Synthesis of pyruvate kinase activator

Abstract

Methods for preparing pyruvate kinase (PK) activators or salts or hydrates thereof are provided herein. Synthetic methods for preparing pyruvate kinase (PK) activators, or salts or hydrates thereof, are provided herein. Such activators may be prepared using compounds having formula (A-1) and / or formula (B-1). Specific PK activators and various intermediates prepared by and / or used by the synthetic methods described herein are also disclosed.

Description

[Technical Field]

[0001] Related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 525,079, filed on 5 July 2023, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Pyruvate kinase (PK) is a metabolic enzyme that converts phosphoenolpyruvate to pyruvate during glycolysis. There are four PK isoforms in mammals: the L and R isoforms are expressed in the liver and erythrocytes, the M1 isoform is expressed in most adult tissues, and the M2 isoform is a splice variant of M1 that is expressed during embryonic development. The well-known difference between the M1 and M2 isoforms of PK is that M2 is a low-activity enzyme that depends on allosteric activation by the upstream glycolytic intermediate fructose-1,6-bisphosphate (FBP), while M1 is a constitutively active enzyme. PK activators can be used to treat many different diseases, including various types of anemia, such as PKD (pyruvate kinase deficiency), thalassemia (e.g., alpha and beta thalassemia), hereditary ellipticosis, abetalipoproteinemia or Bassen-Kohnzweig syndrome, sickle cell anemia, paroxysmal nocturnal hemoglobinuria, and congenital anemia (e.g., enzyme deficiencies) and hemolytic anemia (e.g., hereditary and / or congenital hemolytic anemia, acquired hemolytic anemia, chronic hemolytic anemia caused by phosphoglycerate kinase deficiency, anemia resulting from MDS (myelodysplastic syndrome), nonspheroidal hemolytic anemia and hereditary spherocytosis). [Overview of the project] [Means for solving the problem]

[0003] A synthetic method for preparing a pyruvate kinase (PK) activator, or a salt or hydrate thereof, is provided herein. Such an activator can be prepared using a compound having formula (A-1) and / or formula (B-1):

[0004]

Chemical formula

[0005] In the formula, X, R , ,

[0010] , , ,

[0009] , ,

[0008] , , , , , , R 4 , and Q are as defined herein.

[0006] Also disclosed are specific PK activators and various intermediates prepared by the synthetic methods described herein and / or used in the synthetic methods.

Brief Description of the Drawings

[0007] [Figure 1] Shows the nuclear magnetic resonance (NMR) spectrum of tert-butyl 2-(6-((6-aminopyridin-2-yl)methyl)-4-methyl-5-oxo-5,6-dihydro-4H-thiazolo[5‘,4‘:4,5]pyrrolo[2,3-d]pyridazin-2-yl)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)acetate. [Figure 2] Shows the nuclear magnetic resonance (NMR) spectrum of 2-chloro-6-formyl-4-methyl-4H-pyrrolo[2,3-d]thiazole-5-carboxylic acid.

Modes for Carrying Out the Invention

[0008] In one embodiment, a compound of formula (A-1):

[0009]

Chemical formula

[0010] or a method for preparing the salt thereof, wherein in the formula, R 1 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with 1 to 3 groups selected from halo, hydroxyl, NH2, and CN. X is a halo, L is a bond or C1-C6 alkylene. Q is a C3-C6 cycloalkyl, a 5-14 member heterocyclyl, a 6-12 member aryl, or a 5-14 member heteroaryl, each of which is optionally substituted with 1-3 groups selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxyl, C1-C6 aminoalkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, CN, and NO2. The method involves the compound of formula (A-2):

[0011] [ka]

[0012] or its salt, Compound of formula (A-3):

[0013] [ka]

[0014] And it will react, A method is provided that includes forming a compound of formula (A-1) or a salt thereof.

[0015] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to the extent of this disclosure. The terms used herein are for illustrative purposes only to describe specific embodiments and are not intended to limit this disclosure.

[0016] The use of any and all example or illustrative language provided herein (e.g., "etc." and "for example") is intended to better describe the Disclosure and is not limited to the scope of the Disclosure unless expressly requested otherwise. The phrases "in one aspect," "in one embodiment," "in some embodiments," "in further embodiments," and similar phrases should not be construed as indicating that such elements occur or exist independently, or that such elements are not shared by other aspects or embodiments of the Disclosure. Rather, it should be understood that all aspects and embodiments may be freely combined with any and all other aspects and embodiments of the Disclosure described herein. The language herein should not be construed as indicating that any unclaimed element is essential for the practice of the Disclosure.

[0017] The term "C1-C6 alkyl" refers to a linear or branched hydrocarbon group having 1 to 6 carbon atoms. Examples of C1-C6 alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C5) (e.g., n-pentyl, 3-pentyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C6) (e.g., n-hexyl).

[0018] The term "C1-C6 alkylene" refers to a divalent radical of a saturated, linear, or branched hydrocarbon. Exemplary alkylene groups include, but are not limited to, C1-C4 alkylenes, C1-C3 alkylenes, C1-C2 alkylenes, and alkylenes corresponding to any of the other exemplary alkyl groups described above.

[0019] When a range of carbon atoms is used herein, for example, C 1~ C6 encompasses all ranges, as well as individual numbers of carbon atoms. For example, "C 1- "C3" is C 1- C3, C 1- C2, C 2- Includes C3, C1, C2, and C3.

[0020] As used herein, the term "C2-C6 alkenyl" refers to a linear or branched group having 2 to 6 carbon atoms in the group and containing at least one carbon-carbon double bond. Examples of C2-C6 alkenyl groups include vinyl (-CH=CH2; C2 alkenyl), allyl (-CH2-CH=CH2; C3 alkenyl), propenyl (-CH=CHCH3; C3 alkenyl), isopropenyl (-C(CH3)=CH2; C3 alkenyl), butenyl (-CH=CHCH2CH3; C4 alkenyl), sec-butenyl (-C(CH3)=CHCH3; C4 alkenyl), iso-butenyl (-CH=C(CH3)2; C4 alkenyl), and 2-butenyl (-CH2CH=CHCH3; C4 alkyl).

[0021] As used herein, the term "C2-C6 alkynyl" refers to a linear or branched group having 2 to 6 carbon atoms in the group and containing at least one carbon-carbon triple bond. Examples of alkynyl groups include ethynyl (-C≡CH; C2 alkynyl), propargyl (-CH2-C≡CH; C3 alkynyl), propynyl (-C≡CCH3; C3 alkynyl), butynyl (-C≡CCH2CH3; C4 alkynyl), and pentynyl (-C≡CCH2CH2CH3; C5 alkynyl).

[0022] The term "C3-C6 cycloalkyl" refers to a non-aromatic hydrocarbon group containing a ring with 3 to 6 carbon atoms. Examples of C3-C6 cycloalkyl groups include cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), and cyclohexyl (C6).

[0023] The term "halo" or "halogen," used by itself or as part of another group, refers to a fluorine, chlorine, bromine, or iodine atom.

[0024] As used herein, the term "C1-C6 haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are substituted with one or more halogen atoms, which may be the same or different. In some embodiments, the alkyl is substituted with at least one halogen. In other embodiments, the alkyl is substituted with one, two, or three F and / or Cl atoms. Examples of haloalkyl groups include fluoromethyl (CH2F), 1-fluoroethyl (CH(CH3)F), 2-fluoroethyl, difluoromethyl (CHF2), trifluoromethyl (CF3), pentafluoroethyl, 1,1-difluoroethyl (C(CH3)F2), 2,2-difluoroethyl (CH2CHF2), 2,2,2-trifluoroethyl (CH2CF3), 2-fluoropropan-2-yl (C(CH3)2F), 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, trichloromethyl, and the like.

[0025] The term “C1-C6 cyanoalkyl” used by itself or as part of another group refers to an alkyl group as defined herein, which is substituted by one or more CNs. In some embodiments, the alkyl group is substituted by at least one CN. In other embodiments, the alkyl group is substituted by one, two, or three CNs. Examples of cyanoalkyl groups include CH2CN, CH2CH2CN, CH(CN)CH3, CH2CH2CH2CN, C(CH3)2CN, CH2CH(CN)CH3, CH(CN)CH2CH3, and the like.

[0026] The term “C1-C6 hydroxyalkyl,” used by itself or as part of another group, refers to an alkyl group as defined herein in which one or more hydrogen atoms are substituted with one or more hydroxyls (i.e., -OH). In some embodiments, the hydroxyalkyl group contains one OH. In other embodiments, the hydroxyalkyl group contains two OH. In further embodiments, the hydroxyalkyl group contains three OH. Examples of hydroxyalkyl groups include hydroxymethyl, hydroxyethyl (e.g., 1-hydroxyethyl, 2-hydroxyethyl), 1,2-dihydroxyethyl, hydroxypropyl (e.g., 2-hydroxypropyl, 3-hydroxypropyl), hydroxybutyl (e.g., 3-hydroxybutyl, 4-hydroxybutyl), 2-hydroxy-1-methylpropyl, 1,3-dihydroxypropyl-2-yl, and the like.

[0027] The term “C1-C6 aminoalkyl,” used by itself or as part of another group, refers to an alkyl group as defined herein, substituted with one or more NH2 groups. In some embodiments, the alkyl group is substituted with at least one NH2 group. In other embodiments, the alkyl group is substituted with one, two, or three NH2 groups. Examples of cyanoalkyl groups include CH2NH2, CH2CH2NH2, CH2CH2CH2NH2, and C(CH3)2NH2.

[0028] The term "6- to 12-membered aryl" refers to monocyclic or bicyclic aromatic hydrocarbon ring structures having six or twelve carbon atoms in the ring. Examples of aryl groups include phenyl, indenyl, naphthyl, and 1,2,3,4-tetrahydronaphthyl.

[0029] The term "5-14 member heteroaryl" refers to monocyclic or bicyclic aromatic ring structures having 5-14 ring atoms including carbon atoms, and up to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Examples of heteroaryl groups include thienyl, benzo[b]thienyl, furanyl, benzofuryl, pyranyl, thiophenyl, isobenzofuranyl, benzoxazonyl, clomenyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridadinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, quinoxalyl, phthalazinyl, naphthylidinyl, cinnolinyl, triazolyl, tetrazolyl, thiadiazolyl Examples include oxadiazolyl, quinazolinil, pteridinil, pyrimidinil, thiazolyl, isothiazolil, oxazolil, isoxazolil, flazanil, pyrazolo[1,5-a]pyridinil, pyrazolo[1,5-a]pyridinil, benzoisothiazolyl, imidazole[1,5-a]pyridinil, pyrrolo[1,2]pyridazinil, benzo[d]thiazolyl, benzo[d]imidazolil, benzo[d]oxazolil, benzoisoxazolil, isothiazolil, and tetrahydropyrazolo[1,5-a]pyridinil.

