Synthesis of Bruton's tyrosine kinase inhibitors

Abstract

The present disclosure provides a method of synthesizing a compound of formula (I), wherein the R groups are defined herein: [Formula 1] TIFF2025506671000201.tif36128 and a method of synthesizing the compound of formula (II). [chemical 2] TIFF2025506671000202.tif39128 Some embodiments of the present disclosure are directed to converting the compound of formula (II) to its P form.

Description

[Technical field]

[0001] (Priority Claim) This application claims priority to Greek Application No. 20220100151, filed February 18, 2022, European Application No. 22167032.6, filed April 6, 2022, and European Application No. 22178413.5, filed June 10, 2022, each of which is incorporated by reference in its entirety herein.

[0002] FIELD OF THEINVENTION The present disclosure is directed to the synthesis of small molecule tyrosine kinase inhibitors. [Background technology]

[0003] Human Bruton's Tyrosine Kinase ("BTK") is a protein of approximately 76 kDa that belongs to the Tec family of non-receptor tyrosine kinases. Tec kinases form the second large family of cytoplasmic tyrosine kinases in mammalian cells, consisting of BTK plus four other members: the homologous kinases TEC, ITK, TXK / RLK, and BMX. Tec kinases are evolutionarily conserved throughout vertebrates. They are related to, but structurally distinct from, the larger Src and Syk kinase families. Tec family proteins are abundantly expressed in hematopoietic tissues and play important roles in the proliferation and differentiation of mammalian blood and endothelial cells. Based on BTK expression from IHC studies described in the art, Btk inhibition has the potential to modulate the biology associated with B cells, macrophages, mast cells, osteoclasts, and platelet microparticles. Corneth,OB,et al.Curr.Top.Microbiol.Immunol.BTK Signaling in B Cell Differentiation and Autoimmunity.2015 Sept.5. Summary of the Invention

[0004] Disclosed herein are methods of synthesizing compounds of formula (I), including solvates or pharma- ceutically acceptable salt forms thereof, wherein R groups are defined herein.

[0005] [ka]

[0006] Also disclosed is a method of synthesizing a compound of formula (II), including a solvate or a pharma- ceutically acceptable salt form thereof.

[0007] [ka]

[0008] The compound of formula (II) is also known as N-((1R,2S)-2-acrylamidocyclopentyl)-5-(6-isobutyl-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide. In some embodiments, the compound of formula (II) exists as a mixture of atropisomers P and M forms.

[0009] Some embodiments further comprise converting the compound of formula (II) to its P form.

[0010] [ka] The compound of formula P-(II) is also known as N-((1R,2S)-2-acrylamidocyclopentyl)-5-(S)-(6-isobutyl-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide.

[0011] The compound of formula M-(II) is also known as N-((1R,2S)-2-acrylamidocyclopentyl)-5-(R)-(6-isobutyl-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide.

[0012] [ka] [Brief description of the drawings]

[0013] [Figure 1] Draw an example of a reactor configuration used for the CIDT process. [Diagram 2] FIG. 1 depicts a typical evolution of the P (left bar at each time point) and M (right bar at each time point) isomer concentrations in the recirculating liquid in the loop reactor in a 1-propanol / water system. [Diagram 3] FIG. 1 depicts a typical evolution of the P (left bar at each time point) and M (right bar at each time point) isomer concentrations in the recirculating liquid in a loop reactor in a propylene carbonate / water system. [Figure 4] 1 depicts the X-ray powder diffraction (XRPD) spectrum of crystalline form B of formula P-(II) dihydrate. [Diagram 5] 1 depicts the infrared (IR) spectrum of crystalline form B of formula P-(II) dihydrate. [Figure 6] A differential scanning calorimetry (DSC) spectrum of crystalline form B of formula P-(II) dihydrate using standard pan conditions is plotted. [Figure 7] 4 depicts the DSC spectrum of crystalline form B of formula P-(II) dihydrate utilizing Tzero sealed pan conditions. [Figure 8]A thermogravimetry (TGA) spectrum of crystalline form B of formula P-(II) dihydrate utilizing Tzero sealed pan conditions is plotted. [Figure 9] The decay of diastereomeric excess in propylene carbonate at 100° C. as measured by HPLC (left) and a linear plot of t vs. ln(1 / (de)) (right) are plotted; the slope of the linear plot gives the value of 2ke. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] The present disclosure may be more fully understood by reference to the following description, including the following glossary and concluding examples. It is also understood that certain features of the compositions and methods of the present disclosure, which are described herein in the context of separate embodiments for clarity, may be provided in combination in a single embodiment. Conversely, various features of the compositions and methods of the present disclosure, which are described in the context of a single embodiment for brevity, may be provided separately or in any subcombination. In general, those skilled in the art will understand that the terms used herein, and in particular in the appended claims (e.g., the body of the appended claims), are generally intended as "open" terms (e.g., the term "including" should be interpreted as "including but not limited to", the term "having" should be interpreted as "having at least", the term "includes" should be interpreted as "includes but is not limited to", etc.). Those skilled in the art will further understand that where a specific number is intended in an introduced claim recitation, such intent will be expressly recited in the claim, and in the absence of such recitation, no such intent exists. For example, as an aid to understanding, the claims at the following appended claims may include the introductory phrases "at least one" and "one or more" to introduce the claim recitations.However, the use of such phrases should not be construed as suggesting that a claim statement introduced by the indefinite article "a" or "an" limits any particular claim containing such an introduced claim statement to an embodiment containing only one such statement, even when the same claim includes the introductory phrase "one or more" or "at least one" and an indefinite article such as "a" or "an" (e.g., "a" and / or "an" should be construed to mean "at least one" or "one or more"), and the same is true when a definite article is used to introduce a claim statement. In addition, those skilled in the art will recognize that even if a specific number of introduced claim statements is explicitly recited, such a recitation should be construed to mean at least the recited number (e.g., the bare recitation of "two statements" without other modifiers means at least two statements, or two or more statements). Furthermore, in instances where notation similar to "at least one of A, B, and C, etc." is used, such syntax is generally intended in the sense that one of ordinary skill in the art would understand such notation (e.g., "a system having at least one of A, B, and C" includes, but is not limited to, systems having only A, only B, only C, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). In instances where notation similar to "at least one of A, B, or C, etc." is used, such syntax is generally intended in the sense that one of ordinary skill in the art would understand such notation (e.g., "a system having at least one of A, B, or C" includes, but is not limited to, systems having only A, only B, only C, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). Those skilled in the art will further appreciate that virtually all disjunctive words and / or phrases presenting two or more alternative terms, whether in the specification, claims, or drawings, should be understood to contemplate the possibility of including one of the terms, either of the terms, or both terms. For example, the phrase "A or B" is understood to include the possibilities of "A" or "B" or "A and B."

[0015] In addition, when features or aspects of the disclosure are described in terms of a Markush group, one of skill in the art will recognize that the disclosure is also thereby described in terms of any individual members or subgroups of members of the Markush group.

[0016] As used herein, the term "about," when immediately preceding a numerical value, means a range of plus or minus 10% of that value, unless the context of this disclosure indicates otherwise or is inconsistent with the interpretation below; for example, "about 50" means 45 to 55, "about 25,000" means 22,500 to 27,500, etc.

[0017] When used alone or as part of a substituent group, the term “alkyl” refers to an alkyl group having 1 to 12 carbon atoms (e.g., C 1~12 "), preferably 1 to 6 carbon atoms ("C 1~6 "). Examples of alkyl groups include methyl (Me, C1 alkyl), ethyl (Et, C2 alkyl), n-propyl (C3 alkyl), isopropyl (C3 alkyl), butyl (C4 alkyl), isobutyl (C4 alkyl), sec-butyl (C4 alkyl), tert-butyl (C4 alkyl), pentyl (C5 alkyl), isopentyl (C5 alkyl), tert-pentyl (C5 alkyl), hexyl (C6 alkyl), isohexyl (C6 alkyl), and groups that would be considered equivalent to any one of the foregoing examples in light of the skill of the art and the teachings provided herein.

[0018] A range of carbon atoms, e.g., C 1~6 When "C" is used, all ranges as well as individual numbers of carbon atoms are included. For example, "C 1~3 " is C 1~3 , C 1~2 , C 2~3 , C1, C2, and C3.

[0019] "C 1~6The term "alk" refers to an aliphatic linker having 1, 2, 3, 4, 5, or 6 carbon atoms, including, for example, CH2, CH(CH3), CH(CH3)-CH2, and C(CH3)2-. The term "-C0alk-" refers to a bond. In some embodiments, C 1~6 The alk may be substituted with an oxo or OH group.

[0020] The term “alkenyl” when used alone or as part of a substituent group means an alkyl group having 2 to 12 carbon atoms ("C 2~12 "), preferably 2 to 6 carbon atoms ("C 2~6 ") refers to a straight and branched carbon chain having at least one, preferably one to two, more preferably one double bond, and the carbon chain contains at least one double bond. For example, alkenyl moieties include, but are not limited to, allyl, 1-propen-3-yl, 1-buten-4-yl, propa-1,2-dien-3-yl, and the like.

[0021] The term "alkynyl" when used alone or as part of a substituent group means an alkynyl group having 2 to 12 carbon atoms ("C 2~12 "), preferably 2 to 6 carbon atoms ("C 2~6 ") refers to a straight and branched carbon chain having at least one, preferably one to two, more preferably one triple bond, and the carbon chain contains at least one triple bond. For example, alkynyl moieties include, but are not limited to, vinyl, 1-propyn-3-yl, 2-butyn-4-yl, and the like.

[0022] The term "aryl" refers to aryl groups having 6 to 10 carbon atoms ("C 6~10 ").

[0023] The term "cycloalkyl" refers to a group having 3 to 10 carbon atoms ("C 3~10 "), preferably 3 to 6 carbon atoms ("C 3~6"). Examples of cycloalkyl groups include, for example, cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclohexyl (C6), 1-methylcyclopropyl (C4). 、 2-Methylcyclopentyl (C4), Adamantanyl (C 10 ) etc.

[0024] The term "heterocycloalkyl" refers to any 5-10 membered monocyclic or bicyclic saturated ring structure containing at least one heteroatom selected from the group consisting of O, N, and S. The heterocycloalkyl group may be attached at any heteroatom or carbon atom of the ring that results in a stable structure. Suitable heterocycloalkyl groups include, but are not limited to, azepanyl, aziridinyl, azetidinyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, piperazinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, oxazepanyl, oxiranyl, oxetanyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, hexahydro-5H-[1,4]dioxino[2,3-c]pyrrolyl, benzo[d][1,3]dioxolyl, and the like.

[0025] The term "heteroaryl" refers to a monocyclic or bicyclic aromatic ring structure that contains carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur. Heteroaryl rings can have a total of 5, 6, 9, or 10 ring atoms ("C 5~10Examples of heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, oxazolyl, imidazolyl, prazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl, isoindolinyl, indazolyl, benzofuryl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolidinyl, quinolinyl, isoquinolinyl, isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, and the like.

[0026] The term "halogen" refers to chlorine, fluorine, bromine, or iodine. The term "halo" refers to chloro, fluoro, bromo, or iodo.

[0027] The term "haloalkyl" refers to an alkyl moiety in which one or more hydrogen atoms are replaced with one or more halogen atoms. One exemplary substituent is fluoro. Preferred alkyl groups of the present disclosure include trihalogenated alkyl groups, such as trifluoromethyl groups.

[0028] The term "oxo" refers to a =O moiety, in which two hydrogens from the same carbon atom are replaced with a carbonyl. For example, an oxo-substituted pyrrolidinyl moiety can be a pyrrolidin-2-one moiety or a pyrrolidin-3-one moiety.

[0029] The term "phenyl" refers to the following moiety:

[0030] [ka] The phenyl moiety may be attached via any of the carbon atoms.

[0031] The term "pyridyl" refers to the moiety:

[0032] [ka] The pyridyl moiety may be attached via any one of the 2-, 3-, 4-, 5-, or 6-carbon atoms.

[0033] The term "compounds of the present disclosure" and equivalent expressions are meant to include compounds of formula (I), compounds of formula (II), compounds of formula P-(II), and compounds of formula M-(II) as described herein, including, where permitted by the context, their pharma- ceutically acceptable salts and solvates, such as hydrates, dihydrates, and polymorphs. Compounds of the present disclosure also include their stereoisomers (including, but not limited to, enantiomers and diastereomers) and their tautomeric forms. Similarly, references to intermediates, whether or not they are themselves claimed, are meant to include their salts and solvates, where permitted by the context.

[0034] Suitable pharma- ceutically acceptable salts of the compounds of the present disclosure include, for example, acid addition salts that may be formed by mixing a solution of the compound with a solution of a pharma- ceutically acceptable acid, such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid, or phosphoric acid. Additionally, when the compounds of the present disclosure contain an acidic moiety, suitable pharma- ceutically acceptable salts thereof may include salts formed with suitable organic ligands, such as alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, and quaternary ammonium salts. Thus, representative pharma- ceutically acceptable salts include acetate, benzenesulfonate, benzoate, bicarbonate, hydrogen sulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolyl arsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, and the like. The salts include, but are not limited to, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, theoclate, tosylate, triethiodide, and valerate.

[0035] As used herein, a "solvate" can be a solvate with water (ie, a hydrate, a dihydrate) or with an organic solvent.

[0036] For the purposes of this disclosure, the terms "crystalline form" and "polymorph" are synonymous. Characterization information for crystalline forms is provided herein. It should be understood that the determination of a particular form may be accomplished using any portion of the characterization information that a person skilled in the art would recognize as sufficient to establish the presence of a particular form. For example, even a single characteristic peak may be sufficient for a person skilled in the art to recognize that a particular form is present.

[0037] As used herein, the term "isotopic variant" refers to a compound that contains an unnatural proportion of an isotope at one or more of the atoms that constitute such compound. For example, an "isotopic variant" of a compound may be radiolabeled, i.e., contain one or more non-radioactive isotopes, such as deuterium ( 2 H or D), carbon 13 ( 13 C), or nitrogen-15 ( 15 In such isotopically substituted compounds, the subsequent atom, if present, may vary, so that, for example, any hydrogen may be replaced with 2 H / D, any carbon may be 13 C or any nitrogen may be 15 It will be understood that the atom may be N, and the presence or location of such an atom can be determined within the skill of the art. Similarly, the present disclosure may include the preparation of isotopic variants with radioisotopes, for example, where the resulting compounds may be used in drug and / or substrate tissue distribution studies. Radiolabeled compounds of the present disclosure may be used in diagnostic methods such as single-photon emission computed tomography (SPECT). The radioisotope tritium, i.e. 3 H and carbon 14, i.e. 14 C are particularly useful due to their ease of incorporation and ready means of detection. Additionally, positron emitting isotopes, e.g. 11 C. 18 F, 15 O, and 13N-substituted compounds can be prepared and are useful in Positron Emission Topography (PET) studies to examine substrate receptor occupancy.

[0038] All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

[0039] It is also understood that compounds that have the same molecular formula but differ in the nature or sequence of bonds of their atoms or the arrangement of their atoms in space are referred to as "isomers." Isomers that differ in the arrangement of their atoms in space are referred to as "stereoisomers," e.g., diastereomers, enantiomers, and atropisomers.

[0040] Stereoisomers that are not mirror images of each other are termed "diastereomers" and stereoisomers that are non-superimposable mirror images of each other are termed "enantiomers". When a compound has an asymmetric center, for example, when it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R and S ordering rules of Cahn and Prelog or by the way the molecule rotates the plane of polarized light and are designated as dextrorotatory or levorotatory (i.e., as (+) or (-) isomers, respectively). Chiral compounds can exist as either individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

[0041] "Atropisomer" refers to a stereoisomer that arises due to hindered rotation about a single bond. Atropisomers are designated throughout as either M or P.

[0042] "Tautomers" refer to compounds that are interchangeable forms of a particular compound structure, differing in the replacement of hydrogen atoms and electrons. Thus, two structures can be in equilibrium through the shifting of pi electrons and atoms (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the acid and nitro forms of phenylnitromethane, which are similarly formed by treatment with acid or base.

[0043] Tautomeric forms may be relevant in achieving optimal chemical reactivity and biological activity of a compound of interest.

[0044] Compounds of the present disclosure may possess one or more asymmetric centers and such compounds may therefore be produced as individual (R) or (S) stereoisomers or as mixtures thereof.

[0045] Unless otherwise indicated, the description or naming of a particular compound in the present specification and claims is intended to include both its individual enantiomers and mixtures, racemic or otherwise. Within this disclosure, any open valency appearing on a carbon, oxygen, or nitrogen atom in any structure described herein indicates the presence of a hydrogen atom. When a chiral center is present in a structure and no specific stereochemistry is shown for that center, both enantiomers, either separately or as mixtures, are encompassed by the structure. Methods for determining stereochemistry and separating stereoisomers are well known in the art.

[0046] Synthesis method The present disclosure relates to a method of synthesizing a compound of formula (I), including a solvate or a pharma- ceutically acceptable salt form thereof, comprising:

[0047] [ka] During the ceremony, R 1 But, C 5~10 Aryl and C 4~9heteroaryl, wherein the aryl or heteroaryl is optionally selected from C 1~6 substituted with one or more groups independently selected from alkyl; R 2 But, C 1~6 Alkyl and C 2~6 alkenyl, compound

[0048] [ka] with an acid and a first solvent, and then

[0049] [ka] in the presence of one or more coupling reagents, an amine base, and a second solvent to obtain a compound of formula (I).

[0050] The synthesis of compounds of formula (I) is outlined in Scheme 1.

[0051] [ka]

[0052] In some embodiments, R 1 But, C 4~9 In some embodiments, C is heteroaryl. 4~9 Heteroaryl is

[0053] [ka] In some embodiments, R 2 But, C 2~6 In some embodiments, C is an alkenyl. 2~6 Alkenyl is

[0054] [ka] In some embodiments, Pg is Boc (tert-butyloxycarbonyl).

