Synthesis of KIF18A inhibitors

Abstract

The present invention relates to an improved preparation of KIF18A inhibitors having the chemical structure compound (1), or salts thereof, compound (1a), wherein HA is as defined herein, as well as key intermediates thereof, namely, compound (2a), compound (3a), compound (5) or salts thereof, and compound (6a) or hydrates thereof, preferably compound (6a-1), of the formulas: compound (2a), compound (3a), compound (5) or salts thereof, and compound (6a) or hydrates thereof. The present invention further relates to solid forms of compound (6a), preferably crystalline hydrate forms of compound (6a-1). [Formula 1] TIFF2025505892000080.tif42165 [C2] TIFF2025505892000081.tif42165 [3] TIFF2025505892000082.tif84165 [C4] TIFF2025505892000083.tif22165

Description

[Technical field]

[0001] The present invention relates to an improved, efficient and scalable process for preparing KIF18A inhibitor compound, i.e., N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (compound 1), or a pharma- ceutically acceptable salt thereof, which is carried out in a batchwise process, a continuous process, or a mixture thereof. The present invention also relates to the preparation of a key intermediate compound useful for preparing compound 1 or a pharma- ceutically acceptable salt thereof. The present invention further relates to a solid form of compound 6a, preferably a crystalline hydrate form of compound 6a (compound 6a-I). [Background technology]

[0002] The free base compound 2-(6-azaspiro[2.5]octan-6-yl)-N-[2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl]-4-[(2-hydroxyethanesulfonyl)amino]benzamide (Compound 1), or a pharma- ceutically acceptable salt thereof, is useful as an inhibitor of the motor protein kinesin family member 18A (KIF18A): [ka]

[0003] Kinesins are molecular motors that play an important role in cell division and the transport of vesicles and organelles within cells. Mitotic kinesins play a role in several aspects of spindle assembly, chromosome segregation, centrosome separation, and dynamics. Human kinesins are classified into 14 subfamilies based on sequence homology within the so-called "motor domain," whose ATPase activity induces unidirectional movement along microtubules (MTs). The non-motor domains of these proteins are involved in binding cargo, which may include any one of a wide variety of different membranous organelles, signaling scaffolding systems, and chromosomes. Kinesins use the energy of ATP hydrolysis to move cargo along polarized microtubules. Thus, kinesins are often referred to as "plus-end" or "minus-end" directed motors.

[0004] The KIF18A gene belongs to the kinesin-8 subfamily and is a plus-end directed motor. KIF18A is thought to affect the dynamics at the plus end of kinetochore microtubules to control correct chromosome positioning and spindle tension. Loss of human KIF18A leads to longer spindles, increased chromosome oscillations at metaphase, and activation of the mitotic spindle assembly checkpoint in HeLa cervical cancer cells. KIF18A may be a target for cancer therapy. KIF18A is overexpressed in various types of cancer, including but not limited to colon, breast, lung, pancreatic, prostate, bladder, head, neck, cervical, and ovarian cancer. Furthermore, deletion or knockdown or inhibition of the gene for KIF18A affects the mitotic spindle apparatus in cancer cell lines. In particular, inhibition of KIF18A has been shown to induce arrest of mitotic cells, a known vulnerability that may promote cell death during mitosis via apoptosis, mitotic catastrophe, or multipolarity-induced lethality or death after mitotic slippage in interphase.

[0005] Compound 1, and exemplary methods of making it, are described in U.S. Patent No. 11 / 236,069, issued February 1, 2022, which is incorporated herein by reference in its entirety. Solid forms of Compound 1, including crystalline anhydrous Compound 1 or amorphous Compound 1, as well as stable salts, hydrates, solvates, or cocrystals of Compound 1, particularly those for commercial pharmaceutical manufacture of Compound 1, are described in U.S. Provisional Patent Application No. US63 / 224,208, filed July 21, 2021, which is incorporated herein by reference in its entirety.

[0006] US Patent No. 11 / 236,069 disclosed a method for preparing Compound 1, which relied on the introduction of a key intermediate compound in the penultimate step. The disclosed process was found to have an unpredictable impurity control strategy involving a key intermediate compound with undesirable physical properties (hygroscopicity) and requiring multiple recrystallizations of the key intermediate compound. To overcome the commercial risks identified in the disclosed method, the inventors have developed the novel and improved method of the present invention for preparing Compound 1, or a pharma- ceutically acceptable salt thereof, preferably its HCl salt, which utilizes an improved impurity control strategy, improved convergence, scalability, and improved stability of the key intermediate compound. The key intermediate compound of the present invention that may be used in the synthesis of Compound 1, or a pharma- ceutically acceptable salt thereof, has the following formula: [ka] or a salt thereof; and [ka] Compounds 2a, 3a, 5 or salts thereof, and compound 6a, preferably a hydrate of compound 6a: [ka] It is.

[0007] The new key intermediate compounds are named as follows:

[0008] (1) 4-((2-(benzyloxy)ethyl)sulfonamido)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (compound 2a),

[0009] (2) 4-((2-(benzyloxy)ethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (compound 3a),

[0010] (3) 4-nitro-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (compound 5),

[0011] (4) Calcium 2-(benzyloxy)ethane-1-sulfinate (compound 6a), and

[0012] (5) 2-(benzyloxy)ethane-1-sulfinic acid calcium salt 4 / 3 hydrate (compound 6a-I).

[0013] The present invention further relates to solid forms of compound 6a, preferably the crystalline hydrate form of compound 6a (compound 6a-I). Summary of the Invention

[0014] In an aspect 1 of the present invention, the present invention provides a compound having the following chemical structure: [ka] The present invention provides a novel method for preparing a KIF18A inhibitor having the structure: [ka] [Wherein, PG is C 1-6 Alkyl, C 1-6 Alkyl-OC 1-6the hydroxyl protecting group being selected from alkyl, tetrahydropyranyl, allyl, or benzyl, preferably methyl-O-methyl, tetrahydropyranyl, or benzyl, more preferably benzyl, by reacting compound 2 having a hydroxyl protecting group selected from alkyl, tetrahydropyranyl, allyl, or benzyl, with a suitable deprotecting agent in a suitable solvent to form said compound 1.

[0015] In a second aspect of the invention, the present invention provides a compound of formula: [ka] [PG is C 1-6 Alkyl, C 1-6 Alkyl-OC 1-6 wherein the hydroxyl protecting group is selected from alkyl, tetrahydropyranyl, allyl, or benzyl, preferably methyl-O-methyl, tetrahydropyranyl, or benzyl, more preferably benzyl, [ka] or a salt thereof in the presence of an amide coupling reagent and a base in an organic solvent to form said compound 2.

[0016] In a third aspect of the invention, the present invention provides a compound of formula: [ka] or a salt thereof, [ka] [Wherein, PG is C 1-6 Alkyl, C 1-6 Alkyl-OC 1-6and n is an integer selected from 1 or 2, preferably 2; and n is an integer selected from 1 or 2, preferably 2; and m is a hydroxyl protecting group selected from alkyl, tetrahydropyranyl, allyl, or benzyl, preferably methyl-O-methyl, tetrahydropyranyl, or benzyl, more preferably benzyl; M is a metal, e.g., an alkali, alkaline earth metal, or transition metal, preferably sodium, calcium, or zinc metal, more preferably calcium; and n is an integer selected from 1 or 2, preferably 2;

[0017] In a fourth aspect of the invention, the present invention provides a compound of formula: [ka]

[0043] In the above, compound 7 having the formula: [ka] The method of embodiment 3 further comprises preparing compound 5, or a salt thereof, comprising reacting compound 8, having a leaving group, preferably halo, more preferably chloro or fluoro, and most preferably fluoro, in the presence of a base at elevated temperature in an organic solvent to form compound 5, or a salt thereof.

[0018] In a fifth aspect of the invention, the present invention provides a compound of formula: [ka]

[0043] wherein LG2 is a leaving group, preferably halo, more preferably chloro or fluoro, most preferably chloro, by reacting compound 9 having the formula [ka] The method of embodiment 2 further comprises preparing compound 4 by reacting compound 10 having the formula: wherein X2 is a halide, preferably chloride or bromide, more preferably chloride, in an organic solvent at elevated temperature in the presence of a base to form compound 4.

[0019] In a sixth aspect of the present invention, the present invention provides compound 2, wherein PG is benzyl, structure [ka] The present invention provides a compound having the formula:

[0020] In aspect 7 of the present invention, the present invention provides compound 3, wherein PG is benzyl, the structure: [ka] The present invention provides a compound having the formula:

[0021] In an eighth aspect of the present invention, the present invention provides a method for producing a composition comprising: [ka] or a salt thereof.

[0022] In a ninth aspect of the invention, the present invention provides a compound having the following chemical structure: [ka] wherein PG is C 1-6 Alkyl, C 1-6 Alkyl-OC 1-64. The method of embodiment 3, further comprising preparing a hydroxyl protecting group selected from alkyl, tetrahydropyranyl, allyl, or benzyl, preferably methyl-O-methyl, tetrahydropyranyl, or benzyl, more preferably benzyl; M is a metal, e.g., an alkali, alkaline earth metal, or transition metal, preferably sodium, calcium, or zinc metal, more preferably calcium; and n is an integer selected from 1 or 2, preferably 2, or a hydrate thereof, comprising the structure [ka] [Wherein, PG is C 1-6 Alkyl, C 1-6 Alkyl-OC 1-6 wherein the hydroxyl protecting group is selected from alkyl, tetrahydropyranyl, allyl, or benzyl, preferably methyl-O-methyl, tetrahydropyranyl, or benzyl, more preferably benzyl, is reacted with a base in a polar solvent at moderately elevated temperature to give compound 6, or preferably a hydrate thereof, most preferably [ka] The method includes forming a

[0023] In a tenth aspect of the invention, the present invention provides a compound having the following chemical structure: [ka] [Wherein, PG is C 1-6 Alkyl, C 1-6 Alkyl-OC 1-6 The method of embodiment 9 further comprises preparing compound 11 by reacting compound 12 having a hydroxyl protecting group selected from alkyl, tetrahydropyranyl, allyl, or benzyl, preferably methyl-O-methyl, tetrahydropyranyl, or benzyl, more preferably benzyl, with an oxidizing agent in the presence of a catalyst in a solvent at slightly elevated temperature to form compound 11.

[0024] In an eleventh aspect of the invention, the present invention provides a compound having the following chemical structure: [ka] Compound 13 having the following chemical structure: [ka] [Wherein, PG is C 1-6 Alkyl, C 1-6 Alkyl-OC 1-6 and LG3 is a leaving group, preferably LG3 is halo, more preferably fluoro, chloro, or bromo, more preferably bromo, in the presence of a base in a solvent at moderately elevated temperature to form compound 12.