[0030] In this disclosure, the term “5- to 14-membered heterocycle,” used by itself or as part of another group, refers to a cyclic group comprising 1, 2, or 3 rings having 5 to 14 ring members, which are unaromatically saturated or partially unsaturated and include, for example, one or two double bonds, wherein at least one carbon atom of one of the rings is substituted with a heteroatom. Each heteroatom can be independently selected from oxygen, sulfur (including sulfoxides and sulfones), and / or nitrogen atoms, and can be oxidized or quaternized. Examples of heterocyclyl groups include azetidinyl, dioxanil, tetrahydropyranil, pyrrolidinyl, piperidinyl, morpholinil, piperazinyl, pyrrolidinyl, indolinil, oxetanil, tetrahydrofuranil, tetrahydrothiophenyl, azepanil, azilidinyl, dioxolanil, imidazolidinyl, pyrazolidinyl, thianil, dithianil, thiomorpholinil, oxazepanil, oxyranil, and tetrahydropyranil. In some embodiments, heterocyclyl groups include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinil, and 6-azaspiro[2.5]octanil.

[0031] As used herein, the terms “single salt,” “multiple salts,” or “salt form” refer to the acid-addition or base-addition salt of the described compound. Acid-addition salts can be formed from inorganic and organic acids. Examples of inorganic acids from which salts may be derived include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of organic acids from which salts may be derived include acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, and sulfosalicylic acid. It should be understood that the terms “single salt,” “multiple salts,” or “salt form” refer to all stoichiometry of salts of the described compound, including, for example, bis-salts of the described compound. Examples of such bis-salts include bis-salts such as bis-hydrochloride or bis-hydrobromide, and bis-basic salts such as bis-sodium salt.

[0032] In some examples, a compound may be repeated throughout this description, and different reference numbers may be given simply to facilitate reading. For example, compounds 10A and 10B have the same structure but different reference numbers depending on the scheme in which they appear. In case of any contradiction, the illustrated structure takes precedence over the reference numbers.

[0033] In some embodiments, R in the method for preparing formula (A-1) 1 is C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments, R in the method for preparing formula (A-1) 1 is methyl.

[0034] In some embodiments, X in the method for preparing formula (A-1) is Cl.

[0035] In some embodiments, L in the method for preparing formula (A-1) is C1-C6 alkylene. In some embodiments, L in the method for preparing formula (A-1) is -CH2-.

[0036] In some embodiments, Q in the method for preparing formula (A-1) is a 6- to 12-membered aryl or a 5- to 14-membered heteroaryl, each of which is optionally substituted with 1 to 3 groups selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxyl, C1-C6 aminoalkyl, NH2, -NH(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, and NO2. In some embodiments, Q in the method for preparing formula (A-1) is a 5- to 7-membered heteroaryl substituted with -NH2.

[0037] In some embodiments, the compound of formula (A-1) in the method of the present disclosure is:

[0038]

Chemical formula

[0039] or its salt.

[0040] In some embodiments, the compound of formula (A-2) in the method of the present disclosure is:

[0041] [ka]

[0042] or its salt.

[0043] In some embodiments, the compound of formula (A-2) is a salt. In some embodiments, the compound of formula (A-2) is a bis-salt. In other embodiments, the compound of formula (A-2) is a bis-acid. In other embodiments, the compound of formula (A-2) is a bis-HCl salt.

[0044] Similarly, in some embodiments, the compound of formula (4) is a salt. In some embodiments, the compound of formula (4) is a bis-salt. In other embodiments, the compound of formula (4) is a bis-acid. In other embodiments, the compound of formula (4) is a bis-HCl salt.

[0045] In some embodiments, the compound of formula (A-3) in the method of the present disclosure is:

[0046] [ka]

[0047] or its salt.

[0048] In some embodiments, the compound of formula (A-2) or a salt thereof reacts with the compound of formula (A-3) in the presence of an acid (e.g., hydrochloric acid, acetic acid, phosphoric acid, sulfuric acid, citric acid, formic acid, methanesulfonic acid, or p-toluenesulfonic acid) and one or more solvents (e.g., polar protic solvents such as water, methanol, ethanol, n-propanol, i-propanol, or t-butanol, or any combination thereof). In some embodiments, the compound of formula (A-2) or a salt thereof reacts with the compound of formula (A-3) in the presence of citric acid and one or more solvents (e.g., polar protic solvents such as water, methanol, ethanol, n-propanol, i-propanol, or t-butanol, or any combination thereof). In some embodiments, one or more solvents are alcohols. In some embodiments, the compound of formula (A-2) or a salt thereof reacts with the compound of formula (A-3) in the presence of an acid (e.g., hydrochloric acid, acetic acid, phosphoric acid, sulfuric acid, citric acid, formic acid, methanesulfonic acid, or p-toluenesulfonic acid) and ethanol. In some embodiments, the compound of formula (A-2) or a salt thereof reacts with the compound of formula (A-3) in the presence of an acid (e.g., hydrochloric acid, acetic acid, phosphoric acid, sulfuric acid, citric acid, formic acid, methanesulfonic acid, or p-toluenesulfonic acid) and ethanol, as well as at least one other solvent. In some embodiments, the compound of formula (A-2) or a salt thereof reacts with the compound of formula (A-3) in the presence of citric acid and ethanol. In other embodiments, the compound of formula (A-2) or a salt thereof reacts with the compound of formula (A-3) in the presence of citric acid, as well as a mixture of ethanol and i-propanol (IPA). In other embodiments, the compound of formula (A-2) or a salt thereof reacts with the compound of formula (A-3) in the presence of citric acid and n-propanol. In some embodiments, the compound of formula (4) or a salt thereof reacts with the compound of formula (8A) in the presence of an acid and one or more solvents. In some embodiments, the bis-salt of the compound of formula (4) reacts with the compound of formula (8A) in the presence of an acid and one or more solvents.In some embodiments, the bis-salt of the compound of formula (4) reacts with the compound of formula (8A) in the presence of citric acid or hydrochloric acid and one or more alcoholic solvents. In some embodiments, the bis-HCl salt of the compound of formula (4) reacts with the compound of formula (8A) in the presence of citric acid or hydrochloric acid, as well as one or more of ethanol, isopropyl alcohol, and n-propanol. In other embodiments, the bis-salt of the compound of formula (4) reacts with the compound of formula (8A) in the presence of one or more solvents without the presence of additional acids.

[0049] In one embodiment, the compound of formula (A-3):

[0050] [ka]

[0051] (In the formula, R 1 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with 1 to 3 groups selected from halo, hydroxyl, NH2, and CN. A method for preparing X (where X is a halo), The method is Compound of formula (A-6):

[0052] [ka]

[0053] (In the formula, R 2A method is provided herein that comprises hydrolyzing a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with 1 to 3 groups selected from halo, hydroxyl, NH2, and CN) to form a compound of formula (A-3). In one embodiment, R 2 It is a C1-C6 alkyl group.

[0054] In some embodiments, R in a method for preparing the compound of formula (A-3) 1 is a C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments, R in the compound of formula (A-3) 1 It is methyl.

[0055] In some embodiments, X in the method for preparing the compound of formula (A-3) is Cl or Br. In one embodiment, X in the method for preparing the compound of formula (A-3) is Cl.

[0056] In some embodiments, R in a method for preparing the compound of formula (A-3) 2 It is ethyl.

[0057] In some embodiments, the compound of formula (A-3) in the method of the present disclosure is:

[0058] [ka]

[0059] That is the case.

[0060] In some embodiments, the compound of formula (A-6) in the method of the present disclosure is:

[0061] [ka]

[0062] That is the case.

[0063] In some embodiments, the compound of formula (A-4) in the method of the present disclosure is:

[0064] [ka]

[0065] That is the case.

[0066] In some embodiments, the compounds of formula (A-6) are hydrolyzed in the presence of a base (e.g., lithium hydroxide (LiOH), calcium hydroxide (Ca(OH)2), potassium hydroxide (KOH), sodium hydroxide (NaOH), or barium hydroxide (Ba(OH)2)) and one or more solvents (e.g., a mixture of water and at least one polar aprotic solvent). In some embodiments, the compounds of formula (A-6) are hydrolyzed in the presence of a base (e.g., lithium hydroxide (LiOH), calcium hydroxide (Ca(OH)2), potassium hydroxide (KOH), sodium hydroxide (NaOH), or barium hydroxide (Ba(OH)2)), water, and at least one polar aprotic solvent selected from dimethylacetamide (DMAC), 2-methyltetrahydrofuran (2-Me THF), tetrahydrofuran (THF), acetonitrile (ACN), or dimethyl sulfoxide (DMSO), or any combination thereof. In some embodiments, the compounds of formula (A-6) are hydrolyzed in the presence of sodium hydroxide (NaOH), water, and at least one polar aprotic solvent. In some embodiments, the compounds of formula (A-6) are hydrolyzed in the presence of sodium hydroxide (NaOH), water, and at least one polar aprotic solvent selected from dimethylacetamide (DMAC), 2-methyltetrahydrofuran (2-Me THF), tetrahydrofuran (THF), acetonitrile (ACN), or dimethyl sulfoxide (DMSO), or any combination thereof. In some embodiments, the compounds of formula (A-6) are hydrolyzed in the presence of sodium hydroxide (NaOH), water, and tetrahydrofuran.

[0067] In some embodiments, the compound of formula (A-6) is the compound of formula (A-5),

[0068] [ka]

[0069] The compounds of formula (A-6) are prepared by reacting phosphorus oxychloride (POCl3), dimethylformamide (DMF), and one or more additional solvents (e.g., nonpolar solvents such as dioxane, dichloroethane, benzene, toluene, chlorobenzene, dichlorobenzene, or xylene). In some embodiments, the compounds of formula (A-6) are prepared by reacting the compounds of formula (A-5) with phosphorus oxychloride (POCl3) and dimethylformamide (DMF) in chlorobenzene.

[0070] In some embodiments, the compound of formula (A-5) in the method of the present disclosure is:

[0071] [ka]

[0072] That is the case.

[0073] In some embodiments, the compound of formula (A-5) is the compound of formula (A-4):

[0074] [ka]

[0075] These are prepared by reacting a halogenating agent (e.g., elemental halogens, carbon tetrachloride, hexachloroethane, carbon tetrabromide, n-bromosuccinimide (NBS), or n-chlorosuccinimide (NCS)), a base (e.g., lithium diisopropylamide (LDA), sodium bis(trimethylsilyl)amide (NaHMDS), lithium bis(trimethylsilyl)amide (LiHMDS), potassium bis(trimethylsilyl)amide (KHMDS), and sodium hydride (NaH)) with at least one solvent (e.g., polar aprotic solvents such as dimethylacetamide (DMCA), 2-methyltetrahydrofuran (2-Me THF), tetrahydrofuran (THF), acetone, dimethylformamide (DMF), acetonitrile (ACN), and dimethyl sulfoxide (DMSO), or any combination thereof) to form the compounds of formula (A-5).

[0076] In some embodiments, the compounds of formula (A-5) are prepared by reacting the compounds of formula (A-4) with hexachloroethane, a base (e.g., lithium diisopropylamide (LDA), sodium bis(trimethylsilyl)amide (NaHMDS), lithium bis(trimethylsilyl)amide (LiHMDS), potassium bis(trimethylsilyl)amide (KHMDS), and sodium hydride (NaH)) and at least one solvent (e.g., a polar aprotic solvent) to form the compounds of formula (A-5). In some embodiments, the compound of formula (A-5) is prepared by reacting the compound of formula (A-4) with hexachloroethane, lithium bis(trimethylsilyl)amide (LiHMDS), and at least one solvent (e.g., a polar aprotic solvent) to form the compound of formula (A-5).

[0077] In some embodiments, the compound of formula (A-4) in the method of the present disclosure is:

[0078] [ka]

[0079] That is the case.

