activity), and / or a downstream decrease in JNK expression (e.g., decreased JNK2 and / or JNK3 expression). Thus, administration of Form A of Compound I according to the methods of the present disclosure may result in decreased activity of downstream kinase targets in the DLK signaling cascade, for example, (i) decreased JNK phosphorylation, activity, and / or expression; (ii) decreased cJun phosphorylation, activity, and / or expression; and / or (iii) decreased p38 phosphorylation, activity, and / or expression.

[0445] Form A of Compound I can be used in a method for inhibiting neuron or axon degeneration. Thus, the inhibitor is useful for treating, for example, (i) nervous system disorders (e.g., neurodegenerative diseases), (ii) nervous system conditions secondary to diseases, conditions, or treatments that primarily affect the outside of the nervous system, (iii) nervous system damage caused by physical, mechanical, or chemical trauma, (iv) pain, (v) eye-related neurodegeneration, (vi) memory loss, and (vii) psychiatric disorders. Some non-limiting examples of these diseases, conditions, and disorders are provided below.

[0446] Examples of neurodegenerative diseases and conditions that may be prevented or treated in accordance with the present disclosure include amyotrophic lateral sclerosis (ALS), trigeminal neuralgia, glossopharyngeal neuralgia, Bell's palsy, myasthenia gravis, muscular dystrophy, progressive muscular atrophy, primary lateral sclerosis (PLS), pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, progressive bulbar palsy, hereditary muscular atrophy, invertebrate disc syndromes (e.g., herniated, ruptured, and prolapsed disc syndromes), cervical spondylosis, plexopathies, thoracic outlet disruption syndrome, peripheral neuropathies, porphyria, mild cognitive impairment, Alzheimer's disease, Huntington's disease, Parkinson's disease, Parkinson's plus diseases (e.g., multiple system atrophy, progressive nuclear These include: dementia with Lewy bodies, frontotemporal dementia, demyelinating diseases (e.g., Guillain-Barré syndrome and multiple sclerosis), Charcot-Marie-Tooth disease (CMT, also known as hereditary motor and sensory neuropathy (HMSN), hereditary sensorimotor neuropathy (HSMN), and peroneal muscular atrophy), prion diseases (e.g., Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome (GSS), fatal familial insomnia (FFI), and bovine spongiform encephalopathy (BSE, commonly known as mad cow disease)), Pick's disease, epilepsy, and AIDS dementia complex (also known as HIV dementia, HIV encephalopathy, and HIV-associated dementia).

[0447] The methods of the present disclosure may also be used to prevent and treat eye-related neurodegeneration and related diseases and conditions such as glaucoma, lattice dystrophies, retinitis pigmentosa, age-related macular degeneration (AMD), photoreceptor degeneration associated with wet or dry AMD, other retinal degenerations, optic nerve drusen, optic neuropathies and optic neuritis. Non-limiting examples of various types of glaucoma that may be prevented or treated in accordance with the present disclosure include primary glaucoma (also known as primary open-angle glaucoma, chronic open-angle glaucoma, chronic simplex glaucoma, and simplex glaucoma), low-tension glaucoma, primary angle-closure glaucoma (also known as primary angle-closure glaucoma, narrow-angle glaucoma, pupillary block glaucoma, and acute congestive glaucoma), acute angle-closure glaucoma, chronic angle-closure glaucoma, intermittent angle-closure glaucoma, chronic open-angle closure glaucoma, pigmentary glaucoma, exfoliation glaucoma (also known as pseudoexfoliation or capsular glaucoma), developmental glaucoma (e.g., primary congenital glaucoma and pediatric glaucoma), secondary glaucoma (e.g., inflammatory glaucoma (e.g., uveitis and Fuchs iridocyclitis)), and )), lens-induced glaucoma (e.g., angle-closure glaucoma with mature cataract, phacosensitivity glaucoma secondary to rupture of the lens capsule, phacolytic glaucoma due to meshwork destruction harmful to the lens, and lens subluxation), glaucoma secondary to intraocular hemorrhage (e.g., hyphema and hemolytic glaucoma, also known as erythrocytic glaucoma), traumatic glaucoma (e.g., angle recession glaucoma, traumatic recession of the anterior chamber angle, postoperative glaucoma, aphakic pupil closure and ciliary block glaucoma), neovascular glaucoma, drug-induced glaucoma (e.g., corticosteroid-induced glaucoma and α-chymotrypsin glaucoma), toxic glaucoma, and glaucoma associated with intraocular tumors, retinal detachment, severe chemical burns to the eye, and iris atrophy.

[0448] Examples of pain include chronic pain, fibrosis, spinal pain, carpel tunnel syndrome, cancer pain, arthritis, sciatica, headache, surgical pain, muscle spasm, back pain, visceral pain, injury pain, dental pain, neuralgia such as neurogenic or neuropathic pain, nerve inflammation or damage, shingles, herniated disc, ligament injury and diabetes.

[0449] Certain diseases and conditions that have a primary effect other than the nervous system may lead to nervous system damage, which can be treated according to the method of the present disclosure.Examples of such conditions include peripheral neuropathy and neuralgia caused by diabetes, cancer, AIDS, hepatitis, kidney dysfunction, Colorado tick fever, diphtheria, HIV infection, leprosy, Lyme disease, polyarteritis nodosa, rheumatoid arthritis, sarcoidosis, Sjogren's syndrome, syphilis, systemic lupus erythematosus and amyloidosis.

[0450] Additionally, the methods of the present disclosure may be used to treat nerve damage, such as peripheral neuropathy, caused by exposure to toxic compounds, including heavy metals (e.g., lead, arsenic, and mercury) and industrial solvents, as well as drugs, including chemotherapeutic agents (e.g., vincristine and cisplatin), dapsone, HIV drugs (e.g., zidovudine, didanosine, stavudine, zalcitabine, ritonavir, and amprenavir), cholesterol-lowering drugs (e.g., lovastatin, indapamide, and gemfibrozil), heart or blood pressure medications (e.g., amiodarone, hydralazine, perhexiline), and metronidazole.

[0451] The method of the present disclosure can also be used to treat the nervous system damage caused by physical, mechanical or chemical trauma.Therefore, the method can be used to treat the peripheral nerve damage caused by physical injury (for example, burns, wounds, surgery and accident-related), ischemia, prolonged exposure to low temperature (for example, frostbite), and central nervous system damage caused by, for example, stroke or intracerebral hemorrhage (for example, cerebral hemorrhage).

[0452] Furthermore, the method of the present disclosure can be used to prevent or treat memory impairment, such as age-related memory deterioration.The types of memory that are affected by memory impairment and can therefore be treated according to the present disclosure include episodic memory, semantic memory, short-term memory and long-term memory.Examples of diseases and conditions related to memory impairment that can be treated according to the present disclosure include mild cognitive impairment, Alzheimer's disease, Parkinson's disease, Huntington's disease, chemotherapy, stress, stroke and traumatic brain injury (e.g., concussion).

[0453] The methods of the disclosure may also be used to treat mental disorders including, for example, schizophrenia, delusional disorder, schizoaffective disorder, schizophreniform disorder, shared psychotic disorder, psychosis, paranoid personality disorder, schizotypal personality disorder, borderline personality disorder, antisocial personality disorder, narcissistic personality disorder, obsessive-compulsive disorder, delirium, dementia, mood disorders, bipolar disorder, depression, stress disorders, panic disorder, agoraphobia, social phobia, post-traumatic stress disorder, anxiety disorders, and impulse control disorders (e.g., kleptomania, pathological gambling, pyromania, and trichotillomania).

[0454] In addition to the in vivo methods described above, the disclosed methods may be used to treat nerves ex vivo, which may be useful in the context of nerve grafts or nerve transplants. Thus, the inhibitors described herein may be useful as components of culture media for use in culturing nerve cells in vitro.

[0455] Thus, in another aspect, the present disclosure provides a method for inhibiting or preventing degeneration of a central nervous system (CNS) neuron or portion thereof, comprising administering Form A of Compound I to a CNS neuron.

[0456] In one embodiment of the method for suppressing or preventing degeneration of central nervous system neurons or a portion thereof, the administration to the CNS neurons is carried out in vitro.In another embodiment of the method for suppressing or preventing degeneration of central nervous system neurons or a portion thereof, the method further comprises the step of transplanting or implanting the CNS neurons into a human patient after administering the agent.In another embodiment of the method for suppressing or preventing degeneration of central nervous system neurons or a portion thereof, the CNS neurons are present in a human patient.

[0457] In another embodiment, in the method of inhibiting or preventing degeneration of a central nervous system neuron or a portion thereof, administering to a CNS neuron comprises administering Form A of Compound I in a pharmaceutically acceptable carrier, diluent, or excipient.

[0458] In another embodiment of the method of inhibiting or preventing degeneration of a central nervous system neuron or portion thereof, administration to the CNS neuron is by a route of administration selected from the group consisting of parenteral, subcutaneous, intravenous, intraperitoneal, intracerebral, intralesional, intramuscular, intraocular, intra-arterial interstitial injection, and an implantable delivery device.

[0459] In another embodiment of the method for inhibiting or preventing degeneration of a central nervous system neuron or portion thereof, the method further comprises administering one or more additional pharmaceutical agents.

[0460] In some cases, the inhibitor can be administered in combination with other drugs known to be useful for treating related diseases or conditions.Therefore, for example, in the treatment of ALS, the inhibitor can be administered in combination with riluzole (Rilutek), minocycline, insulin-like growth factor 1 (IGF-1) and / or methylcobalamin.In another example, in the treatment of Parkinson's disease, the inhibitor can be administered in combination with L-dopa, dopamine agonists (for example, bromocriptine, pergolide, pramipexole, ropinirole, cabergoline, apomorphine and lisuride), dopa decarboxylase inhibitors (for example, levodopa, benserazide and carbidopa), and / or MAO-B inhibitors (for example, selegiline and rasagiline). In a further example, in the treatment of Alzheimer's disease, the inhibitor may be administered with an acetylcholinesterase inhibitor (e.g., donepezil, galantamine, and rivastigmine) and / or an NMDA receptor antagonist (e.g., memantine). Combination therapy may include simultaneous or sequential administration by the same or different routes, as determined appropriate by those skilled in the art. The present disclosure also includes pharmaceutical compositions and kits comprising the combinations described herein.