[0025] In an aspect 12 of the present invention, the present invention provides the method of aspect 1, wherein PG is benzyl and said suitable deprotecting agent is a palladium on carbon catalyst.

[0026] In a thirteenth aspect of the invention, the present invention provides the method of the first aspect, wherein the solvent is a polar solvent.

[0027] In a fourteenth aspect of the invention, the present invention provides the method of the thirteenth aspect, wherein the solvent is a mixture of acetone and water.

[0028] In aspect 15 of the invention, the invention provides the method of aspect 2, wherein said amide coupling reagent is selected from chloroform amidinium salts, 2-chloro-1,3-dimethylimidazolinium chloride (DMC), 1-(chloro-1-pyrrolidinylmethylene)pyrrolidinium hexafluorophosphate (PyCIU), 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), or N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ).

[0029] In a sixteenth aspect of the invention, the invention provides the method of aspect 2, wherein the base is selected from N-methylmorpholine (NMM), N,N-diisopropylethylamine (DIPEA), triethylamine (TEA), 2,4,6-trimethylpyridine (collidine), or 2,6-lutidine.

[0030] In aspect 17 of the present invention, the present invention provides the method of aspect 2, wherein the chloroformamidinium salt is chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH) and the base is 2,4,6-trimethylpyridine (collidine).

[0031] In an eighteenth aspect of the present invention, the present invention provides a method according to aspect 2, wherein said method is carried out at a temperature between 25°C and 50°C, preferably between 40°C and 50°C, more preferably at 50°C.

[0032] In aspect 19 of the present invention, the present invention provides a process according to aspect 2, wherein the solvent is an organic solvent selected from 2-methylTHF, acetonitrile, isopropyl acetate, dichloromethane, THF, DMF, NMP, methylene chloride, or a mixture thereof, preferably 2-methylTHF and acetonitrile.

[0033] In a 20th aspect of the invention, the invention provides the process of aspect 3, wherein said process is carried out without a catalyst or in the presence of a metal catalyst selected from an iron catalyst, a gold catalyst, or a palladium catalyst.

[0034] In aspect 21 of the present invention, the present invention provides the process of aspect 20, wherein the process is carried out in the presence of a metal catalyst, and the catalyst is iron(III) chloride hexahydrate.

[0035] In aspect 22 of the present invention, the present invention provides the method of aspect 3, wherein the base is sodium bisulfite.

[0036] In a twenty-third aspect of the present invention, the present invention provides a process according to the third aspect, wherein said elevated temperature is the solvent reflux temperature or 60°C to 100°C, preferably 70°C to 90°C, more preferably 70°C.

[0037] In aspect 24 of the present invention, the present invention provides the method of aspect 3, wherein the solvent is NMP.

[0038] In aspect 25 of the invention, the invention provides the method of aspect 4, wherein the base is a hydroxide or an amine, preferably a hydroxide.

[0039] In aspect 26 of the invention, the present invention provides the process of aspect 25, wherein the base is potassium hydroxide or diisopropylethylamine, preferably potassium hydroxide.

[0040] In aspect 27 of the present invention, the present invention provides a method according to aspect 4, wherein said solvent is a polar aprotic solvent selected from NMP, DMAC, DMF or DMSO, preferably NMP.

[0041] In aspect 28 of the present invention, the present invention provides a method of aspect 4, wherein said elevated temperature is the solvent reflux temperature or 80°C to 140°C, preferably 100°C to 140°C, more preferably 120°C.

[0042] In a twenty-ninth aspect of the invention, the invention provides the method of embodiment four, wherein said compound 5 is crystallized by the addition of an acid.

[0043] In an aspect 30 of the present invention, the present invention provides the method of aspect 29, wherein the acid is phosphoric acid.

[0044] In aspect 31 of the present invention, the present invention provides the method of aspect 5, wherein the base is an amine or a hydroxide, preferably an amine.

[0045] In aspect 32 of the present invention, the present invention provides the method of aspect 31, wherein the base is triethylamine.

[0046] In aspect 33 of the present invention, the present invention provides a process according to aspect 5, wherein said elevated temperature is the solvent reflux temperature or 60°C to 100°C, preferably 60°C to 85°C, more preferably 80°C.

[0047] In aspect 34 of the present invention, the present invention provides the method of aspect 5, wherein the solvent is a mixture of acetonitrile and water.

[0048] In aspect 35 of the present invention, the present invention provides the process of aspect 9, wherein the base is a hydroxide, preferably calcium hydroxide, sodium hydroxide, more preferably calcium hydroxide.

[0049] In aspect 36 of the present invention, the present invention relates to a process for the preparation of a solubility-based ... 1-6 The method of embodiment 9 is provided, wherein the alkyl alcohol is a mixture of water, preferably a mixture of methanol and water.

[0050] In aspect 37 of the present invention, the present invention provides a compound of formula 6, which is obtained by crystallizing the compound 6 in a mixture of methanol / ethanol / water. [ka] The method of embodiment 9 is provided, wherein the hydrous compound 6a-I is formed having the formula:

[0051] In embodiment 38 of the present invention, the present invention provides the method of embodiment 9, wherein the temperature is 25°C to 50°C, 40°C to 50°C, preferably 50°C.

[0052] In aspect 39 of the present invention, the present invention provides the method of aspect 10, wherein the oxidizing agent is a peroxide or a peroxycarboxylic acid, preferably hydrogen peroxide or metaperoxycarboxylic acid (mCPBA), more preferably hydrogen peroxide.

[0053] In an aspect 40 of the present invention, the present invention provides the method of aspect 10, wherein the catalyst is sodium tungstate.

[0054] In embodiment 41 of the present invention, the present invention provides the method of embodiment 10, wherein the temperature is 25°C to 40°C, preferably 30°C to 35°C, more preferably 30°C.

[0055] In an aspect 42 of the present invention, the present invention provides the method of aspect 10, wherein the solvent is a mixture of acetonitrile and water.

[0056] In embodiment 43 of the present invention, the present invention provides the method of embodiment 10, wherein said compound 12 is crystallized in acetone or a mixture of acetone and water.

[0057] In aspect 44 of the invention, the invention provides the method of aspect 10, wherein said compound 12 is not isolated and said solvent is acetonitrile.

[0058] In a forty-fifth aspect of the present invention, the present invention provides a method for producing a composition comprising the steps of:

[0059] The method of embodiment 11 is provided, wherein the base is a bicarbonate, carbonate, hydroxide, or phosphate, preferably potassium carbonate, sodium carbonate, sodium hydroxide, or potassium hydroxide, more preferably potassium carbonate.

[0060] In an aspect 46 of the present invention, the present invention provides the method of aspect 11, wherein the base is calcium carbonate.

[0061] In aspect 47 of the present invention, the present invention provides the process of aspect 11, wherein the solvent is an alcohol, preferably methanol.

[0062] In embodiment 48 of the present invention, the present invention provides the process of embodiment 11, wherein the temperature is the solvent reflux temperature or 70°C to 100°C, preferably 75°C to 90°C, more preferably 82°C.

[0063] In a 49th aspect of the present invention, the present invention provides a compound of formula (I) by reacting said compound 1 with an acid HA in a solvent. [ka] The method of any one of aspects 1-5 or 9-48 further comprises forming a pharma- ceutically acceptable salt of compound 1 having the formula:

[0064] In embodiment 50 of the invention, the invention provides the method of embodiment 49, wherein the acid HX is HCl, methanesulfonic acid, or paratoluenesulfonic acid.

[0065] In embodiment 51 of the present invention, the present invention provides the method of embodiment 49, wherein the acid HX is HCl dissolved in DMSO.

[0066] In an aspect 52 of the present invention, the present invention provides the method of aspect 49, wherein the solvent is water.

[0067] In aspect 53 of the invention, the invention provides a method according to any one of aspects 1 to 5 or 9 to 52, wherein said PG is benzyl.

[0068] In aspect 54 of the present invention, the present invention provides a compound having the chemical structure: [ka] [Wherein, PG is C 1-6 Alkyl, C 1-6 Alkyl-OC 1-6M is a hydroxyl protecting group selected from alkyl, tetrahydropyranyl, allyl, or benzyl, preferably methyl-O-methyl, tetrahydropyranyl, or benzyl, more preferably benzyl; M is a metal such as a monovalent metal, a divalent metal, or a trivalent metal, preferably M is a monovalent metal or a divalent metal, more preferably M is Na, Ca, or Zn, most preferably M is Ca; and n is an integer selected from 1, 2, or 3, preferably n is 1 or 2, more preferably n is 2.

[0069] In embodiment 55 of the present invention, the present invention provides a compound having the structure: [ka] 55. The compound of embodiment 54, or a solid form thereof, is provided, comprising:

[0070] In aspect 56 of the invention, the present invention provides a solid form of said compound 6a according to aspect 55, which is crystalline or amorphous.

[0071] In aspect 57 of the present invention, the present invention provides a compound of formula [ka] wherein the compound contains 4 / 3 water molecules and is crystalline.

[0072] In aspect 58 of the present invention, the present invention provides a solid form of said compound 6a according to aspect 55, which is crystalline form 1 of said compound 6a hydrate (compound 6a-I), further characterized by XRPD pattern peaks at 4.2, 8.2, and 12.2±0.2 degrees 2θ using Cu Kα radiation.

[0073] In aspect 59 of the present invention, the present invention provides a solid form of said compound 6a according to aspect 58, which is crystalline form 1 of said compound 6a-I of aspect 58, further characterized by an XRPD pattern peaks at 13.6, 14.2, 18.3, 19.5, 20.6, 20.9, and 22.9±0.2 degrees 2θ using Cu Kα radiation.

[0074] In embodiment 60 of the present invention, the present invention provides a solid form of said compound 6a according to embodiment 59, which is crystalline compound 6a-I of embodiment 59, further characterized by an XRPD pattern peaks at 16.2, 16.7, 19.2, 21.4, 23.9, 24.4, 24.7, 25.5, 27.6, 28.1, 30.3, 33.3, and 36.6±0.2 degrees 2θ using Cu Kα radiation.

[0075] In embodiment 61 of the present invention, the present invention provides a solid form of said compound 6a according to embodiment 60, which is crystalline compound 6a-I having an XRPD pattern substantially as shown in FIG.

[0076] In aspect 62 of the invention, the present invention provides a solid form of compound 6a according to aspect 58, which is crystalline compound 6a-I having a first endothermic transition at 124.96°C to 130.96°C and a second endothermic transition at 256.11°C to 262.11°C, as measured by differential scanning calorimetry, substantially as shown in Figure 2.