[0055] In some embodiments, the acid is methanesulfonic acid. In some embodiments, the first solvent is selected from dichloromethane (DCM), ethyl acetate (EtOAc), 2-methyltetrahydrofuran (MeTHF), tetrahydrofuran (THF), and acetonitrile (ACN). In some embodiments, the coupling reagent is selected from 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), hydroxybenzotriazole (HOBt), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), propylphosphonic anhydride (T3P), 1,1'-carbonyldiimidazole (CDI), and 2-hydroxypyridine-N-oxide (HOPO). In some embodiments, the amine base is selected from N,N-diisopropylethylamine (DIPEA), triethylamine, tributylamine, N-methylmorpholine, and N-methylpiperidine. In some embodiments, the second solvent is selected from dichloromethane, ethyl acetate, 2-methyltetrahydrofuran, tetrahydrofuran, and acetonitrile.

[0056] In another embodiment of the method of synthesizing a compound of formula (I), the method comprises:

[0057] [ka] with a base and an ammonium salt in a solvent to form compound CMPD-02. In some embodiments, the base is selected from potassium trimethylsilanolate (TMSOK), lithium hydroxide (LiOH), or sodium hydroxide (NaOH). In some embodiments, the ammonium salt is selected from tetrabutylammonium bromide (TBAB), tetrabutylammonium hydrogen sulfate, benzyltrimethylammonium bromide, benzyltrimethylammonium chloride, and Aliquat 336. In some embodiments, the solvent is tetrahydrofuran.

[0058] In another embodiment of the method of synthesizing a compound of formula (I), the method comprises:

[0059] [ka] with a carbonyl source and a solvent to form compound CMPD-03. In some embodiments, the carbonyl source is selected from N,N'-carbonyldiimidazole (CDI), phosgene, triphosgene, and N,N'-disuccinimidyl carbonate (DSC). In some embodiments, the solvent is tetrahydrofuran.

[0060] In another embodiment of the method of synthesizing a compound of formula (I), the method comprises:

[0061] [ka] with a sulfur reagent and a base in a solvent to form compound CMPD-04, where X is selected from Cl and Br. In some embodiments, X is Cl. In some embodiments, the sulfur reagent is methyl 2-mercaptoacetate. In some embodiments, the base is sodium methoxide (NaOMe). In some embodiments, the solvent is methanol.

[0062] In another embodiment of the method of synthesizing a compound of formula (I), the method comprises:

[0063] [ka] In a solvent system, a compound R having a base is 1 -NH2, and an amine base to form compound CMPD-05. In some embodiments, X is Cl. In some embodiments, R 1 but,

[0064] [ka] In some embodiments, the base is KCO. In some embodiments, the amine base is N,N-diisopropylethylamine (DIPEA). In some embodiments, the solvent system is toluene / NMP.

[0065] In another embodiment of the method of synthesizing a compound of formula (I), the method comprises: 1 -NO2 with a hydride source, a catalyst, and a solvent system to produce a compound R 1The method further comprises forming -NH2. In some embodiments, the hydrogen source is ammonium formate, NaBH4, or H2. In some embodiments, the catalyst is from NiCl2, Pd / C, palladium II acetate (Pd(OAc)2), Pd(OH)2, Raney Ni, sponge Ni, Pt / V / C, Pt / Fe / C, NiBr2, NiCl2. In some embodiments, the solvent system is selected from toluene / water, xylene, THF, selected MeTHF, MeOH, THF / MeOH, toluene / MeOH, MeTHF / water, and THF / water.

[0066] In another embodiment of the method of synthesizing a compound of formula (I), the method comprises:

[0067] [ka] with a cyano source and a solvent to form compound CMPD-06. In some embodiments, X is Cl. In some embodiments, the cyano source is CuCN. In some embodiments, the solvent is butyronitrile.

[0068] In another embodiment of the method of synthesizing a compound of formula (I), the method comprises:

[0069] [ka] with a base and an electrophilic halogen in a solvent to form compound CMPD-07. In some embodiments, X is Cl. In some embodiments, the base is lithium diisopropylamine. In some embodiments, the solvent is tetrahydrofuran.

[0070] In another embodiment of the method of synthesizing a compound of formula (I), the method comprises:

[0071] [ka] The base,

[0072] [ka] and a solvent to form compound CMPD-01. 2 But, C 2~6 In some embodiments, C is an alkenyl. 2~6 Alkenyl is

[0073] [ka] In some embodiments, Pg is Boc. In some embodiments, the base is NaHCO3. In some embodiments, the solvent is 2-methyltetrahydrofuran.

[0074] In another embodiment of the method of synthesizing a compound of Formula (I), the method further comprises synthesizing CMPD-04 according to Scheme 2.

[0075] [ka]

[0076] In another embodiment of the method of synthesizing a compound of formula (I), the method comprises:

[0077] [ka] in a solvent with an alkylating reagent in the presence of a base to form compound CMPD-04. In some embodiments, the alkylating reagent is methyl chloroacetate. In some embodiments, the base is selected from sodium carbonate (Na2CO3) and potassium carbonate (K2CO3). In some embodiments, the solvent is selected from one or more solvents such as N,N-dimethylformamide (DMF), acetonitrile (ACN), methanol, 2-methyltetrahydrofuran (MeTHF), and water.

[0078] In another embodiment of the method of synthesizing a compound of formula (I), the method comprises:

[0079] [ka] in a solvent.

[0080] [ka] and a base to form compound CMPD-05', wherein R 5 But, C 1~6 In some embodiments, C is alkyl. 1~6 The alkyl is methyl and ethyl. In some embodiments, the CMPD-25 is selected from N,N-dimethylformamide dimethyl acetal and N,N-dimethylformamide diethyl acetal. In some embodiments, the base is selected from sodium hydroxide (NaOH), tribasic potassium phosphate (K3PO4), potassium carbonate (K2CO3), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and morpholine. In some embodiments, the solvent is selected from one or more solvents such as N,N-dimethylformamide (DMF), isopropyl acetate, 2-methyltetrahydrofuran (MeTHF), tetrahydrofuran (THF), acetonitrile (ACN), toluene, ethanol, tert-butyl methyl ether (TBME), and water.

[0081] In another embodiment of the method of synthesizing a compound of formula (I), the method comprises:

[0082] [ka] in a solvent to obtain compound R 1 -NH2 to form compound CMPD-24, wherein R4 is (C 1~6 Alkyl)2N and C1~6 In some embodiments, C is alkyl. 1~6 The alkyl is selected from methyl and ethyl. In some embodiments, the solvent is selected from one or more solvents such as N,N-dimethylformamide (DMF), 1-methyl-2-pyrrolidone (NMP), isopropyl acetate, 2-methyltetrahydrofuran (MeTHF), tetrahydrofuran (THF), acetonitrile (ACN), ethanol, and methanol.

[0083] In another embodiment of the method of synthesizing a compound of Formula (I), the method further comprises the synthesis of CMPD-02 according to Scheme 3.

[0084] [ka]

[0085] In another embodiment of the method of synthesizing a compound of formula (I), the method comprises:

[0086] [ka] with a base and an ammonium salt in a solvent to form compound CMPD-02, wherein X 1is H or Na. In some embodiments, the base is selected from potassium trimethylsilanolate (TMSOK), lithium hydroxide (LiOH), potassium hydroxide (KOH), or sodium hydroxide (NaOH). In some embodiments, the ammonium salt is selected from tetramethylammonium bromide, tetraethylammonium bromide, tetraethylammonium chloride, tetrabutylammonium bromide (TBAB), tetrabutylammonium hydrogen sulfate, benzyltrimethylammonium bromide, benzyltrimethylammonium chloride, didodecyldimethylammonium bromide, and Aliquat 336. More generally, those skilled in the art will recognize that alkylammonium salts and substituted alkylammonium salts can be used. In some embodiments, the solvent is tetrahydrofuran or methyltetrahydrofuran.

[0087] In another embodiment of the method of synthesizing a compound of formula (I), the method comprises reacting a compound, wherein X is selected from Cl and Br, in the presence of one or more bases and an ammonium salt in a solvent.

[0088] [ka] , R 3 C 1~6 Compounds that are alkyl

[0089] [ka] and a sulfur reagent to form compound CMPD-03', wherein X 1 is H or Na. In some embodiments, X 1 Compound CMPD-03', where X is H, 1 More generally, one skilled in the art can convert X 1 It will be appreciated that C may be a monovalent alkali metal or ammonium. In some embodiments, X is Cl. In some embodiments, C 1~6The alkyl is selected from methyl, ethyl, and tert-butyl. In some embodiments, the sulfur reagent is methyl 2-mercaptoacetate. In some embodiments, the base is selected from one or more bases such as sodium hydroxide (NaOH), potassium hydroxide (KOH), tribasic potassium phosphate (K3PO4), sodium carbonate (Na2CO3), potassium carbonate (K2CO3), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,1,3,3-tetramethylguanidine (TMG), sodium methanolate (NaOMe), and sodium tert-butoxide (t-BuONa). In some embodiments, the ammonium salt is selected from tetrabutylammonium bromide (TBAB), tetrabutylammonium chloride (TBAC), benzyltrimethylammonium chloride, and tetramethylammonium chloride. More generally, one skilled in the art will recognize that alkylammonium salts and substituted alkylammonium salts may be used. In some embodiments, the solvent is selected from one or more solvents such as N,N-dimethylformamide (DMF), isopropyl acetate, 2-methyltetrahydrofuran (MeTHF), tetrahydrofuran (THF), acetonitrile (ACN), toluene, tetrahydrofuran (THF), methanol, isopropyl alcohol, tert-butyl methyl ether (TBME), and water.

[0090] In another embodiment of the method of synthesizing a compound of formula (I), the method comprises: 1 -NH2 in a solvent with an acylating agent in the presence or absence of a base or acid to form compound CMPD-27, 1~6 In some embodiments, C is alkyl. 1~6The alkyl is selected from methyl, ethyl, and tert-butyl. In some embodiments, the acylating agent is selected from methyl chloroformate, dimethyl carbonate, ethyl chloroformate, diethyl carbonate, di-tert-butyl dicarbonate. In some embodiments, the acid is selected from acetic acid (AcOH), pivalic acid (PivOH), ammonium chloride (NH4Cl), sodium hydrogen sulfate (NaHSO4). In some embodiments, the base is selected from potassium tribasic phosphate (K3PO4), potassium carbonate (K2CO3), sodium carbonate (Na2CO3), cesium carbonate (Cs2CO3), sodium bicarbonate (NaHCO3), and sodium bis(trimethylsilyl)amide (NaHMDS), potassium tert-butoxide. In some embodiments, the solvent is selected from one or more solvents such as N,N-dimethylformamide (DMF), 1-methyl-2-pyrrolidone (NMP), isopropyl acetate, ethyl acetate (EtOAc), toluene, acetone, 2-methyltetrahydrofuran (MeTHF), tetrahydrofuran (THF), acetonitrile (ACN), isopropyl alcohol, ethanol, and methanol, and water, 4-methyl-2-pentanone, tert-butyl methyl ether (TBME), cyclopentyl methyl ether (CPME).

[0091] In another embodiment of the method of synthesizing a compound of Formula (I), the method further comprises the synthesis of CMPD-01 according to Scheme 4.

[0092] [ka]

[0093] In some embodiments, the conversion of CMPD-09 to CMPD-01 is achieved by the reaction of ClC(O)-R in the presence of one or more bases and a solvent. 2 ', where R 2 ', but R 2 C 2~6 In some embodiments, R 2 'but,

[0094] [ka] and

[0095] [ka] The conversion of CMPD-09 to CMPD-01 may be accomplished with or without isolation of CMPD-22. In some embodiments, the base is selected from one or more of the following: sodium bicarbonate (NaHCO3), lithium hydroxide (LiOH), sodium hydroxide (NaOH), potassium hydroxide (KOH), potassium phosphate monobasic (KH2PO4), potassium phosphate dibasic (K2HPO4), potassium phosphate tribasic (K3PO4), sodium carbonate (Na2CO3), potassium carbonate (K2CO3), pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,1,3,3-tetramethylguanidine (TMG), N,N-diisopropylethylamine (DIPEA), triethylamine (TEA), and N,N-dicyclohexylmethylamine (Cy2NMe). In some embodiments, the solvent is selected from one or more solvents such as isopropyl acetate, ethyl acetate (EtOAc), toluene, 2-methyltetrahydrofuran (MeTHF), tetrahydrofuran (THF), acetonitrile (ACN), 4-methyl-2-pentanone, tert-butyl methyl ether (TBME), cyclopentyl methyl ether (CPME), and water.

[0096] The present disclosure also provides a method of synthesizing a compound of formula (II), including a solvate or a pharma- ceutically acceptable salt form thereof, comprising:

[0097] [ka] compound

[0098] [ka] with an acid and a first solvent, and then

[0099] [ka] in the presence of one or more coupling reagents, an amine base, and a second solvent to obtain a compound of formula (II).

[0100] In some embodiments, the acid is methanesulfonic acid. In some embodiments, the first solvent is selected from dichloromethane (DCM), ethyl acetate (EtOAc), 2-methyltetrahydrofuran (MeTHF), tetrahydrofuran (THF), and acetonitrile (ACN). In some embodiments, the coupling reagent is selected from 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), hydroxybenzotriazole (HOBt), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), propylphosphonic anhydride (T3P), 1,1'-carbonyldiimidazole (CDI), and 2-hydroxypyridine-N-oxide (HOPO). In some embodiments, the amine base is selected from N,N-diisopropylethylamine (DIPEA), triethylamine, tributylamine, N-methylmorpholine, and N-methylpiperidine. In some embodiments, the second solvent is selected from dichloromethane (DCM), ethyl acetate (EtOAc), 2-methyltetrahydrofuran (MeTHF), tetrahydrofuran (THF), and acetonitrile (ACN).

[0101] In some embodiments, the synthesis of compounds of formula (II) follows Scheme 5.

[0102] [ka]

[0103] In another embodiment of the method of synthesizing a compound of formula (II), the method comprises:

[0104] [ka] with a base and an ammonium salt in a solvent to form compound CMPD-11. In some embodiments, the base is potassium trimethylsilanolate (TMSOK). In some embodiments, the ammonium salt is selected from tetrabutylammonium bromide (TBAB), tetrabutylammonium hydrogen sulfate, benzyltrimethylammonium bromide, benzyltrimethylammonium chloride, and Aliquat 336. In some embodiments, the solvent is tetrahydrofuran.

[0105] In another embodiment of the method of synthesizing a compound of formula (II), the method comprises:

[0106] [ka] with a carbonyl source and a solvent to form compound CMPD-12. In some embodiments, the carbonyl source is selected from N,N'-carbonyldiimidazole (CDI), phosgene, triphosgene, and N,N'-disuccinimidyl carbonate (DSC). In some embodiments, the solvent is tetrahydrofuran.

[0107] In another embodiment of the method of synthesizing a compound of formula (II), the method comprises:

[0108] [ka] with a sulfur reagent and a solvent to form compound CMPD-13. In some embodiments, the sulfur reagent is 2-mercaptoacetate methyl. In some embodiments, the base is NaOMe. In some embodiments, the solvent is methanol.

[0109] In another embodiment of the method of synthesizing a compound of formula (II), the method comprises:

[0110] [ka] In a solvent system, a compound having a base is

[0111] [ka] and an amine base to form compound CMPD-14. In some embodiments, the base is KCO. In some embodiments, the amine base is N,N-diisopropylethylamine (DIPEA). In some embodiments, the solvent system is toluene / NMP.

[0112] In another embodiment of the method of synthesizing a compound of formula (II), the method comprises:

[0113] [ka] with a hydride source, a catalyst, and a solvent system to form the compound CMPD-16. In some embodiments, the hydride source is NaBH4. In some embodiments, the catalyst is NiCl2. In some embodiments, the solvent system is toluene / water.

[0114] In another embodiment of the method of synthesizing a compound of formula (II), the method comprises:

[0115] [ka] with a catalyst, a phosphorus reagent, a boron reagent, a first base, a second base, and a solvent system to form compound CMPD-17. In some embodiments, the catalyst is Pd(OAc)2. In some embodiments, the phosphorus reagent is di(1-adamantyl)-n-butylphosphine. In some embodiments, the boron reagent is isobutylboronic acid. In some embodiments, the first base is K2CO3. In some embodiments, the second base is potassium acetate (KOAc). In some embodiments, the solvent system is toluene / water.

[0116] In some embodiments, the synthesis of compounds of formula (II) follows Scheme 6.

[0117] [ka]

[0118] In another embodiment of the method of synthesizing a compound of formula (II), the method comprises:

[0119] [ka] with a cyano source and a solvent to form compound CMPD-15. In some embodiments, the cyano source is CuCN. In some embodiments, the solvent is butyronitrile.

[0120] In another embodiment of the method of synthesizing a compound of formula (II), the method comprises:

[0121] [ka] with a base and an electrophilic halogen in a solvent to form compound CMPD-18. In some embodiments, the base is lithium diisopropylamine. In some embodiments, the solvent is tetrahydrofuran.

[0122] In another embodiment of the method of synthesizing a compound of formula (II), the method comprises:

[0123] [ka] The base,

[0124] [ka] and a solvent to form compound CMPD-10. In some embodiments, the base is NaHCO. In some embodiments, the solvent is 2-methyltetrahydrofuran.

[0125] In another embodiment of the method of synthesizing a compound of Formula (I), the method comprises the synthesis of CMPD-14 according to Scheme 7.

[0126] [ka]

[0127] In another embodiment of the method of synthesizing a compound of formula (I), the method comprises:

[0128] [ka] in a solvent.