[0461] In addition to the above combination, other combinations included in the present disclosure are combinations of inhibitors of degeneration of different neuronal regions.Therefore, the present disclosure includes the combination of drugs that (i) inhibit the degeneration of neuronal cell bodies and (ii) inhibit axon degeneration.For example, GSK and transcription inhibitors have been found to prevent the degeneration of neuronal cell bodies, and EGFR and p38MAPK inhibitors have been found to prevent the degeneration of axons. Thus, the present disclosure includes combinations of inhibitors of GSK and EGFR (and / or p38MAPK), combinations of transcription inhibitors and EGF (and / or p38MAPK), and further combinations of inhibitors of dual leucine zipper kinase (DLK), glycogen synthase kinase 3β (GSK3), p38MAPK, EGFR, phosphoinositide 3-kinase (PI3K), cyclin-dependent kinase 5 (cdk5), adenylyl cyclase, c-Jun N-terminal kinase (JNK), BCL2-associated X protein (Bax), In channels, calcium / calmodulin-dependent protein kinase (CaMKK), G proteins, G protein-coupled receptors, transcription factor 4 (TCF4), and β-catenin. The inhibitors used in these combinations may be any of the inhibitors described herein or other inhibitors of these targets described in WO 2011 / 050192, which is incorporated herein by reference.

[0462] Combination therapy can provide "synergy," an effect achieved when the active ingredients used together are greater than the sum of the effects resulting from using the compounds separately. Synergistic effects can be achieved when the active ingredients are (1) co-formulated in a combined unit dose formulation and administered or delivered simultaneously, (2) delivered alternately or in parallel as separate formulations, or (3) by some other regimen. When delivered in alternation therapy, synergistic effects can be achieved when the compounds are administered or delivered sequentially, for example, by separate injections in separate syringes, separate pills or capsules, or separate infusions. Generally, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e., serially, while in combination therapy, effective dosages of two or more active ingredients are administered together. [Example]

[0463] Compound 10 of compound genus (i) and compound 11 of compound genus (ii) were analyzed by HPLC using a 100 × 4.6 mm column; C18, 2.7 μm (e.g., Ascentis Express C18) stationary phase; column temperature: 25°C; DAD, 298 nm, 8 nm bandwidth detection; flow rate: 1.0 mL / min; injection volume: 5.0 μL; diluent: water / acetonitrile 3:7 v / v; mobile phase A: 0.05% v / v TFA in water; mobile phase B: 0.05% v / v TFA in acetonitrile; acquisition time: approximately 14 min. The gradient program was as follows, and the RRTs of compounds 10 and 11 were 1.34 and 1.00, respectively. JPEG0007805356000093.jpg35170

[0464] Compound 11 of the compound genus (ii) and compound 16 of the compound genus (iii) were analyzed by HPLC using a 150 × 3.0 mm column; Agilent Infinity LabPoroshell HPH-C18 stationary phase, 2.7 μm; column temperature: 33 °C; DAD, 260 nm, 8 nm bandwidth detection; flow rate: 0.75 mL / min; injection volume: 5.0 μL; diluent: water / acetonitrile 8:2 v / v; mobile phase A: 10 mM (NH4)2HPO4 in water, pH 7.3 ± 0.2; mobile phase B: acetonitrile; acquisition time: approximately 10.5 min. The gradient program was as follows, and the RRTs of compounds 11 and 16 were 1.65 and 1.00, respectively. JPEG0007805356000094.jpg44170

[0465] Compound genus (iii) species 16, compound genus (iv) species 23, and compound genus (v) species 24 were analyzed by HPLC using a 150 × 3.0 mm column; Agilent Infinity Lab Poroshell HPH-C18 stationary phase, 2.7 μm; column temperature: 33 °C; DAD, 238 nm, 8 nm bandwidth detection; flow rate: 0.5 mL / min; injection volume: 3.0 μL; diluent: water / acetonitrile 1:1 v / v; mobile phase A: 10 mM (NH4)2HPO4 in water, pH 7.3 ± 0.2; mobile phase B: acetonitrile; acquisition time: approximately 25 min. The gradient program was as follows, and the RRTs for compounds 23, 16, and 24 were 0.3, 0.79, and 1.00, respectively. JPEG0007805356000095.jpg40170

[0466] Compound 1 (crude) was analyzed by HPLC using a 150 × 3.0 mm column; Poroshell HPH-C18 stationary phase, 2.7 μm; column temperature, 33 °C; DAD, 276 nm, 8 nm bandwidth detection; flow rate, 0.5 mL / min; injection volume, 5.0 μL; diluent, water / acetonitrile, 1:1 v / v; mobile phase A, 10 mM (NH4)2HPO4 in water, pH 7.3 ± 0.2; mobile phase B, acetonitrile; acquisition time, approximately 20 min. The gradient program was as follows: JPEG0007805356000096.jpg44170

[0467] The peak table is as follows: JPEG0007805356000097.jpg49170

[0468] For purified Compound 1, the same method was carried out for Compound 1 (crude) using the following gradient program: JPEG0007805356000098.jpg40170

[0469] The peak table is as follows: JPEG0007805356000099.jpg48170

[0470] Example 1: Preparation of 3-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (compound (23))

[0471] Compound (23) is a type of compound (iii).

[0472] Step 1: Preparation of 3-(difluoromethoxy)-2-nitropyridine (compound (19)) JPEG0007805356000100.jpg74170

[0473] In step 1(1), a reaction mixture was formed by combining 2-nitropyridin-3-ol (compound (17)) with sodium 2-chloro-2,2-difluoroacetate (compound (18)) and aqueous potassium carbonate in dimethylformamide. The reaction mixture was heated to 70°C and maintained at that temperature to form a reaction product mixture containing compound (19). In step 1(2), compound (19) was extracted with ethyl acetate and water to form a solution containing compound (19). In step 1(3), the solution of compound (19) was washed with 10% brine, and then in step 1(4), the washed solution of compound (19) was concentrated to two volumes.

[0474] Step 2: Preparation of 3-(difluoromethoxy)pyridin-2-amine (compound (20)) JPEG0007805356000101.jpg58170

[0475] In step 2(1), a solution of compound (19) was diluted with ethanol and catalytically hydrogenated at 40°C using a palladium-carbon catalyst to form a solution of compound (20). In step 2(2), a Celite filter aid was added to the solution of compound (20) and the solution was filtered. In step 2(3), the solvent was exchanged to methyl tert-butyl ether (MTBE), and then n-heptane anti-solvent was added to precipitate compound (20) and form a slurry. In step 2(4), the slurry of compound (20) was filtered to recover compound (20).

[0476] Step 3: Preparation of 5-bromo-3-(difluoromethoxy)pyridin-2-amine (compound 21) JPEG0007805356000102.jpg62170

[0477] In step 3(1), compound (20) from step 2 was mixed with N-bromosuccinimide (NBS) in acetonitrile and reacted at 0° C. to form a solution of compound (21). In step 3(2), compound (21) was neutralized with aqueous sodium bisulfite and extracted into 13:1 ethyl acetate / n-heptane. In step 3(3), the solution of compound (21) in ethyl acetate / n-heptane was washed with 10% brine. In step 3(4), the solution was filtered through Celite. In step 3(5), the filtrate containing compound (21) was concentrated and subsequently diluted with toluene in step 3(6) to form a solution of compound (21).

[0478] Step 4: Preparation of 3-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine maleic acid (compound (22)) JPEG0007805356000103.jpg60170

[0479] In step 4(1), the solution of compound (21) from step 3 was mixed with bis(pinacolato)diboron (bis-pin-diborane), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (PdCl(dppf)), triphenylphosphine (PPh), potassium acetate, and toluene to form a reaction mixture. The reaction mixture was reacted at 100°C to form a solution containing the free base of compound (22). In step 4(2), the solution was filtered through Celite. In step 4(3), the solvent of the solution of compound (22) was exchanged with methyl tert-butyl ether. In step 4(4), the solution of the free base of compound (22) was mixed with maleic acid and methanol and held at -10°C for at least 2 hours to form a slurry of compound (22). In step 4(5), compound (22) was recovered from the slurry of step 4(4) by filtration, washed with methyl tert-butyl ether, and dried to obtain compound (22).

[0480] Step 5: Preparation of 3-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (compound (23)) JPEG0007805356000104.jpg54170

[0481] In step 5(1), compound 22 from step 4 was dissolved in toluene and neutralized with aqueous sodium bicarbonate to form the free base of compound 23 in solution. In step 5(2), the solution of compound 23 was filtered through Celite, the filtrate separated into organic and aqueous phases, and the aqueous phase was removed. The organic phase containing compound 23 in solution was washed with water, followed by phase separation and removal of the aqueous phase. The organic phase was concentrated and mixed with n-heptane anti-solvent at −10° C., causing compound 23 to precipitate from solution and form a slurry. The slurry was filtered, washed with n-heptane, and dried to form the finished compound 23.

[0482] Example 2: Preparation of 3,3-difluoropyrrolidine hydrochloride (compound (28)) Step 1: Preparation of 1-benzyl-3,3-difluoropyrrolidine hydrochloride (compound (26)) JPEG0007805356000105.jpg27170

[0483] Step 2: Preparation of 1-benzyl-3,3-difluoropyrrolidine hydrochloride (compound 27) JPEG0007805356000106.jpg32170

[0484] In step 1, 1-benzylpyrrolidin-3-one (compound (25)) was dissolved in dichloromethane (DCM) and cooled to -50°C. Hydrofluoric acid and sulfur tetrafluoride were added and reacted at 0°C to form compound (26). The reaction mixture was quenched by adding aqueous KOH at 0°C. The layers were separated, and the organic phase was washed with 10% brine. DCM was removed by distillation, and 1-propanol was added. The solution was filtered through a C pad. In step 2, a solution of HCl in 1-propanol was added to obtain a slurry. The slurry was heated to 40°C, then MTBE was added, and the slurry was cooled to 0°C and filtered. The solid was washed with 1-propanol / MTBE and dried.

[0485] Step 3: Preparation of 3,3-difluoropyrrolidine hydrochloride (compound (28)) JPEG0007805356000107.jpg34170

[0486] In step 3(1), compound 27 was diluted with methanol and acetic acid and catalytically hydrogenated at 40°C using a palladium-carbon catalyst to form a solution of compound 28. In step 3(2), the suspension was filtered through dicalite, and the methanol was exchanged for 1-propanol. MTBE was added to the suspension at 40-45°C, which was then cooled to 0°C and aged for at least 2 hours. The precipitate was filtered and washed with 1-propanol / MTBE to obtain compound 28.