[0077] In embodiment 63 of the present invention, the present invention provides a solid form of compound 6a according to embodiment 58, which is crystalline compound 6a-I, wherein the first endothermic transition occurs at 127.96°C±3°C and the second endothermic transition occurs at 259.11°C±3°C.

[0078] In embodiment 64 of the present invention, the present invention provides a solid form of said compound 6a according to embodiment 58, which is crystalline compound 6a-I having a thermogravimetric analysis (TGA) substantially as shown in FIG.

[0079] In aspect 65 of the present invention, the present invention provides a solid form of compound 6a according to aspect 58, which has a stable crystalline form and low hygroscopicity. In one embodiment, the solid form stability can be confirmed by no change in crystalline form and substantially identical XRPD peaks shown for the crystalline sample before and after DVS. In another embodiment, the low hygroscopicity property of the crystalline sample can be demonstrated by measuring the mass of the sample at the start and end of the DVS experiment and calculating the mass change to be 0.10% to 0.20%, preferably 0.15%.

[0080] In embodiment 66 of the present invention, the present invention provides a solid form of compound 6a according to embodiment 58, which is crystalline compound 6a-I having a single crystal structure substantially as shown in FIG.

[0081] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. Methods and materials for use in this disclosure are described herein, but other suitable methods and materials known in the art can also be used. Materials, methods, and examples are illustrative only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned in the brief description of the invention and in the following sections of this specification are incorporated herein by reference in their entirety. In case of conflict, the present specification, including definitions, will take precedence. Other features and advantages of the present disclosure will be apparent from the following further description, examples, and claims. [Brief description of the drawings]

[0082] [Figure 1] 1 shows (1) the X-ray powder diffraction ("XRPD") patterns of crystalline compound 6a-I before and after humidity stress as measured by dynamic vapor sorption (DVS), and (2) a simulated XRPD pattern from the single crystal structure of compound 6a-I. [Diagram 2] 1 shows a differential scanning calorimetry (DSC) thermogram of crystalline compound 6a-I. [Diagram 3] 1 shows the thermogravimetric analysis (TGA) of crystalline compound 6a-I. [Figure 4] The single crystal structure of crystalline compound 6a-I is shown.

[0083] definition The following definitions should be further helpful in understanding the terminology used herein and the scope of the invention described herein.

[0084] "C x-y The term "alkyl" refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain and branched-chain alkyl groups containing x to y carbons in the chain.

[0085] The term "haloalkyl" refers to an alkyl group in which at least one hydrogen atom is replaced with halo (e.g., fluoro, chloro, bromo, iodo), such as CH2F, CHF2, trifluoromethyl, and 2,2,2-trifluoroethyl.

[0086] The term "comprising" is intended to be open-ended, including the indicated component(s) but not excluding other elements.

[0087] The term "equivalent" is intended to mean molar equivalents as commonly understood by those of skill in the art.

[0088] The term "pharmaceutical acceptable salts" refers to relatively non-toxic inorganic and organic acid addition salts of compound 5 of the present invention. The nature of the salt is not critical, provided that it is pharmaceutical acceptable. These salts can be prepared in situ during the final isolation and purification of the compound(s), or separately, by reacting the purified compound in free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Suitable pharmaceutical acceptable acid addition salts of the compounds can be prepared from either inorganic or organic acids. Examples of such inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid. Examples of organic acids include, without limitation, aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are formic acid, acetic acid, adipic acid, butyric acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, mesylic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic acid (pamoic acid), methanesulfonic acid, ... Phosponic acid, ethanedisulfonic acid, benzenesulfonic acid, pantothenic acid, 2-hydroxyethanesulfonic acid, toluenesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, camphoric acid, camphorsulfonic acid, digluconic acid, cyclopentanepropionic acid, dodecylsulfonic acid, glucohepranic acid, glycerophosphonic acid, heptanoic acid, hexanoic acid, 2-hydroxyethanesulfonic acid, nicotinic acid, 2-naphthalenesulfonic acid, oxalic acid, palmoic acid, pectinic acid, persulfuric acid, 2-phenylpropionic acid, picric acid, pivalic acid Propionic acid, succinic acid, tartaric acid, thiocyanic acid, mesylic acid, undecanoic acid, stearic acid, algenic acid, β-hydroxybutyric acid, salicylic acid, galactaric acid and galacturonic acid (see, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19.).

[0089] As used herein, the term "hydroxyl protecting group" refers to a protecting group suitable for preventing undesired reactions at a hydroxyl group. Representative hydroxyl protecting groups include tri(C) groups such as trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBS), and the like. 1-6 Silyl groups, including alkylsilyl groups; C such as formyl, acetyl, etc. 1-6 esters including alkanoyl groups (acyl groups); arylmethyl groups such as, but not limited to, benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), diphenylmethyl (benzhydryl, DPM), etc. Numerous protecting groups, and their introduction and removal, are described in TW Greene and PG M Huts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York.

[0090] As used herein, the term "metal" refers to a "monovalent metal," a "divalent metal," or a "trivalent metal."

[0091] As used herein, the term "monovalent metal" refers to a metal that is part of an ionic bond in which the metal forms an ion with a charge of +1. Examples of monovalent metals are the metals in Group 1 of the IUPAC Periodic Table (thus excluding hydrogen). Preferred monovalent metals are Na, K, and Li.

[0092] As used herein, the term "divalent metal" refers to a metal that is part of an ionic bond, where the metal forms an ion with a +2 charge. Examples of divalent metals are the metals in Group 2 of the IUPAC Periodic Table. Preferred divalent metals are Mg, Zn, or Ca.

[0093] As used herein, the term "trivalent metal" refers to a metal that is part of an ionic bond in which the metal forms an ion with a charge of +3. Examples of trivalent metals are Al and Fe.

[0094] As used herein, the term "solvent" includes an "aqueous solvent" or an "organic solvent."

[0095] As used herein, the term "aqueous solvent" means a solvent that contains water.

[0096] As used herein, the term "organic solvent" refers to an organic molecule that can dissolve another substance (i.e., a solute). An organic solvent can be a liquid at room temperature. Examples of organic solvents that can be used in the present invention include hydrocarbon solvents (e.g., n-pentane, n-hexane, n-heptane, n-octane, cyclohexane, methylcyclohexane, decahydronaphthalene, etc.), which also include aromatic hydrocarbon solvents (e.g., benzene, toluene, o-xylene, m-xylene, and p-xylene), halogenated hydrocarbon solvents (e.g., carbon tetrachloride, 1,2-dichloroethane, dichloromethane, chloroform, etc.), ester solvents (e.g., ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, ethyl malonate, etc.), ketone solvents (e.g., acetone, methyl ethyl ketone or 2-butanone, methyl isobutyl ketone, cyclohexanone, cyclopentanone, 3-pentanone, etc.), ether solvents (e.g., diethyl ether, dipropyl ether, diphenyl ether, isopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, ... Examples of suitable organic solvents include, but are not limited to, ethyl amine, 1,4-dioxane, methyl phenyl ether, or anisole, amine solvents (e.g., propylamine, diethylamine, triethylamine, aniline, pyridine), alcohol solvents (e.g., methanol, ethanol, isopropanol, 1-propanol, 2-methyl-1-propanol, 1-butanol, 2-butanol, 1-pentanol, 3-methyl-1-butanol, tert-butanol, 1-octanol, benzyl alcohol, phenol, trifluoroethanol, glycerol, ethylene glycol, propylene glycol, m-cresol, and the like), acid solvents (e.g., acetic acid, hexanoic acid, and the like), nitrobenzene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, N-methyl-2-pyrrolidone, acetonitrile, propionitrile, butyronitrile, and silicone solvents (e.g., silicone oil, polysiloxane, cyclosilicone). In some embodiments, the organic solvent may be formed by a combination of two or more organic solvents.

[0097] As used herein, the term "polar solvent" means a solvent having a dielectric constant of at least 3, the dielectric constant being the ratio of the capacitance of a capacitor filled with the solvent to the capacitance of a vacuum capacitor at 20° C. to 25° C. Values ​​of the dielectric constant of solvents are disclosed in Vogel's Textbook of Practical Organic Chemistry 5th Edition, Appendix 5. Examples of polar solvents are dichloromethane, tetrahydrofuran, ester solvents (e.g., ethyl formate, methyl acetate, ethyl acetate, ethyl malonate, etc.), ketone solvents (e.g., acetone, methyl ethyl ketone or 2-butanone, cyclohexanone, cyclopentanone, 3-pentanone, etc.), amine solvents (e.g., propylamine, diethylamine, triethylamine, aniline, pyridine), alcohol solvents (e.g., methanol, ethanol, isopropanol, 1-propanol, 1-butanol, 1-octanol, benzyl alcohol, phenol, trifluoroethanol, glycerol, ethylene glycol, propylene glycol, m-cresol, etc.), acid solvents (e.g., acetic acid, hexanoic acid, etc.), nitrobenzene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, N-methyl-2-pyrrolidone, acetonitrile, propionitrile, butyronitrile, and silicone solvents (e.g., silicone oil, polysiloxane, cyclosilicone).

[0098] As used herein, the term "alcohol" refers to a hydrocarbon derivative in which one or more hydrogen atoms have been replaced by an -OH group, known as a hydroxyl group. Alcohols suitable for the present invention include linear, cyclic or branched C 1-6 Alkyl alcohols and any mixtures thereof are included, including commercially available alcohols. Examples of alcohols are methanol, ethanol, isopropanol, 1-propanol, 1-butanol, 1-pentanol, 3-methyl-1-butanol, tert-butanol, 1-octanol, benzyl alcohol and phenol.

[0099] As used herein, the term "benzyl" refers to a substituent having the structure C6H5CH2-.

[0100] As used herein, the term "reflux" refers to the temperature at which the reaction mixture boils and varies depending on the solvent used in the reaction. For example, if water is used as the solvent, the reflux temperature is up to 100°C.