[0129] [ka] and a base to form compound CMPD-14, wherein R 5 But, C 1~6 In some embodiments, C is alkyl. 1~6The alkyl is methyl and ethyl. In some embodiments, the CMPD-25 is selected from N,N-dimethylformamide dimethyl acetal and N,N-dimethylformamide diethyl acetal. In some embodiments, the base is selected from sodium hydroxide (NaOH), tribasic potassium phosphate (K3PO4), potassium carbonate (K2CO3), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and morpholine. In some embodiments, the solvent is selected from one or more solvents such as N,N-dimethylformamide (DMF), isopropyl acetate, 2-methyltetrahydrofuran (MeTHF), tetrahydrofuran (THF), acetonitrile (ACN), toluene, ethanol, tert-butyl methyl ether (TBME), and water.

[0130] In another embodiment of the method of synthesizing a compound of formula (I), the method comprises:

[0131] [ka] in a solvent.

[0132] [ka] to form compound CMPD-28, wherein R4 is 1~6 Alkyl)2N and C 1~6 In some embodiments, C is alkyl. 1~6 The alkyl is selected from methyl and ethyl. In some embodiments, the solvent is selected from one or more solvents such as N,N-dimethylformamide (DMF), 1-methyl-2-pyrrolidone (NMP), isopropyl acetate, 2-methyltetrahydrofuran (MeTHF), tetrahydrofuran (THF), acetonitrile (ACN), ethanol, and methanol.

[0133] In another embodiment of the method of synthesizing a compound of Formula (I), the method further comprises the synthesis of CMPD-11 according to Scheme 8.

[0134] [ka]

[0135] In another embodiment of the method of synthesizing a compound of formula (I), the method comprises the steps of: 1 is H or Na

[0136] [ka] with a base and an ammonium salt in a solvent to form compound CMPD-11. In some embodiments, the base is selected from potassium trimethylsilanolate (TMSOK), lithium hydroxide (LiOH), potassium hydroxide (KOH), or sodium hydroxide (NaOH). In some embodiments, the ammonium salt is selected from tetramethylammonium bromide, tetraethylammonium bromide, tetraethylammonium chloride, tetrabutylammonium bromide (TBAB), tetrabutylammonium hydrogen sulfate, benzyltrimethylammonium bromide, benzyltrimethylammonium chloride, didodecyldimethylammonium bromide, and Aliquat 336. More generally, one of skill in the art will recognize that alkylammonium salts and substituted alkylammonium salts may be used. In some embodiments, the solvent is tetrahydrofuran or methyltetrahydrofuran.

[0137] In another embodiment of the method of synthesizing a compound of formula (I), the method comprises reacting a compound, wherein X is selected from Cl and Br, in the presence of one or more bases and an ammonium salt in a solvent.

[0138] [ka] , R 3 C 1~6 Compounds that are alkyl

[0139] [ka] and a sulfur reagent to form compound CMPD-30, wherein X 1 is H or Na. In some embodiments, X 1 Compound CMPD-30, where X is H, 1 More generally, one skilled in the art can convert X 1 It will be appreciated that C may be a monovalent alkali metal or ammonium. In some embodiments, X is Cl. In some embodiments, C 1~6The alkyl is selected from methyl, ethyl, and tert-butyl. In some embodiments, the sulfur reagent is methyl 2-mercaptoacetate. In some embodiments, the base is selected from one or more bases such as sodium hydroxide (NaOH), potassium hydroxide (KOH), tribasic potassium phosphate (K3PO4), sodium carbonate (Na2CO3), potassium carbonate (K2CO3), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,1,3,3-tetramethylguanidine (TMG), sodium methanolate (NaOMe), and sodium tert-butoxide (t-BuONa). In some embodiments, the ammonium salt is selected from tetrabutylammonium bromide (TBAB), tetrabutylammonium chloride (TBAC), benzyltrimethylammonium chloride, and tetramethylammonium chloride. More generally, one skilled in the art will recognize that alkylammonium salts and substituted alkylammonium salts may be used. In some embodiments, the solvent is selected from one or more solvents such as N,N-dimethylformamide (DMF), isopropyl acetate, 2-methyltetrahydrofuran (MeTHF), tetrahydrofuran (THF), acetonitrile (ACN), toluene, tetrahydrofuran (THF), methanol, isopropyl alcohol, tert-butyl methyl ether (TBME), and water.

[0140] In another embodiment of the method of synthesizing a compound of formula (I), the method comprises:

[0141] [ka] with an acylating agent in a solvent, in the presence or absence of a base or an acid, to form compound CMPD-29, 1~6 In some embodiments, C is alkyl. 1~6The alkyl is selected from methyl, ethyl, and tert-butyl. In some embodiments, the acylating agent is selected from methyl chloroformate, dimethyl carbonate, ethyl chloroformate, diethyl carbonate, di-tert-butyl dicarbonate. In some embodiments, the acid is selected from acetic acid (AcOH), pivalic acid (PivOH), ammonium chloride (NH4Cl), sodium hydrogen sulfate (NaHSO4). In some embodiments, the base is selected from potassium tribasic phosphate (K3PO4), potassium carbonate (K2CO3), sodium carbonate (Na2CO3), cesium carbonate (Cs2CO3), sodium bicarbonate (NaHCO3), and sodium bis(trimethylsilyl)amide (NaHMDS), potassium tert-butoxide. In some embodiments, the solvent is selected from one or more solvents such as N,N-dimethylformamide (DMF), 1-methyl-2-pyrrolidone (NMP), isopropyl acetate, ethyl acetate (EtOAc), toluene, acetone, 2-methyltetrahydrofuran (MeTHF), tetrahydrofuran (THF), acetonitrile (ACN), isopropyl alcohol, ethanol, and methanol, and water, 4-methyl-2-pentanone, tert-butyl methyl ether (TBME), cyclopentyl methyl ether (CPME).

[0142] Method for conversion to a single atropisomer The present disclosure is also directed to a method for isolating the P atropisomer from a mixture of M and P isomers of a compound of formula (II), comprising the steps of: 1) A compound of formula (II) is dissolved in one or more solvents in a container to form a solution. 2) Optionally, heating the solution to a first temperature of about 75°C to about 140°C for a first period of about 8 hours to about 12 hours and cooling the solution to a second temperature of about 20°C to about 30°C. 3) Add water and wait a second time period of about 2 hours to about 24 hours to form a suspension. Optionally, seed with a compound of formula P-(II) during this step. Optionally, cool the solution to a third temperature of about 5° C. to about 15° C. for a third time period of about 6 hours to about 12 hours to form a suspension. 4) The suspension is filtered to obtain crystals of the compound of formula P-(II). 5) Collecting the filtrate and heating the filtrate to a fourth temperature of about 75° C. to about 150° C. for a fourth period of about 5 minutes to about 1 hour. 6) Cooling the filtrate to a fifth temperature of about 20°C to about 30°C. 7) Repeat steps 4-6 approximately 20-100 times until all M isomers are converted to P isomers. 8) Collect the precipitate, wash, and dry the solid under humid conditions.

[0143] In some embodiments, repeating steps 4-6 can also be carried out by returning the filtrate heated in step 5 to the vessel of step 1, allowing it to cool to form a suspension, and filtering the suspension to obtain crystals of the compound of formula P-(II). This process is repeated 20-100 times until all the M isomers are converted to the P isomer.

[0144] In some embodiments, the one or more solvents are selected from the group consisting of isopropanol, propylene carbonate, water, 1-propanol, 1-butanol, 2-butanol, isobutanol, propylene glycol, ethylene glycol, dimethylacetamide (DMA), benzyl alcohol, N-methyl-2-pyrrolidone (NMP), propylene glycol methyl ether, 2-ethoxyethanol, (s)-1,2-butanediol, transcutol, ethylene glycol diacetate, and combinations thereof. In some embodiments, the one or more solvents are 1-propanol. In some embodiments, the one or more solvents are 1-propanol and water.

[0145] In some embodiments, the first temperature is about 75°C to about 140°C, about 80°C to about 140°C, about 85°C to about 140°C, about 90°C to about 140°C, about 95°C to about 140°C, about 75°C to about 135°C, about 75°C to about 130°C, about 75°C to about 125°C, about 75°C to about 120°C, about 75°C to about 115°C, about 75°C to about 110°C, about 75°C to about 105°C, about 75°C to about 100°C, about 75°C to about 95°C, about 80°C to about 135°C, about 85°C to about 130°C, or about 90°C to about 125°C. In some embodiments, the first temperature is about 75° C., about 80° C., about 85° C., 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., or about 140° C. In some embodiments, the first temperature is about 95° C.

[0146] In some embodiments, the first time period is about 8 hours to about 12 hours, about 9 hours to about 12 hours, about 10 hours to about 12 hours, about 11 hours to about 12 hours, about 8 hours to about 11 hours, about 8 hours to about 10 hours, about 8 hours to about 9 hours, or about 9 hours to about 11 hours. In some embodiments, the first time period is about 8 hours, about 9 hours, about 10 hours, about 11 hours, or about 12 hours. In some embodiments, the first time period is about 10 hours.

[0147] In some embodiments, the second temperature is about 20° C. to about 30° C., about 25° C. to about 30° C., or about 20° C. to about 35° C. In some embodiments, the second temperature is about 25° C. In some embodiments, the second temperature is about 30° C. In some embodiments, the second temperature is about 35° C.

[0148] In some embodiments, the second time period is about 2 hours to about 24 hours, about 3 hours to about 24 hours, about 4 hours to about 24 hours, about 5 hours to about 24 hours, about 6 hours to about 24 hours, about 7 hours to about 24 hours, about 8 hours to about 24 hours, about 9 hours to about 24 hours, about 10 hours to about 24 hours, about 11 hours to about 24 hours, about 12 hours to about 24 hours, about 13 hours to about 24 hours, about 14 hours to about 24 hours, about 15 hours to about 24 hours, about 16 hours to about 24 hours, about 17 hours to about 24 hours, about 18 hours to about 24 hours, about 19 hours to about 24 hours, about 20 hours to about 24 hours, about 21 hours to about 24 hours, about 24 hours, about 26 hours to about 24 hours, about 28 hours to about 24 hours, about 29 hours to about 24 hours, about 30 hours to about 24 hours, about 31 hours to about 24 hours, about 32 hours to about 24 hours, about 33 hours to about 24 hours, about 34 hours to about 24 hours, about 35 hours to about 24 hours, about 36 hours to about 24 hours, about 37 hours to about 24 hours, about 38 hours to about 24 hours, about 39 hours to about 24 hours, about 40 hours to about 24 hours, about 41 hours to about 24 hours, about 42 hours to about 24 hours, about 43 hours to about 24 hours, about 44 hours to about 24 hours, about 45 hours to about 24 hours, about 46 hours to about 24 hours, about 47 hours to about 24 hours, about 48 hours to about 24 hours, 2 hours to about 24 hours, about 32 hours to about 24 hours, about 2 hours to about 23 hours, about 2 hours to about 22 hours, about 2 hours to about 21 hours, about 2 hours to about 20 hours, about 2 hours to about 19 hours, about 2 hours to about 18 hours, about 2 hours to about 17 hours, about 2 hours to about 16 hours, about 2 hours to about 15 hours, about 2 hours to about 14 hours, about 2 hours to about 13 hours, about 2 hours to about 12 hours, about 2 hours to about 11 hours, about 2 hours to about 10 hours, about 2 hours to about 9 hours, about 2 hours to about 8 hours, about 2 hours to about 7 hours, about 2 hours to about 6 hours, about 2 hours to about 5 hours, about 2 hours to about 4 hours, or about 2 hours to about 3 hours. In some embodiments, the second period of time is about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours. In some embodiments, the second period of time is about 5 hours.

[0149] In some embodiments, the third temperature is about 5° C. to about 15° C., about 10° C. to about 15° C., or about 5° C. to about 10° C. In some embodiments, the third temperature is about 5° C. In some embodiments, the third temperature is about 10° C. In some embodiments, the third temperature is about 15° C.

[0150] In some embodiments, the third time is about 6 hours to about 12 hours, about 7 hours to about 12 hours, about 8 hours to about 12 hours, about 9 hours to about 12 hours, about 10 hours to about 12 hours, about 11 hours to about 12 hours, about 6 hours to about 11 hours, about 6 hours to about 10 hours, about 6 hours to about 9 hours, about 6 hours to about 8 hours, about 6 hours to about 7 hours, about 7 hours to about 11 hours, or about 8 hours to about 10 hours. In some embodiments, the fourth time is about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, or about 12 hours. In some embodiments, the third time is about 8 hours.

[0151] In some embodiments, the fourth temperature is about 75°C to about 150°C, about 80°C to about 150°C, about 85°C to about 150°C, about 95°C to about 150°C, about 100°C to about 150°C, about 105°C to about 150°C, about 110°C to about 150°C, about 115°C to about 150°C, about 120°C to about 150°C, about 125°C to about 150°C, about 130°C to about 150°C, about 135°C to about 150°C, about 140°C to about 150°C, about 145°C to about 150°C, about 75°C to about 145°C, about 75°C to about 140°C. , about 75°C to about 135°C, about 75°C to about 130°C, about 75°C to about 125°C, about 75°C to about 120°C, about 75°C to about 115°C, about 75°C to about 110°C, about 75°C to about 105°C, about 75°C to about 100°C, about 75°C to about 95°C, about 75°C to about 90°C, about 75°C to about 85°C, about 75°C to about 80°C, about 75°C to about 135°C, about 80°C to about 130°C, about 85°C to about 125°C, about 90°C to about 120°C, about 95°C to about 115°C, or about 100°C to about 110°C. In some embodiments, the fourth temperature is about 75°C, about 80°C, about 85°C, 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, or about 150°C.

[0152] In some embodiments, the fourth time period is from about 5 minutes to about 1 hour, from about 10 minutes to about 1 hour, from about 15 minutes to about 1 hour, from about 20 minutes to about 1 hour, from about 25 minutes to about 1 hour, from about 30 minutes to about 1 hour, from about 35 minutes to about 1 hour, from about 40 minutes to about 1 hour, from about 45 minutes to about 1 hour, from about 50 minutes to about 1 hour, from about 55 minutes to about 1 hour, from about 10 minutes to about 55 minutes, from about 10 minutes to about 50 minutes, from about 10 minutes to about 45 minutes, from about 10 minutes to about 40 minutes, from about 10 minutes to about 35 minutes, from about 10 minutes to about 30 minutes, from about 10 minutes to about 25 minutes, from about 10 minutes to about 10 minutes, or from about 10 minutes to about 15 minutes. In some embodiments, the fourth period of time is about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, or about 1 hour.

[0153] In some embodiments, the fifth temperature is about 20° C. to about 30° C., about 25° C. to about 30° C., or about 20° C. to about 35° C. In some embodiments, the fifth temperature is about 25° C. In some embodiments, the second temperature is about 30° C. In some embodiments, the second temperature is about 35° C.

[0154] In embodiments, steps 4-6 are repeated about 20 times, about 25 times, about 30 times, about 35 times, about 40 times, about 45 times, about 50 times, about 55 times, about 60 times, about 65 times, about 70 times, about 75 times, about 80 times, about 85 times, about 90 times, about 95 times, about 100 times, or until all M isomers are converted to P isomers.

[0155] The present disclosure is also directed to a method for converting a compound of formula (II) to a compound of formula P-(II), comprising the steps of: 1) dissolving a compound of formula (II) in one or more solvents in a container to form a solution; 2) heating the solution to a first temperature of about 75° C. to about 120° C. and holding the solution at the first temperature for a first time of about 4 hours to about 8 hours, and then cooling the solution to a second temperature of about 60° C. to about 100° C.; 3) adding water and adding a compound of formula (II) to the solution, and then cooling the solution to a third temperature, about 10° C. to about 30° C., over a second period of about 2 hours to about 8 hours, and waiting a third period of about 3 hours to about 9 hours to form a suspension; 4) The suspension is filtered to obtain crystals of the compound of formula P-(II). 5) collecting the filtrate and heating the filtrate to a fourth temperature of about 110° C. to about 150° C. for a fourth period of about 1 hour to about 5 hours; 6) Cooling the filtrate to a fifth temperature of about 20°C to about 30°C. 7) Repeat steps 4 to 6 10 to 100 times. 8) Collect the precipitate, wash, and dry the solid under humid conditions.

[0156] In some embodiments, the one or more solvents are selected from the group consisting of isopropanol, propylene carbonate, water, 1-propanol, 1-butanol, 2-butanol, isobutanol, propylene glycol, ethylene glycol, dimethylacetamide (DMA), benzyl alcohol, N-methyl-2-pyrrolidone (NMP), propylene glycol methyl ether, 2-ethoxyethanol, (s)-1,2-butanediol, transcutol, ethylene glycol diacetate, and combinations thereof. In some embodiments, the one or more solvents are propylene carbonate. In some embodiments, the one or more solvents are propylene carbonate and water.

[0157] In some embodiments, the first temperature is about 80°C to about 120°C, about 85°C to about 120°C, about 90°C to about 120°C, about 95°C to about 120°C, about 100°C to about 120°C, about 105°C to about 120°C, about 110°C to about 120°C, about 115°C to about 120°C, about 75°C to about 115°C, about 75°C to about 110°C, about 75°C to about 105°C, about 75°C to about 100°C, about 75°C to about 95°C, about 75°C to about 90°C, about 75°C to about 85°C, about 75°C to about 80°C, about 80°C to about 115°C, about 85°C to about 110°C, or about 90°C to about 100°C. In some embodiments, the first temperature is about 75° C., about 80° C., about 85° C., about 90° C., about 95° C., about 100° C., about 105° C., about 110° C., about 115° C., or about 120° C. In some embodiments, the first temperature is about 100° C.

[0158] In some embodiments, the first time period is about 5 hours to about 8 hours, about 6 hours to about 8 hours, about 7 hours to about 8 hours, about 4 hours to about 7 hours, about 4 hours to about 6 hours, about 4 hours to about 5 hours, or about 5 hours to about 7 hours. In some embodiments, the first time period is about 4 hours, about 5 hours, about 7 hours, or about 8 hours. In some embodiments, the first time period is about 6 hours.