[0487] Example 3: (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (compound (5)) Compound (5) is a type of compound (vii).

[0488] Step 1: Preparation of BOC-protected methyl (2S,4R)-4-(tosyloxy)pyrrolidine-2-carboxylate (compound (2)) JPEG0007805356000108.jpg48170

[0489] In step 1(1), a reaction vessel was charged with BOC-protected methyl (2S,4R)-4-hydroxypyrrolidine-2-carboxylate (compound (2a)), pyridine, and a catalytic amount of 4-dimethylaminopyridine (DMAP). The reaction mixture was cooled to 0-10°C. 4-Toluenesulfonyl chloride (TsCl) was added within 1 hour. The temperature was brought to 20-30°C within 4-6 hours, and the reaction mixture was stirred at 20-30°C for at least 16 hours to form a reaction product mixture containing compound (2). In step 1(2), the reaction product mixture from step 1(1) was mixed with methyl tert-butyl ether and aqueous citric acid. In steps 1(3) and 1(4), the solution from step 1(2) was neutralized with aqueous sodium bicarbonate and washed with brine, respectively. In step 1(5), a solvent exchange to tetrahydrofuran (THF) was performed to produce a solution of compound (2).

[0490] Step 2: Preparation of BOC-protected (3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl 4-methylbenzenesulfonate (compound (3)) JPEG0007805356000109.jpg75170

[0491] In step 2(1), the solution of compound (2) from step 1 was cooled to 10-20°C, and calcium chloride, ethanol, and water were added while maintaining the temperature at 10-20°C. Sodium borohydride (NaBH4) was added slowly in several portions. Stirring was continued at 10-20°C for 1-2 hours, then at 20-30°C for 1-4 hours to form a solution of compound (3). In step 2(2), the solution was mixed with ethyl acetate and a mixture of aqueous citric acid and brine. The aqueous phase was extracted with ethyl acetate. In step 2(3), the organic phase from step 2(3) was washed with brine, a mixture of aqueous sodium carbonate and brine, and finally with brine. In step 2(4), the organic phase containing compound (3) in solution was distilled to remove THF and ethanol, and the resulting concentrate was seeded with BOC-protected (3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl 4-methylbenzenesulfonate in step 2(5), and n-heptane anti-solvent was added to the seed solution to form a slurry of compound (3) in step 2(6). In step 2(7), the slurry from step 2(6) was filtered, washed with n-heptane, and dried to provide compound (3) in 84% yield over two steps.

[0492] Step 3: Preparation of BOC-protected (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane (compound (4)) JPEG0007805356000110.jpg48170

[0493] In step 3(1), compound (3) from step 2 was dissolved in a 10:1 mixture of methanol and ethanol. Sodium methoxide was added portionwise at 15-30°C, and the reaction mixture was then heated to 60-70°C and stirred at this temperature for 2 hours to form the BOC-protected bicyclic amine compound (4) by ring closure. The solvent mixture was exchanged for methyl tert-butyl ether, and the organic solution was washed with diluted brine. The aqueous phase was extracted with TBME. The combined organic layers were washed with brine, polished, filtered, and concentrated under reduced pressure.

[0494] Step 4: (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (compound (5)) JPEG0007805356000111.jpg33170

[0495] In step 4(1), a solution of compound (4) was diluted with additional methyl tert-butyl ether, and HCl (gas) was added in three portions at 20-30°C, aging for 1-2 hours after each addition to deprotect the amine and form a slurry of compound (5). Excess HCl was removed by three cycles of distillation and the addition of MTBE. In step 4(2), the slurry from step 4(1) was cooled to 0-5°C, aged for 1-2 hours, and filtered to isolate compound (5), which was then washed with TBME and dried to provide compound (5) in 84% yield.

[0496] Optionally, compound (5) can be recrystallized. Compound (5) is dissolved in methanol at 20-30°C, and the solution is triturated and filtered. The solvent is exchanged with MTBE, and the suspension is aged at 0-5°C. The precipitate is filtered off, washed with MTBE, and dried to give purified compound (5) in 96% yield.

[0497] Example 4: 4,6-Dichloro-2-(methylthio)pyrimidine (compound (10)) Compound (10) is a type of compound (i).

[0498] Step 1: Preparation of 2-mercaptopyrimidine-4,6-diol (compound (8)) JPEG0007805356000112.jpg32170

[0499] Thiourea (compound (6)) and diethyl malonate (compound (7)) were mixed with sodium ethoxide base in ethanol to form compound (8).

[0500] Step 2: Preparation of 2-(methylthio)pyrimidine-4,6-diol (compound (9)) JPEG0007805356000113.jpg33170

[0501] Compound (8) was mixed with methyl bisulfate and petroleum ether ("PE'") in DMF and ethyl acetate and reacted to form compound (9).

[0502] Step 3: Preparation of 4,6-dichloro-2-(methylthio)pyrimidine (compound (10)) JPEG0007805356000114.jpg34170

[0503] In step 3(1), compound 9 was mixed with phosphoryl chloride (POCl) and PE in toluene and ethyl acetate and reacted to form a solution containing compound 10. In step 3(2), the solution of compound 10 was distilled to form the completed compound 10.

[0504] Example 5: 5-(6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(3,3-difluoropyrrolidin-1-yl)pyrimidin-4-yl)-3-(difluoromethoxy)pyridin-2-amine (Compound 1) Step 1: Preparation of (1S,4S)-5-(6-chloro-2-(methylthio)pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (compound (11))

[0505] Compound (11) is a type of compound (ii). JPEG0007805356000115.jpg42170

[0506] (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (23.4 grams; 172.6 mmol; 1.12 equivalents) (Compound (5)), 4,6-dichloro-2-(methylthio)pyrimidine (Compound (10)) (30.0 grams; 153.8 mmol; 1.0 equivalents), and ethanol (236.7 grams; 300 mL; 10 volumes) were charged to a 500 mL double-jacketed reactor equipped with a mechanical stirrer, thermometer, cryostat, argon / nitrogen inlet, and vacuum filter under an inert atmosphere. A colorless solution formed within 20 minutes of stirring, and the solution was heated to 35°C. Triethylamine (37.5 grams; 369.1 mmol; 2.4 equivalents) was added dropwise over a 2-hour period. A precipitate formed during the addition, giving a white suspension, which was further stirred at 35° C. for approximately 5 hours until the remaining amount of compound 10 reached a predetermined amount, as determined by in-process control ("IPC"). The reaction mixture was cooled to 22° C. and then stirred at room temperature for approximately 16 hours. Solid compound 11 was isolated by filtration and washed twice with 85 mL of water / EtOH 85:15. Compound 11 was dried under high vacuum for at least 14 hours to yield 37.5 grams (94.5%) as a white powder.

[0507] In some embodiments, the method of step 1 above is carried out at a reaction temperature of 22° C., 7.5 volumes of ethanol, and 2.2-2.6 equivalents of triethylamine for 4-5 hours.

[0508] In some embodiments, the method of step 1 above is carried out at a reaction temperature of 35° C., 10 vol of ethanol, and 2.4 equivalents of triethylamine for 5 hours.

[0509] Step 2: Preparation of (1S,4S)-5-(6-chloro-2-(methylsulfonyl)pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (compound (16))

[0510] Compound (16) is a type of compound (iii). JPEG0007805356000116.jpg49170

[0511] A 500 mL double-jacketed reactor was charged with methanol (200 mL) and water (100 mL) under an inert atmosphere, followed by the addition of compound (11) (20.0 grams; 77.6 mmol; 1.0 equivalent) and sodium tungstate dihydrate (0.78 mmol; 0.1 equivalent) to form a white suspension. The suspension was heated to 60°C, followed by the addition of 35% hydrogen peroxide (178.5 mmol HO; 2.3 equivalents) over 4 hours. The reaction mixture was stirred at 60°C until IPC compliance was achieved. The suspension of compound (16) was cooled to room temperature, and 40% aqueous sodium bisulfite (20.2 grams of sodium bisulfite; 77.6 mmol; 1.0 equivalent) was added over approximately 30 minutes and stirred at room temperature for 3 hours. Solid compound (16) was isolated by filtration and washed twice with 134 mL of water. Compound (16) was dried under reduced pressure for at least 14 hours to yield 20.6 grams (91.6%) of compound (16) as a white powder.

[0512] Step 3: Preparation of 5-(6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(methylsulfonyl)pyrimidin-4-yl)-3-(difluoromethoxy)pyridin-2-amine (Compound 1)

[0513] Compound (24) is a type of compound (v). JPEG0007805356000117.jpg53170

[0514] A 500 mL double-jacketed reactor was charged with tetrahydrofuran (300 mL) and water (87.5 mL) under argon, followed by the addition of compound (16) (25.0 grams; 86.3 mmol; 1.0 equivalent) and 3-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (compound (23)) (28.4 g; 99.2 mmol; 1.15 equivalent) to form a brown suspension. The reactor was evacuated and backfilled with argon three times. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) ("Pd(dppf)Cl") (0.31 grams; 0.43 mmol; 0.005 equivalent) was added, and the suspension was then heated to 60-65 °C and stirred until IPC compliance was achieved. The reaction mixture was then cooled to 55-58°C, followed by the addition of N-acetylcysteine ​​(1.41 grams; 8.6 mmol; 0.1 equivalents) in 15 grams of water. The mixture was stirred for approximately 30 minutes, after which n-heptane (51.3 grams; 75 mL) was added. The mixture was stirred overnight at room temperature. The solid compound (24) was recovered from the mixture by filtration and then washed twice with a mixture of THF (50 grams) and water (50 grams). The washed solid compound (24) was dried under reduced pressure at room temperature for 16 hours to yield 30.75 grams (86.2%) of an off-white powder.