[0101] As used herein, the term "oxidizing agent" refers to a substance that, as an electron acceptor, can oxidize other substances. Common oxidizing agents include oxygen (O2); ozone (O3); hydrogen peroxide (H2O2) (including other inorganic peroxides or Fenton's reagent); organic peroxides such as peroxycarboxylic acids having the formula RCO3H, where R is an alkyl or aryl group, including peracetic acid or meta-chloroperbenzoic acid (mCPBA); fluorine (F2), chlorine (Cl2), or other halogens; nitric acid (HNO3) or nitrate compounds; sulfuric acid (H2SO4); peroxodisulfuric acid (H2S2O8); peroxomonosulfuric acid (H2SO5); hypochlorite, chlorite, chlorate, perchlorate, or other similar halogen compounds. hexavalent chromium compounds such as chromic acid, dichromate, chromium trioxide, pyridinium chlorochromate (PCC), or chromate / dichromate compounds; permanganate compounds such as potassium permanganate (KmNO4); sodium perborate; nitrous oxide (N2O), nitrogen dioxide / nitrogen tetroxide (NO2 / N2O4); potassium nitrate (KNO3); sodium bismuthate (NaBiO3); cerium(IV) compounds such as ammonium cerium nitrate or ceric sulfate; lead dioxide (PbO2); or sodium dichromate (Na2Cr2O7).

[0102] As used herein, the term "substituted" refers to a moiety having a substituent replacing a hydrogen on one or more non-hydrogen atoms of a molecule. One of ordinary skill in the art will appreciate that "substituted" or "substituted with" includes the implicit proviso that such substitution is in accordance with the permissible valences of the atom and substituent being substituted, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformations such as rearrangement, cyclization, elimination, and the like. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, heteroatoms, such as nitrogen, can have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valence of the heteroatom. Substituents can include, for example, halogen moieties, hydroxyl moieties, carbonyl moieties (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl moieties (such as thioester, thioacetate, or thioformate), alkoxy moieties, phosphoryl moieties, phosphate moieties, phosphonate moieties, phosphinate moieties, amino moieties, amide moieties, amidine moieties, imine moieties, cyano moieties, nitro moieties, azide moieties, sulfhydryl moieties, alkylthio moieties, sulfate moieties, sulfonate moieties, sulfamoyl moieties, sulfonamide moieties, sulfonyl moieties, heterocyclyl moieties, aralkyl moieties, or aromatic or heteroaromatic moieties. Those skilled in the art will understand that the moieties substituted on the hydrocarbon chain can themselves be substituted, where appropriate and valences permit.

[0103] As used herein, the term "continuous process" or "continuous" refers to a manufacturing process that uses one or more reagent or product stream(s) that flow continuously from one unit operation to the next, with all operations occurring simultaneously while the system is in steady state.

[0104] The term "batch process" or "batch" refers to a manufacturing process in which a given unit operation must be run to completion before the next unit operation begins. Typically, the product of the previous unit operation is isolated or purified before it is used as the starting material for the next unit operation.

[0105] General Synthesis and Representative Examples of the Invention The following abbreviations used throughout this description, including the general schemes and examples, have the following meanings:

[0106] DIPEA N,N-diisopropylethylamine (N,N-Diisopropylethylamine)

[0107] DMF dimethylformamide

[0108] DMSO dimethyl sulfoxide

[0109] eq, equiv equivalent(molar)

[0110] EtOAc ethyl acetate

[0111] g.gm gram

[0112] GC gas chromatography

[0113] HPLC high-performance liquid Chromatography (high performance liquid chromatography)

[0114] IPAc isopropyl acetate

[0115] MeCN acetonitrile

[0116] MeOH (methanol)

[0117] 2-MeTHF 2-methyltetrahydrofuran (2-Methyltetrahydrofuran)

[0118] mL, ml milliliter

[0119] mpk,mg / kg milligram per kilogram (milligrams per kilogram)

[0120] NaCl sodium chloride

[0121] NaOH sodium hydroxide

[0122] RT, rt room temperature

[0123] THF tetrahydrofuran

[0124] Materials and Methods

[0125] Unless otherwise stated, commercially available reagents are used as received without further purification.

[0126] PANalytical X'Pert PRO Diffractometer - Reflection Geometry

[0127] XRPD patterns were collected on a PANalytical X'Pert PRO diffractometer unless otherwise stated.

[0128] The single crystal structure was determined using an XtaLAB Synergy, Dualflex, HyPix diffractometer.

[0129] Differential scanning calorimetry (DSC) was performed using a Mettler-Toledo DSC3+ differential scanning calorimeter. Taul lag adjustments are performed with indium, tin, and zinc. Temperature and enthalpy are adjusted with octane, phenyl salicylate, indium, tin, and zinc. The adjustments are then verified with octane, phenyl salicylate, indium, tin, and zinc. Samples were placed in DSC aluminum hermetic pans and the weights were accurately recorded. The lids of the pans were punctured by the instrument and then inserted into the analytical DSC cell. A weighed aluminum pan configured as the sample pan was placed in the reference side of the cell.

[0130] Alternatively, differential scanning calorimetry (DSC) analyses were performed in TA Instruments Q-series and Discovery-series calorimeters under 50 ml / min dry nitrogen in aluminum pans from 25° C. to 250° C. to 350° C. at 10° C. / min.

[0131] Thermogravimetric analysis (TGA) was performed on TA Instruments Q series and Discovery series analyzers in platinum pans under 25 ml / min of dry nitrogen from ambient temperature to 250°C–350°C at 10°C / min.

[0132] Moisture sorption data was collected using a DVS Endeavour. Sample sizes of approximately 30 mg were used. Temperature was 25° C. Relative humidity (RH) was maintained at 80% for 24 hours. Mass was recorded at the start and end of the experiment.

[0133] Solution proton NMR spectra were acquired at 25° C. using a Varian UNITY INOVA-400 spectrometer by Spectral Data Services of Champaign (SSCI), IL. Samples were dissolved in DMSO-d6 unless otherwise stated. In some cases, solution NMR spectra were also acquired at SSCI using an Agilent DD2-400 spectrometer using deuterated DMSO or methanol.

[0134] General embodiment of the present invention The present inventors have developed a novel and improved process for the preparation of compound 1 and its pharma- ceutically acceptable salts, preferably its HCl salt (compound 1a), from five key starting / intermediate compounds, namely, compound 6, compound 7, compound 8, compound 9, and compound 10. The novel synthetic route for compound 1 and its pharma- ceutical acceptable salts employs a late-stage amide coupling strategy. The process exploits the inherent reactivity of 2-fluoro-4-nitrobenzoic acid (compound 8, or a salt thereof) through successive C-N bond formation and S-N bond formation to give a hydroxy-protected, preferably benzyl ether-protected, compound 2, which undergoes deprotection to form the free base compound 1. Subsequent reaction of compound 1 with acid HA for salt formation gives the pharma- ceutical acceptable salt of compound 1.

[0135] Scheme A: Steps 1-3 Preparation of compound 6 and its solid form. [ka]

[0136] Scheme A shows steps 1-3 for preparing compound 6 of the present invention. Compound 6 is a novel calcium sulfinate (sulfinic acid) salt compound, and Scheme A represents a new robust route for preparing calcium sulfinate salts. Routes for preparing sulfinate salts from the literature, e.g. (a) Liang et.al., “Recent Advances in the Synthesis and Direct Application of Sulfinate Salts”, Eur. J. Org. Chem. 2020, 4664 -4676, (b) Gianatassio et.al., “Simple Sulfinate Synthesis Enables CH Trifluoromethyl-cyclopropanation”, Angew. Chem. Int. Ed. 2014, 53, 9851 -9855, (c) Day et.al., “Benzothiazole Sulfinate: A Sulfinic Acid Transfer Reagent under Oxidation-Free Conditions”, Org. Lett. 2017, 19, 3819-3822, (d) Cochran et.al., “Development of a Commercial Process To Prepare AMG 232 Using a Green Ozonolysis-Pinnick Tandem Transformation”, J.Org.Chem.2019,84,4763-4779, and (e)O'Hara et.al.,“Preparation and purification of zinc sulfinate reagents for drug discovery”,doi:10.1038 / nprot.2013.059, are known to be readily accessible to the sodium salts, however the most common route (a) uses reduction of sulfonyl chlorides, typically with sodium sulfite or sodium bisulfonyl chloride as shown in Scheme B below, which are difficult to handle.

[0137] [ka] Scheme B: Current literature method for preparing sulfinate RSO2M, where R is an organic functional group, each Het and Ar is as defined above, and M is a metal.

[0138] Using these literature methods, the sodium sulfinate products may be found to be highly hygroscopic or to have non-ideal physical properties. The methods presented herein produce metal sulfinate salts, such as zinc sulfinate, sodium sulfinate, and calcium sulfinate salts, with improved physical properties and stability.

[0139] In Scheme A, Step 1, compound 13 having the formula LG4-SH, where LG4 is an organic leaving group, preferably unsubstituted benzothiazolyl, is reacted with compound 14 having the formula PG-O-CH2CH2-LG3 in the presence of a base in a solvent to form compound 12 having the formula LG4-O-CH2CH2-OPG. [ka] Preferably, compound 14 has the formula [ka] wherein PG is C 1-6 Alkyl, C 1-6 Alkyl-OC 1-6 LG3 is a hydroxyl protecting group selected from alkyl, tetrahydropyranyl, allyl, or benzyl, preferably methyl-O-methyl, tetrahydropyranyl, or benzyl, more preferably benzyl. LG3 is a leaving group, preferably LG3 is halo, more preferably fluoro, chloro, or bromo, more preferably bromo. Preferably, said compound 12 is of the formula [ka] wherein PG is C 1-6Alkyl, C 1-6 Alkyl-OC 1-6 The hydroxyl protecting group is selected from alkyl, tetrahydropyranyl, allyl, or benzyl, preferably methyl-O-methyl, tetrahydropyranyl, or benzyl, more preferably benzyl. Preferably, the base is a bicarbonate, carbonate, hydroxide, or phosphate, preferably potassium carbonate, sodium carbonate, sodium hydroxide, or potassium hydroxide, more preferably potassium carbonate or calcium carbonate, more preferably potassium carbonate. Preferably, the solvent is an alcohol, more preferably methanol. Preferably, the reaction is carried out at solvent reflux temperature or at a temperature between 70°C and 100°C, preferably between 75°C and 90°C, more preferably 82°C.

[0140] In an alternative preferred embodiment, step 1 is carried out in the presence of potassium carbonate base to produce a steady stream of said compound 12 dissolved in acetonitrile.

[0141] In Scheme A, Step 2, compound 12, as defined above, is reacted with an oxidizing agent in the presence of a catalyst in a solvent at slightly elevated temperature to form compound 11. Preferably, said compound 11 is represented by the formula [ka] wherein PG is C 1-6 Alkyl, C 1-6 Alkyl-OC 1-6 The hydroxyl protecting group is selected from alkyl, tetrahydropyranyl, allyl, or benzyl, preferably methyl-O-methyl, tetrahydropyranyl, or benzyl, more preferably benzyl. An example of the oxidizing agent is a peroxide or a peroxycarboxylic acid, preferably hydrogen peroxide or metaperoxycarboxylic acid, more preferably hydrogen peroxide. An example of the catalyst is sodium tungstate. Preferably, the reaction is carried out at a temperature between 25°C and 40°C, preferably between 30°C and 35°C, more preferably 30°C. Preferably, the solvent is a mixture of acetonitrile and water.