[0159] In some embodiments, the second temperature is about 65°C to about 100°C, about 70°C to about 100°C, about 75°C to about 100°C, about 80°C to about 100°C, about 85°C to about 100°C, about 90°C to about 100°C, about 95°C to about 100°C, about 65°C to about 95°C, about 65°C to about 90°C, about 65°C to about 85°C, about 65°C to about 80°C, about 65°C to about 75°C, about 65°C to about 70°C, about 70°C to about 95°C, about 75°C to about 90°C, or about 80°C to about 85°C. In some embodiments, the second temperature is about 65° C., about 70° C., about 75° C., about 80° C., about 85° C., about 90° C., about 95° C., about 100° C., about 105° C., about 110° C., about 115° C., or about 120° C. In some embodiments, the second temperature is about 80° C.

[0160] In some embodiments, the third temperature is about 10° C. to about 30° C., about 15° C. to about 30° C., about 20° C. to about 30° C., about 25° C. to about 30° C., about 10° C. to about 25° C., about 10° C. to about 20° C., about 10° C. to about 15° C., or about 15° C. to about 25° C. In some embodiments, the third temperature is about 10° C., about 15° C., about 20° C., about 25° C., or about 30° C. In some embodiments, the third temperature is about 25° C.

[0161] In some embodiments, the second time is about 3 hours to about 8 hours, about 4 hours to about 8 hours, about 5 hours to about 8 hours, about 6 hours to about 8 hours, about 7 hours to about 8 hours, about 2 hours to about 7 hours, about 2 hours to about 6 hours, about 2 hours to about 5 hours, about 2 hours to about 4 hours, about 2 hours to about 3 hours, about 3 hours to about 7 hours, or about 4 hours to about 6 hours. In some embodiments, the second time is about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, or about 8 hours. In some embodiments, the second time is about 4 hours.

[0162] In some embodiments, the third time period is about 4 hours to about 9 hours, about 5 hours to about 9 hours, about 6 hours to about 9 hours, about 7 hours to about 9 hours, about 8 hours to about 9 hours, about 3 hours to about 8 hours, about 3 hours to about 7 hours, about 3 hours to about 6 hours, about 3 hours to about 5 hours, about 3 hours to about 4 hours, about 3 hours to about 7 hours, or about 4 hours to about 6 hours. In some embodiments, the third time period is about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, or about 9 hours. In some embodiments, the third time period is about 5 hours.

[0163] In some embodiments, the fourth temperature is about 115°C to about 150°C, about 120°C to about 150°C, about 125°C to about 150°C, about 130°C to about 150°C, about 135°C to about 150°C, about 140°C to about 150°C, about 145°C to about 150°C, about 110°C to about 145°C, about 110°C to about 140°C, about 110°C to about 135°C, about 110°C to about 130°C, about 110°C to about 125°C, about 110°C to about 120°C, about 110°C to about 115°C, about 115°C to about 145°C, about 120°C to about 140°C, or about 125°C to about 135°C. In some embodiments, the fourth temperature is about 110° C., about 115° C., about 120° C., about 125° C., about 130° C., about 135° C., about 140° C., about 145° C., or about 150° C. In some embodiments, the fourth temperature is about 130° C.

[0164] In some embodiments, the fourth time period is about 35 hours to about 70 hours, about 40 hours to about 70 hours, about 45 hours to about 70 hours, about 50 hours to about 70 hours, about 55 hours to about 70 hours, about 60 hours to about 70 hours, about 65 hours to about 70 hours, about 30 hours to about 65 hours, about 30 hours to about 60 hours, about 30 hours to about 55 hours, about 30 hours to about 50 hours, about 30 hours to about 45 hours, about 30 hours to about 40 hours, about 30 hours to about 35 hours, about 35 hours to about 65 hours, about 40 hours to about 60 hours, or about 45 hours to about 55 hours. In some embodiments, the fourth time period is about 30 hours, about 35 hours, about 40 hours, about 45 hours, about 50 hours, about 55 hours, about 60 hours, about 65 hours, or about 70 hours. In some embodiments, the fourth period of time is about 52 hours.

[0165] In some embodiments, the fifth temperature is about 10° C. to about 30° C., about 15° C. to about 30° C., about 20° C. to about 30° C., about 25° C. to about 30° C., about 10° C. to about 25° C., about 10° C. to about 20° C., about 10° C. to about 15° C., or about 15° C. to about 25° C. In some embodiments, the fifth temperature is about 10° C., about 15° C., about 20° C., about 25° C., or about 30° C. In some embodiments, the third temperature is about 25° C.

[0166] The present disclosure also provides a method for converting a compound of formula (II) to a compound of formula P-(II), comprising the steps of: 1) dissolving a compound of formula (II) in one or more solvents to form a solution; 2) heating the solution to a first temperature of about 50° C. to about 100° C. for a period of about 30 hours to about 80 hours; 3) cooling the solution to a second temperature of about 0° C. to about 20° C.; 4) collecting the formed crystals of the compound of formula P-(II) by filtration.

[0167] In some embodiments, the one or more solvents are selected from the group consisting of isopropanol, propylene carbonate, water, 1-propanol, 1-butanol, 2-butanol, isobutanol, propylene glycol, ethylene glycol, dimethylacetamide (DMA), benzyl alcohol, N-methyl-2-pyrrolidone (NMP), propylene glycol methyl ether, 2-ethoxyethanol, (s)-1,2-butanediol, transcutol, ethylene glycol diacetate, and combinations thereof. In some embodiments, the one or more solvents are isopropanol and water.

[0168] In some embodiments, the first temperature is about 55°C to about 100°C, 60°C to about 100°C, 65°C to about 100°C, about 70°C to about 100°C, about 75°C to about 100°C, about 80°C to about 100°C, about 85°C to about 100°C, about 90°C to about 100°C, about 95°C to about 100°C, about 50°C to about 95°C, about 50°C to about 90°C, about 50°C to about 85°C, about 50°C to about 80°C, about 50°C to about 75°C, about 50°C to about 70°C, about 50°C to about 65°C, 50°C to about 60°C, 50°C to about 55°C, about 55°C to about 95°C, about 60°C to about 90°C, about 65°C to about 85°C, about 70°C to about 90°C, or about 75°C to about 85°C. In some embodiments, the first temperature is about 50° C., about 55° C., about 60° C., about 65° C., about 70° C., about 75° C., about 80° C., about 85° C., about 90° C., about 95° C., or about 100° C. In some embodiments, the first temperature is about 80° C.

[0169] In some embodiments, the first time period is about 35 hours to about 80 hours, about 40 hours to about 80 hours, about 45 hours to about 80 hours, about 50 hours to about 80 hours, about 55 hours to about 80 hours, about 60 hours to about 80 hours, about 65 hours to about 80 hours, about 70 hours to about 80 hours, about 75 hours to about 80 hours, about 30 hours to about 75 hours, about 30 hours to about 70 hours, about 30 hours to about 65 hours, about 30 hours to about 60 hours, about 30 hours to about 55 hours, about 30 hours to about 50 hours, about 30 hours to about 45 hours, about 30 hours to about 40 hours, about 30 hours to about 35 hours, about 35 hours to about 75 hours, about 40 hours to about 70 hours, about 45 hours to about 65 hours, or about 50 hours to about 60 hours. In some embodiments, the first period of time is about 35 hours, about 40 hours, about 45 hours, about 50 hours, about 55 hours, about 60 hours, about 65 hours, about 70 hours, about 75 hours, or about 80 hours.

[0170] In some embodiments, the second temperature is about 5° C. to about 20° C., about 10° C. to about 20° C., about 15° C. to about 20° C., about 0° C. to about 15° C., about 0° C. to about 10° C., about 0° C. to about 5° C., or about 5° C. to about 15° C. In some embodiments, the second temperature is about 0° C., about 5° C., about 10° C., about 15° C., or about 20° C. In some embodiments, the second temperature is about 10° C.

[0171] Crystal form B The present disclosure includes embodiments relating to crystalline form B of formula P-(II) dihydrate:

[0172] [ka]

[0173] In some embodiments, crystalline form B is characterized by an XRPD pattern having a peak at about 5.599°, expressed in degrees 2θ (±0.2). In some embodiments, crystalline form B is further characterized by an XRPD pattern having a peak at about 20.426°, expressed in degrees 2θ (±0.2). In some embodiments, crystalline form B is further characterized by an XRPD pattern having a peak at about 24.665°, expressed in degrees 2θ (±0.2). In some embodiments, crystalline form B is further characterized by an XRPD pattern having peaks at about 11.135° and about 26.373°, expressed in degrees 2θ (±0.2). In some embodiments, crystalline form B is further characterized by an XRPD pattern having peaks at about 12.134°, about 23.187°, about 19.065°, and about 30.316°, expressed in degrees 2θ (±0.2). In some embodiments, crystalline form B is characterized by an XRPD pattern substantially as shown in FIG.

[0174] In some embodiments, the crystalline form B has a molecular weight of about 1522 cm -1 In some embodiments, crystalline form B is characterized by an IR peak at about 1714 cm -1 In some embodiments, crystalline form B is further characterized by an IR peak at about 1642 cm -1 and about 1622 cm -1 In some embodiments, crystalline form B is further characterized by an IR peak at about 1270 cm -1 and approximately 1251 cm -1In some embodiments, crystalline form B is further characterized by an IR peak at about 1541 cm -1 and about 1494 cm -1 In some embodiments, crystalline form B is further characterized by an IR pattern substantially as shown in FIG.

[0175] In some embodiments, crystalline form B may also be characterized by one or more of: 1) a DSC thermogram utilizing standard pan conditions exhibiting an endotherm at about 196.8° C.; 2) a DSC thermogram utilizing Tzero sealed pan conditions exhibiting a first endotherm at about 141.8° C. and a second endotherm at about 155.9° C.; and 3) a water loss of about 6.5% by weight as measured by thermogravimetric analysis.

[0176] compound The present disclosure is also directed to compounds having the structure:

[0177] [ka] EXAMPLES

[0178] Example 1: Synthesis of 2,4-dichloro-3-iodopyridine (CMPD-18)

[0179] [ka] In a reactor, 100g of 2,4-dichloropyridine (100g, 0.68mol) was added to THF (1000mL). The reaction mixture was cooled to -78°C. A solution of LDA (0.72mol) was added slowly while maintaining the reaction temperature below -70°C. Then, a solution of I2 (208g, 0.82mol) in THF (1200mL) was added slowly. The reaction mixture was warmed to 10°C and quenched with 5% aqueous NaHSO3 (400mL). The organic layer was then switched to PrCN and then washed with water (500mL). The final solution in PrCN (400mL) can be used directly in the next step (assay yield 85%). 1 H NMR(400MHz, CDCl3): δ 8.22(d,J=5.2Hz,1H),7.30(d,J=5.2Hz,1H).

[0180] Example 2: Synthesis of 2,4-dichloronicotinonitrile (CMPD-15)

[0181] [ka] To a reactor containing a solution of 2,4-dichloro-3-iodopyridine (83.1 g, 0.30 mol) in PrCN (400 mL) was added CuCN (51.6 g, 0.58 mol). The reaction mixture was heated to 95-100 °C for 10 h. The mixture was filtered and washed with PrCN (80 mL). The filtrate was solvent exchanged into n-BuOH and then toluene. The final solution was filtered. The organic layer was washed with 4% EDTA solution (400 mL) and water (400 mL) and then concentrated to 2-3 V. Heptane (830 mL) was added to crystallize the desired product (41.0 g, 76.5% yield). 1 H NMR(400MHz,DMSO-D6):δ 8.67(d,J=5.5Hz,1H),7.92(d,J=5.5Hz,1H).

[0182] Example 3: Synthesis of tert-butyl ((1R,2S)-2-acrylamidocyclopentyl)carbamate (CMPD-10)

[0183] [ka] In a reactor, tert-butyl ((1R,2S)-2-aminocyclopentyl)carbamate (12.9 kg, 64.4 mol) was added to MeTHF (193.5 L). BHT (64.5 g, 0.29 mol) and a solution of 7% NaHCO3 (193.5 L) were added and the mixture was cooled to 10°C. Acryloyl chloride (6.88 kg, 76.0 mol) was added dropwise to the mixture while maintaining the internal temperature below 10°C. After completion of the reaction, the layers were separated. The organic layer was washed with 10% Na2SO4 (70 L) and then evaporated to about 64.5 L. Heptane (64.5 L) was added to crystallize the product. After filtration, the product was isolated as a solid (14.7 kg, 90% yield). MS (ESI): C 13 H 22 Calculated mass for N2O3: 254.32, measured m / z: 255.0 [M+H] + . 1 H NMR(400MHz,DMSO-D6):δ 7.68-7.50(m,1H),6.47-6.31(m,1H),6.28-6.16(m,1H),6.12-5.96(m,1H),5.60-5.46(m,1 H),4.13-3.98(m,1H),3.88-3.68(m,1H),1.87-1.58(m,3H),1.55-1.37(m,3H),1.32(s,9H). The title compound was also prepared in a similar manner using 3-chloropropionyl chloride. In a reactor, tert-butyl ((1R,2S)-2-aminocyclopentyl)carbamate (50 g, 249.7 mol) was added to MeTHF (400 mL). Triethylamine (41.8 mL, 300 mmol) was added and the mixture was cooled to 10° C. A solution of 3-chloropropionyl chloride (27.4 mL, 287.1 mmol) in MeTHF (200 mL) was added dropwise to the mixture while maintaining the internal temperature below 10° C. After the reaction was complete, water (200 mL) was charged and the aqueous layer was discarded. Water (200 mL) and sodium hydroxide (50 wt %, 50 g, 624.1 mmol) were added and the mixture was warmed to 60° C. After the reaction was complete, the layers were separated at 60° C. The organic layer was washed with 10% aqueous Na2SO4 (200 mL) at 60° C. MeTHF (250 mL) was added and the organic layer was azeotropically dried. Heptane (150 mL) was charged and the reaction mixture was cooled to 20° C. to crystallize the desired product (47.6 g, 74.5% yield).

[0184] Example 4: Synthesis of 2-isobutyl-4-methyl-5-nitropyridine (CMPD-17)

[0185] [ka] In an inert reactor, to a mixture of toluene (2.0 L) and water (500 mL) was added Pd(OAc)2 (2.06 g, 9.2 mmol), Catacxium A (13.60 g, 18.4 mmol). After 30 min, 2-bromo-4-methyl-5-nitropyridine (200 g, 0.92 mol), isobutylboronic acid (140.7 g, 1.38 mol), K2CO3 (381 g, 2.76 mol), and KOAc (9.03 g, 92 mmol) were added successively. The reaction mixture was heated at 100° C. for 16 h. The mixture was cooled to 25° C. and the aqueous layer was discarded. The organic layer was washed with NaOH 30% solution (1000 mL). After filtration, the organic layer containing the desired product was used directly in the next step. (Assay yield 95%). 1H NMR (400MHz, CDCl3): δ 9.1(s,1H),7.09(s,1H),2.69(d,J=7.6Hz,2H)2.63(s,3H),2.14(m,1H),0.94(d,J=6.8Hz,6H).

[0186] Example 5: Synthesis of 6-isobutyl-4-methylpyridin-3-amine (CMPD-16)

[0187] [ka] In a reactor, NiCl2.6H2O (2.07 g, 8.7 mmol) was added to water (680 mL). A solution of 2-isobutyl-4-methyl-5-nitropyridine (169.5 g, 0.87 mol) in 2.1 L toluene was added. The reaction mixture was heated to 50 °C. NaBH4 (65.0 g, 1.74 mol) was added in portions while maintaining the internal temperature at 50-60 °C. The reaction mixture was heated at 60 °C for 17 h. The organic layer was separated and filtered. The filtrate was washed with water (340 mL) to give a solution of the desired product (90-95% assay yield). This solution was solvent exchanged into NMP to prepare it for the next step. 1 H NMR (400MHz, DMSO-D6): δ 7.81(s,1H),6.74(s,1H),4.80(s,2H),2.37(d,J=7.2Hz,2H)2.04(s,3H),1.91(m,1H),0.83(d,J=6.4Hz,6H).

[0188] Example 6: Synthesis of 2-chloro-4-((6-isobutyl-4-methylpyridin-3-yl)amino)nicotinonitrile (CMPD-14)

[0189] [ka] In an inert reactor, a solution of 6-isobutyl-4-methylpyridin-3-amine (30.0 g, 183 mmol) in toluene (600 mL), 2,4-dichloronicotinonitrile (229 mmol), DIPEA (183 mmol), K2CO3 (183 mmol), and LiCl (275 mmol) were added together in NMP (150 mL). The mixture was heated to 120° C. for 40 h. Once the reaction was complete, the mixture was cooled and could be used for the next step (assay yield 89%). 1 H NMR(400MHz,CDCl3):δ 8.37(s,1H),8.04(d,J=6Hz,1H),7.10(s,1H),6.72(s,1H),6.26(d,J=6Hz, 1H),2.65(d,J=7.2Hz,2H),2.23(s,3H),2.10(m,1H),0.95(d,J=6.4Hz,6H).

[0190] Example 7: Synthesis of methyl 3-amino-4-((6-isobutyl-4-methylpyridin-3-yl)amino)thieno[2,3-b]pyridine-2-carboxylate (CMPD-13)

[0191] [ka] To a solution of 2-chloro-4-((6-isobutyl-4-methylpyridin-3-yl)amino)nicotinonitrile (27.5 g, 91.7 mmol) in NMP (130 mL) was added methyl 2-mercaptoacetate (34.8 g, 328 mmol). A solution of NaOMe (12.3 g, 228 mmol) in MeOH was added slowly while maintaining the reaction temperature below 30° C. After the reaction was complete, water (275 mL) was added. The crude product was isolated by filtration. The resulting solid was slurried in water (275 mL) and filtered to give the target product (24.3 g, 72% yield). 1H NMR(400MHz,DMSO-D6):δ 8.36(s,1H),8.34(s,1H),8.11(d,J=5.2Hz,1H),7.22(s,1H),7.18(s,2H),5.98(d,J=5.6H) z,1H),3.79(s,3H),2.59(d,J=6.8Hz,2H),2.13(s,3H),2.08(m,1H),0.90(d,J=6.4Hz,6H).