[0080] In one embodiment, the compound of formula (B-1):

[0081] [ka]

[0082] During the ceremony, R 1 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with 1 to 3 groups selected from halo, hydroxyl, NH2, and CN. R 4 The group is a C1-C6 alkyl, a C1-C6 haloalkyl, a 6-12 membered aryl, or a 5-14 membered heteroaryl, wherein the 6-12 membered aryl or 5-14 membered heteroaryl is optionally substituted with 1-3 groups selected from halo or C1-C6 alkyl. L is a bond or C1-C6 alkylene. A method for preparing a compound where Q is a C3-C6 cycloalkyl, a 5-14 member heterocyclyl, a 6-12 member aryl, or a 5-14 member heteroaryl, each of which is optionally substituted with 1-3 groups selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxyl, C1-C6 aminoalkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, CN, and NO2, The method is Compound of formula (A-2):

[0083] [ka]

[0084] or its salt, Compound of formula (B-5):

[0085] [ka]

[0086] And it will react, A method comprising forming a compound of formula (B-1) is provided herein.

[0087] In some embodiments, the compound of formula (A-2) or a salt thereof reacts with the compound of formula (B-5) in the presence of an acid (e.g., hydrochloric acid, acetic acid, trifluoroacetic acid, phosphoric acid, sulfuric acid, citric acid, formic acid) and at least one solvent (e.g., a polar protic solvent such as methanol, ethanol, n-propanol, i-propanol, sec-butanol, or t-butanol, or any combination thereof). In some embodiments, the compound of formula (A-2) or a salt thereof reacts with the compound of formula (B-5) in the presence of an acid (e.g., hydrochloric acid, trifluoroacetic acid, acetic acid, phosphoric acid, sulfuric acid, citric acid, formic acid, or carbonic acid) in ethanol or n-propanol or any combination thereof. In some embodiments, the compound of formula (A-2) is a bis salt. In some embodiments, the compound of formula (A-2) is a bis salt. In some embodiments, the compound of formula (A-2) is a bis HCl salt.

[0088] In some embodiments, the compound of formula (B-5) in the method of the present disclosure is the compound of formula (B-4):

[0089] [ka]

[0090] (In the formula, R 2 The C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl is prepared by hydrolysis of the C3-C6 cycloalkyl (which is optionally substituted with 1 to 3 groups selected from halo, hydroxyl, NH2, and CN). In another embodiment, R 2 It is a C1-C6 alkyl group.

[0091] In some embodiments, the compounds of formula (B-4) are hydrolyzed in the presence of a base (e.g., lithium hydroxide (LiOH), calcium hydroxide (Ca(OH)2), potassium hydroxide (KOH), sodium hydroxide (NaOH), or barium hydroxide (Ba(OH)2)) and one or more solvents (e.g., a mixture of water and at least one polar aprotic solvent). In some embodiments, the compounds of formula (B-4) are hydrolyzed in the presence of a base (e.g., lithium hydroxide (LiOH), calcium hydroxide (Ca(OH)2), potassium hydroxide (KOH), sodium hydroxide (NaOH), or barium hydroxide (Ba(OH)2)), water, and at least one polar aprotic solvent selected from dimethylacetamide (DMAC), 2-methyltetrahydrofuran (2-Me THF), tetrahydrofuran (THF), dimethylformamide (DMF), acetonitrile (ACN), or dimethyl sulfoxide (DMSO), or any combination thereof. In some embodiments, the compounds of formula (B-4) are hydrolyzed in the presence of sodium hydroxide (NaOH), water, and at least one polar aprotic solvent. In some embodiments, the compounds of formula (B-4) are hydrolyzed in the presence of sodium hydroxide (NaOH), water, and at least one polar aprotic solvent selected from dimethylacetamide (DMAC), 2-methyltetrahydrofuran (2-Me THF), tetrahydrofuran (THF), dimethylformamide (DMF), acetonitrile (ACN), or dimethyl sulfoxide (DMSO), or any combination thereof. In some embodiments, the compounds of formula (B-4) are hydrolyzed in the presence of sodium hydroxide (NaOH), water, and tetrahydrofuran.

[0092] In some embodiments, the compound of formula (B-4) is the compound of formula (B-3),

[0093] [ka]

[0094] The compounds of formula (B-4) are prepared by reacting an oxidizing agent (e.g., hydrogen peroxide and sodium tungstate (Na2WO4), 39% peracetic acid, trichloroisocyanuric acid (TCCA) and (sodium hypochlorite) NaOCl, oxone, hydrogen peroxide and SeO2, or hydrogen peroxide and MoCl2O2) in at least one solvent (e.g., a nonpolar solvent such as dichloromethane, toluene, chlorobenzene, dichlorobenzene, or xylene, or any combination thereof) to form the compounds of formula (B-4). In some embodiments, the compounds of formula (B-4) are prepared by reacting the compound of formula (B-3) with hydrogen peroxide and sodium tungstate (Na2WO4) in chlorobenzene to form the compounds of formula (B-4). In some embodiments, the compounds of formula (B-4) are prepared by reacting the compounds of formula (B-3) with at least one solvent (a polar solvent such as ethanol, tetrahydrofuran (THF), water, acetic acid, ethyl acetate, or any mixture thereof) with an oxidizing agent selected from 39% peracetic acid, trichloroisocyanuric acid (TCCA) and (sodium hypochlorite) NaOCl, oxone, hydrogen peroxide and SeO2, or hydrogen peroxide and MoCl2O2 to form the compounds of formula (B-4).

[0095] In some embodiments, the method for forming the compound of formula (B-4) further comprises at least one phase transfer catalyst, such as methyltrioctylammonium bisulfate or tetrabutylammonium bisulfate. In some embodiments, the phase transfer catalyst is methyltrioctylammonium bisulfate.

[0096] In some embodiments, the method for forming the compound of formula (B-4) further comprises phenylphosphonic acid and at least one acid, such as acetic acid. In some embodiments, the acid is phenylphosphonic acid.

[0097] In some embodiments, the compound of formula (B-3) is a compound of formula (B-2),

[0098] [ka]

[0099] The compounds of formula (B-3) are prepared by reacting phosphorus oxychloride (POCl3), dimethylformamide (DMF), and one or more solvents, such as nonpolar solvents (e.g., toluene, chlorobenzene, dichlorobenzene, or xylene, or any combination thereof). In some embodiments, the compounds of formula (B-3) are prepared by reacting the compounds of formula (B-2) with phosphorus oxychloride (POCl3) and dimethylformamide (DMF) in chlorobenzene.

[0100] In some embodiments, R in a method for preparing compounds of formula (B-1), formula (B-5), formula (B-4), formula (B-3), and / or formula (B-2) 1 R is a C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments, R is used in methods for preparing compounds of formula (B-1), formula (B-5), formula (B-4), formula (B-3), and / or formula (B-2). 1 It is methyl.

[0101] In some embodiments, R in a method for preparing compounds of formula (B-4), formula (B-3), and / or formula (B-2) 2 It is ethyl.

[0102] In some embodiments, L in the method for preparing the compound of formula (B-1) is a C1-C6 alkylene. In some embodiments, L in the method for preparing the compound of formula (B-1) is -CH2-.

[0103] In some embodiments, Q in the method for preparing the compound of formula (B-1) is a 6- to 12-membered aryl or a 5- to 14-membered heteroaryl, each of which is optionally substituted with 1 to 3 groups selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxyl, C1-C6 aminoalkyl, -NH2, -NH(C1-C6 alkyl), N(C1-C6 alkyl)2, -CN, or -NO2. In some embodiments, Q in the method for preparing the compound of formula (B-1) is a 5- to 7-membered heteroaryl substituted with -NH2.

[0104] In some embodiments, R in the method for preparing compound (B-1) 4 is a C1-C6 alkyl, a C1-C6 haloalkyl, a 6-12 membered aryl, or a 5-14 membered heteroaryl, wherein the 6-12 membered aryl or 5-14 membered heteroaryl is optionally substituted with 1-3 groups selected from halo and C1-C6 alkyl. In some embodiments, R 4 These are 6- to 12-membered aryl groups substituted with C1-C6 alkyl groups.

[0105] In some embodiments, the compound of formula (B-1) in the method of the present disclosure is:

[0106] [ka]

[0107] That is the case.

[0108] In some embodiments, the compound of formula (B-2) in the method of the present disclosure is:

[0109] [ka]

[0110] That is the case.

[0111] In some embodiments, the compound of formula (B-3) in the method of the present disclosure is:

[0112] [ka]

[0113] That is the case.

[0114] In some embodiments, the compound of formula (B-4) in the method of the present disclosure is:

[0115] [ka]

[0116] That is the case.

[0117] In some embodiments, the compound of formula (B-5) in the method of the present disclosure is:

[0118] [ka]

[0119] That is the case.

[0120] In some embodiments, the compound of formula (A-2) or a salt thereof in the method of the present disclosure is

[0121] [ka]

[0122] That is the case.

[0123] In some embodiments, compound 4 is a bis salt. In some embodiments, compound 4 is a bis salt. In some embodiments, compound 4 is a bisHCl salt.

[0124] In one embodiment, the compound of formula (C-1):

[0125] [ka]

[0126] or its salt or hydrate (in the formula, R 1 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with 1 to 3 groups selected from halo, hydroxyl, NH2, and CN. L is a bond or C1-C6 alkylene. A method (C) for preparing a compound (Q) in which Q is a C3-C6 cycloalkyl, a 5-14 member heterocyclyl, a 6-12 member aryl, or a 5-14 member heteroaryl, each of which is optionally substituted with 1-3 groups selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxyl, C1-C6 aminoalkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, CN, and NO2, The method is a) Compound of formula (C-2):

[0127] [ka]

[0128] During the ceremony, P1 is a protecting group, R 3 (is a C1-C6 alkyl group) Compound of formula (C-3):

[0129] [ka]

[0130] During the ceremony, X is Halo or S(O)2R 4 And, R 4 (These are C1-C6 alkyl groups, C1-C6 haloalkyl groups, 6-12 membered aryl groups, or 5-14 membered heteroaryl groups, and the 6-12 membered aryl group or 5-14 membered heteroaryl group is optionally substituted with 1-3 groups selected from halo or C1-C6 alkyl groups) and reacted with Compound of formula (C-4):

[0131] [ka]

[0132] The steps of forming, b) A method is provided which includes the step of deprotecting the compound to form a compound of formula (C-1).

[0133] In some embodiments, L in the method for preparing the compound of formula (C-1) is a C1-C6 alkylene. In some embodiments, L in the method for preparing the compound of formula (C-1) is -CH2-.

[0134] In some embodiments, Q in the method for preparing the compound of formula (C-1) is a 6- to 12-membered aryl or a 5- to 14-membered heteroaryl, each of which is optionally substituted with 1 to 3 groups selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxyl, C1-C6 aminoalkyl, NH2, -NH(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, and NO2. In some embodiments, Q in the method for preparing the compound of formula (C-1) is a 5- to 7-membered heteroaryl substituted with -NH2.

[0135] In some embodiments, the compound of formula (C-1) prepared according to the method described above is:

[0136] [ka]

[0137] That is the case.

[0138] In some embodiments, the compound of formula (C-1) can be isolated in the form of a free base or a salt. In some embodiments, the compound of formula (C-1) is compound:

[0139] [ka]

[0140] It can be isolated as a free base or salt.