[0142] In one embodiment of step 2, the compound 12 is crystallized as a crystalline solid in acetone or a mixture of acetone and water.

[0143] In an alternative embodiment of step 2, the compound 12 is not isolated from step 1 and the solvent is acetonitrile. The oxidation of the compound 12 is then carried out using sodium tungstate as a catalyst and hydrogen peroxide as a stoichiometric oxidant.

[0144] Step 2 was a batch reaction process, but the use of H2O2 faced safety issues and required appropriate safety management. To overcome this safety issue, the inventors developed a continuous process for scale-up. There were two main challenges in the early development of the continuous process, one was the poor solubility of compound 12, and the other was the slow conversion rate of the oxidation reaction of compound 12. To overcome the solubility issue, the inventors further screened the composite solvent volume in the continuous process and successfully used a continuous process for scale-up production with improved efficiency and safety of production in step 2. H2O2 was adjusted to 30 w / w%, 3.0 equivalents, the pH range was maintained at 3-4, the addition of H2O2 was optimized to 3-4 parts, and 33% NaHSO3 solution was used as the quench solvent.

[0145] In Scheme A, Step 3, compound 11, as defined above, is reacted with a base in a polar solvent at moderately elevated temperature to give [ka] wherein PG is benzyl, M is calcium, and n is 2. Preferably, compound 6 has the structure [ka] and more preferably, compound 6a has the structure [ka] An example of the base is a hydroxide, preferably calcium hydroxide, sodium hydroxide, more preferably calcium hydroxide. An example of the solvent is 1-6 The solvent is a mixture of an alkyl alcohol and water, preferably a mixture of methanol and water, or is methanol. In one embodiment, the compound 6 product is crystallized, preferably compound 6 is crystallized in a mixture of methanol / ethanol / water to form compound 6a-I. Preferably, the reaction is carried out at a temperature of 25°C to 50°C, 40°C to 50°C, preferably 50°C. Most preferably, cleavage of the benzothiazole leaving group is achieved using aqueous methanol containing calcium hydroxide to produce calcium sulfinate compound 6, which is isolated as a crystalline hydrate form by crystallization with acetone. Water has been found to be important due to its ability to accelerate the mass transfer of calcium hydroxide and its presence in the lattice of the crystal structure of compound 6a. The crystallization product of compound 6a is a crystalline hydrate compound containing about 1 water molecule, more specifically and preferably 4 / 3 water molecules or about 1.33 water molecules (compound 6a-I).

[0146] Scheme B: Steps 4-5 Preparation of Compound 3 [ka] Scheme B illustrates steps 4 to 5 of the present invention. In Scheme B, step 4, the method utilizes a base-mediated aromatic substitution reaction of compound 7 with compound 8 to generate key intermediate compound 5. The synthesis of compound 5 is an aromatic substitution (SNAr) reaction, which is preferably carried out by treating compound 8, where LG1 is a leaving group, preferably halo, more preferably chloro or fluoro, most preferably fluoro, and compound 7, where X1 is a halide, preferably chloride or bromide, more preferably chloride, in NMP containing KOH at high reaction conditions. The SNAr reaction proceeds with high conversion and the desired product is directly isolated after pH adjustment with aqueous phosphoric acid and precipitation with water to give the product compound 5 as a crystalline solid.

[0147] In Scheme B, step 5, the nitroarene / sulfinate coupling of compound 5 with compound 6 or its hydrate (compound 6a-I) then leads to the formation of compound 3 as a key intermediate compound. The synthesis of compound 3 is preferably carried out by iron-catalyzed coupling of compound 5 with compound 6 or its hydrate (compound 6a-I) in NMP with sodium bisulfite as a stoichiometric reducing agent. The nitroarene / sulfinate coupling reaction proceeds with high conversion and good chemoselectivity to the desired sulfonamide product. The product is preferably isolated after aqueous workup to remove inorganic impurities. The product is preferably solvent-exchanged into THF and crystallized from MTBE anti-solvent crystallization to obtain the product of compound 3 as a crystalline solid.

[0148] Scheme C: Step 6 Preparation of compound 4 [ka] Scheme C illustrates step 6 of the present invention, in which compound 4 is synthesized via an acid-mediated aromatic substitution reaction of compound 9 with compound 10. The synthesis of compound 4 is an improvement over the synthesis of compound 4 previously disclosed in US Patent Application Serial No. 11 / 236,069. In the improved process, the product of compound 4 is preferably produced in a tert-butyl alcohol:toluene mixed solvent under high reaction conditions under an acid-catalyzed SNAr reaction of compound 9 with compound 10, where X2 is chloride. The SNAr reaction proceeds with high conversion, and the desired product is isolated after salt decomposition with aqueous NaOH and crystallization from a toluene / n-heptane solvent system, yielding the product as a crystalline solid.

[0149] Scheme D: Steps 7-8 Preparation of compound 1 [ka] Scheme D illustrates steps 7 and 8 of the present invention for preparing compound 1 in free base form. In step 7, a late stage fragment coupling of compound 3 with compound 4 under amide coupling conditions produces the penultimate intermediate, compound 2, as a crystalline intermediate. The synthesis of compound 2 is preferably carried out by chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH) mediated amide coupling of compound 3 with compound 4 in 2-methylTHF, acetonitrile, isopropyl acetate, dichloromethane, THF, NMP, or mixtures thereof, preferably in 2-methylTHF and acetonitrile, in the presence of a base, preferably 2,4,6-trimethylpyridine (collidine), at high reaction conditions. The amide coupling proceeded with high chemoselectivity with 2,4,6-collidine as base to give the desired amide product, compound 2, in high chemical yield after aqueous workup and crystallization from 2-MeTHF / isopropylamine, affording the product as a crystalline solid.

[0150] In step 8, Pd-catalyzed hydrogenation of compound 2 to remove the benzyl ether protecting group results in the production of compound 1 as a crystalline free base compound. In a preferred embodiment, the synthesis of the compound is carried out by hydrogenation of compound 2 in the presence of Pd / C as a heterogeneous catalyst in an acetic acid / water mixture. The hydrogenation proceeds with high conversion and isolation of the product is achieved after filtration of the catalyst and addition of an anti-solvent of 1-propanol to give the product of compound 1 as a crystalline solid.

[0151] Scheme E: Step 9 Preparation of a Pharmacologically Acceptable Salt of Compound 1 [ka] Scheme E shows step 9 of the present invention. In this step 9, salt formation is carried out via HCl treatment of the crystalline free base of compound 1 to produce the HCl salt of compound 1 (compound 1a), with optional milling to narrow the particle size distribution (PSD). In a preferred embodiment, the synthesis of compound 1a is carried out by treating a DMSO solution of compound 1 with aqueous HCl. The product is precipitated by the addition of an aqueous antisolvent to obtain the product as a crystalline solid. Milling can be carried out to reduce particle size. Other preferred salts of compound 1 include the mesylate or tosylate salts. EXAMPLES

[0152] Representative embodiments of the present invention The following syntheses are representative examples of the present invention and are not intended to be construed as limiting the scope of the invention.

[0153] Example 1: Preparation of 2-((2-(benzyloxy)ethyl)thio)benzo[d]thiazole [ka]

[0154] To a vial equipped with a magnetic stirrer was added mercaptobenzothiazole (2.8 kg, 1.00 equiv.), potassium carbonate (3.5 kg, 1.5 equiv.) and anhydrous acetonitrile (22 L). ((2-bromoethoxy)methyl)benzene (3.9 L, 1.00 equiv.) was added dropwise to the stirred solution. The solution was stirred at 82° C. for 18 h. The mixture was filtered through a medium pore fritted glass funnel to remove solids and the filtrate was concentrated to give the product, 2-((2-(benzyloxy)ethyl)thio)benzo[d]thiazole, as an orange oil, which was used in the next step without further purification.

[0155] Example 2: Preparation of 2-((2-(benzyloxy)ethyl)sulfonyl)benzo[d]thiazole [ka]

[0156] The three solutions in separate plug flow reactors were combined in a mixer and circulated in a single plug flow reactor at 50° C. with a residence time of 15 min. Three solutions were prepared as follows: (i) 2-((2-(benzyloxy)ethyl)thio)benzo[d]thiazole (5.0 kg, 1.0 equiv.) in acetonitrile (27.5 L), (ii) Na2WO4 (245 g, 0.05 equiv.), water (2.5 L), phosphoric acid (85%, 125 g, 0.025 equiv.), and (iii) aqueous H2O2 (1.8 kg of 35 w / w% solution, 4.5 equiv.). The solutions were passed through a continuous stirred tank reactor at 60° C. for 10 min and then through another plug flow reactor at 65° C. for 15 min. The mixture was cooled to 20° C. and 55 L of water was added. Aqueous NaHSO3 (10 L of 33 w / w% solution, 1.9 equiv.) was added while maintaining the temperature at 20° C. The mixture was filtered and the cake was washed twice with 15 L of water. The cake was washed with 15 L of heptane and dried under vacuum at 40° C. to give the product 2-((2-(benzyloxy)ethyl)sulfonyl)benzo[d]thiazole.

[0157] Example 3: Preparation of calcium 2-(benzyloxy)ethane-1-sulfinate and its crystalline hydrate salts [ka]

[0158] To a mixture of 2-((2-(benzyloxy)ethyl)sulfonyl)benzo[d]thiazole (4.4 kg, 1.0 equiv.) and Ca(OH)2 (98 g, 0.1 equiv.) in methanol (26 L) at 50° C., Ca(OH)2 (431 g, 0.44 equiv.) was added in four portions over 8 h. The mixture was cooled to 40° C. and filtered. The cake was washed with 18 L of methanol. The filtrate was concentrated to approximately 9 L of solution and warmed to 55° C. Water (2.2 L) was added followed by ethanol (16.5 L) at 55° C. The mixture was cooled to 5° C. over 4 h and stirred at that temperature for 10 h. The slurry was filtered and the cake was washed with 22 L of ethanol. 4.4 L of methanol was added to the cake and the mixture was warmed to 55° C. Water (1.1 L) was added at 55° C., followed by ethanol (16.5 L). The mixture was cooled to 5° C. over 4 hours and stirred at that temperature for 10 hours. The slurry was filtered and the cake was washed with 44 L of ethanol. The cake was dried under vacuum at 40° C., thereby obtaining a 1,2-dichloro-2,3-diphenyl-2,4-diphenyl-2,5-diphenyl-2,6 ... [ka] The crystalline hydrate having the formula: 1 H NMR (500 MHz, D2O): δ 7.43 (m, 10H), 4.58 (s, 4H), 3.84 (t, 6.2 Hz, 4H), 2.62 (t, 6.2 Hz, 4H); 13 C NMR (125 MHz, D2O): δ 138.3, 129.8, 129.5, 129.4, 74.0, 65.8, 62.3. HRMS-ESI (m / z): [M] - [C9H 11 O3S] - Calculated value for: 199.0434; Measured value: 199.0429.