[0192] Example 8: Synthesis of methyl 5-(6-isobutyl-4-methoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate (CMPD-12)

[0193] [ka] In an inert reactor, methyl 3-amino-4-((6-isobutyl-4-methylpyridin-3-yl)amino)thieno[2,3-b]pyridine-2-carboxylate (46.5 kg, 125.5 mol) was dissolved in THF (232 L). CDI (20.4 kg, 251 mol) was added. The mixture was stirred at 60° C. for 6-10 hours. Upon completion of the reaction, water (465 L) was slowly charged at 25° C. After filtration, the desired product was obtained (44.4 kg, 89.2% yield). 1 H NMR(400MHz,DMSO-D6):δ 10.79(s,1H),8.47(s,1H),8.38(d,J=5.6Hz,1H),7.36(s,1H),5.97(d,J=5.6Hz,1H) ,3.85(s,3H),2.63(d,J=7.2Hz,2H),2.13(s,3H),2.11(m,1H),0.94(d,J=6.8Hz,6H).

[0194] Example 9: Synthesis of 5-(6-isobutyl-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylic acid (CMPD-11)

[0195] [ka] In an inert reactor, methyl 5-(6-isobutyl-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate (36.0 kg, 90.8 mol), TMSOK (34.9 kg, 272 mol), and TBAB (7.0 kg, 45.4 mol) were charged in THF (720 L). The mixture was heated to 60° C. for 10-16 h. Once complete conversion was achieved, the reaction was cooled and adjusted to pH 4-5 by adding 0.5 M H2SO4 solution (900 L). THF was removed under vacuum at <40° C. Water (180 L) was added and the product was obtained by filtration after washing with water and MTBE. The solid was dried in an oven at 50° C. to give the desired product (32.9 kg, 98% yield). MS (ESI): C 19 H 18 Calculated mass of N4O3S: 382.11 m / z, measured value: 383.1 [M+H] + .

[0196] Example 10: Synthesis of N-((1R,2S)-2-acrylamidocyclohexyl)-5-(6-isobutyl-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide (Formula (II))

[0197] [ka] In a separate reactor, tert-butyl ((1R,2S)-2-acrylamidocyclopentyl)carbamate (730 g, 2.87 mol) was added to DCM (10 L). MSA (506.9 g, 5.22 mol) was added slowly at 25-35° C. The solution was stirred and used directly in the next step. To a solution of 5-(6-isobutyl-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylic acid (1.0 kg, 2.61 mol) in DCM (10 L) was added EDCI (751 g, 3.92 mol) and HOBt (530 g, 3.92 mol) at 0-10° C. After 2 h, a solution of the previous diamine and BHT (5.0 g) was added. DIPEA (13.1 mol) was then added slowly while maintaining the reaction temperature below 10° C. Upon completion of the reaction, the mixture was washed once with water (5 L), twice with citric acid 5% (5 L), once with NaHCO3 5% (5 L), and once with NaHSO4 5% (10 L). The organic layer (assay yield 91%) was solvent exchanged into 1-propanol and used directly in the next step.

[0198] Example 11: Synthesis of tert-butyl ((1R,2S)-2-(3-chloropropanamido)cyclopentyl)carbamate (CMPD-31)

[0199] [ka] In a reactor, tert-butyl ((1R,2S)-2-aminocyclopentyl)carbamate (3.0 g, 15.0 mmol) was added to MeTHF (30 mL). Aqueous sodium bicarbonate (7.0 wt%, 45 mL, 37.5 mmol) was charged and the mixture was cooled to 10° C. A solution of 3-chloropropionyl chloride (2.19 g, 17.2 mmol) in MeTHF (15 mL) was added dropwise to the mixture while maintaining the internal temperature below 10° C. After completion of the reaction, the layers were separated. The organic layer was washed with aqueous sodium bicarbonate (7.0 wt%, 45 mL). The organic layer was concentrated by distillation to crystallize the desired product (4.46 g, 100%). 1H NMR 4Hz,00MHz,DMSO-D6):δ 7.56(d,J:=7.6Hz,1H),6.28(d,J:=7.6Hz,1H),4.04(m,1H),3.85-3.70(m,1H),3.76(td,J:=6.8,1 .6Hz,2H),2.61-2.52(m,2H),1.86-1.71(m,2H),1.71-1.60(m,1H),1.55-1.37(m,3H),1.36(s,9H).

[0200] Example 12: Synthesis of (E)-2-cyano-3-((6-isobutyl-4-methylpyridin-3-yl)amino)but-2-enethioamide (CMPD-28)

[0201] [ka] In a reactor, 2-cyano-3-ethoxybut-2-enethioamide (513 g, 3.02 mol) was added in tetrahydrofuran (4.5 L) at 20° C. 6-isobutyl-4-methylpyridin-3-amine (449 g, 2.74 mol) was added at 20° C. and the reaction mixture was warmed to 60° C. After completion of the reaction, the solvent was exchanged to isopropanol (2.25 L) and water (4.5 L) was added to crystallize the desired product (706.8 g, 89.4% yield). 1 H NMR(400MHz,CDCl3):δ 14.20(s,1H),8,27(s,1H),7,08(s,1H),7.00(brs,1H),6,76(brs,1H),2.65(d,J=7. 2Hz,2H),2.32(s,3H),2.25(s,3H),2.10(sept.,J=6,4Hz,1H),0.94(d,J=6,4Hz,6H).

[0202] Example 13: Synthesis of 4-((6-isobutyl-4-methylpyridin-3-yl)amino)-2-mercaptonicotinonitrile (CMPD-29)

[0203] [ka] In a reactor, 2-cyano-3-((6-iso-butyl-4-methylpyridin-3-yl)amino)but-2-enethioamide (711 g, 2.47 mol) was added to 2-methyltetrahydrofuran (7.1 L) and the reaction mixture was warmed to 40° C. N,N-dimethylformamide diethyl acetal (909 g, 6.17 mol) was charged and the reaction mixture was stirred for 17 hours. 8.7% K2CO3 (3.55 L, 2.47 mol) was added to the reaction mixture at 40° C. After completion of the reaction, the reaction mixture was cooled to 0° C. and glacial acetic acid (420 mL, 7.34 mol) was added to reach pH=5-6. The reaction mixture was warmed to 20° C. and the layers were separated. The organic layer was washed with 4% Na2SO4 (3.55 L) and then 2-methyltetrahydrofuran (5.0 L) was removed by distillation. tert-Butyl methyl ether (7.1 L) was added and the reaction mixture was cooled to 20° C., causing the desired product to crystallize (653 g, 88.9% yield). 1 H NMR(400MHz,DMSO-D6):δ 12.7(brs,1H),9.21(brs,1H),8.27(s,1H),7,41(d,J=7.2Hz,1H),7.22(s,1H),5.66(d,J=7.2H z,1H),2.58(d,J=7.2Hz,2H),2.15(s,3H),2.06(sept.,J=6,8Hz,1H),0.89(d,J=6,8Hz,6H)ppm.

[0204] Example 14: Synthesis of tert-butyl (6-isobutyl-4-methylpyridin-3-yl)carbamate (CMPD-32)

[0205] [ka] In a reactor, a solution of 6-isobutyl-4-methylpyridin-3-amine (6.9 wt%, 2.9 kg, 1.218 mol) in toluene was concentrated to 2.0 L (10 wt% solution). An aqueous solution of ammonium chloride (33.3 wt%, 391.2 g, 2.435 mol) was charged at 25° C. Di-tert-butyl dicarbonate (399 g, 1.857 mol) was charged and the reaction mixture was warmed to 50° C. After completion of the reaction, the reaction mixture was cooled to 25° C., water (200 mL) was added and the layers were separated. The organic layer was washed with water (1.0 L). The organic layer was concentrated to 0.5 L by distillation and heptane (4.0 L) was charged at 50° C., then the reaction mixture was cooled to 0° C. to crystallize the desired product (277 g, 86.2% yield). 1 H NMR(400MHz,DMSO-D6):δ 8.66(brs,1H),8.30(s,1H),7.03(s,1H),4.11(q,J=6.8Hz,2H),2.50(d,J =7.2Hz,3H),2.17(s,3H),2.00(m,1H),1.45(s,9H),0.86(d,J=6.4Hz,6H).

[0206] Example 15: Synthesis of ethyl (6-isobutyl-4-methylpyridin-3-yl)carbamate (CMPD-33)

[0207] [ka] In a reactor, 6-isobutyl-4-methylpyridin-3-amine (100 g, 609 mmol) in solution in tetrahydrofuran (150 mL) was slowly added to a mixture of tetrahydrofuran (200 mL), potassium tert-butoxide (103 g, 909 mmol), and diethyl carbonate (111 mL, 914 mmol) at 50° C. (the reaction is exothermic). After completion of the reaction, heptane (200 mL) was charged at 50° C., and the reaction mixture was then cooled to 20° C. Water (150 mL) was slowly added (the reaction is exothermic) and the layers were separated. The organic layer was washed with aqueous sodium chloride (23.5 wt %, 150 mL). The solution was solvent exchanged into heptane and cooled to 5° C. to crystallize the desired product (134 g, 93.0% yield).1 H NMR(400MHz,DMSO-D6):δ 8.93(brs,1H),8.34(s,1H),7.04(s,1H),4.11(q,J=6.8Hz,2H),2.51(d,J=7.2 Hz,2H),2.18(s,3H),2.02(m,1H),1.23(t,J=6.8Hz,3H),0.83(d,J=6.8Hz,6H).

[0208] Example 16: Synthesis of methyl (6-isobutyl-4-methylpyridin-3-yl)carbamate (CMPD-34)

[0209] [ka] The title compound was prepared in a similar manner to Example 15 using 6-isobutyl-4-methylpyridin-3-amine (60 g, 365 mmol), potassium tert-butoxide (82.8 g, 731 mmol), and dimethyl carbonate (52.5 mL, 621 mmol) instead of diethyl carbonate to give the desired product (76.0 g, 93.6% yield). 1 H NMR(400MHz,DMSO-D6):δ 8.96(brs,1H),8.34(s,1H),7.05(s,1H),3.65(s,3H),2.51(d,J=7.2Hz,2H),2.18(s,3H),2.02(m,1H),0.86(d,J=6.8Hz,6H).

[0210] Example 17: Synthesis of sodium 5-(6-isobutyl-4-methylpyridin-3-yl)-2-(methoxycarbonyl)-4-oxo-4,5-dihydro-1-thia-3,5,8-triazaacenaphthylene-3-ide (CMPD-35)

[0211] [ka] In a reactor, tert-butyl (6-isobutyl-4-methylpyridin-3-yl)carbamate (75 g, 283.7 mmol), 2,4-dichloro-3-iodopyridine (51.5 g, 297.8 mmol), and tetrabutylammonium bromide (9.2 g, 28.4 mmol) were added to toluene (450 mL) at 25° C. Water (37.5 mL) and 50 wt% sodium hydroxide (37.5 mL, 710 mmol) were added and the reaction mixture was stirred at 25° C. After completion of the reaction, water (90 mL) and methyl thioglycolate (51 mL, 569.4 mmol) were added to the reaction mixture. After completion of the reaction, the layers were separated. Methanol (225 mL) was added to the organic layer and the reaction mixture was warmed to 50° C. 50 wt% sodium hydroxide (22.5 mL, 425.9 mmol) was added slowly and the reaction mixture was stirred at 50° C. After completion of the reaction, the reaction mixture was cooled to 20° C. and filtered to isolate the desired product which was cooled to 20° C. and crystallized (112 g, 85.0% yield). 1 H NMR(400MHz,DMSO-D6):δ 8.20(s,1H),8.08(d,J=5.6Hz,1H),7.27(s,1H),5.62(d,J=5.6Hz,1H),3.70( s,3H),2.62(d,J=7.2Hz,2H),2.11(m,1H),2.04(s,3H),0.93(d,J=6.0Hz,6H).

[0212] Example 18: Synthesis of potassium 5-(6-isobutyl-4-methylpyridin-3-yl)-2-(methoxycarbonyl)-4-oxo-4,5-dihydro-1-thia-3,5,8-triazaacenaphthylene-3-ide (CMPD-36)

[0213] [ka] The title compound was prepared in a similar manner to Example 17, then methyl 5-(6-isobutyl-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate (15.0 g, 37.83 mmol) was dissolved in tetrahydrofuran (300 mL) at 20° C., potassium tert-butoxide (4.28 g, 37.83 mmol) was added slowly to the reaction mixture, cooled to 5° C., and the desired product was crystallized (15.4 g, 80.8% yield). 1 H NMR(400MHz,DMSO-D6):δ 8.18(s,1H),8.07(d,J=5.6Hz,1H),7.26(s,1H),5.61(d,J=5.6Hz,1H),3.69( s,3H),2.63(d,J=6.8Hz,2H),2.10(m,1H),2.04(s,3H),0.93(d,J=6.8Hz,6H).

[0214] Example 19: Crystallization-Induced Diastereomer Transformation (CIDT) of Formula (II) Crystallization-Induced Diastereomeric Conversion (CIDT) for the compound of formula (II). The CIDT process is used to convert the P,M atropisomer (in any diastereomeric ratio, dr 100:0 to 0:100) to the desired P-isomer, which is isolated by the same process as a dihydrate solid.

[0215] The developed CIDT process works by preferentially removing the P isomer from a solution containing a 1 / 1 P / M isomer ratio by crystallization, which results in an enrichment in favor of the M isomer in the solution. An epimerization reaction then converts the M isomer to the P isomer, which is further crystallized in the reactor. This process continues until most / all of the M isomer is converted to the P isomer. The preferential crystallization can be carried out in the same reactor as the epimerization, or most efficiently, the two processes can be spatially separated (by combined stirred tanks, or by a stirred tank combined with a tubular reactor in a loop configuration), as shown in FIG. 1.

[0216] Solubility and Epimerization Extensive solvent screening was carried out in standard organic solvents (both water-miscible and water-immiscible) to determine the epimerization rate, and the main results were reported as the rotational energy barrier, ΔG (kJ / mol) for the epimerization of formula (II), and the half-lives, t 1 / 2 The results are presented in Table 1.

[0217] [Table 1]

[0218] In parallel, extensive solvent screening for the solubility and form of the P and M isomers showed that important solubility differences between the P and M forms exist in many solvent systems (Table 2, showing the solubility of the P and M forms of formula (II) at 10°C, 25°C, and 50°C in various solvent systems and their water mixtures). In some solvent compositions (e.g., 1-propanol / water), the solubility difference is more than 10-fold. Moreover, this solubility difference can be tuned by varying the 1-propanol / water ratio. Thus, the M form can be efficiently converted even starting from a 1:1 dr mixture.

[0219] [Table 2] * The morphological changes were observed after 24 h of equilibration.

[0220] CIDT protocol in 1-propanol / water solvent mixture Step 1: Crude dissolution and epimerization During this step, the crude P / M isomer mixture (of any dr) is dissolved in 1-propanol to obtain a homogeneous solution, followed by heating the mixture to an appropriate temperature and holding for an appropriate time to allow complete epimerization (1 / 1 P / M ratio).

[0221] Detailed process steps: 1) Charge 1 kg of crude P or M isomer or mixture (crude purity used

[0222]

number

[0223] If a crude solution is used, a solvent exchange to 1-propanol is performed. If the crude is already a 1 / 1 ratio P / M mixture, the 10 hour hold time is not necessary. Thus, the hold time can be adapted to ensure complete dissolution (homogeneous mixture).

[0224] Step 2: Seeded preferential crystallization of the P-isomer During this stage, supersaturation is created in the P / M isomer mixture (1 / 1 ratio) by the addition of water, and seeds of the P-isomer are introduced to initiate preferential crystallization of that isomer. However, even in the absence of seeds, the P-isomer will preferentially crystallize and the M will remain in solution.

[0225] Detailed process steps: 1) Add 0.5L / kg of water 2) Seed with 0.01 kg / kg of pure P-isomer (dihydrate). 3) Wait 5 hours (seed crystal aging) 4) Add 1.5L / kg of water for 3 hours 5) Cool to 10°C at 0.2°C / min. 6) Wait overnight for complete desaturation. Sample liquid to confirm preferential P-isomer crystallization → LC for P and M concentrations.

[0226] Step 3: Combined crystallization / epimerization in a flow reactor During this stage, the mother liquor enriched in the M-isomer is continuously filtered from the suspension and pumped to a tubular reactor maintained at a higher temperature to allow conversion to the desired P-isomer. The converted mother liquor is then returned to the crystallizer to allow crystallization of additional P-isomer.

[0227] Detailed process steps: 1) Start recirculating the mother liquor through the heated tubular loop reactor Parameters: a. Inline filter (KIMBLE 2um Ultra-Ware SS Inlet filter) b. Loop reactor jacket: T=120° C. c.Flow rate=0.055L / kg min d. Volume of the heated tube

[0228]

number

[0229]

number

[0230] Step 4: Product isolation During this stage, the product is isolated from the suspension by filtration, washing is carried out and then moist drying is carried out.

[0231] Detailed process steps: 1) Filter out the solids 2) Wash the solid twice with 0.7 L / kg of 1-propanol / water 30 / 70 w / w% 3) Dry the solid under vacuum at 40°C and humid conditions for 24 hours. Crystal yield 86% / purity

[0232]

number

[0233] FIG. 2 shows a typical evolution of the P and M isomer concentrations in the recirculating liquid in the loop reactor in a 1-propanol / water system.

[0234] CIDT protocol in propylene carbonate / water solvent mixtures Step 1: Crude dissolution and epimerization During this stage, the crude P / M isomer mixture (of any dr) is dissolved in propylene carbonate to obtain a homogeneous solution, followed by heating the mixture to an appropriate temperature and holding for an appropriate time to allow complete epimerization (1 / 1 P / M ratio).