[0141] In some embodiments, X in the method for preparing the compound of formula (C-1) is Cl. In some embodiments, the compound of formula (C-3) is the compound of formula (A-1). In other embodiments, the compound of formula (C-3) is the compound of formula (A-1), and the compound of formula (A-1) is prepared by the method of the present disclosure.

[0142] In some embodiments, X in a method for preparing the compound of formula (C-1) is S(O)2R 4 And R 4 X is a 6-12 membered aryl group, and the 6-12 membered aryl group is optionally substituted with 1-3 groups selected from halo and C1-C6 alkyl groups. In some embodiments, X in a method for preparing the compound of formula (C-1) is S(O)2R 4 And R 4 is 4-methylbenzene. In some embodiments, the compound of formula (C-3) is the compound of formula (B-1). In other embodiments, the compound of formula (C-3) is the compound of formula (B-1), and the compound of formula (B-1) is prepared by the method of the present disclosure.

[0143] In some embodiments, the compound of formula (C-3) in the method of the present disclosure is:

[0144] [ka]

[0145] That is the case.

[0146] In some embodiments, the compound of formula (C-3) in the method of the present disclosure is:

[0147] [ka]

[0148] That is the case.

[0149] In some embodiments, P1 in a method for preparing the compound of formula (C-1) is t-butyloxycarbonyl (BOC), fluorenylmethyloxycarbonyl (FMOC), acetate, benzyl, trityl, tetrahydropyranyl ether (THP), pivaloyl, or tosylate. In some embodiments, P1 is tetrahydropyranyl ether (THP).

[0150] In some embodiments, R in a method for preparing the compound of formula (C-1) 3 It is t-butyl.

[0151] In some embodiments, the compound of formula (C-2) is:

[0152] [ka]

[0153] That is the case.

[0154] In some embodiments, the compound of formula (C-4) is:

[0155] [ka]

[0156] That is the case.

[0157] In some embodiments, the compound of formula (C-2) reacts with the compound of formula (C-3) in the presence of a base (e.g., lithium bis(trimethylsilyl)amide (LiHMDS), lithium t-butoxide (LiOtBu), sodium t-butoxide (NaOtBu), potassium t-butoxide (KOtBu), or sodium hydride (NaH)) and one or more solvents (e.g., polar aprotic solvents such as tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), acetone, dimethylformamide (DMF), dimethylacetamide (DMA), acetonitrile (ACN), or dimethyl sulfoxide (DMSO), or any combination thereof). In some embodiments, the compound of formula (C-2) reacts with the compound of formula (C-3) in the presence of lithium bis(trimethylsilyl)amide (LiHMDS) and one or more solvents (e.g., polar aprotic solvents such as tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), acetone, dimethylformamide (DMF), dimethylacetamide (DMA), acetonitrile (ACN), or dimethyl sulfoxide (DMSO), or any combination thereof). In some embodiments, the compound of formula (C-2) reacts with the compound of formula (C-3) in the presence of lithium t-butoxide (LiOtBu) and one or more solvents (e.g., polar aprotic solvents such as tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), acetone, dimethylformamide (DMF), dimethylacetamide (DMA), acetonitrile (ACN), or dimethyl sulfoxide (DMSO), or any combination thereof). In some embodiments, the compound of formula (C-2) reacts with the compound of formula (C-3) in the presence of lithium bis(trimethylsilyl)amide (LiHMDS) and tetrahydrofuran (THF). In some embodiments, the compound of formula (C-2) reacts with the compound of formula (C-3) in the presence of lithium t-butoxide (LiOtBu) and 2-methyltetrahydrofuran (2-MeTHF), and dimethylacetamide (DMA) and acetonitrile (ACN).

[0158] In some embodiments, the compound of formula (C-4) is deprotected in the presence of an acid (e.g., hydrochloric acid, acetic acid, phosphoric acid, sulfuric acid, citric acid, trifluoroacetic acid, formic acid) and one or more solvents (e.g., polar protic solvents such as water, methanol, ethanol, n-propanol, i-propanol, or t-butanol, or any combination thereof) to provide the compound of formula (C-1). In some embodiments, the compound of formula (C-4) is deprotected in the presence of hydrochloric acid and one or more solvents (e.g., polar protic solvents such as water, methanol, ethanol, n-propanol, i-propanol, or t-butanol, or any combination thereof). In some embodiments, the compound of formula (C-4) is deprotected in the presence of an acid (e.g., hydrochloric acid, acetic acid, phosphoric acid, sulfuric acid, citric acid, formic acid) and n-propanol. In some embodiments, the compound of formula (C-4) is deprotected in the presence of hydrochloric acid and n-propanol.

[0159] In some embodiments, the compound of formula (C-1) prepared according to the method disclosed above is:

[0160] [ka]

[0161] or its salts, tautomers, or hydrates.

[0162] In one embodiment, a compound having the following structure:

[0163] [ka]

[0164] Salts, tautomers, or hydrates thereof are provided herein.

[0165] In one embodiment, a compound having the following structure:

[0166] [ka]

[0167] Salts, tautomers, or hydrates thereof are provided herein.

[0168] In one embodiment, a compound having the following structure:

[0169] [ka]

[0170] Salts, tautomers, or hydrates thereof are provided herein.

[0171] In one embodiment, the compound has the following structure:

[0172] [ka]

[0173] Salts, tautomers, or hydrates thereof are provided herein.

[0174] In one embodiment, a compound having the following structure:

[0175] [ka]

[0176] Salts, tautomers, or hydrates thereof are provided herein.

[0177] In one embodiment, a compound having the following structure:

[0178] [ka]

[0179] Salts, tautomers, or hydrates thereof are provided herein.

[0180] In one embodiment, a compound having the following structure:

[0181] [ka]

[0182] Salts, tautomers, or hydrates thereof are provided herein.

[0183] In one embodiment, a bis-acid compound having the following structure: [ka]

[0184] Or tautomers or hydrates thereof are provided herein. [Examples]

[0185] Examples While several embodiments are described, the scope of this disclosure is defined by the appended claims and not by the specific embodiments shown as examples. All references cited throughout this application (including references to literature, published patents, published patent applications, and concurrently pending patent applications) are expressly incorporated herein by reference in their entirety. Unless otherwise defined, all technical and scientific terms used herein are given meanings generally known to those skilled in the art.

[0186] The following are some of the typical abbreviations used.

[0187] [Table 1-1] [Table 1-2]

[0188] [ka]

[0189] Synthesis of tert-butyl(E)-2-((6-((tert-butoxycarbonyl)amino)pyridine-2-yl)methylene)hydrazine-1-carboxylate(2):

[0190] [ka]

[0191] (1) AcOH (0.05 vol, 0.2 equivalents) was added to a room temperature mixture of (1 wt) and MeOH (2 vol). The mixture was heated to 50°C, and then a methanol solution of Boc-hydrazine (0.61 wt) (1 vol) was added over 2.5 hours. The mixture was stirred at 50°C until the reaction was complete. The mixture was cooled to 20°C, water (1.5 vol) was added over 1 hour, stirred for a further 4 hours, and filtered. The wet cake was washed with a 2:1 MeOH:water (1.5 vol), dried under vacuum at 40°C for 20 hours, and (2) was recovered as a slightly yellowish-white solid.

[0192] Synthesis of tert-butyl 2-((6-((tert-butoxycarbonyl)amino)pyridine-2-yl)methyl)hydrazine-1-carboxylate (3):

[0193] [ka]

[0194] The mixture of (2) (1 wt) in MeOH (8 vol) at 25 °C was evacuated and flushed three times with nitrogen. 10% Pd / C (0.04 wt) was added, the reactor was evacuated, and flushed three times with hydrogen. The mixture was heated to 50 °C, the pressure was adjusted to 15 - 20 psi, and stirred for 6 - 12 hours. Upon completion, the reaction mixture was cooled to 20 °C, evacuated, and flushed three times with nitrogen. The mixture was quickly filtered through celite (0.6 wt), and the solids were rinsed with MeOH (1 wt). The filtrate was added to the reactor at 25 °C. Water (7.5 vol) was added dropwise over 2 hours to induce precipitation. The suspension was stirred for 3 hours, filtered, washed with 4:3 MeOH:water (1 vol), and dried under vacuum at 50 °C for 24 hours to obtain (3) as a slightly yellowish - white solid.

[0195] Synthesis of 6 - (hydrazinylmethyl)pyridin - 2 - amine dihydrochloride (4):

[0196]

Chemical formula

[0197] (3) (1.0 wt) was added portionwise to a reactor containing HCl (6N, 5 vol) while maintaining the internal temperature at 10 - 20 °C. The mixture was heated to 50 °C over 2 hours (or until completion), cooled to 20 °C, treated with EtOH (10 vol) over 2 hours to induce precipitation, and held for an additional 2 hours. The suspension was filtered, washed with EtOH (2 vol), and dried under vacuum at 50 °C for 24 hours to obtain (4) as a white solid.

[0198] Synthesis of ethyl 4 - methyl - 4H - pyrrolo[2,3 - d]thiazole - 5 - carboxylate (5A):

[0199]

Chemical formula

[0200]

Chemical formula

[0201] Commercially available 2,4-thiazolidinedione is aromatized and brominated through treatment with phosphorus pentoxide and TBAB in a manner similar to that reported by Sampson (see Grubb, M.; Schmidt, MJ; Seed, AJ; Sampson, P. Synthesis 2012, 44, 1026-1029) to produce 2,4-dibromothiazole. To produce compound (6-1), formylation of 2,4-dibromothiazole at the 5-position is achieved via deprotonation with lithium-tetramethylpiperiden (TMP) and introduction of a formyl group from ethyl formate. The formyl group is reacted with readily available N-benzoylglycine (hippuric acid) and acetic anhydride in an Erlenmeyer-Plochl type reaction, followed by esterification under treatment with ethanol (see Zhao, H. Koenig SG Dankwardt, JW Singh, SP OPRD 18(1):198-204, 2013). Removal of bromine at the 2-thiazole position is achieved by treatment with zinc metal to provide (6-2). Cyclization of (6-2) is carried out under copper-catalyzed amidation, and benzoyl is removed by treatment with ethylenediamine. The final step of N-methylation is carried out in acetone through treatment with dimethyl sulfate to obtain compound (5A).

[0202] Synthesis of ethyl 2-chloro-4-methyl-4H-pyrrolo[2,3-d]thiazole-5-carboxylate (6A):

[0203] [ka]

[0204] Hexachloroethane (1.35 wt) was added to a reactor containing (5A) (1 wt) and THF (10 vol) at 10°C. The mixture was cooled to -40°C, and LiHMDS (1.0 M, 4.5 wt) was added dropwise over 1 hour, while stirring for a further 2 hours, maintaining the temperature between -30 and -50°C. Once complete, AcOH (0.66 wt) was added over 30 minutes at -40°C, and the mixture was then heated to 25°C over 1 hour. Water (5 vol) was added over 2 hours at 25°C. The layers were separated. The organic layer was washed with 5% Na2SO4 (5 wt), concentrated to 2.5 vol under vacuum, and DCM (6.65 wt) was added. After stirring for 20 minutes, the mixture was allowed to stand and the layers were separated. The organic layer was concentrated to 2.5 vol at 30°C under vacuum. Acetone (3.85 wt) was added, and the mixture was concentrated again to 2.5 vol (2×). Acetone (2.5 vol) was added, and the mixture was transferred dropwise to water (5.0 vol) at 5°C over 2 hours. The suspension was stirred at 5°C for up to 10 hours, filtered, and washed with a 4:3 water:acetone (4.5 vol) mixture at 5°C. The wet cake was dried under vacuum at 25°C for 24 hours to obtain (6A) as a yellow solid.