[0159] X-ray powder diffraction: The XRPD pattern of crystalline compound 6a-I is shown in Figure 1. The sample was scanned at ambient temperature in continuous mode from 5 to 45 degrees or 2 to 45 degrees (2θ) with CuKα radiation (1.54 Å) at 0.0334 degree step size, 45 kV, and 40 mA. The incident beam path was equipped with 0.02 rad Soller slits, a 15 mm mask, a 4 degree fixed anti-scatter slit, and a programmable divergence slit. The diffracted beam was equipped with 0.02 rad Soller slits, a programmable anti-scatter slit, and a 0.02 mm nickel filter. The sample was prepared on a low background sample holder and mounted on a rotation stage with a rotation time of 2 seconds.

[0160] Stability and hygroscopicity properties of crystalline compound 6a-I as shown by XRPD experiments before and after DVS: Using a DVS Endeavor instrument, crystalline compound 6a-I was exposed to 80% relative humidity at 25°C for 24 hours. The mass was recorded at the beginning and end of exposure. We found that the starting mass was 32.3989mg, while the ending mass was 32.4479, which is calculated as a mass change of 0.15%. The mass change indicated that crystalline compound 6a-I absorbed 0.15% water by weight. This indicates that crystalline compound 6a-I has low hygroscopicity. No change in crystalline morphology was observed after exposure to 80% relative humidity at 25°C for 24 hours, as shown by the virtually identical XRPD peaks of the crystalline sample before and after DVS (see Tables 1 and 2).

[0161] [Table 1-1] [Table 1-2]

[0162] [Table 2-1] [Table 2-2]

[0163] XPRD Peak Characterization: Crystalline compound 6a-I was further characterized by X-ray powder diffraction pattern (XPRD) and found to be a stable polymorphic form with peaks at 4.2, 8.2, and 12.2±0.2 degrees 2θ using Cu Kα radiation. Crystalline compound 6a-I can optionally be further characterized by an X-ray powder diffraction pattern with additional peaks at 13.6, 14.2, 18.3, 19.5, 20.6, 20.9, and 22.9±0.2 degrees 2θ using Cu Kα radiation. Crystalline compound 6a-I can optionally be further characterized by an X-ray powder diffraction pattern with additional peaks at 16.2, 16.7, 19.2, 21.4, 23.9, 24.4, 24.7, 25.5, 27.6, 28.1, 30.3, 33.3, and 36.6 ±0.2° 2θ using Cu Kα radiation. In some embodiments, crystalline compound 6a-I has an X-ray powder diffraction pattern substantially as shown in FIG. 1, where "substantially" means that the reported peaks may vary by ±0.2°. Those skilled in the art of XRPD know that the relative peak heights of a spectrum vary depending on a number of factors, such as sample preparation and instrument configuration, but the peak positions are relatively unaffected by experimental details.

[0164] A differential scanning calorimetry (DSC) thermograph of crystalline compound 6a-I was obtained. The DSC curve shows an endothermic transition at 127.96°C ± 3°C. Thus, in some embodiments, crystalline compound 6a-I can be characterized by a DSC thermograph with an endothermic transition at onset between 124.96°C and 130.96°C. For example, in some embodiments, crystalline compound 6a-I is characterized by a DSC as shown in FIG. 2.

[0165] Thermogravimetric analysis (TGA): The crystalline compound 6a-I can also be characterized by TGA. Thus, the crystalline compound 6a-I can be characterized by a weight loss ranging from about 4.5% to about 4.7% with an onset temperature of 124.96°C to 130.96°C. For example, the crystalline compound 6a-I can be characterized by a weight loss of about 4.62% up to about 127.96°C. In some embodiments, the crystalline compound 6a-I has a thermogravimetric analysis substantially as shown in FIG. 3, where "substantially" means that the reported TGA properties can vary by ±3°C.

[0166] Dynamic Vapor Sorption (DVS): Crystalline compound 6a-I can be characterized by DVS moisture sorption profile. Characterization of XPRD peaks before and after DVS showed that crystalline compound 6a-I has a stable polymorphic form and is low hygroscopic, with only 0.15% weight loss corresponding to water loss.

[0167] Single crystal experiment: A colorless needle-shaped single crystal of compound 6a-I was used. The size was 0.23 × 0.09 × 0.01 mm. 3 A suitable crystal of was selected and mounted on a Mylar loop with paraton oil on an XtaLAB Synergy, Dualflex, HyPix diffractometer. The crystal was kept constant at T = 100.00 (10) K during data collection. The structure was solved using the ShelXT 2018 / 2 (Sheldrick, 2018) solution program using dual methods, with Olex2 1.5-alpha (Dolomanov et al., 2009) as the graphical interface. 2 The model was refined in ShelXL 2018 / 3 (Sheldrick, 2015) using full matrix least-squares minimization against . Table 3 provides a summary of the crystal structure data for crystalline compound 6a-I, shown in Figure 4.

[0168] [Table 3]

[0169] Example 4: Preparation of 4-nitro-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid [ka]

[0170] To a 2 L vessel, 2-fluoro-4-nitrobenzoic acid (150 g, 1.0 equiv.), 6-azaspiro[2.5]octane hydrochloride (131.6 g, 1.10 equiv.), and NMP (900 ml) were added. The resulting mixture was stirred at 20° C. for 30 min. KOH (112.3 g, 2.10 equiv.) was added and the mixture was heated to 120° C. The mixture was stirred at 120° C. for 16 h and cooled to 90° C. Aqueous H3PO4 (0.6 equiv. H3PO4 in 750 ml water) was added at 90° C. for 2 h. After addition, the suspension was stirred at 90° C. for 1 h, cooled to 20° C. for 5 h, and stirred at 20° C. for 5 h. The product was isolated by filtration, washing with a 1 / 1 mixture of NMP / water (500 mL), followed by washing with water (500 mL). The cake was dried under vacuum to give 4-nitro-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid as a crystalline solid in 90% yield. 1 H NMR (500 MHz, DMSO-D6): δ 15.46 (bs, 1H), 8.15 (bs, 1H), 7.98 (bd, 8.6 Hz, 1H), 7.94 (bd, 8.9 Hz, 1H), 3.17 (m, 4H), 1.53 (m, 4H), 0.39 (s, 4H); 13 C NMR (125 MHz, dmso-d6): δ 166.8, 151.6, 149.8, 131.8, 130.5, 117.7, 115.6, 52.1, 34.4, 16.6, 11.2;HRMS-ESI (m / z): [M+H] + [C 14 H 16 N2O4+H] + Calculated value for, 277.1183; measured value, 277.1183.

[0171] Example 5 Preparation of 4-((2-(benzyloxy)ethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid [ka]

[0172] 4-Nitro-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (150 g, 1.0 equiv.), calcium 2-(benzyloxy)ethane-1-sulfinate (143 g, 0.6 equiv.), NaHSO3 (226 g, 4.0 equiv.), and FeCl3·6H2O (14.5 g, 0.1 equiv.) were added to the reaction vessel. NMP (750 mL) was added. The mixture was warmed to 70 °C over 1 h and stirred at that temperature for 8 h. The batch was cooled to 50 °C and diluted with THF (2.25 L). Aqueous EGTA (20%) and 20 w / w% aqueous sodium chloride (450 mL), adjusted to pH 7 with 10 M NaOH (1.05 L), were added. The mixture was warmed to 50 °C and the pH was adjusted to 7-8 with 10 M NaOH. The mixture was stirred for 30 minutes and the layers were allowed to separate. The lower aqueous layer was drained. 20% w / w aqueous sodium chloride (1.5 L) was added and the contents were warmed to 50° C. The pH was adjusted to 5 with 6M HCl. The mixture was stirred for 20 minutes, the layers were allowed to separate and the lower aqueous layer was drained. 20% w / w aqueous sodium chloride (1.5 L) was added and the contents were warmed to 50° C. The mixture was stirred for 20 minutes, the layers were allowed to separate and the lower aqueous layer was drained. 20% w / w aqueous sodium chloride (1.5 L) was added and the contents were warmed to 50° C. The mixture was stirred for 20 minutes, the layers were allowed to separate and the lower aqueous layer was drained. The organic layer was distilled twice under vacuum from 3 L to 750 mL with fresh THF. The organic layer was diluted to 3 L with THF and polish filtered. The organic layer was concentrated to 750 mL. The mixture was heated to 50° C. to ensure complete dissolution. The mixture was cooled to 40° C. over 1 hour. At 40° C., 4-((2-(benzyloxy)ethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid seeds (2.5 wt %) from a previous batch were added and the slurry was stirred for 1 hour. Toluene (5 L / kg) was added over 5 hours at 40° C. The mixture was heated to 50° C. and stirred for 1 hour. Toluene (5 L / kg) was added over 3 hours at 50° C. The suspension was cooled to 20° C. over 12 hours and stirred for 1 hour. The solid product was filtered. The cake was washed with premixed 1:2 THF / toluene (900 mL) and then with toluene (900 mL).The cake was dried under vacuum at 40° C. under a stream of nitrogen and the product, 4-((2-(benzyloxy)ethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid, was isolated as a crystalline solid in 79% yield. When no crystal seed was used, the yield was about 1% lower. Melting point: 150.5-164.7° C.; 1 H NMR (500 MHz, dmso-d6): δ 10.38 (br, 1H), 7.24-7.37 (m, 4H), 7.19-7.23 (m, 2H), 7.17 (dd, 1H), 4.42 (s, 2H), 3.79 (t, 2H), 3.57 (t, 2H), 2.94 (t, 4H), 1.55 (br, 4H), 0.41 (s, 4H); 13 C NMR (125 MHz, DMSO-D6): δ 166.7, 152.8, 138.2, 132.9, 128.6, 127.9, 119.4, 116.5, 111.8, 72.4, 64.2, 53.7, 52.0, 34.9, 16.9, 11.7;HRMS-ESI (m / z): [M+H] + [C 23 H 28 N2O5S+H] + Calculated value for: 445.1792; Measured value: 445.1782.