[0235] Detailed process steps: 1) Charge 1 kg of crude P or M isomer or mixture (crude purity used

[0236]

number

[0237] Step 2: Preferential crystallization of the P-isomer During this stage, the addition of water creates supersaturation in the P / M isomer mixture (1 / 1 ratio) resulting in preferential crystallization of the P-isomer.

[0238] Detailed process steps: 1) Add 0.42L / kg of water. 2) Cool to 25°C over 4 hours. 3) Wait 5 hours Sample liquid to confirm preferential P-isomer crystallization → LC for P and M concentrations.

[0239] Step 3: Combined crystallization / epimerization in a flow reactor During this stage, the mother liquor enriched in the M-isomer is continuously filtered from the suspension and pumped to a tubular reactor maintained at a higher temperature to allow conversion to the desired P-isomer. The converted mother liquor is then returned to the crystallizer to allow crystallization of additional P-isomer.

[0240] Detailed process steps: 1) Start recirculating the mother liquor through the heated tubular loop reactor JNJ setup parameters: a. Inline filter (KIMBLE 2um Ultra-Ware SS Inlet filter) b. Loop reactor jacket: T=130° C. c.Flow rate=0.055L / kg min d. Volume of the heated tube

[0241]

number

[0242]

number

[0243] Step 4: Product isolation During this stage, the product is isolated from the suspension by filtration, washing is carried out and then moist drying is carried out.

[0244] Detailed process steps: 1) Filter out the solids 2) Wash the solid twice with 0.75 L / kg of propylene carbonate / water 93 / 7 w / w% 3) Dry the solid under vacuum at 45°C and humid conditions for 24 hours. Crystal Yield

[0245]

number

[0246] FIG. 3 shows a typical evolution of the P and M isomer concentrations in the recirculating liquid in the loop reactor in a propylene carbonate / water system.

[0247] Batch CIDT Protocol In a flask, 5.0 g of a 1:1 ratio of P / M was added to a 2 / 1 mixture of IPA / water (25 mL). The mixture was heated to 80° C. for 1 h and then cooled to 50° C. The mixture was stirred at 50° C. for 54 h. The suspension was then cooled to 10° C. The in situ yield was 60% P (and 40% M). The suspension was filtered to give P as a white solid (2.7 g, 88.9% assay, 48% yield).

[0248] Example 20: NMR of N-((1R,2S)-2-acrylamidocyclohexyl)-5-(6-isobutyl-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide dihydrate (formula P-(II))

[0249] [ka] Below is the NMR spectrum of the material produced in Example 11. 1 H NMR(400MHz,DMSO-D6):δ 10.1(s,1H),8.46(s,1H),8.33(d,J=5.6Hz,1H),7.88(d,J=7.6Hz,1H),7.7 7(d,J=7.6Hz,1H),7.36(s,1H),6.22(dd,J=6.8,16.8Hz,1H),6.11(dd,J=2. 4,17.2Hz,1H),5.94(d,J=5.6Hz,1H),5.57(dd,J=2,10Hz,1H),4.32(m,2H), 2.65(d,J=6.8Hz,2H),2.13(m,4H),2.10-1.4(m,6H),0.93(d,J=6.8Hz,1H).

[0250] Example 21: SAR Test Initial structure-activity relationships (Table 3) for a new series of BTK inhibitors exemplified by compound A have been previously performed (Tichenor, et al., ACS Med. Chem. Lett. 2021, 12, 782-790), designed with an acrylamide electrophile involved in a covalent bond with Cys481. Despite strong covalent inhibitory potency in vitro and in vivo, the developability of compound A is limited by its poor aqueous solubility and poor oral bioavailability (<1%) when administered as a crystalline suspension, preventing its development as a therapeutic agent. Subsequent optimization of compound A has therefore focused on increasing aqueous solubility and oral bioavailability from a solid formulation suitable for preclinical tolerability evaluation and progression to human clinical trials. The development of structure-activity relationships was based on the non-covalent binding affinity (K) of each inhibitor for BTK. I ) and the first-order rate constant for irreversible covalent bond formation (k inact This was carried out by characterizing the second-order rate constant k inact / K I The ratio is used to evaluate covalent inhibitor potency because it is independent of incubation time and substrate concentration (Copeland, R.A. Evaluation of Enzyme Inhibitors in Drug Discovery: a Guide for Medicinal Chemists and Pharmacologists; 2nd ed.; Wiley: Hoboken, NJ, 2013).

[0251] [ka]

[0252] [Table 3]

[0253] The initial set of analogs was designed to reduce lipophilicity by performing nitrogen scans to the right of the proximal phenyl while maintaining the tricyclic core and acrylamide (Table 4). The highly potent phenyl derivative 2 (k inact / K I =13832s -1 ), pyridyl isomers C and D conferred modestly increased water solubility but a 20-fold loss in BTK potency. Incorporation of a methyl group ortho to the core heterocycle (5-10) restricts rotation around the N-aryl bond, resulting in a pair of stable atropisomers (Tichenor, et al., ACS Med. Chem. Lett. 2021, 12, 782-790). Incorporation of the ortho-methyl into examples C and D increases the reversible binding affinity K I By increasing inact / K I Compound F increased BTK potency by improving the ratio by 16-fold (0.0276 μM), but the first-order rate constant for covalent bond formation, k inact (0.000352±6e -05 s -1 ) remained unchanged across the series. 4-Methylpyridyl Compound F maintained comparable BTK potency to Compound A with reduced cLogP, but possessed persistently poor water solubility and metabolic instability.

[0254] [Table 4]

[0255] Subsequent analogues have been modified to reduce lipophilicity and 3 To increase the proportion of hybridized carbon atoms, we focused on substituting the distal aromatic ring with a low molecular weight aliphatic substituent (compound B, Fsp 3 = 13%). The cyclopentyloxy substituent in compound G showed comparable potency compared to the phenoxy derivative F, but the corresponding BTKk was reduced as the alkoxy substituent was repeatedly further cleaved with smaller alkoxy groups (Examples H-J) with a corresponding reduction in cLogP. inact / K IThe value was reduced by 8-fold for compound I compared to compound B (1663M -1 s -1 ), with concomitant improvements in microsomal stability and aqueous solubility at pH 2 and 7. Substitution of the oxygen bond with a carbon, as in the isobutyl derivative J, further improves aqueous solubility at pH 2 and 7 (350 / 23 μM) and provides a moderate improvement in potency compared to compound I. The improved profile of compound I, compared to compound B, is due to the increased Fsp 3 This corresponded to an increase in cLogP (32%) and a decrease in cLogP (3.6). Consistent with the SAR trends in Table 4, the noncovalent binding affinity component K I had the greatest effect on the difference in inhibitor potency, while k inact Values ​​varied less than two-fold across a series of structurally diverse examples.

[0256] Further optimization of J was approached with the goal of identifying the optimal linker length for positioning the acrylamide to bind to Cys481 and participate in covalent bond formation (Table 5). I was proven to be sensitive to the length and orientation of the linker. Replacing the amino-piperidine of J with amino-pyrrolidine (K) or ethylenediamine (L) resulted in the formation of K I Lowering the pH to micromolar levels reduced potency by approximately 20-fold (2.55, 2.43, respectively). However, the improved microsomal stability of K and L relative to J justifies additional linker exploration. A linker based on cis-cyclopentyldiamine (M) conferred significantly improved potency compared to other linkers (10, 11, 12) and increased microsomal stability compared to the piperidine derivative J (38 min vs. 6 min). Compound M also maintained high pH 2 solubility and measurable pH 7 solubility, making it an attractive candidate for in vivo profiling.

[0257] [Table 5] a each k inact and K IValues ​​were obtained from the mean (±SD) of two independent determinations. b Data corresponds to the more potent atropisomer

[0258] Compared to the series benchmark compound A, compound M exhibits reduced lipophilicity and increased Fsp corresponding to increased water solubility at pH 2 and 7 while maintaining comparable potency in suppressing anti-IgM-induced B cell activation in human whole blood. 3 Compound M was characterized by a 5'-fold increase in the free fraction (32%) (Table 6). Compound M's activity was evaluated in rat and human whole blood assays using anti-IgD and anti-IgM stimulation, respectively, to induce B cell activation via the B cell receptor. Compound M exhibits reduced potency in mouse CD69 splenocyte assays, while Compound M is 3-fold more potent in rat whole blood and equipotent in human whole blood potency compared to Compound A. Compound M's potent rat whole blood activity can be attributed to a 6-10-fold increase in the free fraction.

[0259] [Table 6]

[0260] Example 22: XRPD analysis of crystalline form B of formula P-(II) dihydrate X-ray powder diffraction (XRPD) studies were performed on a Bruker D8 Advance X-ray powder diffractometer. The compounds were spread on a single crystal silicon plate and weighing paper and slight pressure were used to obtain a flat and homogenous surface before testing. Details of the XRPD method used for testing are given in Table 7.

[0261] [Table 7]

[0262] The XRPD spectrum is shown in FIG. 4 and the significant peaks, d-spacings, and their intensities are shown in Table 8.

[0263] [Table 8]

[0264] Example 23: IR analysis of crystalline form B of formula P-(II) dihydrate IR was performed on a Thermo Nicoletis5 FT-IR spectrometer equipped with an iD7 ATR-Diamond accessory. The compound was placed at the center of the crystal surface and then the pressure control ring was rotated until the sample was firmly pressed against the crystal surface and then analyzed using the method shown in Table 9. The IR spectrum is shown in Figure 5.

[0265] [Table 9]

[0266] Example 24: DSC analysis of crystalline form B of formula P-(II) dihydrate Tested with standard pans: Differential scanning calorimetry was performed on a TA Instruments discovery DSC-2500 differential scanning calorimeter equipped with an RCS cooling unit. Approximately 3.4 mg of compound is transferred to a standard aluminum sample pan from TA instruments. The sample pan is closed with a standard lid and the DSC curve is recorded. The DSC test with standard pan parameters is shown in Table 10.

[0267] [Table 10]

[0268] The DSC curve of crystalline form B of formula P-(II) dihydrate tested by standard DSC pan shows one broad endothermic peak (midpoint at 137.4° C. with a thermal melt of 219 J / g), which is attributed to the dehydration of water present in the crystalline structure concomitant with the melting of the dehydrated structure ( FIG. 6 ).

[0269] Tested with Tzero sealed pans: Differential scanning calorimetry was performed on a TA Instruments Discovery DSC-2500 differential scanning calorimeter equipped with an RCS cooling unit. Approximately 1.6 mg of compound is transferred to a Tzero aluminum sample pan from TA instruments. The sample pan is closed (sealed) with a Tzero lid and the DSC curve is recorded. The DSC run with Tzero sealed pan parameters is shown in Table 11.

[0270] [Table 11]

[0271] The DSC curve of crystalline form B of formula P-(II) dihydrate tested by Tzero sealed pan shows two endothermic peaks, the first of which should be the melting point of the compound at 141.8° C. (midpoint) with a thermal melt of 110 J / g, and the second occurs at 155.9° C. (midpoint) with a thermal melt of 4 J / g (FIG. 7). The second endotherm cannot be assigned to a specific form under the specific measurement conditions.

[0272] Example 25: XRPD analysis of crystalline form B of formula P-(II) dihydrate Thermogravimetric analysis (TGA) was performed on a TA Instruments Q5000IR thermogravimetric analyzer. Approximately 8.7 mg of compound was tared and transferred into a standard aluminum sample pan from TA instruments, and the TGA curve was recorded. The TGA test parameters are shown in Table 12.

[0273] [Table 12]

[0274] For crystalline form B of formula P-(II) dihydrate, a weight loss of 6.5% (2 equivalents of water) is recorded in the temperature range from 35° C. to 142° C. (FIG. 8).

[0275] Example 26: Rotational barrier of compounds of formula (II) The rotational energy barrier of the atropisomeric compound of formula (II) was estimated according to methods known in the art. The rotational barrier was determined in several solvents and their aqueous mixtures, and the results are reported in Table 13, with a value of 120.5 kJ mol 2 corresponding to epimerization half-lives of 63.8 and 4.0 months at 20° C. and 37° C., respectively. -1 or 28.8 kcal mol -1 The average value of 100% was obtained, placing this compound in the upper segment of class 2 atropisomers according to classification systems known in the art. The rotational barrier was slightly affected by the solvent, increasing in the order 1-butanol < 2-butanol < 1-propanol < propylene carbonate. In addition, increasing the amount of water substantially increased the rotational barrier in all solvents, with the highest value being obtained in the 1-propanol / water 33 / 67 w / w% system. Unfortunately, due to the low water solubility of the compound of formula (II) in water, epimerization studies could not be performed accurately in pure water.

[0276] [Table 13]

[0277] Compounds of formula (II) enriched in the P isomer were dissolved in the respective solvents to give a concentration of about 1 wt% and placed in standard screw-cap vials (1.8 mL) equipped with a magnetic stir bar. The vials were then placed in a heating block of a parallel reactor (Crystal16, Technobis BV) preheated to the desired temperature (80°C-100°C depending on the solvent). At given time intervals, small aliquot samples were taken in HPLC vials, diluted and the diastereomeric excess of the mixture was determined by a UPLC instrument equipped with an Acquity UPLC BEH C18 column (0.6 ml / min, gradient 10 mM ammonium acetate acetonitrile 95-5 v / v% and acetonitrile at 35°C). The time points and corresponding decays of the diastereomeric excess (de) were plotted as t vs. ln(1 / (de)) to determine the interconversion rate constants, rotational energy barriers and epimerization half-lives in the respective solvents and temperatures.

[0278]

number

[0279]

number

[0280] Aspects The present disclosure is also directed to the following aspects: Aspect 1. A method of synthesizing a compound of formula (I), comprising:

[0281] [ka] During the ceremony, R 1 But, C 5~10 Aryl and C 4~9 heteroaryl, wherein the aryl or heteroaryl is optionally selected from C 1~6 substituted with one or more groups independently selected from alkyl; R 2 But, C 1~6 Alkyl and C 2~6 alkenyl, compound

[0282] [ka] with an acid and a first solvent, and then

[0283] [ka] in the presence of one or more coupling reagents, an amine base, and a second solvent to obtain a compound of formula (I). Aspect 2.R 1 But, C 1~6 C optionally substituted with one or more groups independently selected from alkyl 4~9 The method of embodiment 1, wherein the compound is heteroaryl. Aspect 3.R 1 but,

[0284] [ka] 3. The method of embodiment 2, wherein Aspect 4.R 2 But, C 2~6 The method of embodiment 1, 2, or 3, wherein said alkenyl is alkenyl. Aspect 5.C 2~6 Alkenyl is

[0285] [ka] 5. The method of embodiment 4, wherein Aspect 6. The method of any one of aspects 1 to 5, wherein Pg is Boc. Aspect 7. The method of any one of aspects 1 to 6, wherein the acid is methanesulfonic acid. Aspect 8. The method of any one of aspects 1-7, wherein the first solvent is selected from dichloromethane (DCM), ethyl acetate (EtOAc), 2-methyltetrahydrofuran (MeTHF), tetrahydrofuran (THF), and acetonitrile (ACN). Aspect 9. The method of aspect 8, wherein the first solvent is dichloromethane. Aspect 10. The method of any one of aspects 1 to 9, wherein the coupling reagent is selected from 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), hydroxybenzotriazole (HOBt), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), propylphosphonic anhydride (T3P), 1,1'-carbonyldiimidazole (CDI), 2-hydroxypyridine-N-oxide (HOPO), and combinations thereof. Aspect 11. The method of aspect 10, wherein the coupling reagent is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), hydroxybenzotriazole (HOBt), or a combination thereof. Aspect 12. The method of any one of aspects 1 to 11, wherein the amine base is selected from N,N-diisopropylethylamine (DIPEA), triethylamine, tributylamine, N-methylmorpholine, and N-methylpiperidine. Aspect 13. The method of aspect 12, wherein the amine base is N,N-diisopropylethylamine (DIPEA). Aspect 14. The method of any one of aspects 1 to 13, wherein the second solvent is selected from dichloromethane (DCM), ethyl acetate (EtOAc), 2-methyltetrahydrofuran (MeTHF), tetrahydrofuran (THF), and acetonitrile (ACN). Aspect 15. The method of aspect 14, wherein the second solvent is dichloromethane. 16. Compound

[0286] [ka] with a base and an ammonium salt in a solvent to form compound CMPD-02. Aspect 17. The method of aspect 16, wherein the base contacted with CMPD-03 is selected from potassium trimethylsilanolate (TMSOK), lithium hydroxide (LiOH), or sodium hydroxide (NaOH). Aspect 18. The method of aspect 16 or 17, wherein the ammonium salt is selected from tetrabutylammonium bromide (TBAB), tetrabutylammonium hydrogen sulfate, benzyltrimethylammonium bromide, benzyltrimethylammonium chloride, and Aliquat 336. Aspect 19. The method of aspect 18, wherein the ammonium salt is tetrabutylammonium bromide (TBAB). Aspect 20. The method of any of aspects 16-19, wherein the solvent in which CMPD-03 is converted to CMPD-02 is tetrahydrofuran. 21. Compound

[0287] [ka] with a carbonyl source and a solvent to form compound CMPD-03. Aspect 22. The method of aspect 21, wherein the carbonyl source is selected from N,N'-carbonyldiimidazole (CDI), phosgene, triphosgene, and N,N'-disuccinimidyl carbonate (DSC). Aspect 23. The method of aspect 22, wherein the carbonyl source is N,N'-carbonyldiimidazole (CDI). Aspect 24. The method of aspect 21, 22, or 23, wherein the solvent in which CMPD-04 is converted to CMPD-03 is tetrahydrofuran. 25. Compound

[0288] [ka] with a sulfur reagent and a base in a solvent to form compound CMPD-04, wherein X is selected from Cl and Br. The method of embodiment 25, wherein X is Cl. Aspect 27. The method of aspect 25 or 26, wherein the sulfur reagent is methyl 2-mercaptoacetate. Embodiment 28 The method of embodiment 25, 26, or 27, wherein the base contacted with CMPD-05 is NaOMe. Aspect 29. The method of aspect 25, 26, 27, or 28, wherein the solvent in which CMPD-05 is converted to CMPD-04 is methanol. 30. Compound