[0205] Synthesis of ethyl 2-chloro-6-formyl-4-methyl-4H-pyrrolo[2,3-d]thiazole-5-carboxylate (7A):

[0206] [ka]

[0207] POCl3 (2.5 wt) was added to a reactor containing (6A) (1 wt) and 1,2-dichlorobenzene (2.6 wt) at 25°C. The mixture was heated to 100°C, then DMF (0.90 wt) was added over 12 hours, and the mixture was stirred at 100°C for 6 hours, or until complete. Once complete, the reaction was cooled to 50°C, and DMF (5.25 wt) was added over 1 hour. This mixture was added to a cooled (10-20°C) solution of EtOH (9.5 wt) and water (6.0 wt), maintaining the temperature below 30°C during the addition. The resulting suspension was stirred at 15-30°C for 20 hours and filtered. The wet cake was washed with 1:1 v:v EtOH:H2O (2.0 vol). The wet cake was slurryed with 1:1 EtOH:H2O (5 vol) at 50°C for 2 hours, cooled to 20°C, filtered, rinsed with 4:3 H2O:EtOH (3.8 vol), and dried under vacuum at 50°C for 24 hours to obtain (7A) as a light brown solid.

[0208] Synthesis of 2-chloro-6-formyl-4-methyl-4H-pyrrolo[2,3-d]thiazole-5-carboxylic acid (8A):

[0209] [ka]

[0210] In a reactor containing (7A) (1 wt), THF (5 vol), and water (5 vol) at 15°C, NaOH (5% w / w, 5.0 vol, 1.5 equivalents) was added dropwise over 30 minutes while maintaining the temperature below 30°C. After the addition, the mixture was stirred at 20-30°C for 4 hours, or until complete. Once complete, HCl (1N) was added at 15°C until the pH reached 1-2, thereby inducing precipitation. The suspension was filtered, washed with water (8 vol), and the wet cake was dried under vacuum at 55°C for 24 hours to obtain (8A) as a brown solid (see Figure 2).

[0211] Synthesis of 6-((6-aminopyridin-2-yl)methyl)-2-chloro-4-methyl-4,6-dihydro-5H-thiazolo[5’,4’:4,5]pyrrolo[2,3-d]pyridazin-5-one (9A):

[0212]

Chem.

[0213] Sodium citrate monobasic acid (1.75 wt) and citric anhydride (0.39 wt) were added to a reactor containing (4) (0.95 wt) in EtOH (20 vol) at 20 °C, and the mixture was stirred for 30 minutes. Compound (8A) (1.0 wt) was added, and the mixture was heated to 75 °C for a maximum of 10 hours (or until completion by IPC), then cooled to 10 °C and stirred for 10 hours. The suspension was filtered, and the wet cake was washed with cold EtOH (2.0 vol). [Note: If necessary, the following procedure may be repeated to improve purity. The wet cake was transferred to a reactor containing water (25 vol), mixed at 20 °C, and treated dropwise with ammonium hydroxide (25 wt%) until the pH of the solution reached 8 - 9. The basified mixture was stirred at 20 °C for a maximum of 8 hours, filtered, and the wet cake was washed with water (4 vol).] When the desired purity was obtained, the wet cake was dried under vacuum at 50 - 60 °C for 24 hours to produce (9A) as a light brown solid.

[0214]

Chem.

[0215] Synthesis of 2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)acetic acid (11):

[0216]

Chem.

[0217] A reactor containing (10) (1.0 wt), TsOH-H2O (0.12 wt), and 2-MeTHF (8.0 vol) was heated to 60°C at 25°C. DHP (1.2 wt) was added dropwise at 60°C, and the mixture was stirred at 60°C for 4 hours. Upon complete conversion, the mixture was cooled to 25°C, MTBE (3.75 wt) was added, and the reaction mixture was cooled to 10°C. NaOH (1N, 8.0 wt) was added dropwise at 10°C, and the mixture was then heated to 20°C. The layers were separated. DCM (5.0 vol) was added to the aqueous layer. The two-phase mixture was cooled to 10°C and treated with HCl (2N) for 1 hour until the pH was 3-4. After mixing at 20°C for 1 hour, the two layers were separated, and the organic layer was secured. The aqueous layer was re-extracted at least three more times with DCM (5.0 vol). The combined organic layers were washed with water (3.0 vol) and concentrated to 2.5 vol under vacuum in the reactor. Depositphotos (10 vol) was added, and the mixture was concentrated to 2.5 vol. An additional Depositphotos (5.0 vol) was added, and the mixture was concentrated again to 2.5 vol. The concentrate was heated to 55°C to produce a solution, cooled to 35°C, and seed (0.010 wt) was added. The mixture was stirred at 35°C for 3 hours, cooled to 0°C over 8 hours, and held at this temperature for 8 hours. The suspension was filtered, washed with cold Depositphotos (0.5 vol), and dried under vacuum at 35°C for 25 hours to obtain (11) as a slightly yellowish-white solid.

[0218] Synthesis of tert-butyl 2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-yl)acetate (12):

[0219] [ka]

[0220] (11) DMAP (0.03 wt) and THF (2.5 vol) were added to a reactor containing (1.0 wt) and t-BuOH (2.5 vol) at 25°C. After 30 minutes, the mixture was heated to 50°C, and then a solution of Boc2O (1.15 wt) in THF (2.0 vol) was added dropwise over at least 5 hours, followed by stirring for a maximum of 2 hours. Upon completion, the reaction mixture was cooled to 25°C, and both heptane (5.0 vol) and water (5.0 vol) were added. The mixture was stirred at 25°C for 2 hours, and then the layers were separated. The organic layer was concentrated to 2 vol under vacuum. Heptane (10 vol) was added, and the mixture was concentrated again to 2 vol. Additional heptane (10 vol) was added, and the diluted mixture was circulated through a charcoal filter for 24 hours. The filtrate was concentrated to 2 vol, 2-MeTHF (6.3 vol) was added, and this cycle was repeated at least two more times. This solution from (12) was used in the next step without further processing.

[0221] Synthesis of tert-butyl 2-(6-((6-aminopyridine-2-yl)methyl)-4-methyl-5-oxo-5,6-dihydro-4H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-2-yl)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-yl)acetate (10A):

[0222] [ka]

[0223] To a reactor containing (9A) (1.0 wt, 1.0 equivalent) and THF (13 vol), (12) (1.1 equivalents) of 2-MeTHF solution and more THF (2.8 vol) were added. The mixture was cooled to -25°C and LiHMDS (1.0 M, 7.0 wt, 2.5 equivalents in THF) was added dropwise over at least 1 hour. The mixture was stirred at -25°C for 3 hours, then heated to -10°C and stirred at -10°C for 3 hours. At completion, AcOH (0.98 wt) in 2-MeTHF (2.0 vol) was added dropwise at -10°C until the pH was 7-8. The mixture was stirred at -10°C for 2 hours, then heated to 10°C over 1 hour, water (8 vol) was added, and then it was further heated to 20°C and maintained for 1 hour. The reaction mixture was filtered over Celite (1.2 wt), and the Celite bed was washed with THF (2.0 vol). The two-phase mixture was separated, the organic layer was washed with 10% Na2SO4 (5 vol), and then concentrated to 4 vol under vacuum. Toluene (5.4 vol) was added, and the mixture was concentrated to 4 vol, and this procedure was repeated at least once (KF < 0.5%). Toluene (7.0 vol) was added, and the mixture was heated to 60°C to dissolve all solids. The reaction mixture was cooled to 43°C, seed (0.05 wt) was added, and the dilute suspension was stirred at 43°C for 8 hours, and then heptane (10 vol) was added dropwise over 8 hours. The suspension was cooled to 33°C, held for 24 hours, and then filtered. The wet cake was washed with heptane (2.0 vol) and then dried under vacuum at 40°C for 24 hours to produce (10A) as a brown solid (see Figure 1).

[0224] Synthesis of 2-((1H-pyrazole-3-yl)methyl)-6-((6-aminopyridine-2-yl)methyl)-4-methyl-4,6-dihydro-5H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazine-5-one hydrate (14):

[0225] [ka]

[0226] To a reactor containing (10A) (1.0 wt) and n-PrOH (10 vol) at 25°C, concentrated HCl (3.0 vol, 20 equivalents) was added over at least 30 minutes, and the mixture was then heated to 75°C and stirred for at least 1 hour (or until the reaction was complete). The reaction mixture was then cooled to 25°C over 2 hours. Isopropyl acetate (20 vol) was added, and the suspension was stirred at 25°C for 4 hours, then filtered. The wet cake was washed with IPAc (3.0 vol), transferred to another reactor, dissolved in water (20 vol), and heated to 35°C. Ammonium hydroxide (25 wt%) was added until the pH of the solution was 3-4. Seed (0.005 wt) was added, and after 2 hours at 35°C, more ammonium hydroxide (25 wt%) was added over 2 hours until the pH was 8-9. After 4 hours, the suspension was filtered, the wet cake was washed with water (4.0 vol), and transferred to the reactor. n-propanol (13 vol) and water (2.5 vol) were added to the wet cake, and the suspension was heated to 80°C. Once total dissolution was achieved, the solution was cooled to 65°C, and seed (0.005 wt) was added. The dilute suspension was stirred at 65°C for 2 hours, cooled to 20°C over at least 3 hours, held for 2 hours, filtered, and washed with n-propanol / heptane (0.1 vol:1 vol), then heptane (2 vol). The wet cake was dried under vacuum at 30°C for 10 hours to obtain (14).

[0227] Synthesis of 2-((1H-pyrazole-3-yl)methyl)-6-((6-aminopyridine-2-yl)methyl)-4-methyl-4,6-dihydro-5H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazine-5-on phosphate (15):

[0228] [ka]

[0229] All solvents were degassed by foaming with nitrogen to remove oxygen. (14)(1.0 wt) was added at 25°C to a reactor containing DMSO (8.0 vol) and phosphoric acid (85%, 0.31 wt). The mixture was heated to 55°C, filtered by polishing into a reactor at 50°C, and then rinsed with 1.0 vol of DMSO. A 1 / 7.2 / 1.8 DMSO / EtOH / H2O mixture (1.3 wt) was added to the solution at 50°C under nitrogen. Seed (0.010 wt) was added, and the dilute suspension was stirred at 50°C for 5 hours. A larger amount of the 1 / 7.2 / 1.8 DMSO / EtOH / H2O mixture (20 wt) was added over at least 4 hours, then the suspension was cooled to 25°C over 3 hours and held at 25°C for 7 hours. The suspension was wet-milled at 25°C for at least 2 hours, filtered, and rinsed at least three times with 2.5 / 4 / 1 DMSO / EtOH / H2O (2 volumes), then with 4 / 1 EtOH / H2O (2 volumes), until DMSO < 4000 ppm. The wet cake was dried under vacuum at 50°C for 20 hours to obtain (15) as a slightly yellowish-white solid.