[0173] Example 6: Preparation of 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine [ka]

[0174] 2-Chloro-6-methylpyrimidin-4-amine (commercially available, 150 g, 1.0 equiv.), 4,4-difluoropiperidin-1-ium chloride (commercially available, 189 g, 1.15 equiv.), acetonitrile (360 mL), water (240 mL) and triethylamine (148 g, 1.4 equiv.) were added to the vessel. The mixture was stirred for 10 min, warmed to 80° C. and stirred for 16 h. The mixture was cooled to 5° C. and 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine seeds (24 gl) obtained from a previous batch were added. The mixture was stirred for 15 min and aqueous KOH (1.1 M, 150 mL) was added. The mixture was stirred for 1 h and aqueous KOH (1.1 M, 1.62 L) was added over 10 h. The mixture was stirred for 1 h and filtered. The cake was washed with a pre-stirred mixture of acetonitrile (60 mL) and water (540 mL). The cake was dried under vacuum at 60° C. and 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine was isolated as a crystalline solid in 89% yield. Without crystal seeding, the yield was about 1% lower. 1 H NMR (500 MHz, DMSO-D6): δ 6.30 (bs, 2H), 5.64 (d, 0.7 Hz, 1H), 3.79 (t, 5.8 Hz, 4H), 2.06 (s, 3H), 1.90 (tt, 14.2,5.8 Hz, 4H); 13 C NMR (125 MHz, DMSO-D6): δ 164.4, 164.4, 160.8, 123.4 (t, 1 J C-F =-240.8 Hz), 93.7, 40.1 (t, 3 J C-F =5.1 Hz), 33.2 (t, 2 J C-F =22.1 Hz), 23.7; 19 F NMR (471 MHz, DMSO-d6) δ -94.7;HRMS-ESI (m / z): [M+H] + [C 23 H 28 N2O5S+H] + Calculated value for: 445.1792; Measured value: 445.1782.

[0175] Example 7: Preparation of 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine [ka]

[0176] A solution of 4-((2-(benzyloxy)ethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (150.3 g, 1.0 equiv.), 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine (90.8 g, 1.2 equiv.), and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH) (139.3 g, 1.5 equiv.) in 2-MeTHF (1300 mL) and acetonitrile (150 mL) was added to a reaction vessel. 2,4,6-trimethylpyridine (collidine) (109 mL, 2.5 equiv.) was added and the reaction mixture was stirred at 25° C. for 90 min. The reaction mixture was warmed to 50° C. and stirred for an additional 4 h. Upon completion of the reaction, 2M NaOH solution (600 mL) was added followed by aqueous sodium chloride solution (600 mL, 15 wt%). The resulting mixture was stirred at 50° C. for 10 min. The phases were separated and the organic layer was further washed with aqueous NaH2PO4 solution (1200 mL, 25 wt%). The resulting mixture was stirred at 50° C. for 10 min. The phases were separated and 1200 mL of water was added to the organic layer. The resulting mixture was stirred at 50° C. for 10 min and the layers were allowed to separate. The organic layer was concentrated to a volume of approximately 525 mL. 2-MeTHF was added (975 mL) and the organic layer was concentrated to a volume of approximately 525 mL. 2-MeTHF was added (975 mL) and the organic layer was concentrated to a volume of approximately 525 mL. 2-MeTHF was added (975 mL) and charcoal was added (3 g, 2 wt%). The resulting suspension was stirred at 20° C. for 12 h. The suspension was filtered through CELITE® and washed with 150 mL MeTHF. The filtered solution was warmed to 50° C. The mixture was seeded with 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine (1.5 g, 1 wt%) from a previous batch and stirred for 1 h. The mixture was cooled to 35° C. and IPA (788 mL) was added over 3 h. The mixture was stirred for an additional 1 h and IPA (788 mL) was added over 1 h. The mixture was stirred for an additional 1 h and cooled to 20° C. The mixture was stirred for 12 h and filtered. The cake was washed with 2-MeTHF / IPA (25% MeTHF (v / v), 600 mL) and then with IPA (600 mL, 2 times). The cake was dried under vacuum at 40° C. for 24 h.The product, 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine, was isolated as an off-white crystalline solid (173.3 g, 80%). Without seeding, the yield was approximately 1% lower. Melting point = 156-160 °C. 1 H NMR (500 MHz, DMSO-d6): δ 13.29 (s, 1H), 10.31 (s, 1H), 8.03 (d, J = 8.6 Hz, 1H), 7.40 (s, 1H), 7.30 - 7.21 (m, 6H), 7.14 (dd, J = 8.7, 2.1 Hz, 1H), 4.41 (s, 2H), 3.91 - 3.89 (m, 4H), 3.80 (t, J = 5.8 Hz, 2H), 3.56 (t, J = 5.9 Hz, 2H), 2.91 - 2.89 (m, 4H), 2.31 (s, 3H), 2.01 - 1.94 (m, 4H), 1.91 - 1.52 (m, 4H), 0.36 (s, 4H). 13 C NMR (126 MHz, DMSO-d6): δ 169.0, 163.6, 160.2, 158.2, 153.6, 143.1, 137.7, 132.3, 128.0, 127.37, 127.35, 123.0 (t, J = 241.0 Hz), 120.7, 114.4, 111.2, 98.5, 71.9, 63.7, 53.5, 51.4, 40.2, 34.2, 33.1 (t, J = 22.3 Hz), 24.3, 16.8, 11.1; 19 F NMR (471 MHz, DMSO-d6) δ -94.8;HRMS-ESI (m / z): [M+H] + [C 33 H 40 F2N6O4S+H] + Calculated value for, 655.2873; measured value, 655.2895.

[0177] Example 8: Preparation of N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide [ka]

[0178] 2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine (700 g, 1.0 equiv.), 10% Pd / C (105 g, 15 wt. %, 50% wet), acetic acid (6 L) and water (1.05 L) were added to the hydrogenation vessel. The vessel was inerted with N2 (4 cycles) and placed under 45 psi of H2. Hydrogenation was carried out at 20° C. for 25 h. After completion of the reaction, the batch was filtered and the catalyst cake was rinsed with methyl isobutyl ketone (MIBK) (4.9 L). The filtrate was washed with water (7 L) and the aqueous layer was extracted twice with MIBK (2×3.5 L). The combined MIBK extracts were washed twice with aqueous NaOH (7 L, 3 wt. %). The solution was concentrated to a total volume of 7 L and polish filtered. The polish filtration was followed by a 2 L MIBK rinse. The solution was concentrated under reduced pressure to a total volume of 1.5, heated to 100° C., and toluene (7 L) was added. The solution was cooled to 85° C. and seeded with N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (11 g) from a previous batch. The mixture was stirred at 85° C. for 1 h, cooled to 50° C. over 3 h, and heated to 70° C. for 1 h. The suspension was stirred at 70° C. for 1 h and cooled to 15° C. over 6 h. The suspension was stirred at 15° C. for 2 h and filtered. The cake was rinsed with 2.1 L of toluene. The solid was dried under vacuum at 40° C. N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide was isolated as a crystalline product in 85% yield. Without seeding, the yield was approximately 1% lower.1 H NMR (500 MHz, DMSO-d6) δ 13.34 (s, 1H), 10.23 (s, 1H), 8.05 (d, 8.6 Hz, 1H), 7.28 (d, 2.2 Hz, 1H), 7.14 (dd, 8.6,2.2 Hz, 1H), 4.93 (t, 6.2 Hz, 1H), 3.90 (bt, 6.0 Hz, 4H), 3.77 (q, 6.2 Hz, 2H), 3.36 (t, 6.2 Hz, 2H), 2.97 (t, 5.3 Hz, 4H), 2.30 (s, 3H), 1.98 (tt, 13.8,6.0 Hz, 4H), 1.72 (m, 4H), 0.38 (s, 4H) 13 C NMR (126 MHz, DMSO-d6) δ 169.1, 163.6, 160.3, 158.3, 153.7, 143.2, 132.4, 123.1 (t, 1 J C-F =-241.0 Hz), 120.7, 114.6, 111.3, 98.5, 55.4, 53.8, 53.6, 40.2 (t, 3 J C-F =5.0 Hz), 33.1 (t, 2 J C-F =22.3 Hz), 34.2, 24.4, 16.8, 11.1; 19 F NMR (471 MHz, DMSO-d6) δ -94.8;HRMS-ESI (m / z): [M+H] + [C 26 H 34 F2N6O4S+H] + Calculated value for, 565.2409; measured value, 565.2407.

[0179] Example 9: Preparation of N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide hydrochloride [ka]

[0180] To N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (100 g, 1.0 equiv.) was added 1800 mL of a 8 / 1 premix of acetone and water. The mixture was heated to 47° C. and stirred at that temperature for 30 min. The solution was polish filtered and the polish filtration was chased with 450 mL of a 8 / 1 premix of acetone and water. To the mixture was added 150 mL of water and concentrated aqueous hydrochloric acid (1.2 equiv. HCl, 24.3 g) over 30 min at 47° C. Water was added to the mixture (100 mL) and it was stirred at 47° C. for 30 min. The reactor was cooled to 15° C. over 4 h. The batch was subjected to slurry milling to reduce particle size. The product was isolated by filtration, washed with acetone (300 mL) and dried under vacuum at 40° C. to give N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide hydrochloride as a crystalline solid in 92% yield. 1 H NMR (500 MHz, DMSO-d6) δ 13.87 (bs, 1H), 10.41 (s, 1H), 8.05 (d, 8.7 Hz, 1H), 7.54 (s, 1H), 7.34 (d, 2.2 Hz, 1H), 7.19 (dd, 8.7,2.2 Hz, 1H), 3.99 (bt, 6.1 Hz, 4H), 3.76 (t, 6.4 Hz, 2H), 3.37 (t, 6.4 Hz, 2H), 2.98 (bt, 5.3 Hz, 4H), 2.47 (s, 3H), 2.08 (btt, 13.6,6.1 Hz, 4H), 1.69 (m, 4H), 0.39 (s, 4H), ; 13 C NMR (126 MHz, DMSO-d6) δ 165.1, 164.0, 159.6, 156.6, 153.8, 143.8, 132.5, 122.6 (t, 1 J C-F=-241.2 Hz), 120.1, 114.8, 111.5, 99.2, 55.4, 54.0, 53.6, 41.4, 34.2, 33.0 (t, 2 J C-F =22.8 Hz), 21.9, 16.8, 11.2 ; 19 F NMR (471 MHz, DMSO-d6) δ -95.0;HRMS-ESI (m / z): [M+H] + [C 26 H 34 F2N6O4S+H] + Calculated value for, 565.2409; measured value, 565.2407.