[0515] Step 4: Preparation of 5-(6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(3,3-difluoropyrrolidin-1-yl)pyrimidin-4-yl)-3-(difluoromethoxy)pyridin-2-amine (Compound 1) JPEG0007805356000118.jpg55170

[0516] A 250 mL double-jacketed reactor was charged with compound (24) (20.0 g; 48.4 mmol; 1 equivalent), 3,3-difluoropyrrolidin-1-ium chloride (compound (28)) (10.4 g; 72.6 mmol; 1.5 equivalents), and di-n-butylamine (80.0 mL) under an inert atmosphere, followed by the addition of 1,8-diazabicyclo[5.4.0]undec-7-ene ("DBU") (11.1 g; 72.6 mmol; 1.5 equivalents). The mixture was stirred at 125° C. for approximately 20 hours. The reaction was monitored by IPC for completion. 1-Propanol (80 mL) was added to the reaction mixture over approximately 30 minutes, followed by cooling to 20° C. over 6 hours, forming a precipitate of the crude compound of Formula I. Solid Compound 1 was recovered from the mixture by filtration and then washed twice with 1-propanol (80 mL), followed by drying at 60° C. and up to 20 mbar for about 16 hours, yielding 16.8 grams of crude Compound 1 as a nearly white to pale yellow powder with clumps, in 77.9% yield.

[0517] Example 6: 5-(6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(3,3-difluoropyrrolidin-1-yl)pyrimidin-4-yl)-3-(difluoromethoxy)pyridin-2-amine (Compound 1) Step 1: Preparation of 4,6-dichloro-2-(methylsulfonyl)pyrimidine (compound (15)) JPEG0007805356000119.jpg48170

[0518] A reaction vessel was charged with 4,6-dichloro-2-(methylthio)pyrimidine (compound (10)) (25.0 g, 128.2 mmol), sodium tungstate dihydrate (426 mg, 1.29 mmol), methanol (250 mL), and water (125 mL). The reaction mixture was heated to 52 °C, and HO (35%, 28.3 g, 291.3 mmol) was added within 3 hours. The reaction mixture was stirred for another 2 hours and then cooled to 22 °C. Aqueous sodium bisulfite solution 40% (25.0 mL, 127.8 mmol) was added within 30 minutes, and the mixture was stirred at 22 °C for 1 hour and at 0 °C for 1 hour to form a slurry of compound (15). The slurry was filtered to isolate compound (15), which was then washed with water. The yield of compound (15) was 74% with a purity of 99.6 area % by HPLC.

[0519] Step 2: Preparation of (1S,4S)-5-(6-chloro-2-(methylsulfonyl)pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (compound (16)) JPEG0007805356000120.jpg86170

[0520] In step 2, under an inert atmosphere, compound 15 (3.0 g, 13.2 mmol), compound 5 (2.0 g, 14.8 mmol, 1.12 equiv.), and ethanol (18 mL) were charged to a 50 mL reaction vessel. Upon stirring, a colorless solution formed, and the solution was heated to 35 °C. Triethylamine (3.23 g, 31.7 mmol, 2.4 equiv.) was added dropwise over 2 h. The reaction mixture was further stirred at 35 °C for 3 h to yield a reaction product mixture containing compound 16 (approximately 80% HPLC area %) and regioisomer 17 (approximately 6-7% HPLC area %) in solution. The reaction mixture was cooled to 22 °C, water (30 mL) was added, and the suspension was stirred at 22 °C for 1 h. The precipitate was filtered off and washed with water / EtOH. The isolated solid was dried under high vacuum for at least 14 hours to give compound 16 in 98.3 area% purity and 82% yield. Water was added, and the reaction mixture was cooled to 22 °C and then stirred at room temperature for approximately 16 hours. Since regioisomer 17 is more soluble in the solvent mixture than compound 16, compound 16 primarily crystallizes, while regioisomer 17 primarily remains in solution. The solid was isolated by filtration and washed twice with water / EtOH. The isolated solid was dried under high vacuum for at least 14 hours to give compound 16 in 98.3 area% purity and 82% yield.

[0521] Steps 3 and 4: Preparation of Compound 1

[0522] Compound 1 can be prepared from compound (16) according to steps 3 and 4 corresponding to steps 3 and 4 of Example 5.

[0523] Example 7: Purification of crude Compound 1 Crude compound 1 was purified according to the following scheme: JPEG0007805356000121.jpg66170

[0524] Step 1: Dissolution of crude compound of formula I

[0525] MIBK (399 mL) and crude Compound 1 (25 g) were charged to a first 1000 mL double-jacketed reactor and heated to 90°C with stirring to form a solution. The solution was filtered through a 0.2 μm PTFE polished filter into a second 1000 mL double-jacketed reactor, and the temperature was maintained at 90°C. The 90°C MIBK was rinsed through the first reactor and sent to the second reactor through the polished filter. A clear solution of crude Compound 1 was produced. The solution was cooled to 75°C.

[0526] Step 2: Seeding and cooling

[0527] In a glass vial, 0.1 grams of jet-milled purified crystalline Compound 1 free base (Form "A") was suspended in 3 mL of MIBK at 20-25°C with stirring for at least 15 minutes. The seed slurry was added to the crude Compound 1 solution with stirring to form a suspension. After confirming the presence of fine particles, the suspension was aged at 75°C with stirring for 1 hour. The suspension was cooled to -10°C with stirring at a rate of approximately 12 K / hour over approximately 7 hours, and then aged at the final temperature with stirring for at least 6 hours.

[0528] Step 3: Filtration, washing and drying

[0529] The first wash of 40 mL of MIBK and the second wash of 40 mL of ethanol were each cooled to 5°C. The suspension from step 2 was filtered under reduced pressure through a Nutsche filter to recover the crystallized Compound 1. The wet Compound 1 was washed sequentially with an MIBK wash and an ethanol wash to produce wet purified Compound 1. The wet Compound 1 was dried at 65°C under 20 mbar or less pressure in a drying cabinet until a constant weight was obtained. 22.15 grams of purified Compound 1, which was nearly white in appearance and had an assay of 100% by weight, were produced in 89.1% yield. Purified Compound 1 is a crystalline free base with a melting point of 197-200°C.

[0530] Example 8

[0531] According to the following scheme, the monosubstitution of 4,6-dichloro-2-methylsulfanyl-pyrimidine (10) with 2-oxa-5-azabicyclo[2.2.1]heptane (5) (1.12 equiv.) was evaluated in various solvents in the presence of di-isopropyl-ethylamine (2.4 equiv.) at room temperature (22 °C). JPEG0007805356000122.jpg42170

[0532] The product (11) precipitated in the reaction medium and was isolated by simple filtration after adding 10 mL of water per gram of compound (10) to dissolve the salt. The results of the solvent screening are summarized in Table 1. Test 3 was performed at 50°C, and test 7 used trimethylamine base.

[0533] [Table 1]

[0534] THF, 2-MeTHF, and isopropyl acetate were very slow with incomplete conversion even after 18 hours. DMSO, acetonitrile, and ethanol gave conversions of over 98% within 2-4 hours with isolated yields of over 90%. Triethylamine base gave slightly faster conversions and higher isolated yields.

[0535] Test samples 8 and 9 (ethanol solvent and triethylamine base) were repeated at a reaction temperature of 35° C. with 7.5 mL of ethanol per gram of compound 10, varying the equivalent ratio of base to compound 10 from 2.2:1 to 2.6:1. The conversion of compound 10, the isolated yield of compound 11, and the amount of the following impurities were evaluated (based on LC-MS): JPEG0007805356000124.jpg25170

[0536] The results are summarized in Table 2.

[0537] [Table 2]

[0538] When compound (10) was converted, the impurity decreased from 2.20 to 2.40 equivalents with increasing equivalents of base, but increased again when 2.60 equivalents were applied.

[0539] Calorimetric studies showed a total adiabatic temperature rise of 68°C when triethylamine was added in 7.5 volumes of ethanol at 22°C over 2 hours. A completely adiabatic event would reach a temperature of 90°C, equal to the safe temperature determined for this reaction. When the base was added at 35°C under more dilute conditions (10 volumes of ethanol), the total adiabatic temperature rise dropped to 46°C, and the maximum temperature of the synthesis reaction (MTSR) was 81°C, below the safe temperature. Thus, the safer, more diluted version was applied on a larger scale. The desired conversion was typically achieved 3 hours after the addition of the base. During the addition of EtN, the product began to precipitate. Upon complete conversion, the suspension was cooled to 22°C, and water was added to promote precipitation and dissolve the salts. Compound (11) was isolated by filtration. Residual compound (10) and impurities were typically always observed at less than 0.05% in the isolated product. This process was successfully carried out on a scale of 50 kg of compound (10) to give pyrimidine compound (11) in 90% yield and 99.9% w / w assay.

[0540] Example 9

[0541] A prior art method for preparing compound 16 by oxidation of compound 11 used 5 mol% sodium tungstate dihydrate in MeOH / water, charged 2.5 equivalents of HO, and aged at 20-30 °C for 30 h. Process control testing typically showed that 1-2% of compound 11 and the intermediate sulfoxide (Scheme 3) remained. After adding an additional 0.5 equivalents of HO and aging at 55-62 °C for an additional 48 h, the system was quenched with aqueous NaSO, and 90% of the sulfone compound 16 was isolated by filtration. Prior art methods have the potential for HO accumulation and the attendant risk of uncontrolled HO decomposition.

[0542] In Example 9, we evaluated the development of a safe method to minimize the risk of H2O2 accumulation while shortening the reaction time. Room temperature was not sufficient to achieve complete conversion, so the reaction was tested at 45 °C using 3 equivalents of H2O2. 5 mol% Na2WO4 . 2H2O catalyst, 1 mol% Na2WO4 . A similar conversion profile to that observed with the 2H2O catalyst was observed after 20 h. Further increasing the reaction temperature to 55 °C using 1 mol% catalyst enabled conversions of over 99.5% after 4–6 h.

[0543] The reaction scheme was as follows: JPEG0007805356000126.jpg48170

[0544] Calorimetric measurements of four reaction procedures were carried out. The results are summarized in Table 2. The reaction conditions were: 1 mol% Na2WO4 . The solvents were 2:1 HO and MeOH / water. The equivalents of HO and HO dosing regimens are shown in Table 2. In Table 2: Td is the temperature during dosing; Tr is the temperature of the reaction; ΔrH is the enthalpy of the reaction; Acc is the amount of HO accumulated; ΔadiaTmax is the total adiabatic temperature rise; and MTSR is the maximum temperature of the synthesis reaction, calculated as Tr + Acc × ΔadiaTmax. Residual sulfoxide intermediates were measured over a total reaction time of 19-22 hours and are reported as area % HPLC.