[0230] Route B:

[0231] [ka]

[0232] Synthesis of tert-butyl(E)-2-((6-((tert-butoxycarbonyl)amino)pyridine-2-yl)methylene)hydrazine-1-carboxylate(2):

[0233] [ka]

[0234] (1) AcOH (0.05 vol, 0.2 equivalents) was added to a room temperature mixture of (1 wt) and MeOH (2 vol). The mixture was heated to 50°C, and then a methanol solution of Boc-hydrazine (1 vol) (0.62 wt) was added over 2.5 hours. The mixture was stirred at 50°C for at least 2 hours (or until IPC indicated that the reaction was complete). The mixture was filled with water (3.5 vol) over 2 hours, cooled to 20°C over 7 hours, and filtered. The wet cake was washed with 2:1 MeOH:water (1.5 vol) and dried under vacuum at 60°C for 20 hours to recover (2) as a slightly yellowish-white solid.

[0235] Synthesis of tert-butyl 2-((6-((tert-butoxycarbonyl)amino)pyridine-2-yl)methyl)hydrazine-1-carboxylate (3):

[0236] [ka]

[0237] The mixture of (2) (1 wt) in MeOH (8 vol) at 25°C was discharged and flushed three times with nitrogen. 10% Pd / C (0.04 wt) was added, the reactor was evacuated, and flushed three times with hydrogen. The mixture was heated to 50°C, the pressure was adjusted to 15-20 psi, and stirred for at least 6 hours. Once complete, the reactants were cooled to 20°C, evacuated, and flushed three times with nitrogen. The mixture was rapidly filtered over Celite (0.6 wt), and the solids were rinsed with MeOH (2 vol). The filtrate was added to the reactor at 25°C. Water (7.5 vol) was added dropwise over 2 hours to induce precipitation. The suspension was stirred for 12 hours, filtered, washed with 4:3 MeOH:water (1 vol), and dried under vacuum at 50°C for 24 hours to obtain (3) as a slightly yellowish-white solid.

[0238] Synthesis of 6-(hydrazineylmethyl)pyridine-2-amine (4):

[0239] [ka]

[0240] In a reactor containing HCl (6N, 5 vol) at 15°C, (3) (1.0 wt) was added in small amounts while maintaining the internal temperature at 10-20°C. The mixture was heated to 50°C for 2 hours (or until complete), cooled to 20°C, treated with EtOH (10 vol) for 2 hours to induce precipitation, and held for a further 2 hours. The suspension was filtered, washed with EtOH (2 vol), and dried under vacuum at 50°C for 20 hours to obtain (4) as a white solid.

[0241] Synthesis of ethyl 6-formyl-4-methyl-2-(p-tolylthio)-4H-pyrrolo[2,3-d]thiazole-5-carboxylate (6B):

[0242] [ka]

[0243] A reactor at 25°C was filled with (5B) (1 wt), chlorobenzene (3.5 vol), and POCl3 (1.12 vol, 4.0 equivalents) and heated to 100°C. DMF (0.70 vol, 3.0 equivalents) was added dropwise over at least 4 hours, and the reactor was maintained at 100°C for at least another 4 hours (or longer if necessary) to complete the reaction. The temperature was reduced to 20°C, and the mixture was added over 6 hours to another reactor containing 5% Na2SO4 (10 vol) at 5°C. SiO2 (5.0 vol) was added, and the two-phase mixture was stirred at 20°C for 2 hours to separate the layers. The organic phase was gradually neutralized to pH 7-9 by adding NaHCO3 (approximately 5 vol) at 20°C. The organic phase was separated, washed with water (5 vol), and then circulated through a charcoal filter at 25°C for 15 hours. The filtrate was concentrated to 3V under vacuum, heated to 40°C, filled with heptane (5.0 vol) over 3 hours, and then filled with seed (0.005 wt). The dilute suspension was held at 40°C for 3 hours, and then an additional heptane (3.0 vol) was added over 3 hours at 40°C. The suspension was gradually cooled to 0°C over 5 hours, held at 0°C for 9 hours, and filtered. The wet cake was washed and rinsed with heptane (4.5 vol), dried under vacuum at 50°C for at least 18 hours to provide (6B) as a pale yellow solid.

[0244] Synthesis of ethyl 6-formyl-4-methyl-2-tosyl-4H-pyrrolo[2,3-d]thiazole-5-carboxylate (7B):

[0245] [ka]

[0246] The reactor was packed with (6B) (1 wt), chlorobenzene (16 vol), sodium tungstate dihydrate (0.046 wt, 0.05 equivalent), phenylphosphonic acid (0.022 wt, 0.05 equivalent), and methyltrioctylammonium bisulfate (0.065 wt, 0.05 equivalent). The mixture was stirred and cooled to 5°C. Hydrogen peroxide (30%, 0.79 wt, 2.5 equivalent) was added dropwise at 5°C over 2 hours, and the reaction was then heated to 35°C and held for at least 4 hours (or until complete). The reaction was cooled to 20°C and treated with 10% Na2SO3 (10 vol) over 2 hours at 20°C. The two-phase mixture was stirred at 20°C for 2 hours to separate the layers. The organic layer was stirred with water (5 vol) for 1 hour, the organic layer was heated to 40°C, and heptane (16 vol) was added dropwise over 4 hours. The mixture was held for 2 hours, cooled to 0°C over 4 hours, held for 6 hours, and then filtered. The wet cake was rinsed with heptane (3 vol) at 0°C and dried under vacuum at 45°C for at least 24 hours to provide (7B) as a slightly yellowish-white solid.

[0247] Synthesis of 6-formyl-4-methyl-2-tosyl-4H-pyrrolo[2,3-d]thiazole-5-carboxylic acid (8B):

[0248] [ka]

[0249] (7B) (1 wt) and THF (10 vol) were added to a reactor at 10°C with an aqueous LiOH solution (14%, 2.3 vol, 3.0 equivalents) over 2 hours. The mixture was stirred at 20°C for at least 8 hours (or until the reaction was complete). The reaction mixture was cooled to 10°C and an aqueous HCl solution (2N) was added until the pH was 1-2. The reaction mixture was heated to 20°C and stirred for 2 hours, water (10 vol) was added, and the suspension was stirred for 7 hours. The suspension was filtered, washed with water (6.0 vol), and dried under vacuum at 55°C for 24 hours to provide (8B) as a yellow solid.

[0250] Synthesis of 6-((6-aminopyridine-2-yl)methyl)-4-methyl-2-tosyl-4,6-dihydro-5H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5-one (9B):

[0251] [ka]

[0252] To a reactor containing (8B) (1.0 wt) in EtOH (12 vol) at 20°C, (4) (1.1 equivalents), EtOH (7 vol) and i-PrOH (1 vol) were added. Sodium citrate monobasic acid (1.18 wt) and citric acid (anhydrous, 0.26 wt) were added, and the mixture was heated to 75°C and stirred for at least 40 hours (or longer, until the reaction was complete). The reaction mixture was cooled to 20°C over 4 hours and filtered. The wet cake was washed with ethanol (4.0 vol), then returned to the reactor and dissolved in water (25 vol) at 20°C. Ammonium hydroxide (25%, approximately 1.2 vol) was added over 30 minutes to adjust the pH to 8-9. The suspension was stirred at 20°C for 8 hours, then filtered, washed with water (4.0 vol), and dried under vacuum at 55°C for 24 hours to produce (9B) as a slightly yellowish-white solid.

[0253] [ka]

[0254] Synthesis of tert-butyl 2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-yl)acetate (12):

[0255] [ka]

[0256] (11) DMAP (0.03 wt) and THF (2.5 vol) were added to a reactor containing (1.0 wt) and t-BuOH (2.5 vol) at 25°C. After 30 minutes, the mixture was heated to 50°C, and then a solution of Boc2O (1.15 wt) in THF (2.0 vol) was added dropwise over at least 5 hours, followed by stirring for a maximum of 2 hours. Upon completion, the reaction mixture was cooled to 25°C, and both heptane (5.0 vol) and water (5.0 vol) were added. The mixture was stirred at 25°C for 2 hours, and then the layers were separated. The organic layer was concentrated to 2 vol under vacuum. Heptane (10 vol) was added, and the mixture was concentrated again to 2 vol. Additional heptane (10 vol) was added, and the diluted mixture was circulated through a charcoal filter for 24 hours. The filtrate was concentrated to 2 vol, 2-MeTHF (6.3 vol) was added, and this cycle was repeated at least two more times. This solution from (12) was used in the next step without further processing.

[0257] Alternative synthesis of tert-butyl 2-(6-((6-aminopyridine-2-yl)methyl)-4-methyl-5-oxo-5,6-dihydro-4H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-2-yl)-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-yl)acetate (10B):

[0258] [ka]

[0259] The reactor was filled with (9B) (1.0 wt, 1.0 equivalent), DMAc (5.0 vol), and (12) solution (1.1 equivalent) in 2-MeTHF. After mixing at 25°C, the reaction mixture was cooled to 0°C and filled with lithium tert-butoxide (1 M in THF, 6.5 vol, 3.0 equivalents) dropwise over 2 hours under nitrogen. The mixture was stirred at 0°C for 4 hours. If necessary, additional lithium tert-butoxide solution (0.6 wt) was added and the mixture was stirred at 0°C for 4 hours. Once complete, aqueous acetic acid (6%, approximately 5.1 vol) was added to adjust the pH of the reaction to 5-7. The mixture was stirred at 0°C for 1 hour, then raised to 20°C, packed with 2-MeTHF (5 vol), and the two-phase mixture was stirred for 1 hour. The layers were separated. The organic layer was set aside, and the aqueous layer was extracted with 2-MeTHF (5.0 vol). The second organic layer was combined with the first organic layer and washed sequentially with 5% Na2SO4 (5 vol), water (5 vol), 3% NaHCO3 (5 vol, 2×), and water (5 vol). The organic layer was concentrated to 5 vol under vacuum and diluted and reconcentrated (to 10 vol) in two cycles with toluene (10 vol). The solution was adjusted to 45°C. Seed (0.005 wt) was added, and the dilute suspension was stirred for 2 hours, then heptane (2.0 vol) was added dropwise over 2 hours, followed by stirring at 45°C for 2 hours. The suspension was cooled to 25°C over 4 hours, held at 25°C for 15 hours, filtered, washed with 5:1 toluene:heptane (4 vol), then heptane (4 vol), and dried under vacuum at 55°C for 24 hours to produce (10B) as a pale yellow solid.

[0260] Step 10A: Compound (10B) was recrystallized from a toluene / heptane solution.

[0261] [ka]

[0262] Synthesis of ethyl 4-methyl-2-(methylthio)-4H-pyrrolo[2,3-d]thiazole-5-carboxylate (2C):

[0263] [ka]

[0264] A mixture of ethyl 2-bromo-4-methyl-4H-pyrrolo[2,3-d]thiazole-5-carboxylate ((1C) 500.0 mg, 1.73 mmol) in EtOH (10.0 mL) was mixed with NaSMe (240.0 mg, 3.5 mmol). The reaction mixture was stirred at 25°C for 3 hours, then quenched with ice water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain (2C), which was used directly in the next step without purification. LC-MS: m / z 257 (M+H) + .