[0181] The foregoing is merely illustrative of the present invention and is not intended to limit the invention to the disclosed uses. Variations and modifications that are routine for those skilled in the art are intended to be within the scope and nature of the invention as defined in the appended claims. All references, patents, applications and publications mentioned are incorporated herein by reference in their entirety as if set forth herein.

[0182] The implementation of the methods disclosed herein, and their individual steps, can be performed manually and / or with automation using or provided by electronic devices. Although the steps are described with reference to specific embodiments, those skilled in the art will readily understand that other ways of performing the acts associated with the methods can also be used. For example, unless otherwise indicated, the order of various steps may be changed without departing from the scope or spirit of the method. Furthermore, some of the individual steps may be combined, omitted, or further subdivided into additional steps.

[0183] The use of the terms "a," "an," "the," and similar referents in the context of this disclosure (particularly in the context of the claims) are to be construed as including both the singular and the plural unless otherwise indicated. The recitation of numerical ranges herein is merely intended to be used as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated herein as if it were individually recited herein. The use of all examples or exemplary language (e.g., "such as") provided herein is intended to better illustrate the disclosure herein and does not limit the scope of the disclosure herein, unless otherwise indicated. No language within this specification should be construed as indicating any non-claimed element as essential to the practice of the disclosure.

Claims

1. The chemical structure below: 【Chemistry 1】 1. A method for preparing a KIF18A inhibitor compound having the structure: 【Chemistry 2】 [Wherein PG is C １－６ Alkyl, C １－６ Alkyl-O-C １－６ wherein R is a hydroxyl protecting group selected from alkyl, tetrahydropyranyl, allyl, or benzyl, with a suitable deprotecting agent in a suitable solvent to form compound 1.

2. formula: 【Transformation 3】 [Wherein PG is C １－６ Alkyl, C １－６ Alkyl-O-C １－６ wherein the hydroxyl protecting group is selected from alkyl, tetrahydropyranyl, allyl, or benzyl, or a salt thereof, is treated with a compound 3 having the formula 【Chemistry 4】 or a salt thereof, in the presence of an amide coupling reagent and a base in an organic solvent to form said compound 2.

3. formula: 【Transformation 5】 or a salt thereof, 【Transformation 6】 [Wherein PG is C １－６ Alkyl, C １－６ Alkyl-O-C １－６ 3. The method of claim 2, further comprising preparing compound 3 or a salt thereof by reacting compound 6 or a hydrate thereof having a hydroxyl protecting group selected from alkyl, tetrahydropyranyl, allyl, or benzyl, M being a metal, and n being an integer selected from 1 or 2, with a base, optionally in the presence of a catalyst, at elevated temperature in an organic solvent to form compound 3 or a salt thereof.

4. formula: 【Transformation 7】 [In the formula, X １ is a halide], 【Transformation 8】 [In the formula, LG １ is a leaving group] in the presence of a base at elevated temperature in an organic solvent to form compound 5, or a salt thereof.

5. formula: 【Chemistry 9】 [In the formula, LG ２ is a leaving group], by reacting compound 9 having the formula: 【Chemistry 10】 [In the formula, X ２ is a halide] in the presence of a base in an organic solvent at elevated temperature to form compound 4.

6. A compound comprising: 【Chemistry 11】 wherein PG is benzyl (compound 2a).

7. A compound comprising: 【Chemistry 12】 wherein PG is benzyl (compound 3a). 【Request Item 8】 【Chemistry 13】 or a salt thereof.

9. The chemical structure below: 【Chemistry 14】 wherein PG is a hydroxyl protecting group, M is a metal, and n is 1 or 2 (Compound 6), or a hydrate thereof; 【Chemistry 15】 [Wherein PG is C １－６ Alkyl, C １－６ Alkyl-O-C １－６ 4. The method of claim 3, comprising reacting compound 11, having a hydroxyl protecting group selected from alkyl, tetrahydropyranyl, allyl, or benzyl, with a base in a polar solvent at moderately elevated temperature to form compound 6 or a hydrate thereof.

10. The chemical structure below: 【Chemistry 16】 [Wherein PG is C １－６ Alkyl, C １－６ Alkyl-O-C １－６ 10. The method of claim 9, further comprising preparing compound 11 by reacting compound 12, having a hydroxyl protecting group selected from alkyl, tetrahydropyranyl, allyl, or benzyl, with an oxidizing agent in the presence of a catalyst in a solvent at slightly elevated temperature to form compound 11.

11. The chemical structure below: 【Chemistry 17】 Compound 13 having the following chemical structure: [Chemistry 18] [Wherein PG is C １－６ Alkyl, C １－６ Alkyl-O-C １－６ a hydroxyl protecting group selected from alkyl, tetrahydropyranyl, allyl, or benzyl; LG ３ is a leaving group] in the presence of a base in a solvent at a moderately elevated temperature to form compound 12.

12. 2. The method of claim 1, wherein PG is benzyl, the suitable deprotecting agent is a palladium-carbon catalyst, or the solvent is a polar solvent.

13. the amide coupling reagent is selected from chloroformamidinium salts, 2-chloro-1,3-dimethylimidazolinium chloride (DMC), 1-(chloro-1-pyrrolidinylmethylene)pyrrolidinium hexafluorophosphate (PyCIU), 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), or N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), and the base is selected from N-methylmorpholine (NMM), N,N-diisopropylethylamine (DIPEA), triethylamine (TEA), 2,4,6-trimethylpyridine (collidine), or 2,6-lutidine; or the chloroformamidinium salt is chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH) and the base is 2,4,6-trimethylpyridine (collidine); or the method is carried out at a temperature of 25°C to 50°C, 40°C to 50°C, or 50°C; or 3. The method of claim 2, wherein the solvent is an organic solvent selected from 2-methyl THF, acetonitrile, isopropyl acetate, dichloromethane, THF, or a mixture thereof, or the solvent is 2-methyl THF and acetonitrile.

14. The process is carried out without a catalyst or in the presence of a metal catalyst selected from an iron catalyst, a gold catalyst, or a palladium catalyst, or the process is carried out in the presence of a metal catalyst, wherein the catalyst is iron(III) chloride hexahydrate; or the base is sodium bisulfite; or the elevated temperature is solvent reflux temperature or 60°C to 100°C, 70°C to 90°C, or 70°C; or 4. The method of claim 3 wherein the solvent is NMP.

15. the base is a hydroxide or an amine, or the base is potassium hydroxide or diisopropylethylamine, or the base is potassium hydroxide, or the solvent is a polar aprotic solvent selected from NMP, DMAC, DMF, or DMSO, or the solvent is NMP; or the elevated temperature is solvent reflux temperature or 80°C to 140°C, 100°C to 140°C, or 120°C; or 5. The method of claim 4, wherein compound 5 is crystallized by the addition of an acid, or wherein the acid is phosphoric acid.

16. the base is an amine or hydroxide, or the base is triethylamine, or the elevated temperature is solvent reflux temperature or 60°C to 100°C, 60°C to 85°C, or 80°C; or 6. The method of claim 5, wherein the solvent is a mixture of acetonitrile and water.

17. the base is a hydroxide, or the base is calcium hydroxide, sodium hydroxide, or the base is calcium hydroxide; or The solvent is C １－６ a mixture of alkyl alcohol and water, or crystallizing compound 6 in acetone; or 10. The method of claim 9, wherein the temperature is 25°C to 50°C, 40°C to 50°C, or 50°C.

18. the oxidizing agent is a peroxide or a peroxycarboxylic acid, or the oxidizing agent is hydrogen peroxide or a metaperoxycarboxylic acid, or the catalyst is sodium tungstate, or the temperature is between 25°C and 40°C, between 30°C and 35°C, or 30°C; or the solvent is a mixture of acetonitrile and water; or crystallizing compound 12 in acetone or a mixture of acetone and water; or 11. The method of claim 10, wherein compound 12 is not isolated and the solvent is acetonitrile.

19. the base is a bicarbonate, carbonate, hydroxide, or phosphate, or the base is calcium carbonate; or the solvent is an alcohol, or the solvent is methanol, or 12. The method of claim 11, wherein the temperature is solvent reflux temperature or 70°C to 100°C, 75°C to 90°C, or 82°C.

20. The compound 1 is reacted with an acid HA in a solvent to give a compound of the formula 【Chemistry 19】 20. The method of any one of claims 1-5 or 9-19, further comprising forming a pharmaceutically acceptable salt of compound 1 having the formula:

21. 20. The method of any one of claims 1 to 5 or 9 to 19, wherein PG is benzyl.

22. Chemical structure: 【Chemistry 20】 [Wherein PG is C １－６ Alkyl, C １－６ Alkyl-O-C １－６ wherein M is a metal; and n is an integer selected from 1, 2, or 3; or a solid form thereof.

23. PG is benzyl, M is calcium, and n is 2 (compound 6a), 【Chemistry 21】 23. The compound of claim 22, or a solid form thereof, having:

24. 24. The solid form of compound 6a of claim 23, which is crystalline or amorphous.

25. formula 【Chemistry 22】 25. The solid form of compound 6a of claim 24, wherein the compound is compound 6a-I having the formula:

26. or further characterized by an XRPD pattern peaks at 4.2, 8.2, and 12.2±0.2 degrees 2θ using Cu Kα radiation; or further characterized by XRPD pattern peaks at 13.6, 14.2, 18.3, 19.5, 20.6, 20.9, and 22.9±0.2 degrees two-theta using Cu Kα radiation; or further characterized by XRPD pattern peaks at 16.2, 16.7, 19.2, 21.4, 23.9, 24.4, 24.7, 25.5, 27.6, 28.1, 30.3, 33.3, and 36.6±0.2 degrees two-theta using Cu Kα radiation; or having an XRPD pattern substantially as shown in Figure 1; or having a first endothermic transition between 124.96°C and 130.96°C and a second endothermic transition between 256.11°C and 262.11°C, as measured by differential scanning calorimetry, or wherein the first endothermic transition occurs at 127.96°C ± 3°C and the second endothermic transition occurs at 259.11°C ± 3°C; or having a thermogravimetric analysis (TGA) substantially as shown in Figure 3; or 26. The crystalline compound 6a-I of claim 25, having a single crystal structure substantially as shown in FIG.

27. The crystalline compound 6a-I according to any one of claims 25 and 26, which has a stable crystalline form and low hygroscopicity.

28. The method of claim 20, wherein the PG is benzyl.

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