[0545] [Table 2]

[0546] It is clear that a batch process in which 3 equivalents of HO were added within 30 min at 23 °C, followed by heating to 55 °C and aging for 20 h at 55 °C was not a safe method, resulting in 97% accumulation of HO and an MTSR of 93 °C (Test 1). Changing from a full batch to a semibatch process by charging 3 equivalents of HO at 55 °C for 2 h and then aging for 2 h resulted in 0.57% residual sulfoxide intermediate, which only decreased to 0.45% within the next 17 h. The accumulation of HO was still 68% (Test 2). The reaction temperature was increased to 60 °C, and 2 equivalents of HO were initially charged within 160 min, resulting in complete conversion of compound (11) and 25% residual sulfoxide intermediate remaining. After 30 min, 3 equivalents of HO were added within 80 min, resulting in 0.29% residual sulfoxide intermediate. This level remained unchanged over the next 15 h. At this temperature, the accumulation of HO was reduced to 15% (Test 3). Reducing the total amount of HO administered to 2.3 equivalents within 4 hours resulted in 2.2% of the sulfoxide intermediate remaining at the end of the addition, and a level of 0.30% after aging for 16 hours. The maximum accumulation in this method reached only 13%, and the MTSR was 65 °C (Test 4), approximately 10 °C below the boiling point of the mixed solvent, making this procedure a safe method in terms of HO accumulation.

[0547] Example 10

[0548] Suzuki Coupling Reaction

[0549] A prior art method teaches the preparation of compound 24 by Suzuki coupling of boronate 23 with compound 16 in the presence of 1 mol% PdCl2(PCy3)2 and 3 equivalents of K2CO3 in THF / water at 65 °C to give pyrido-pyrimidine 24, which precipitated from the reaction mixture in the organic phase and was isolated by simple filtration after removal of the aqueous phase. To obtain acceptable yields (>80%) from this method, the organic layer had to be azeotropically dried before filtration, which required a large solvent volume. Isolation and purification involved a combination of aqueous workup and treatment with silica gel and charcoal, followed by crystallization. Preliminary assays showed that reducing the catalyst amount to 0.5 mol% could result in complete conversion within 5 h, but further reducing the catalyst amount to 0.25 mol% resulted in incomplete conversion even after 20 h. The reaction was further optimized using 0.5 mol% PdCl2(PCy3)2. Changing the solvent to 2-MeTHF slowed the conversion; after 5 h at 65 °C, approximately 4% of compound 16 remained; phase separation did not improve, and filtration for isolation was very slow. No product was formed in toluene or isopropyl acetate solvents. Therefore, further development was carried out using THF.

[0550] Compound 23, prepared according to Steps 4 and 5 of Example 1, resulted in incomplete conversion of compound 16 after 5 hours at 65 °C, with the reaction halting at approximately 10% unconverted compound 16. Reducing the catalyst amount to 1 mol% increased the conversion to approximately 97% after 20 hours, although the reaction was slower than the previous batch. Without being bound by any particular theory, it was speculated that some residual catalyst in compound 23 resulted in a more effective catalyst in the Suzuki coupling. Therefore, boronate formation in the Suzuki coupling reaction was tested with purified boronate compound 23 containing 0.5 mol% PdCl(dppf) catalyst, and the desired conversion was obtained after 3 hours at 60–65 °C. Reducing the catalyst amount to 0.1 mol% resulted in incomplete conversion even after 20 hours. To isolate compound 24, a reaction performed with PdCl2(PCy3)2 was observed to yield 80% of compound 24 by adding n-heptane after phase separation, omitting azeotropic distillation, and aging at 10 °C. The same procedure, applying azeotropic distillation before adding n-heptane, yielded 83% of compound 24. Further addition of n-heptane at 60 °C without phase separation and cooling to room temperature afforded 85% of compound 24. This last step was repeated with a reaction performed with PdCl2(dppf), and it was observed that aging time had a significant effect on yield. While aging for only 1 hour yielded only 82% of compound 24, aging for 15 hours yielded 87% of compound 24. The Pd levels observed in the product were approximately 100–150 ppm. Because this material was intended for clinical trials, the Pd level in the active pharmaceutical ingredient was limited to a maximum of 10 ppm. Treatment with 0.1 equivalents of N-acetyl-cysteine ​​at 60 °C for 30 min prior to the addition of n-heptane reduced Pd levels to less than 10 ppm. Hydrolysis product impurities, observed at levels up to 0.52% with PdCl(PCy), were consistently less than 0.08% in reactions performed with PdCl(dppf). Boronate dimer impurities were observed at less than 50 ppm in the isolated compound 24.The sulfoxide impurity present in compound 16 at 0.2% (see Example 9) reacted much slower than compound 16 under the conditions of the Suzuki reaction. The Suzuki product of the sulfoxide impurity was observed in compound 24 at levels less than 0.1%, and the sulfoxide impurity content was below the reporting limit. At the 40 kg scale, crystallization did not occur spontaneously, and seeding was performed after the addition of N-acetylcysteine. Pyrido-pyrimidine compound 24 was isolated in 84% yield, 99.3 wt. % assay, with Pd levels below 5 ppm.

[0551] The impurities are as follows: JPEG0007805356000128.jpg61170

[0552] Example 11

[0553] Aromatic nucleophilic substitution (S N Ar)

[0554] In a prior art method, pyrido-pyrimidine compound (24) was replaced with difluoropyrrolidine compound (28) in the presence of K3PO4 in NMP at 130 °C, and the product compound (1) was isolated by precipitation with the addition of a large amount of water. This reaction was heterogeneous, and the particle size of the K3PO4 affected the impurity profile of crude compound (1). NMP has been identified as a SVHC. Experiments were conducted to find alternative solvents and base-solvent combinations that would produce a homogeneous reaction mixture. Initially, a base screen was performed in NMP: pyridine and triethylamine only provided moderate conversion after 17 h and a large amount of hydrolysis product impurity. Tetramethylguanidine (TMG) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) achieved complete conversion within 20 h. The reaction mixture containing TMG was a dark brown, cloudy suspension, and after the addition of water, only a moderately pure product (19%) was isolated. The reaction mixture with DBU was a pale beige suspension, and upon addition of water, 42% clean material was obtained. Therefore, DBU was chosen as the basis for further optimization according to the following scheme. JPEG0007805356000129.jpg54170

[0555] A solvent screen using DBU was performed, and the results are reported in Table 3. Runs 1–10 used 2.5 equivalents of compound 28 and 5.0 equivalents of DBU in 4 mL of solvent per gram of compound 24. Run 9 was performed in a sealed vessel. Run 11 used 2.5 equivalents of compound 28 and 2.4 equivalents of DBU in 4 mL of solvent per gram of compound 24. The remaining runs used 2.1 equivalents of compound 28 and 2.0 equivalents of DBU in 6 mL of solvent per gram of compound 24. Acetonitrile resulted in less than 50% conversion after 18 hours (Run 1). Without being bound to any particular theory, it is believed that the low boiling point of acetonitrile led to the low conversion. DMSO at 125 °C showed over 90% conversion in 8.5 h, but safety concerns regarding the reaction of DMSO with base at high temperatures limited further development at temperatures below 100 °C, where only 90% conversion was achieved after 24 h (Tests 2 and 3). In benzonitrile, cyclohexanone, 1,3-dichlorobenzene, and xylene at 125 °C, conversion was less than 90% after 17 h (Tests 4–7). Toluene and anisole at 120 °C (Tests 9 and 10), and mesitylene at 125 °C (Test 11) showed over 95% conversion after 20, 23, and 22 h, respectively.

[0556] [Table 3]

[0557] With toluene, anisole, and mesitylene, the reaction mixture was biphasic, with a lower product phase and an upper solvent phase. Product isolation from the toluene reaction was achieved by cooling to 50 °C, adding water, and then cooling to room temperature. The resulting suspension was very dense and difficult to stir, so several experiments were performed to identify a more suitable crystallization solvent. The phases of the toluene reaction mixture were separated, and the product phase was diluted with acetonitrile, isopropanol, and acetone at 80 °C, then treated with water and cooled. Acetonitrile and isopropanol produced a suspension that formed a mass upon cooling, while acetone gave a sticky precipitate. Addition of only isopropanol or n-propanol to the product phase produced good suspensions. n-propanol resulted in slightly higher yields and purities, which were also achieved by simply adding n-propanol to the biphasic mixture and selecting n-propanol for further reaction optimization.

[0558] Because higher temperatures result in faster conversions, mesitylene was selected over toluene for further optimization. Experiments with the addition of several base additives are summarized in Table 4. In experiments 1–4, 2.5 equivalents of compound 28 were heated in 4V mesitylene at 125°C for 19–22 hours using an equimolar amount of additive relative to DBU, followed by the addition of n-PrOH, cooling to room temperature, and overnight aging. Experiment 5 was performed similarly, except that 2.0 equivalents of compound 28 were used. Reaction with 2.5 equivalents of compound 28 and 2.4 equivalents of DBU afforded 55% crude compound 1 after precipitation with n-propanol (Experiment 1). Addition of an equimolar amount (based on DBU) of DABCO (Experiment 2) resulted in complete conversion, but the isolated yield was low. 2,6-lutidine (Experiment 3) showed a slightly positive effect on the yield. iPr2EtN (Run 4) induced both complete conversion and a significantly better yield of 80%. Reducing the amount of base to 1.9 equivalents and the amount of compound 28 to 2.0 equivalents resulted in a conversion of over 98% and an isolated yield of 75% (Run 5). Following this observation, liquid amine base was tried as the solvent.