[0265] Synthesis of ethyl 6-formyl-4-methyl-2-(methylthio)-4H-pyrrolo[2,3-d]thiozol-5-carboxylate (3C):

[0266] [ka]

[0267] To a solution of ethyl 4-methyl-2-(methylthio)-4H-pyrrolo[2,3-d]thiazole-5-carboxylate ((2C) 460.0 mg, 1.8 mmol) and N-methyl-N-phenylformamide (490 mg, 3.6 mmol) in DCE (10 mL), POCl3 (550.0 mg, 3.6 mmol) was added. The resulting mixture was stirred at 130 °C for 3 hours, then quenched with ice water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: PE / siRNA = 8 / 1) to obtain the desired intermediate. LC-MS: m / z 285 (M+H) +A solution of the desired intermediate (300.0 mg, 1.06 mmol) in EtOH (5.0 mL) was added to N2H4·H2O (2 mL, 98 wt%). The reaction mixture was stirred at room temperature for 1 hour, then heated to 60°C overnight, and then cooled. The solids were collected by filtration and dried under high vacuum to obtain (3C). LCMS: m / z 253 (M+H) + . 1 H NMR(400MHz,DMSO-d6)δ12.61(s,1H),8.48(s,1H),4.22(s,3H),2.81(s,3H).

[0268] Synthesis of 4-methyl-2-(methylsulfonyl)-4,6-dihydro-5H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5-one-4-methyl-2-(methylthio)-4,6-dihydro-5H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5-one(4C):

[0269] [ka]

[0270] A three-necked flask filled with 4-methyl-4,6-dihydro-5H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5-one ((3C), 30 g, 0.119 mol, 1.0 equivalent) in DCM (600 mL) was filled with m-CPBA (61.5 g, 3 equivalents) in three separate additions at 20°C. The mixture was stirred overnight at 30°C, and LC-MS showed that 100% of the starting material was consumed, forming 20% ​​sulfoxide and 80% sulfone. The mixture was cooled to room temperature, and another volume of m-CPBA (1.0 equivalent) was added. The reaction mixture was stirred at 30°C for 2 hours, and LC-MS showed that the sulfoxide (LCMS: m / z 269 (M+H)) +The concentration of ) was shown to be less than 8%. The mixture was cooled to room temperature and filtered. The filtered cake was suspended in MeOH (500 mL) and stirred at room temperature for 1 hour. The solids were collected by filtration, washed with ethyl acetate, and dried under vacuum to obtain a mixture of 5% sulfoxide and 95% sulfone. The mixture was suspended in DMSO (600 mL) and heated to 120°C-130°C to form a clear solution. It was then cooled to room temperature to precipitate the solids. The mixture was filtered and dried to obtain pure 4-methyl-2-(methylsulfonyl)-4,6-dihydro-5H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5-one (4C), LCMS: m / z 285 (M+H) + The following was obtained: ¹H NMR (400 MHz, DMSO) δ 12.87 (s, ¹H), 8.69 (s, ¹H), 4.32 (s, ³H), 3.56 (s, ³H).

[0271] Synthesis of methyl 1H-pyrazole-3-carboxylate--(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-yl)methanol(6C):

[0272] [ka]

[0273] Under an N2 atmosphere at 0°C, NaH (20.7 g, 0.864 mol, 60%) was added to a stirred solution of methyl 1H-pyrazole-3-carboxylate ((5C), 90 g, 0.72 mol) in THF (1 L). The resulting mixture was gradually warmed to a maximum of room temperature and stirred for 1 hour. The reaction mixture was then cooled again to 0°C, and SEMCl (151.5 mL, 0.842 mol) was added dropwise. Stirring was continued for a further 2 hours, then quenched with saturated NH4Cl and extracted with ethyl acetate (3×). The combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed under vacuum to obtain the crude product, which was used in the next step without purification.

[0274] Crude methyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxylate was added to a suspension of LAH (16.9 g, 0.44 mol) in THF (760 mL) under an N2 atmosphere at 0°C. The resulting mixture was gradually heated to a maximum of room temperature and stirred for 1 hour. The reaction mixture was cooled again to 0°C, and H2O (15.6 mL), 10% NaOH (15.6 mL), and H2O (15.6 mL) were added sequentially. The resulting mixture was filtered through a Celite pad and washed with MTBE (4×). The combined organic fraction was dried over Na2SO4. The solvent was removed under reduced pressure to obtain the crude product (6C), which was used in the next step without purification. LC-MS: m / z 229 (M+H) + .

[0275] Synthesis of (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-yl)methanol--3-(iodomethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole(7C):

[0276] [ka]

[0277] Under an N2 atmosphere at 0°C, (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-yl)methanol ((6C) 61.5 g, theoretically 0.262 mol) was stirred in THF (310 mL), to which TEA (55.42 mL, 0.393 mol) was added, followed by MsCl (24 mL, 0.314 mol). The reaction mixture was heated to a maximum of room temperature and stirred for 1 hour, after which NaI (196.5 g, 1.31 mol, in 310 mL of DMF) was added. The resulting mixture was stirred for a further 1 hour, quenched with ice water, and extracted with MTBE (3×). The combined organic layers were washed with saturated Na₂S₂O₃ and brine, dried over Na₂SO₄, concentrated to obtain (7C), which was used in the next step without purification. LC-MS: m / z 339 (M+H) + .

[0278] Synthesis of 3-((phenylsulfonyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole(8C):

[0279] [ka]

[0280] Under an N2 atmosphere at 0°C, sodium benzenesulfinate (53.5 g, 0.32 mol) was added to a stirred solution of (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-yl)methanol ((7C) 77.5 g, theoretically 0.229 mol) in DMF (600 mL) and stirred at 0°C for 1 hour. After warming to room temperature, the reaction mixture was quenched with ice water and saturated Na2S2O3 and extracted with ethyl acetate (3×). The combined organic layers were successively washed with saturated NaHCO3 and brine and dried over Na2SO4. The solvent was removed under vacuum, and the residue was purified by flash chromatography (silica gel, 20%-70% ethyl acetate in petroleum ether) to obtain (8C) as a pale yellow oil. LCMS:[M+H] + 353.1H NMR(400MHz,DMSO)δ7.85-7.77(m,4H),7.62(dd,2H),6.19(d,1H),5.35(d,2H),4.70(d,2H),3.44-3.38(m,2H),0.88-0.77(m,2H),-0.01(s,9H).

[0281] Synthesis of tert-butyl(tert-butoxycarbonyl)(3-(iodomethyl)phenyl)carbamate--tert-butyl(tert-butoxycarbonyl)(6-((4-methyl-2-(methylsulfonyl)-5-oxo-4,5-dihydro-6H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-6-yl)methyl)pyridine-2-yl)carbamate--4-methyl-2-(methylsulfonyl)-4,6-dihydro-5H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5-one (9C):

[0282] [ka]

[0283] A mixture of 4-methyl-2-(methylsulfonyl)-4H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazine-5(6H)-one ((4C), 7.5g, 26.4 mmol) and K3PO4 (8.3g, 39.3 mmol) in anhydrous MeCN (300 mL) was stirred at 70°C for 1 hour under N2. Subsequently, a solution of tert-butyl N-[(tert-butoxy)carbonyl]-N-[6-(bromomethyl)pyridine-2-yl]carbamate (11.2g, 29.0 mmol) in MeCN (30 mL) was added. After stirring at 70°C under N2 for 2.5 hours, the reaction mixture was quenched with saturated NH4Cl and extracted with EA (300 mL x 3). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and the organic phase was concentrated. The crude product was purified by flash chromatography (silica gel, 0-50% ethyl acetate in petroleum ether) to obtain tert-butyl N-[(tert-butoxy)carbonyl]-N-[6-({4-methanesulfonyl-7-methyl-9-oxo-3-thia-5,7,10,11-tetraazatricyclo[6.4.0.0{2,6}]dodeca-1(8),2(6),4,11-tetraen-10-yl}methyl)pyridine-2-yl]carbamate (9C). LC-MS (ESI) observation: 591.1 (M+H) + .

[0284] tert-butyl(6-((4-methyl-5-oxo-2-((phenylsulfonyl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-yl)methyl)-4,5-dihydro-6H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-6-yl)methyl)pyridin-2-yl)carbamate--tert-butyl(tert-butyl Synthesis of Toxycarbonyl)(6-((4-methyl-2-(methylsulfonyl)-5-oxo-4,5-dihydro-6H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-6-yl)methyl)pyridin-2-yl)carbamate--3-((phenylsulfonyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole(10C):

[0285] [ka]

[0286] To a stirred mixture of 3-((phenylsulfonyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole ((9C) 11.9 g, 33.8 mmol) in anhydrous THF (200 mL), LiHMDS (50 mL, 1 M in THF) was added under argon at -40°C. After 10 minutes, the mixture was heated to 10°C and stirred for 1 hour, then (9) (9.1 g, 15.4 mmol in 35 mL of THF) was added. The reaction mixture was stirred for a further 30 minutes at 10°C. The reaction mixture was poured into an aqueous solution of NH4Cl and extracted with RINKAN (200 mL x 3). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated. The crude product was purified by flash chromatography (silica gel, 0-50% ethyl acetate in petroleum ether) to obtain tert-butyl(6-((4-methyl-5-oxo-2-((phenylsulfonyl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-yl)methyl)-4H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazine-6(5H)-yl)methyl)pyridine-2-yl)carbamate(10C). LC-MS (ESI) observation: 763.2 (M+H) + .

[0287] Synthesis of tert-butyl(6-((4-methyl-5-oxo-2-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-yl)methyl)-4,5-dihydro-6H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-6-yl)methyl)pyridin-2-yl)carbamate--tert-butyl(6-((4-methyl-5-oxo-2-((phenylsulfonyl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-yl)methyl)-4,5-dihydro-6H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-6-yl)methyl)pyridin-2-yl)carbamate (11C):

[0288] [ka]

[0289] A solution of (10C) (6.0 g, 7.86 mmol) in EtOH / AcOH (35 mL / 50 mL) was heated to 50°C for 40 minutes with vigorous stirring in the presence of Zn (2.55 g, 117.9 mmol). Additional zinc was added every 40 minutes (2.55 g, twice), with the reaction monitored by TLC / LC-MS to avoid by-products and excess reduction products. The solution was filtered, and the filter cake was washed with DCM. The filtrate was partially evaporated, neutralized with saturated NaHCO3 solution, dried over MgSO4, and the solvent was removed under vacuum. The crude product was purified by flash chromatography (silica gel, DCM:MeOH = 40:1) to obtain (11C). LC-MS (ESI) observation: 623.3 (M+H) + .

[0290] Synthesis of tert-butyl(6-((4-methyl-5-oxo-2-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-yl)methyl)-4,5-dihydro-6H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-6-yl)methyl)pyridine-2-yl)carbamate-2-((1Hpyrazole-3-yl)methyl)-6-((6-aminopyridine-2-yl)methyl)-4-methyl-4,6-dihydro-5H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5-one (13):

[0291] [ka]

[0292] A mixture of (11C) (3.0 g, 4.8 mmol) in ethanol (30 mL) was mixed with HCl (30 mL, 4 M in dioxane). The reaction mixture was stirred at 80°C for 40 minutes. The reaction mixture was cooled to room temperature, filtered, and the solids were collected. The solids were suspended in water and neutralized with aqueous NaHCO3 at 10°C. Filtered again, the desired compound (13) was obtained. LC-MS (ESI) observation: 393.2 (M + H) + . 1HNMR(400MHz,DMSO-d6)δ12.78(s,1H),8.53(s,1H),7.72(s,1H),7.25(dd,1H),6.33-6.24(m,2H),6.08(d,1H),5.90(s,2H),5.19(s,2H),4.49(s,2H),4.26(s,3H).