[0289] [ka] In a solvent system, a compound R having a base is 1 30. The method of any of embodiments 25, 26, 27, 28, or 29, further comprising contacting with —NH 2 , and an amine base to form compound CMPD-05. The method of embodiment 30, wherein X is Cl. Aspect 32.R 1 but,

[0290] [ka] 32. The method of claim 30 or 31, Embodiment 33 The method of embodiment 30, 31, or 32, wherein the base contacted with CMPD-06 is K2CO3. Aspect 34 The method of aspect 30, 31, 32, or 33, wherein the amine base contacted with CMPD-06 is N,N-diisopropylethylamine (DIPEA). Aspect 35. The method of aspect 30, 31, 32, 33, or 34, wherein the solvent system in which CMPD-06 is converted to CMPD-05 is toluene / NMP. Aspect 36. Compound R 1 -NO2 with a hydride source, a catalyst, and a solvent system to produce a compound R 1 The method of embodiment 30, 31, 32, 33, 34, or 35, further comprising forming -NH2. Aspect 37. The method of aspect 36, wherein the hydrogen source is NaBH4 or H2. Aspect 38. The method of aspect 36 or 37, wherein the catalyst is selected from NiCl2, Pd / C, Pd(OAc)2, Pd(OH)2. Raney Ni, sponge Ni, Pt / V / C, Pt / Fe / C, NiBr2, NiCl2(DME). Aspect 39. The method of aspect 38, wherein the catalyst is NiCl2 or Pd / C. Aspect 40.R 1 -NO2 is R 1 40. The method of embodiment 36, 37, 38, or 39, wherein the solvent system in which -NH2 is converted is selected from toluene / water, xylene, THF, MeTHF, MeOH, THF / MeOH, toluene / MeOH, MeTHF / water, and THF / water. Aspect 41.R 1 -NO2 is R 1 The method of embodiment 40, wherein the solvent system converted to -NH2 is toluene / water. 42. Compound

[0291] [ka] with a cyano source and a solvent to form compound CMPD-06. Embodiment 43. The method of embodiment 42, wherein X is Cl. Aspect 44. The method of aspect 42 or 43, wherein the cyano source is CuCN. Aspect 45. The method of aspect 42, 43, or 44, wherein the solvent in which CMPD-07 is converted to CMPD-06 is butyronitrile. 46. ​​Compound

[0292] [ka] with a base and an electrophilic halogen in a solvent to form compound CMPD-07. Embodiment 47. The method of embodiment 46, wherein X is Cl. Aspect 48 The method of aspect 46 or 47, wherein the base contacted with CMPD-08 is lithium diisopropylamine. Aspect 49. The method of aspect 46, 47, or 48, wherein the solvent in which CMPD-08 is converted to CMPD-07 is tetrahydrofuran. 50. Compound

[0293] [ka] The base,

[0294] [ka] and a solvent to form compound CMPD-01. Aspect 51.R 2 But, C 2~6 The method of embodiment 50, wherein said alkyl group is alkenyl. Aspect 52.C 2~6 Alkenyl is

[0295] [ka] 52. The method of embodiment 51, wherein Aspect 53. The method of claim 50, 51, or 52, wherein Pg is Boc. Embodiment 54. The method of embodiment 50, 51, 52, or 53, wherein the base contacted with CMPD-09 is NaHCO3. Aspect 55. The method of aspect 50, 51, 52, 53, or 54, wherein the solvent in which CMPD-09 is converted to CMPD-01 is 2-methyltetrahydrofuran. A method of synthesizing a compound of formula (II), comprising:

[0296] [ka] compound

[0297] [ka] with an acid and a first solvent, and then

[0298] [ka] in the presence of one or more coupling reagents, an amine base, and a second solvent to obtain a compound of formula (II). Aspect 57. The method of aspect 56, wherein the acid is methanesulfonic acid. Aspect 58. The method of aspect 56 or 57, wherein the first solvent is dichloromethane. Aspect 59. The method of aspect 56, 57, or 58, wherein the coupling reagent is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI). Aspect 60. The method of aspect 56, 57, 58, or 59, wherein the amine base is N,N-diisopropylethylamine (DIPEA). Aspect 61 The method of aspect 56, 57, 58, 59, or 60, wherein the second solvent is dichloromethane. 62. Compound

[0299] [ka] with a base and an ammonium salt in a solvent to form compound CMPD-11. Embodiment 63. The method of embodiment 62, wherein the base contacted with CMPD-12 is potassium trimethylsilanolate (TMSOK). Aspect 64. The method of aspect 62 or 63, wherein the ammonium salt is tetrabutylammonium bromide (TBAB). Aspect 65. The method of aspect 62, 63, or 64, wherein the solvent in which CMPD-12 is converted to CMPD-11 is tetrahydrofuran. 66. Compound

[0300] [ka] with a carbonyl source and a solvent to form compound CMPD-12. Embodiment 67. The method of embodiment 66, wherein the carbonyl source is N,N'-carbonyldiimidazole (CDI). Aspect 68. The method of aspect 66 or 67, wherein the solvent in which CMPD-13 is converted to CMPD-12 is tetrahydrofuran. 69. Compound

[0301] [ka] with a sulfur reagent and a base in a solvent to form compound CMPD-13. Aspect 70. The method of aspect 69, wherein the sulfur reagent is methyl 2-mercaptoacetate. Embodiment 71 The method of embodiment 69 or 70, wherein the base contacted with CMPD-14 is NaOMe. Embodiment 72 The method of embodiment 69, 70, or 71, wherein the solvent in which CMPD-14 is converted to CMPD-13 is methanol. 73. Compound

[0302] [ka] In a solvent system, a compound having a base is

[0303] [ka] and an amine base to form compound CMPD-14. The method of embodiment 73, wherein the base contacted with CMPD-15 and CMPD-16 is K2CO3. Aspect 75. The method of aspect 73 or 74, wherein the amine base contacted with CMPD-15 and CMPD-16 is N,N-diisopropylethylamine (DIPEA). Aspect 76. The method of aspect 73, 74, or 75, wherein the solvent system in which CMPD-15 and CMPD-16 are converted to CMPD-14 is toluene / NMP. 77. Compound

[0304] [ka] with a hydride source, a catalyst, and a solvent system to form compound CMPD-16. Aspect 78. The method of aspect 77, wherein the hydride source is NaBH4. Aspect 79. The method of aspect 77 or 78, wherein the catalyst is NiCl2. Aspect 80. The method of aspect 77, 78, or 79, wherein the solvent system in which CMPD-17 is converted to CMPD-14 is toluene / water. 81. Compound

[0305] [ka] with a catalyst, a phosphorus reagent, a boron reagent, a first base, a second base, and a solvent system to form compound CMPD-17. Embodiment 82. The method of embodiment 81, wherein the catalyst contacted with CMPD-17 is Pd(OAc)2. Aspect 83. The method of aspect 81 or 82, wherein the phosphorus reagent is di(1-adamantyl)-n-butylphosphine. Aspect 84. The method of aspect 81, 82, or 83, wherein the boron reagent is isobutylboronic acid. Aspect 85. The method of aspect 81, 82, 83, or 84, wherein the first base is K2CO3. Embodiment 86 The method of embodiment 81, 82, 83, 84, or 85, wherein the second base is KOAc. Aspect 87. The method of aspect 81, 82, 83, 84, 85, or 86, wherein the solvent system in which CMPD-20 is converted to CMPD-17 is toluene / water. 88. Compound

[0306] [ka] with a cyano source and a solvent to form compound CMPD-15. Embodiment 89. The method of embodiment 88, wherein the cyano source is CuCN. Aspect 90. The method of aspect 88 or 89, wherein the solvent in which CMPD-18 is converted to CMPD-15 is butyronitrile. 91. Compound

[0307] [ka] with a base and an electrophilic halogen in a solvent to form compound CMPD-18. Embodiment 92. The method of embodiment 91, wherein the base contacted with CMPD-19 is lithium diisopropylamine. Aspect 93. The method of aspect 91 or 92, wherein the solvent in which CMPD-19 is converted to CMPD-18 is tetrahydrofuran. 94. Compound

[0308] [ka] The base,

[0309] [ka] and a solvent to form compound CMPD-10. Embodiment 95. The method of embodiment 94, wherein the base contacted with CMPD-20 is NaHCO3. Aspect 96. The method of aspect 94 or 95, wherein the solvent in which CMPD-20 is converted to CMPD-10 is 2-methyltetrahydrofuran. A method for isolating the P atropisomer from a mixture of M and P isomers of a compound of formula (II), comprising: 1) dissolving a compound of formula (II) in one or more solvents in a container to form a solution; 2) optionally heating the solution to a first temperature of about 75° C. to about 140° C. for a first period of about 8 hours to about 12 hours and cooling the solution to a second temperature of about 20° C. to about 30° C.; 3) adding water and waiting a second time period of about 2 hours to about 24 hours to form a suspension, optionally seeding with a compound of formula P-(II) during this step, and optionally cooling the solution to a third temperature of about 5° C. to about 15° C. for a third time period of about 6 hours to about 12 hours to form a suspension; 4) filtering the suspension to obtain crystals of the compound of formula P-(II); 5) collecting the filtrate and heating the filtrate to a fourth temperature of about 75° C. to about 150° C. for a fourth period of about 5 minutes to about 1 hour; 6) repeating steps 3-5 about 20-100 times until all M isomers are converted to P isomers; 7) collecting the precipitate, washing and drying the solid under humid conditions. Aspect 98. The method of aspect 97, wherein the one or more first solvents are selected from the group consisting of isopropanol, propylene carbonate, water, 1-propanol, 1-butanol, 2-butanol, isobutanol, propylene glycol, ethylene glycol, dimethylacetamide (DMA), benzyl alcohol, N-methyl-2-pyrrolidone (NMP), propylene glycol methyl ether, 2-ethoxyethanol, (s)-1,2-butanediol, transcutol, ethylene glycol diacetate, and combinations thereof. Aspect 99. The method of aspect 98, wherein the one or more first solvents is 1-propanol. Aspect 100. The method of aspect 97, 98, or 99, wherein the first temperature is about 95° C. Aspect 101. The method of aspect 97, 98, 99, or 100, wherein the first period of time is about 10 hours. Aspect 102. The method of aspect 97, 98, 99, 100, or 101, wherein the second temperature is about 25° C. Aspect 103. The method of aspect 97, 98, 99, 100, 101, or 102, wherein the second period of time is about 5 hours. Aspect 104. The method of aspect 97, 98, 99, 100, 101, 102, or 103, wherein the third temperature is about 10° C. Embodiment 105. The method of embodiment 97, 98, 99, 100, 101, 102, 103, or 104, wherein the third period of time is about 8 hours. A method for converting a compound of formula (II) to a compound of formula P-(II), comprising: 1) dissolving a compound of formula (II) in one or more first solvents in a first container to form a solution; 2) heating the solution to a first temperature of about 75° C. to about 120° C. and holding the solution at the first temperature for a first period of about 4 hours to about 8 hours; 3) cooling the solution to a second temperature of about 60° C. to about 100° C.; 4) adding water and adding a compound of formula (II) to the solution; 5) cooling the solution to a third temperature, about 10° C. to about 30° C., over a second period of about 2 hours to about 8 hours, and waiting a third period of about 3 hours to about 9 hours to form a Form B suspension. 6) transferring the mother liquor from the formed suspension into a second vessel; 7) heating the mother liquor to a fourth temperature of about 110° C. to about 150° C. for a fourth time of about 30 hours to about 70 hours; 8) returning the mother liquor to the first vessel; 9) collecting the formed crystals of the compound of formula P-(II) by filtration; 10) washing the crystals with one or more second solvents; 11) drying the crystals of the compound of formula P-(II) at a fifth temperature of about 30° C. to about 50° C. under humidified conditions for a fifth time period of about 12 hours to about 36 hours. Aspect 107. The method of aspect 106, wherein the one or more first solvents are selected from the group consisting of isopropanol, propylene carbonate, water, 1-propanol, 1-butanol, 2-butanol, isobutanol, propylene glycol, ethylene glycol, dimethylacetamide (DMA), benzyl alcohol, N-methyl-2-pyrrolidone (NMP), propylene glycol methyl ether, 2-ethoxyethanol, (s)-1,2-butanediol, transcutol, ethylene glycol diacetate, and combinations thereof. Aspect 108. The method of aspect 107, wherein the one or more first solvents is propylene carbonate. Aspect 109. The method of aspect 106, 107, or 108, wherein the first temperature is about 100° C. Embodiment 110. The method of embodiment 106, 107, 108, or 109, wherein the first period of time is about 6 hours. Aspect 111. The method of aspect 106, 107, 108, 109, or 110, wherein the second temperature is about 80° C. Embodiment 112. The method of embodiment 106, 107, 108, 109, 110, or 111, wherein the third temperature is about 25° C. Embodiment 113 The method of embodiment 106, 107, 108, 109, 110, 111, or 112, wherein the second period of time is about 4 hours. Embodiment 114 The method of embodiment 106, 107, 108, 109, 110, 111, 112, or 113, wherein the third period of time is about 5 hours. Aspect 115. The method of aspect 106, 107, 108, 109, 110, 111, 112, 113, or 114, wherein the fourth temperature is about 130° C. Embodiment 116 The method of embodiment 106, 107, 108, 109, 110, 111, 112, 113, 114, or 115, wherein the fourth period of time is about 52 hours. Aspect 117. The method of any one of aspects 106 to 116, wherein the one or more second solvents are selected from the group consisting of isopropanol, propylene carbonate, water, 1-propanol, 1-butanol, 2-butanol, isobutanol, propylene glycol, ethylene glycol, dimethylacetamide (DMA), benzyl alcohol, N-methyl-2-pyrrolidone (NMP), propylene glycol methyl ether, 2-ethoxyethanol, (s)-1,2-butanediol, transcutol, ethylene glycol diacetate, and combinations thereof. Aspect 118. The method of aspect 117, wherein the one or more second solvents are propylene carbonate and water. Embodiment 119. A method according to any one of embodiments 106 to 118, wherein the fifth temperature is about 45°C. Embodiment 120. The method of any one of embodiments 106 to 119, wherein the fifth period of time is about 24 hours. Embodiment 121. Crystalline form B of formula P-(II) dihydrate.

[0310] [ka] Embodiment 122. The crystalline form B according to embodiment 121, wherein the crystalline form B is characterized by an XRPD pattern having a peak at about 5.599° expressed in degrees 2θ (±0.2). Embodiment 123. The crystalline form B according to embodiment 122, wherein form B is further characterized by an XRPD pattern having a peak at about 20.426° expressed in degrees 2θ (±0.2). Embodiment 124. The crystalline form B according to embodiment 123, wherein form B is further characterized by an XRPD pattern having a peak at about 24.665° expressed in degrees 2θ (±0.2). Embodiment 125. The crystalline form B according to embodiment 124, wherein form B is further characterized by an XRPD pattern having peaks expressed in degrees 2θ (±0.2) at about 11.135° and about 26.373°. Embodiment 126. The crystalline form B according to embodiment 125, wherein form B is further characterized by an XRPD pattern having peaks expressed in degrees 2θ (±0.2) at about 12.134°, about 23.187°, about 19.065°, and about 30.316°. Embodiment 127. The crystalline form B according to embodiment 121, wherein form B is characterized by an XRPD pattern substantially as shown in FIG. Embodiment 128. Crystalline form B has a crystal structure of about 1522 cm -1 The crystalline form B according to any of embodiments 121 to 127, characterized by an IR peak at: Form 129. Form B has a molecular weight of about 1714 cm -1 The crystalline form B according to embodiment 128, further characterized by an IR peak at: Form 130. Form B is about 1642 cm -1 and about 1622 cm -1 The crystalline form B according to embodiment 129, further characterized by an IR peak at: Form 131. Form B is about 1270 cm -1 and approximately 1251 cm -1 The crystalline form B according to embodiment 130, further characterized by an IR peak at: Form 132. Form B is about 1541 cm -1 and about 1494 cm -1 The crystalline form B according to embodiment 131, further characterized by an IR peak at: Embodiment 133. The crystalline form B according to embodiment 121, wherein form B is characterized by an IR pattern substantially as shown in FIG. 5. Embodiment 134. The crystalline form B of embodiment 121, wherein form B is characterized by one or more of: 1) a DSC thermogram using standard pan conditions exhibiting an endotherm at about 196.8°C; 2) a DSC thermogram using Tzero sealed pan conditions exhibiting a first endotherm at about 141.8°C and a second endotherm at about 155.9°C; and 3) a water loss of about 6.5% by weight as measured by thermogravimetric analysis. Aspect 135. Structure:

[0311] [ka] A compound having the formula: Aspect 136.

[0312] [ka] and pharma- ceutically acceptable salts thereof. Aspect 137.