[0559] Table 4

[0560] Tri-n-butylamine and di-n-butylamine were tested at 110 °C (Table 3, Runs 12 and 13). Di-n-butylamine showed nearly 95% conversion in 23 h, while tri-n-butylamine showed less than 90% conversion. Increasing the temperature to 125 °C in di-n-butylamine (Table 3, Run 14) resulted in complete conversion in 15 h, and 81.5% of compound (1) was isolated by crystallization after the addition of n-propanol with an area purity approaching 98.3%. The crystals were off-white, offering the possibility of avoiding charcoal filtration before final crystallization. Reducing the amount of compound (28) and DBU to 1.5 equivalents achieved the desired conversion at 125 °C after 20 h with comparable yields. The starting material was mixed with 4 volumes of di-n-butylamine alone. The reaction mixture was a suspension at lower temperatures but turned into a clear emulsion at the reaction temperature. Crystallization was induced by the slow addition of n-propanol at 95°C and further cooling to 20°C. Further cooling to 0°C did not improve the yield. Crystallization effectively purged the remaining starting material compound (24). Levels up to 1.75% were purged at less than 0.20%. Several impurities formed during this step, as shown below: The di-n-butyl analog impurity formed at levels up to 6% and purged at less than 0.10%. The n-butyl and n-pentyl analog impurities, arising from impurities present in di-n-butylamine, formed at low levels and purged at less than 0.20% in the isolated product. The monofluoro and desfluoro analog impurities are downstream products of the impurities present in 3,3-difluoropyrrolidine. The desfluoro analog impurity may also form during the reaction and was always observed below the reporting limit in the crude compound (1). The substitution product impurity of compound 24 with 1-(3-aminopropyl)azepan-2-one, the hydrolysis product of DBU (potentially present as an impurity in DBU), and a dimer impurity formed as a by-product of the reaction were also observed, all present at less than 0.1% in crude compound 1.On a 50 kg scale, an optimized process involving the addition of 1.5 equivalents each of compound (28) and DBU in di-n-butylamine at 125 °C for 20 hours, followed by the addition of n-propanol to induce crystallization, yielded 99.5 wt% of compound (1), with all impurities at less than 0.10% and 75% purity. JPEG0007805356000132.jpg186170

[0561] Example 12: Recrystallization

[0562] Form A is the only known crystalline modification of the free base of Compound (1), and the solubilities shown in Table 5 below refer to this form. Furthermore, crystal structure prediction (CSP) ranked a structure equivalent to Form A as the most thermodynamically stable modification at ambient conditions. The risk of obtaining an alternative form was considered very low. Nevertheless, seeding was used as a method to allow consistent crystal growth conditions and obtain reproducible particle size distributions at the end of crystallization.

[0563] The prior art method for preparing compound (1) uses isopropyl acetate for the final crystallization, resulting in an 84% yield at a relatively low concentration of 3.0 wt%. Therefore, efforts were made to identify alternative solvents or solvent mixtures to improve the productivity of the final step. It was known that the solubility of GDC-0134 in alcohol was too low, reducing the list of possibilities based on previous qualitative experimental data and solubility predictions (numerical simulations). From a process design perspective, simple cooling crystallization is preferred over other designs, such as antisolvent or evaporative crystallization, especially for easier process control. Therefore, a large ratio of solubility between the two temperature levels is desirable. Primarily esters, but also acetonitrile, methyl isobutyl ketone (MIBK), and 2-MeTHF were shortlisted for accurate solubility determination. The solubility of compound (1) in these solvents is shown in Table 5 for 0 °C and their respective maximum process temperatures. The calculated maximum solids concentration and theoretical yield are shown in Table 6. For MeOAc, EtOAc, n-PrOAc, and 2-MeTHF, the solubility at 0 °C is quite high, making them poor alternatives to iPrOAc from the EiH process in terms of yield and concentration. Although solubility in acetonitrile is very low even at high temperatures, mixtures of 2-MeTHF and acetonitrile show synergistic effects, at least for 1:1 mixtures. The solubility at 70 °C is the highest among the systems examined, with theoretical yields approaching 90%. Due to concerns about efficient removal of acetonitrile to acceptable levels after drying, 2-MeTHF / acetonitrile mixtures were not further investigated. MIBK provided the highest theoretical yield and a significant increase in concentration compared to iPrOAc and was selected for more detailed investigation.

[0564] [Table 5]

[0565] [Table 6]

[0566] Seeded cooling crystallization was performed to directly compare experimental yields. The results are shown in Table 7. At a cooling rate of 12 K / h, a short equilibration time at the isolation temperature resulted in yields significantly below those expected for both isopropyl acetate (Run 1) and MIBK (Run 2). Extended equilibration times (Runs 3 and 4) resulted in much higher yields. The crystallization experiments demonstrate that the use of MIBK is superior to isopropyl acetate in terms of yield. Apart from productivity, impurity removal was another very important aspect. For purity evaluation, poor-quality crude compound (1) (98.9 area % HPLC) was used. The cooling rate in Run 6 was 3 K / h from 80 to 40 °C and 6 K / h from 40 to 0 °C. It is known that crystallization conditions can have a significant impact on product quality. For example, the use of a different solvent, rapid cooling, or exceeding the critical yield can adversely affect purity. However, in the experiments shown in Table 7, this was minimal. As a result, there is less depletion of impurities and no data linking MIBK.

[0567] [Table 7]

[0568] Examples 8 to 12 are summarized in the following scheme. JPEG0007805356000136.jpg114170

[0569] The improvement in freshness from the prior art method to the disclosed and exemplified method was evaluated. The PMI for both methods was calculated and the results are shown in Table 8. The total input of ingredients was reduced by more than 40% in the present method. N The Ar step and final crystallization contributed significantly to the improvement, as the material inputs were reduced by 60% and 50%, respectively. Focusing on the solvents used, both SVHC solvents DMF and NMP were eliminated in this process, and only water and sustainable solvents were used. The total amount of solvent used was reduced by one-quarter, and the total amount of water input by two-thirds.

[0570] [Table 8]

[0571] The PMI was calculated for each of steps 1 to 5 shown in the above method scheme. The results are shown in Table 9.

[0572] [Table 9]

[0573] The disclosed method for producing compound (1) offers improved safety and freshness while delivering compound (1) in excellent purity in 43.5% overall yield (steps 1-5) compared to prior art methods. N The DMF used in the prior art method for the Ar reaction was replaced with environmentally friendly ethanol. The safety and speed of the oxidation to sulfone were increased by administering at elevated temperatures, avoiding the accumulation of highly reactive hydrogen peroxide and shortening the reaction time from over 3 days to 6 hours. A more efficient catalyst for Suzuki coupling was identified, and azeotropic distillation was avoided by adding n-heptane without phase separation. A second prior art S N Replacing NMP in the Ar reaction with di-n-butylamine provided a cleaner reaction and yielded crude compound (1) of high purity. Finally, crystallization to pure compound (1) from MIBK was performed without prior charcoal treatment. Using MIBK instead of isopropyl acetate allowed the final crystallization to be performed at a higher temperature. This method has a significantly lower environmental impact than prior art methods, with a PMI reduction of over 40%. Utilizing this, 150 kg of API was successfully produced to support clinical trials per Example 13 below.

[0574] Example 13

[0575] Steps 1 to 5 of Examples 8 to 12 were scaled up.

[0576] Example 13A: Synthesis of (1S,4S)-5-(6-chloro-2-methylsulfanyl-pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (Compound 11)

[0577] To a solution of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane (compound 5) (40.6 kg, 0.30 kgmol) and 4,6-dichloro-2-methylsulfanyl-pyrimidine (compound 10) (52.0 kg, 0.27 kgmol) in ethanol (395 kg) at 31–34 °C, triethylamine (65.0 kg, 0.64 kgmol) was added within 120 min, and the addition vessel was rinsed with ethanol (9.0 kg). The resulting suspension of compound 11 was stirred at 32–34 °C for at least 3 h. When in-process control testing (IPC) indicated that the reaction was essentially complete, the suspension was cooled to 22 °C within 3 h, and water (315.0 kg) was added with stirring within 40 min. The suspension was further stirred at 22°C for at least 3 hours, and the precipitate was isolated by centrifugation, washed with a mixture of ethanol (28.0 kg) and water (213.0 kg), and dried under reduced pressure at 45°C for 7 hours to give 61.6 kg of compound 11 (90% yield, 99.9 wt%, HPLC assay) as a white solid. 1 H NMR(600 MHz,CDCl3)δ ppm 5.72-6.28(m,1 H),5.21(br s,1 H),4.72(br s,1 H),3.78-3.93(m,2 H),3.18-3.48(m,2 H),2.49(s,3H),1.80-2.13(m,2H). 13 C NMR(151 MHz,CDCl3)δ ppm 172.1,160.2,159.1,97.0,76.1,73.8,56.6,55.2,36.4,14.1.C 10 H 12 HRMS calculated for ClN3OS: 257.0395; found: 297.0395. 1 H NMR, 13 C NMR and 19F NMR spectra were measured on a Bruker 600 MHz NMR spectrometer at 600, 150, and 565 MHz, respectively. Relative chemical shifts are reported in ppm relative to TMS.

[0578] Example 13B: Synthesis of (1S,4S)-5-(6-chloro-2-methylsulfonyl-pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (Compound 16)

[0579] At 60 °C, compound 11 (47.3 kg, 0.18 kgmol) and Na2WO4 . To a suspension of 2H2O (0.61 kg, 1.85 mol) in methanol (368 kg) and water (241 kg), 35% H2O2 (40.8 kg, 0.42 mol) was added within 4 hours. The O2 level in the reactor was controlled at a limit of 5% or less. The feed tank was rinsed into the reaction vessel with water (10.6 kg), and the suspension was stirred at 60 °C for 3 hours. When the IPC was met, the reaction mixture was cooled to 22 °C within 75 minutes. 38% aqueous NaHSO3 solution (47.8 kg) was added within 20 minutes, and the feed tank was rinsed into the vessel with water (5.4 kg). The solution was stirred at 22 °C for 3 hours. The precipitate of compound 16 was collected by centrifugation, and water (168 kg) was used to ensure complete transfer, and the filter cake was washed with water (483 kg). Compound 16 was dried under reduced pressure (45-7 mbar) at 45° C. for 5 hours to give 47.6 kg of compound 16 (89.3% yield, 99.6% w / w HPLC assay) as a white solid. 1 H NMR (600 MHz, CDCl3), Main rotamer: δ ppm 6.31(s,1 H),5.33(s,1 H),4.79(s,1 H),3.80-4.01(m,2 H),3.37-3.45(m,2 H),3.28(s,3H),1.78-2.07(m,2H). Trace amount of rotamer: δ ppm 6.51(s,1 H),4.75(br s,1 H),4.51(br s,1 H),3.80-4.01(m,2 H),3.37-3.45(m,2 H),3.28(s,3H),1.98-2.16(m,2H). 13C NMR(151 MHz,CDCl3)δ ppm 165.7,160.8,160.5,159.9,104.0,103.5,75.9,75.5,73.7,72.9,57.7,57.6,56.6,55.6,38.8,38.7,37.1,36.5.C 10 H 12 HRMS calculated for ClN3O3S: 289.0288, found: 289.0292.