[0313] [ka] A compound selected from: A method for producing tert-butyl ((1R,2S)-2-(3-chloropropanamido)cyclopentyl)carbamate, comprising:

[0314] [ka] A process comprising contacting tert-butyl ((1R,2S)-2-aminocyclopentyl)carbamate with 3-chloropropionyl chloride in the presence of a solvent and a base. Aspect 139. The method of aspect 138, wherein the solvent is methyltetrahydrofuran. Aspect 140. The method of aspect 138 or 139, wherein the base is sodium bicarbonate. A method for producing (E)-2-cyano-3-((6-isobutyl-4-methylpyridin-3-yl)amino)but-2-enethioamide, comprising:

[0315] [ka] A process comprising contacting 2-cyano-3-ethoxybut-2-enethioamide with 6-isobutyl-4-methylpyridin-3-amine in the presence of a solvent. Aspect 142. The method of aspect 141, wherein the solvent is tetrahydrofuran. A method for producing 4-((6-isobutyl-4-methylpyridin-3-yl)amino)-2-mercaptonicotinonitrile, comprising the steps of:

[0316] [ka] A process comprising contacting 2-cyano-3-((6-isobutyl-4-methylpyridin-3-yl)amino)but-2-enethioamide with N,N-dimethylformamide diethyl acetal in a solvent in the presence of a base, followed by the addition of an acid. Aspect 144. The method of aspect 143, wherein the solvent is 2-methyltetrahydrofuran. A method according to any one of claims 143 to 144, wherein the base is K2CO3. Aspect 146. The method of aspect 143, 144, or 145, wherein the acid is acetic acid. A method for producing tert-butyl (6-isobutyl-4-methylpyridin-3-yl)carbamate, comprising the steps of:

[0317] [ka] 1. A process comprising contacting 6-isobutyl-4-methylpyridin-3-amine with di-tert-butyl decarboxylate in the presence of a solvent system and a salt. Aspect 148. The method of aspect 147, wherein the solvent system is toluene and water. Aspect 149. The method of aspect 147 or 148, wherein the salt is ammonium chloride. A method for producing ethyl (6-isobutyl-4-methylpyridin-3-yl)carbamate, comprising:

[0318] [ka] A process comprising contacting 6-isobutyl-4-methylpyridin-3-amine with diethyl carbonate in the presence of a solvent and a base. Embodiment 151. The method of embodiment 150, wherein the solvent is tetrahydrofuran. A method according to any one of claims 150 to 151, wherein the base is potassium tert-butoxide. 153. A method for producing methyl (6-isobutyl-4-methylpyridin-3-yl)carbamate, comprising:

[0319] [ka] A process comprising contacting 6-isobutyl-4-methylpyridin-3-amine with dimethyl carbonate in the presence of a solvent and a base. Aspect 154. The method of aspect 153, wherein the solvent is tetrahydrofuran. A method according to any one of claims 153 to 154, wherein the base is potassium tert-butoxide. A method for producing sodium 5-(6-isobutyl-4-methylpyridin-3-yl)-2-(methoxycarbonyl)-4-oxo-4,5-dihydro-1-thia-3,5,8-triazaacenaphthylene-3-ide, comprising:

[0320] [ka] a) preparing a mixture of tert-butyl (6-isobutyl-4-methylpyridin-3-yl)carbamate with 2,4-dichloro-3-iodopyridine and tetrabutylammonium bromide in toluene; b) preparing a second reaction mixture by adding water and sodium hydroxide to the mixture prepared in step a, and then stirring the second reaction mixture for a time interval of 10 minutes to 10 hours; c) at the end of the time interval from step b, adding water and methyl thioglycolate to the second reaction mixture, followed by stirring for a time interval of 10 minutes to 10 hours to produce a third reaction mixture; d) at the end of the time interval from step c, partitioning the reaction mixture into an aqueous layer and an organic layer; e) adding methanol to the organic layer from step d to form a fourth reaction mixture; f) preparing a fifth reaction mixture by adding sodium hydroxide to the fourth reaction mixture and then heating the fifth reaction mixture to a temperature between 40° C. and 70° C. for a time interval between 10 minutes and 10 hours; g) at the end of the time interval from step f, cooling the fifth reaction mixture to a temperature between 10° C. and 30° C., and then filtering to isolate sodium 5-(6-isobutyl-4-methylpyridin-3-yl)-2-(methoxycarbonyl)-4-oxo-4,5-dihydro-1-thia-3,5,8-triazaacenaphthylene-3-ide. A method for producing potassium 5-(6-isobutyl-4-methylpyridin-3-yl)-2-(methoxycarbonyl)-4-oxo-4,5-dihydro-1-thia-3,5,8-triazaacenaphthylene-3-ide, comprising:

[0321] [ka] a) preparing a mixture of tert-butyl (6-isobutyl-4-methylpyridin-3-yl)carbamate with 2,4-dichloro-3-iodopyridine and tetrabutylammonium bromide in toluene; b) preparing a second reaction mixture by adding water and sodium hydroxide to the mixture prepared in step a, and then stirring the second reaction mixture for a time interval of 10 minutes to 10 hours; c) at the end of the time interval from step b, adding water and methyl thioglycolate to the second reaction mixture, followed by stirring for a time interval of 10 minutes to 10 hours to produce a third reaction mixture; d) at the end of the time interval from step c, partitioning the reaction mixture into an aqueous layer and an organic layer; e) adding tetrahydrofuran to the organic layer from step d to form a fourth reaction mixture; f) adding potassium tert-butoxide to the fourth reaction mixture at a time interval of 10 minutes to 10 hours to form a fifth reaction mixture; g) at the end of the time interval from step f, cooling the fifth reaction mixture to a temperature of −5° C. to 15° C., and then filtering to isolate potassium 5-(6-isobutyl-4-methylpyridin-3-yl)-2-(methoxycarbonyl)-4-oxo-4,5-dihydro-1-thia-3,5,8-triazaacenaphthylene-3-ide.

Claims

1. A method of synthesizing a compound of formula (I), comprising the steps of: 【Chemistry 1】 During the ceremony, R １ But, C ５～１０ Aryl and C ４～９ heteroaryl, wherein said aryl or heteroaryl is optionally selected from １～６ substituted with one or more groups independently selected from alkyl; R ２ But, C １～６ Alkyl and C ２～６ alkenyl, compound 【Chemistry 2】 with an acid and a first solvent, and then 【Chemistry 3】 in the presence of one or more coupling reagents, an amine base, and a second solvent to obtain a compound of formula (I).

2. R １ but, 【Chemistry 4】 The method of claim 1, wherein

3. R ２ But, C ２～６ The method according to claim 1 or 2, wherein the alkyl group is alkenyl.

4. 4. The method of claim 1, 2, or 3, wherein Pg is Boc.

5. 5. The method of claim 1, 2, 3, or 4, wherein the acid is methanesulfonic acid.

6. 6. The method of claim 1, 2, 3, 4, or 5, wherein the first solvent is selected from dichloromethane (DCM), ethyl acetate (EtOAc), 2-methyltetrahydrofuran (MeTHF), tetrahydrofuran (THF), and acetonitrile (ACN).

7. 7. The method of any one of claims 1 to 6, wherein the coupling reagent is selected from 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), hydroxybenzotriazole (HOBt), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), propylphosphonic anhydride (T3P), 1,1'-carbonyldiimidazole (CDI), 2-hydroxypyridine-N-oxide (HOPO), and combinations thereof.

8. 8. The method of any one of claims 1 to 7, wherein the amine base is selected from N,N-diisopropylethylamine (DIPEA), triethylamine, tributylamine, N-methylmorpholine, and N-methylpiperidine. In some aspects, the second solvent is selected from dichloromethane, ethyl acetate, 2-methyltetrahydrofuran, tetrahydrofuran, and acetonitrile.

9. 9. The method of any one of claims 1 to 8, wherein the second solvent is selected from dichloromethane (DCM), ethyl acetate (EtOAc), 2-methyltetrahydrofuran (MeTHF), tetrahydrofuran (THF), and acetonitrile (ACN).

10. compound 【Chemistry 5】 with a base and an ammonium salt in a solvent to form the compound 【Chemistry 6】 The method of any one of claims 1 to 9, further comprising forming

11. 11. The method of claim 10, wherein the base is selected from potassium trimethylsilanolate (TMSOK), lithium hydroxide (LiOH), or sodium hydroxide (NaOH).

12. 12. The method of claim 10 or 11, wherein the ammonium salt is selected from tetrabutylammonium bromide (TBAB), tetrabutylammonium hydrogen sulfate, benzyltrimethylammonium bromide, benzyltrimethylammonium chloride, and Aliquat 336.

13. 13. The method of claim 10, 11, or 12, wherein the solvent is tetrahydrofuran.

14. compound 【Chemistry 7】 with a carbonyl source and a solvent to form the compound 【Chemistry 8】 The method of claim 12 , further comprising forming:

15. 15. The method of claim 14, wherein the carbonyl source is selected from N,N'-carbonyldiimidazole (CDI), phosgene, triphosgene, and N,N'-disuccinimidyl carbonate (DSC).

16. compound 【Chemistry 9】 with a sulfur reagent and a base in a solvent to form the compound 【Chemistry 10】 16. The method of claim 14 or 15, further comprising forming:

17. compound 【Chemistry 11】 In a solvent system, a compound R having a base is １ -NH ２ and an amine base to form the compound 【Chemistry 12】 The method of claim 16 , further comprising forming:

18. compound 【Chemistry 13】 with a cyano source and a solvent to form the compound 【Chemistry 14】 The method of claim 17 , further comprising forming:

19. compound 【Chemistry 15】 in a solvent with a base and an electrophilic halogen to produce the compound 【Chemistry 16】 The method of claim 18 , further comprising forming:

20. compound 【Chemistry 17】 The base, 【Chemistry 18】 and a solvent to form the compound 【Chemistry 19】 The method of claim 1 further comprising forming:

21. A method for synthesizing a compound of formula (II), comprising the steps of: 【Chemistry 20】 compound 【Chemistry 21】 with an acid and a first solvent, and then 【Chemical 22】 in the presence of one or more coupling reagents, an amine base, and a second solvent to obtain a compound of formula (II).

22. 22. The method of claim 21 , wherein the acid is methanesulfonic acid.

23. 23. The method of claim 21 or 22, wherein the first solvent is dichloromethane.

24. 24. The method of claim 21, 22, or 23, wherein the coupling reagent is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI).

25. 25. The method of claim 21, 22, 23, or 24, wherein the amine base is N,N-diisopropylethylamine (DIPEA).

26. 25. The method of claim 21, 22, 23, or 24, wherein the second solvent is dichloromethane.

27. compound 【Chemistry 23】 with a base and an ammonium salt in a solvent to form the compound 【Chemistry 24】 The method of any one of claims 21 to 26, further comprising forming

28. compound 【Chemistry 25】 with a carbonyl source and a solvent to form the compound 【Chemistry 26】 30. The method of claim 27, further comprising forming:

29. compound 【Chemical 27】 with a sulfur reagent and a base in a solvent to form the compound 【Chemistry 28】 30. The method of claim 28, further comprising forming:

30. compound ​ In a solvent system, a compound having a base 【Chemistry 30】 and an amine base to form the compound 【Chemistry 31】 30. The method of claim 29, further comprising forming

31. compound 【Chemistry 32】 with a hydride source, a catalyst, and a solvent system to produce the compound 【Chemical 33】 31. The method of claim 30, further comprising forming:

32. compound 【Chemical 34】 with a catalyst, a phosphorus reagent, a boron reagent, a first base, a second base, and a solvent system to produce a compound 【Chemistry 35】 32. The method of claim 31 further comprising forming:

33. compound 【Chemical Formula 36】 with a cyano source and a solvent to form the compound 【Chemical 37】 33. The method of claim 32, further comprising forming:

34. compound 【Chemical 38】 in a solvent with a base and an electrophilic halogen to produce the compound 【Chemical Formula 39】 34. The method of claim 33, further comprising forming:

35. compound 【Chemistry 40】 The base, 【Chemistry 41】 and a solvent to form the compound 【Chemistry 42】 35. The method of claim 34, further comprising forming:

36. 1. A process for isolating the P atropisomer from a mixture of M and P isomers of a compound of formula (II), comprising the steps of: 1) dissolving a compound of formula (II) in one or more solvents in a container to form a solution; 2) adding water to the solution and waiting for a period of about 2 hours to about 24 hours to form a suspension; 3) filtering the suspension to obtain crystals of the compound of formula P-(II); 4) collecting the filtrate and heating the filtrate to a temperature of about 75° C. to about 150° C. for a time period of about 5 minutes to about 1 hour; 5) cooling the filtrate to a temperature of about 20° C. to about 30° C.; 6) repeating steps 3-5 about 20-100 times until the M isomer is converted to the P isomer; 7) collecting the precipitate, washing the precipitate, and drying the precipitate under humid conditions to obtain the compound of formula P-(II).

37. 37. The method of claim 36, wherein the one or more first solvents are selected from the group consisting of isopropanol, propylene carbonate, water, 1-propanol, 1-butanol, 2-butanol, isobutanol, propylene glycol, ethylene glycol, dimethylacetamide (DMA), benzyl alcohol, N-methyl-2-pyrrolidone (NMP), propylene glycol methyl ether, 2-ethoxyethanol, (s)-1,2-butanediol, transcutol, ethylene glycol diacetate, and combinations thereof.

38. 37. The method of claim 36, further comprising heating the solution of step 1 to a temperature of about 75° C. to about 140° C. for a time period of about 8 hours to about 12 hours, cooling the solution to a temperature of about 20° C. to about 30° C., and carrying out step 2.

39. 37. The method of claim 36, further comprising contacting a small number of crystals of the compound of formula P-(II) during step 2.

40. 40. The method of claim 39, further comprising cooling the solution to a temperature of about 5° C. to about 15° C. for a period of about 6 hours to about 12 hours to form a suspension.

41. Crystalline Form B of Formula P-(II) Dihydrate. 【Chemistry 43】

42. 42. The crystalline form B of claim 41, wherein the crystalline form B is characterized by an XRPD pattern having a peak at about 5.599° expressed in degrees 2θ (±0.2).

43. 43. The crystalline form B of claim 42, wherein form B is further characterized by an XRPD pattern having peaks expressed in degrees 2θ (±0.2) at about 20.426°, about 24.665°, about 11.135°, about 26.373°, about 12.134°, about 23.187°, about 19.065°, and about 30.316°. 【Request 44】 【Chemical 44】 and pharma- ceutically acceptable salts thereof.

45.

45. A compound selected from:

46. 1. A process for preparing tert-butyl ((1R,2S)-2-(3-chloropropanamido)cyclopentyl)carbamate, comprising the steps of: 【Chemistry 46】 A process comprising contacting tert-butyl ((1R,2S)-2-aminocyclopentyl)carbamate with 3-chloropropionyl chloride in the presence of a solvent and a base.

47. 1. A process for preparing (E)-2-cyano-3-((6-isobutyl-4-methylpyridin-3-yl)amino)but-2-enethioamide, comprising the steps of: 【Chemistry 47】 A process comprising contacting 2-cyano-3-ethoxybut-2-enethioamide with 6-isobutyl-4-methylpyridin-3-amine in the presence of a solvent.

48. 1. A process for producing 4-((6-isobutyl-4-methylpyridin-3-yl)amino)-2-mercaptonicotinonitrile, comprising the steps of: 【Chemistry 48】 A process comprising contacting 2-cyano-3-((6-isobutyl-4-methylpyridin-3-yl)amino)but-2-enethioamide with N,N-dimethylformamide diethyl acetal in a solvent in the presence of a base, followed by addition of an acid.

49. 1. A process for producing tert-butyl (6-isobutyl-4-methylpyridin-3-yl)carbamate, comprising the steps of: 【Chemistry 49】 A process comprising contacting 6-isobutyl-4-methylpyridin-3-amine with di-tert-butyl decarboxylate in the presence of a solvent system and a salt.

50. 1. A process for producing ethyl (6-isobutyl-4-methylpyridin-3-yl)carbamate, comprising the steps of: 【Chemistry 50】 A process comprising contacting 6-isobutyl-4-methylpyridin-3-amine with diethyl carbonate in the presence of a solvent and a base.

51. Method for producing methyl (6-isobutyl-4-methylpyridin-3-yl)carbamate 【Chemistry 51】

52. It involves contacting 6-isobutyl-4-methylpyridin-3-amine with dimethyl carbonate in the presence of a solvent and a base.

53. 1. A process for preparing sodium 5-(6-isobutyl-4-methylpyridin-3-yl)-2-(methoxycarbonyl)-4-oxo-4,5-dihydro-1-thia-3,5,8-triazaacenaphthylene-3-ide, comprising the steps of: 【Chemistry 52】 a. contacting tert-butyl (6-isobutyl-4-methylpyridin-3-yl)carbamate with 2,4-dichloro-3-iodopyridine and tetrabutylammonium bromide in toluene to form a first reaction mixture; b. contacting the first reaction mixture with water and sodium hydroxide to form a second reaction mixture; c. contacting the second reaction mixture with water and methyl thioglycolate to form a third reaction mixture; d. separating the third reaction mixture into an aqueous layer and an organic layer; e. contacting the organic layer with methanol to form a fourth reaction mixture; f. contacting the fourth reaction mixture with sodium hydroxide to form a fifth reaction mixture and heating the fifth reaction mixture to a temperature between 40° C. and 70° C. for a time interval between 10 minutes and 10 hours; g. cooling the fifth reaction mixture to a temperature between 10° C. and 30° C. and then filtering to isolate sodium 5-(6-isobutyl-4-methylpyridin-3-yl)-2-(methoxycarbonyl)-4-oxo-4,5-dihydro-1-thia-3,5,8-triazaacenaphthylene-3-ide.

54. 1. A process for preparing potassium 5-(6-isobutyl-4-methylpyridin-3-yl)-2-(methoxycarbonyl)-4-oxo-4,5-dihydro-1-thia-3,5,8-triazaacenaphthylene-3-ide, comprising the steps of: 【Chemistry 53】 a) contacting tert-butyl (6-isobutyl-4-methylpyridin-3-yl)carbamate with 2,4-dichloro-3-iodopyridine and tetrabutylammonium bromide in toluene to form a first reaction mixture; b) contacting the first reaction mixture with water and sodium hydroxide to form a second reaction mixture; c) contacting the second reaction mixture with water and methyl thioglycolate to form a third reaction mixture; d) separating the third reaction mixture into an aqueous layer and an organic layer; e) contacting the organic layer with tetrahydrofuran to form a fourth reaction mixture; f) contacting the fourth reaction mixture with potassium tert-butoxide to form a fifth reaction mixture; g) cooling the fifth reaction mixture to a temperature of −5° C. to 15° C. and then filtering to isolate potassium 5-(6-isobutyl-4-methylpyridin-3-yl)-2-(methoxycarbonyl)-4-oxo-4,5-dihydro-1-thia-3,5,8-triazaacenaphthylene-3-ide.

Images