[0580] Example 13C: Synthesis of 3-(difluoromethoxy)-5-[2-methylsulfonyl-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyridin-2-amine (Compound 24)

[0581] To a suspension of compound 16 (47.5 kg, 0.164 kgmol), 3-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (compound 23) (54.0 kg, 0.189 kgmol), and KCO (68.0 kg, 0.492 kgmol) in THF (510 kg) and water (165.0 kg) in a feed tank, PdCl(dppf) (0.60 kg, 0.82 mol) was added at 20 °C. The reaction mixture was heated to 63 °C within 1 hour and stirred at this temperature for 3 hours. According to the IPC standard, the reaction mixture was cooled to 58 °C, and a solution of N-acetyl-cysteine ​​(2.8 kg, 0.017 kgmol) in water (20.2 kg) was added within 15 minutes. The feed tank was rinsed with water (9.6 kg) and stirring was continued for 2 hours. The reaction mixture was seeded with compound 24 (160 g) and stirring was continued for 75 minutes. n-Heptane (97.0 kg) was added with stirring within 40 minutes, and the suspension was cooled to 22 °C within 3 hours and stirred at 22 °C for 6 hours to form a precipitate of compound 24. The precipitate was isolated by centrifugation, washed with a mixture of THF (189.2 kg) and water (191.2 kg), and dried under reduced pressure at 45 °C for 9.5 hours to give 57.0 kg of compound 24 (84% yield, 99.3 wt %, HPLC assay) as a white solid. 1H NMR(600 MHz,CDCl3)δ ppm 8.56(d,J=2.0 Hz,1 H),7.96(s,1H),6.51(br s,1 H),6.46-6.74(m,1 H),5.38(br s,1 H),5.08(s,2 H),4.80(br s,1 H),3.88-3.94(m,2 H),3.41-3.61(m,2 H),3.34(s,3H),2.06(br d,J=8.7 Hz,1 H),1.94(br d,J=9.4 Hz,1 H). 13 C NMR(151 MHz,CDCl3)δ ppm 165.7,160.9,160.7,153.3,144.0,133.1,124.8,122.9,116.0,98.0,76.1,73.9,57.1,55.6,38.7,36.5. 19 F NMR(565 MHz,CDCl3)δ ppm-80.61(d,J=73.0 Hz,2 F),C 16 H 17 HRMS calculated for F2N5O4S: 413.0969, found: 413.0975.

[0582] Example 13D: Synthesis of Compound 1

[0583] To a suspension of compound 24 (64.0 kg, 0.155 kgmol) and 3,3-difluoropyrrolidine hydrochloride (compound 28) (33.2 kg, 0.231 kgmol) in di-n-butylamine (197.4 kg) at 25°C, DBU (35.5 kg, 0.233 kgmol) was added within 20 minutes (exothermic). The resulting suspension was heated to 125°C within 10 hours and aged at this temperature for 20 hours. To comply with IPC compliance, n-propanol (205.0 kg) was added within 35 minutes while maintaining the internal temperature above 90°C to form a solution. The solution was heated to 103°C, stirred for 15 minutes, and then cooled to 20°C within 7 hours. After stirring for an additional 30 min at 20°C, the solid was isolated by centrifugation, washed with n-propanol (114 kg), and dried under reduced pressure at 45°C for 6 h to give 51.9 kg of compound 1 (76% yield, 99.5%, HPLC assay) as a pale yellow solid. 1H NMR(600 MHz,CDCl3)δ ppm 8.52(d,J=1.8 Hz,1 H),7.96(s,1H),6.55(7,J=73.3 Hz,1 H),5.98(br s,1 H),4.96(s,3 H),4.71(s,1 H),3.96(br t,J=13.3 Hz,2 H),3.88(s,2 H),3.84(br t,J=7.3 Hz,2 H),3.50(br d,J=9.1 Hz,2 H),2.43(tt,J=13.8,7.1 Hz,2 H),1.87-2.07(m,2 H). 13 C NMR(151 MHz, CDCl3)δ ppm 161.6,160.3,160.1,152.4,143.5,133.2,128.1,125.6,124.8,116.2,88.2,76.4,73.7,56.3,55.4,53.5,43.8,36.4,34.2. 19 F NMR(565 MHz,CDCl3)δ ppm-80.19(d,J=73.0 Hz,2 F),-100.65(quin,J=13.2 Hz,2 F),C 19 H 20 For F4N6O2, HRMS calculated: 440.1584, found: 440.1588.

[0584] Example 13E: Purification of Compound 1

[0585] Crude Compound 1 (42.9 kg, 97.4 kgmol) was charged to a reactor along with MIBK (610.0 kg). The reactor contents were heated to 90°C to form a solution. The solution was polish filtered, and MIBK (120.4 kg) was poured through the filter. This portion of the solvent was then substantially removed by vacuum distillation. The solution was cooled to 75°C to achieve supersaturation, after which a seed suspension (0.17 kg of Compound 1 Form A in 4.2 kg of MIBK) was added. The suspension was aged at 75°C for 1 hour, then cooled to -10°C within 7 hours and aged for 6 hours. The Compound 1 wet cake was isolated by centrifugation. The wet cake was washed with MIBK (109.8 kg) in a first step and with ethanol (54.0 kg) in a second step. The wet Compound 1 product was dried under full vacuum at 45°C for 2 hours and then at 60°C for 4 hours until an end point in the residual solvent was reached. This process yielded 36.8 kg of purified Compound 1 (85% yield, 99.9% by weight, HPLC assay) as an almost white solid.

[0586] Example 14: Crystallinity and thermal analysis evaluation

[0587] In Example 14, for X-ray powder diffraction ("XRPD"), a sample of Compound 1 was prepared in an open quartz glass capillary with a diameter of 0.9 mm (without further processing such as grinding). Each temperature condition was controlled by a STOE low-temperature-high-temperature attachment (operating range -50 to 300°C) equipped with a NiCr / Ni thermocouple for temperature measurement. Measurements were performed using a rotating capillary tube and the following parameters: STOE STADI diffractometer; MYTHEN 1K detector; CuKα, 1.5406 Å radiation; Ge monochromator, 40 kV, 40 mA; translation scan; 1800 sec / step; 2θ = 3-42 degrees; 5°C / min ramp rate; and 5°C temperature step.

[0588] Compound 1 was prepared from crude Compound 1 according to the following procedure. Crude Compound 1 (46 kg) was dissolved in 1080 kg of isopropyl acetate at 88.6 °C. After cooling to 71 °C, the solution was passed through a pre-washed and pre-heated charcoal filter. The charcoal filter was rinsed with 400 kg of hot isopropyl acetate. The combined filtrate was concentrated under reduced pressure to a total volume of 760–780 L. The resulting suspension was heated to 88 °C. Isopropyl acetate was then added in small portions (85 kg total) and completely dissolved at 88 °C. The solution was cooled to 69 °C to obtain a suspension, which was then cooled to 0 °C within 190 min and stirred at this temperature for 900 min. The product was isolated by filtration and rinsed with portions of cold isopropyl acetate (400 kg total). After drying at 465 °C / 10 mbar for approximately 40 h, 38.5 kg (approximately 84% of the theoretical yield) of crystalline Compound 1 was obtained.

[0589] Crystalline Compound 1 was evaluated. The crystallization test procedure was based on the solubility of Compound 1 in the solvent being evaluated as follows: If the solubility at 22°C was greater than 50 mg / mL, crystallization was evaluated by evaporation crystallization at 22°C, addition of antisolvent (n-heptane) at 22°C, and cooling crystallization from 22°C to 0°C or to -20°C for 8 hours. If the solubility was less than 50 mg / mL at 22°C but greater than 50 mg / mL at 65°C, crystallization was evaluated by evaporation crystallization at 65°C, addition of antisolvent (n-heptane) at 65°C, and cooling crystallization from 65°C to 22°C or to -20°C for 8 hours. If the solubility at 22°C and 65°C was less than 50 mg / mL, crystallization was evaluated by slurry equilibration at 22°C for 14 days or more and slurry equilibration at 65°C for 14 days or more.

[0590] The results are shown in Table 10 below. * refers to compound 1 prepared as above, ** refers to Compound 1 prepared as above and further incubated at 22° C. for 17 days at 100% relative humidity.

[0591] [Table 10]

[0592] Single crystals of Compound 1, Form A, were prepared as follows: 98 mg of recrystallized Compound 1 was suspended in 5 mL of isopropyl acetate at ambient temperature. 1 mL of the clear supernatant was transferred to a 2 mL vial. This 2 mL vial was then placed in a 15 mL vial containing 2 mL of ethanol as an antisolvent. After closing the 15 mL vial, the system was stored for 12 days for vapor diffusion crystallization. Single crystals were then isolated and analyzed by single crystal X-ray diffraction, confirming Form A.

[0593] Amorphous Compound 1

[0594] Amorphous Compound 1 can be prepared by rapidly cooling a melt of Compound 1. 194 mg of Compound 1 was melted in a glass vial by heating to about 214° C. to about 224° C. The molten material was rapidly cooled by immersing the glass vial in liquid nitrogen to form amorphous Compound 1, as confirmed by XRPD.

[0595] Amorphous Compound 1 can be converted to Form A by heating to a temperature above 70° C., above the glass transition temperature, followed by cooling and crystallization.

[0596] Mechanical stress evaluation of compound 1

[0597] Micronization

[0598] Compound 1, prepared generally according to the method of Example 5, was evaluated for changes in induced mechanical stress conditions, crystallinity was evaluated by XRPD, and thermal analysis properties were measured by differential scanning calorimetry ("DSC"), thermogravimetric analysis ("TGA"), and dynamic vapor sorption ("DVS").

[0599] In the first evaluation, Compound 1 was micronized by jet milling and evaluated by XRPD and DSC. Jet milling was determined to have no significant effect on the crystallinity as determined by SRPD and only a minor effect on the thermal analysis data, as shown in Table 11 below.

[0600] [Table 11]

[0601] Dry Granulation

[0602] To simulate the shear stress encountered during dry granulation, approximately 500 mg of Compound 1 was dry-milled for approximately 5 minutes at ambient conditions using a mortar and pestle. As shown in Figure 2, pattern (d), XRPD analysis of the sample after such treatment showed no decrease in crystallinity compared to untreated Compound 1 (Figure 2, pattern (a)). Furthermore, thermal analysis data measured by DSC, TGA, and DVS were slightly different from the starting material of Compound 1 (see Table 12 below).

[0603] Tableting

[0604] The effect of pressure was investigated to determine whether Compound 1 undergoes a phase transformation during tableting. Conditions were 1.8T / 5mm compact, 900 MPa, approximately 30 mg of Compound 1, and a residence time of approximately 6 seconds. Tablets were analyzed without further processing and after gently crushing the tablets with a pestle. Some reduction in crystallinity was observed by XRPD analysis, regardless of whether the tablets were crushed. Pattern (b) in Figure 2 is the XRPD pattern of a crushed tablet. Pattern (c) in Figure 2 is the XRPD pattern of an uncrushed tablet.

[0605] Thermal analysis showed that the total weight loss during the TGA measurements was somewhat higher than the starting material, but DVS measurements showed no significant increase in hygroscopicity for the compressed samples (see Table 12 below).

[0606] Wet grinding

[0607] To simulate wet milling, a wet manual milling experiment was performed. Approximately 500 mg of compound 1 and approximately 0.5 mL of water were mixed in a mortar and pestle for approximately 5 minutes. Approximately 100 mg of the wet material was analyzed by XRPD. The remainder of the material was dried overnight in an oven at 50 °C and ambient pressure. The dried material was analyzed by SRPD, DSC, TGA, and DVS.

[0608] XRPD after manual wet-milling (see pattern (e) in Figure 2) and after thermal drying of the wet-milled material (see pattern (f) in Figure 2) showed no decrease in the crystallinity of the compound. Furthermore, the thermal analysis data measured by DSC, TGA, and DVS were slightly different from the starting material of Compound 1 (see Table 12 below).

[0609] [Table 12]

[0610] This written description uses examples to disclose the invention, including the best mode, and to enable any person skilled in the art to practice the invention, including making and using any device or system, and performing any incorporated methods. The patentable scope of the invention is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they contain equivalent structural elements that have no substantial difference from the literal language of the claims.

[0611] It is to be understood that the present invention is not limited to the particular embodiments and aspects of the disclosure described above, and therefore variations of the particular embodiments and aspects can be made and are within the scope of the claims. All documents cited or relied upon herein are expressly incorporated by reference.

Claims

1. 1. A method for preparing Compound 1, said method comprising the steps of: (1) The following scheme reacting compound (vii) with compound (i) in the presence of a solvent and an organic base to form a reaction mixture comprising compound (ii) according to the solvent is selected from the group consisting of dimethyl sulfoxide, acetonitrile, and ethanol; the equivalent ratio of the organic base to compound (vii) is 2.2:1 to 2.6:1; (2) The following reaction scheme According to the method described above, sodium tungstate dihydrate (Na ２ WO ４ ・2H ２ Oxidizing compound (ii) with hydrogen peroxide in the presence of O to form a reaction product mixture comprising compound (iii); adding said hydrogen peroxide to said reaction product mixture from step (1), wherein the equivalent ratio of hydrogen peroxide to compound (ii) is from 2:1 to 3.5:1; (3) The following scheme (i) carrying out Suzuki coupling of compound (iii) with compound (iva) in the presence of an alkali metal carbonate base, a palladium catalyst, and a solvent to form a reaction product mixture compound (v); and (ii) adding a catalyst scavenger to the reaction product mixture to scavenge palladium, according to the method of The solvent is tetrahydrofuran and water, and the palladium catalyst is PdCl ２ (dppf); and (4) The following reaction scheme reacting compound (v) with compound (vi) in the presence of at least one organic base and a solvent to form a reaction product mixture comprising compound 1 according to the at least one organic base is selected from the group consisting of 1,1,3,3-tetramethylguanidine and 1,8-diazabicyclo[5.4.0]undec-7-ene, and the solvent is selected from the group consisting of toluene, anisole, mesitylene, diethylamine, di-n-propylamine, di-isopropylamine, di-n-butylamine, and combinations thereof. A method comprising:

2. 2. The method according to claim 1, wherein in step (1), the solvent is ethanol, the organic base is triethylamine, and the reaction temperature is 30°C to 40°C.

3. Regarding step (2), The hydrogen peroxide is added over a period of 4 to 6 hours; The reaction temperature is 55°C to 65°C; The Na ２ WO ４ However, in methanol and water, Na ２ WO ４ ・2H ２ The method of claim 1 or 2, wherein the hydroxyl group is O.

4. A method according to any one of claims 1 to 3, wherein for step (2), hydrogen peroxide is added in two or more additions during the course of the reaction, and 1.5 to 2.5 equivalents of hydrogen peroxide are added within the first 3 hours of the reaction.

5. Regarding step (3), The equivalent ratio of the alkali metal carbonate base to the compound (iii) is 3:1, and the alkali metal carbonate base is K ２ CO ３ or Na ２ CO ３ and The content of the palladium catalyst is 0.5 mol% based on the compound (iii); the catalyst scavenger is N-acetylcysteine; The process according to any one of claims 1 to 4, wherein the reaction temperature is from 55°C to 65°C.

6. 6. The method of any one of claims 1 to 5, wherein for step (3), compound (v) is isolated from the reaction product mixture by the following order of steps: adding seed crystals to the reaction product mixture; adding n-heptane; cooling to form a slurry comprising solid compound (v); and isolating solid compound (v).

7. Regarding step (4), the solvent is di-n-butylamine; the at least one organic base further comprises a second base selected from the group consisting of 2,6-lutidine, di-isopropylethylamine, and 1,4-diazabicyclo[2.2.2]octane; The process according to any one of claims 1 to 6, wherein the reaction temperature is from 115°C to 125°C.

8. 8. The method of any one of claims 1 to 7, further comprising isolating Compound 1 from the reaction product mixture by the following order of steps: adding to the reaction product mixture an anti-solvent selected from the group consisting of isopropanol and n-propanol; cooling to form a slurry comprising solid Compound 1; and isolating solid Compound 1.

9. The method further comprises the steps of: forming a supersaturated solution of Compound 1 and methyl isobutyl ketone; seeding the supersaturated solution with crystalline Compound 1 Form A; cooling the solution to form a slurry comprising crystalline Compound 1 Form A; and isolating crystalline Compound 1 Form A from the slurry, wherein crystalline Compound 1 Form A is obtained at 7.7±0.05(°2θ), 12.1±0.05(°2θ), 16.2±0.05(°2θ), 16.4±0.05(°2θ), 16.6±0.05(°2θ), 17.1±0.

9. The method of any one of claims 1 to 8, wherein the compound has an X-ray powder diffraction pattern (CuKα, 1.5406 Å radiation) with at least ten peaks at positions selected from the group consisting of 18.8±0.05 (°2θ), 19.4±0.05 (°2θ), 19.8±0.05 (°2θ), 20.3±0.05 (°2θ), 20.5±0.05 (°2θ), 23.3±0.05 (°2θ), 24.7±0.05 (°2θ), 25.3±0.05 (°2θ), and 26.5±0.05 (°2θ).

10. A process for preparing Form A of crystalline Compound 1, comprising: (1) The following reaction scheme reacting compound (vii) with compound (i) in the presence of ethanol and triethylamine to form compound (ii) according to the equivalent ratio of trimethylamine to compound (vii) is 2.4:1; (2) The following reaction scheme According to the method described above, sodium tungstate dihydrate (Na ２ WO ４ ・2H ２ Oxidizing compound (ii) with hydrogen peroxide in the presence of O to form a reaction product mixture comprising compound (iii); adding the hydrogen peroxide to the reaction product mixture from step (1) over a period of 4 to 6 hours, the equivalent ratio of hydrogen peroxide to compound (ii) being 3:1; (3) (i) The following scheme According to K. ２ CO ３ or Na ２ CO ３ (ii) adding N-acetylcysteine ​​to the reaction product mixture to scavenge palladium, K for compound (iii) ２ CO ３ or Na ２ CO ３ is an equivalent ratio of 3:1 and the PdCl2(dppf) content is 0.5 mol% based on compound (iii); (4) The following reaction scheme reacting compound (v) with compound (vi) in the presence of at least one base and a solvent to form a reaction product mixture comprising compound 1 according to the at least one base is selected from the group consisting of 1,1,3,3-tetramethylguanidine and 1,8-diazabicyclo[5.4.0]undec-7-ene; the solvent is selected from the group consisting of toluene, anisole, mesitylene, diethylamine, di-n-propylamine, di-isopropylamine, di-n-butylamine, and combinations thereof; (5) isolating Compound 1 from the reaction product mixture of step (4) by the following steps, in order: adding an anti-solvent selected from isopropanol and n-propanol to the reaction product mixture; cooling the reaction product mixture to form a slurry containing solid Compound 1; and isolating solid Compound 1 from the reaction product mixture; and (6) forming a supersaturated solution of Compound 1 and methyl isobutyl ketone; seeding the supersaturated solution with crystalline Compound 1 Form A; cooling the solution to form a slurry comprising crystalline Compound 1 Form A; and isolating crystalline Compound 1 Form A from the slurry. Including, Form A of crystalline Compound 1 exhibited the following peaks: 7.7±0.05 (°2θ), 12.1±0.05 (°2θ), 16.2±0.05 (°2θ), 16.4±0.05 (°2θ), 16.6±0.05 (°2θ), 17.1±0.05 (°2θ), 18.8±0.05 (°2θ), 19.4±0.05 (°2θ), 19.8±0.05 (°2θ), 20.3± 0.05 (°2θ), 20.5±0.05 (°2θ), 23.3±0.05 (°2θ), 24.7±0.05 (°2θ), 25.3±0.05 (°2θ), and 26.5±0.05 (°2θ).

11. 11. The method of claim 10, wherein for step (2), hydrogen peroxide is added in two or more additions over the course of the reaction, and 1.5 to 2.5 equivalents of hydrogen peroxide are added within the first 3 hours of the reaction.

12. In step (3), the reaction temperature is 55°C to 65°C; ２ WO ４ However, in methanol and water, Na ２ WO ４ ・H ２ The method of claim 10 or 11, wherein the hydroxyl group is O.

13. 13. The method of any one of claims 10 to 12, wherein compound (v) is isolated from the reaction product mixture by the following order of steps for step (3): adding seed crystals to the reaction product mixture; adding n-heptane to the reaction product mixture; cooling the reaction product mixture to form a slurry comprising solid compound (v); and isolating solid compound (v).

14. 14. The method of any one of claims 10 to 13, wherein for step (4), the solvent is di-n-butylamine, the at least one base further comprises a second base selected from the group consisting of 2,6-lutidine, di-isopropylethylamine, and 1,4-diazabicyclo[2.2.2]octane; and the reaction temperature is 115°C to 125°C.

15. A method for preparing Compound 1, said method being as follows:

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