Claims

1. Compound of formula (A-1), 【Chemical 86】 or its salt (in the formula, R １ is hydrogen, C １ -C ６ -alkyl, C １ -C ６ -haloalkyl, C １ -C ６ -hydroxyalkyl, C １ -C ６ -aminoalkyl, C １ -C ６ -cyanoalkyl C ２ -C ６ -alkenyl, C ２ -C ６ -alkynyl, or C ３ -C ６ -cycloalkyl, and the C ３ -C ６ -cycloalkyl is optionally substituted with 1 to 3 groups selected from halo, hydroxyl, NH ２ , and CN, X is a halo, L is a combination or C １ -C ６ It is alkylene, Q is C ３ -C ６ They are cycloalkyls, 5-14 membered heterocyclines, 6-12 membered aryls, or 5-14 membered heteroaryls, each of which is a halo, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, hydroxyl, C １ -C ６ Aminoalkyl, -NH ２ ,-NH(C １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ , CN, and NO ２ A method for preparing (which is optionally substituted with one to three groups selected from), The above method involves a compound of formula (A-2): 【Transformation 87】 or its salt, Compound of formula (A-3): 【Chemical 88】 And it will react, A method comprising forming a compound of formula (A-1) or a salt thereof.

2. R １ However, C １ -C ６ Alkyl or C １ -C ６ The method according to claim 1, wherein the material is a haloalkyl.

3. R １ The method according to claim 1 or claim 2, wherein is methyl.

4. The method according to any one of claims 1 to 3, wherein X is Cl.

5. L is C １ -C ６ The method according to any one of claims 1 to 4, wherein the material is alkylene.

6. L is -CH ２ - The method according to any one of claims 1 to 5.

7. Q is a 6- to 12-membered aryl or a 5- to 14-membered heteroaryl, and each of these is a halo, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, hydroxyl, C １ -C ６ Aminoalkyl, NH ２ ,-NH(C １ -C ６ Alkyl), N (C １ -C ６ Alkyl) ２ , CN, and NO ２ The method according to any one of claims 1 to 6, wherein the base is optionally replaced with one to three bases selected from the above.

8. Q is -NH ２ The method according to any one of claims 1 to 7, wherein the substituted 5 to 7 member heteroaryl is a 5 to 7 member heteroaryl.

9. The compound of formula (A-1) is: 【Chemical 89】 The method according to any one of claims 1 to 8, wherein the salt thereof.

10. The compound of formula (A-2) is: 【Chemistry 90】 The method according to any one of claims 1 to 9, wherein the bisate thereof is used.

11. The compound of formula (A-2) is: 【Chemistry 91】 The method according to any one of claims 1 to 9, wherein the method is a tautomer or hydrate thereof.

12. The compound of formula (A-3) is 【Chemistry 92】 The method according to any one of claims 1 to 11.

13. The method according to any one of claims 1 to 12, wherein the compound of formula (A-2) or a salt thereof reacts with the compound of formula (A-3) in the presence of an acid and one or more solvents.

14. The method according to any one of claims 1 to 13, wherein the compound of formula (A-3) reacts with a bisate salt of the compound of formula (A-2) in one or more solvents.

15. The method according to claim 11 or 12, wherein the acid is selected from hydrochloric acid, acetic acid, phosphoric acid, sulfuric acid, citric acid, formic acid, methanesulfonic acid, and p-toluenesulfonic acid.

16. The method according to any one of claims 1 to 15, wherein at least one solvent is a polar protic solvent.

17. The method according to claim 16, wherein at least one polar protic solvent is selected from water, methanol, ethanol, n-propanol, i-propanol, and t-butanol, or any combination thereof.

18. The method according to claim 17, wherein at least one polar protic solvent is ethanol or n-propanol.

19. The method according to claim 17, wherein the polar protic solvent is a mixture of ethanol and i-propanol.

20. Compound of formula (A-3): 【Chemistry 93】 (In the formula, R １ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Cyanoalkyl C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, or C ３ -C ６ It is a cycloalkyl, and the C ３ -C ６ Cycloalkyls are halo, hydroxyl, NH ２ , and optionally substituted with 1 to 3 groups selected from CN, A method for preparing X (where X is a halo), The method described above is Compound of formula (A-6): 【Chemical 94】 (In the formula, R ２ C １ -C ６ A method comprising hydrolyzing an alkyl group to form a compound of formula (A-3).

21. The method according to claim 20, wherein the compound of formula (A-6) is hydrolyzed in the presence of a base and one or more solvents.

22. The aforementioned bases are lithium hydroxide (LiOH) and calcium hydroxide (Ca(OH) ２ ), potassium hydroxide (KOH), sodium hydroxide (NaOH), and barium hydroxide (Ba(OH) ２ The method according to claim 21, selected from ).

23. The method according to claim 22, wherein the base is sodium hydroxide (NaOH).

24. The method according to any one of claims 20 to 23, wherein the compound of formula (A-6) is hydrolyzed in the presence of water and one or more solvents.

25. The method according to any one of claims 20 to 24, wherein the compound of formula (A-6) is hydrolyzed in the presence of water and at least one solvent which is a polar aprotic solvent.

26. The method according to claim 25, wherein at least one polar aprotic solvent is selected from dimethylacetamide (DMAC), 2-methyltetrahydrofuran (2-MeTHF), tetrahydrofuran (THF), acetone, dimethylformamide (DMF), acetonitrile (ACN), and dimethyl sulfoxide (DMSO), or any combination thereof.

27. The method according to claim 26, wherein at least one polar aprotic solvent is THF.

28. The compound of formula (A-6) is the compound of formula (A-5): 【Chemical 95】 of, Phosphorus oxychloride (POCl ３ ), dimethylformamide (DMF), and one or more additional solvents to form a compound of formula (A-6), the method according to any one of claims 20 to 27, prepared by reacting.

29. The method according to claim 28, wherein one or more additional solvents are nonpolar solvents.

30. The method according to claim 29, wherein the nonpolar solvent is selected from dioxane, dichloroethane, benzene, toluene, chlorobenzene, dichlorobenzene, and xylene.

31. The method according to claim 30, wherein the nonpolar solvent is chlorobenzene.

32. The compound of formula (A-5) is the compound of formula (A-4): 【Chemistry 96】 of, The method according to any one of claims 28 to 31, which is prepared by reacting a halogenating agent, a base, and at least one solvent to form a compound of formula (A-5).

33. The method according to claim 32, wherein the base is selected from lithium diisopropylamide (LDA), sodium bis(trimethylsilyl)amide (NaHMDS), lithium bis(trimethylsilyl)amide (LiHMDS), potassium bis(trimethylsilyl)amide (KHMDS), and sodium hydride (NaH).

34. The method according to claim 33, wherein the base is lithium bis(trimethylsilyl)amide (LiHMDS).

35. The method according to any one of claims 31 to 34, wherein the halogenating reagent is selected from elemental halogens, carbon tetrachloride, hexachloroethane, carbon tetrabromide, n-bromosuccinimide (NBS), and n-chlorosuccinimide (NCS).

36. The method according to claim 35, wherein the halogenating reagent is hexachloroethane.

37. The method according to any one of claims 31 to 36, wherein at least one solvent is a polar aprotic solvent.

38. The method according to claim 37, wherein the polar aprotic solvent is selected from dimethylacetamide (DMAC), 2-methyltetrahydrofuran (2-MeTHF), tetrahydrofuran (THF), acetonitrile (ACN), and dimethyl sulfoxide (DMSO), or any combination thereof.

39. The method according to claim 38, wherein the polar aprotic solvent is THF.

40. R １ However, C １ -C ６ Alkyl or C １ -C ６ The method according to any one of claims 22 to 39, wherein the material is a haloalkyl.

41. R １ is C １ -C ６ alkyl, the method according to any one of claims 20 to 40.

42. R １ The method according to any one of claims 20 to 41, wherein the substance is methyl.

43. The method according to any one of claims 20 to 42, wherein X is -Cl.

44. R ２ The method according to any one of claims 20 to 43, wherein the substance is ethyl.

45. The method according to any one of claims 20 to 44, wherein the compound of formula (A-3) is as follows: 【Chemistry 97】

46. The compound of formula (A-4) is 【Chem.98】 The method according to any one of claims 32 to 45:

47. The compound of formula (A-6) is 【Chem.99】 The method according to any one of claims 20 to 46.

48. The compound of formula (A-5) is 【Chemistry 100】 The method according to any one of claims 28 to 47.

49. Compound of formula (B-1): 【Chemistry 101】 During the ceremony, R １ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Cyanoalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, or C ３ -C ６ It is a cycloalkyl, and the C ３ -C ６ Cycloalkyls are halo, hydroxyl, NH ２ , and optionally substituted with 1 to 3 groups selected from CN, R ４ C １ -C ６ Alkyl, C １ -C ６ The member is a haloalkyl, a 6-12 membered aryl, or a 5-14 membered heteroaryl, wherein the 6-12 membered aryl or 5-14 membered heteroaryl is a halo or C １ -C ６ It is optionally substituted with 1 to 3 groups selected from alkyl groups. L is a combination or C １ -C ６ It is alkylene, Q is C ３ -C ６ They are cycloalkyls, 5-14 membered heterocyclines, 6-12 membered aryls, or 5-14 membered heteroaryls, each of which is a halo, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, hydroxyl, C １ -C ６ Aminoalkyl, -NH ２ ,-NH(C １ -C ６ Alkyl), -N(C １ -C ６ Alkyl) ２ , CN, and NO ２ A method for preparing (which is optionally substituted with one to three groups selected from), The method described above is Compound of formula (A-2): 【Chemical Engineering 102】 or its salt, Compound of formula (B-5): 【Chemistry 103】 And it will react, A method comprising forming a compound of formula (B-1).

50. The method according to claim 49, wherein the compound of formula (A-2) or a salt thereof reacts with the compound of formula (B-5) in the presence of an acid and at least one solvent.

51. The method according to claim 50, wherein the acid is selected from hydrochloric acid, trifluoroacetic acid, acetic acid, phosphoric acid, sulfuric acid, citric acid, formic acid, and carbonic acid.

52. The method according to any one of claims 49 to 51, wherein at least one solvent is a polar protic solvent.

53. The method according to claim 52, wherein the polar protic solvent is an alcohol.

54. The method according to claim 53, wherein at least one polar protic solvent is selected from methanol, ethanol, n-propanol, i-propanol, sec-butanol, and t-butanol, or any combination thereof.

55. The method according to claim 54, wherein at least one polar protic solvent is ethanol, i-propanol, or n-propanol, or a mixture thereof.

56. The compound of formula (B-5) is the same as the compound of formula (B-4): 【Chemical 104】 (In the formula, R ２ C １ -C ６ The method according to any one of claims 49 to 55, which is prepared by hydrolyzing an alkyl group.

57. The method according to claim 56, wherein the compound of formula (B-4) is hydrolyzed in the presence of a base and one or more solvents.

58. The aforementioned bases are lithium hydroxide (LiOH) and calcium hydroxide (Ca(OH) ２ ), potassium hydroxide (KOH), sodium hydroxide (NaOH), and barium hydroxide (Ba(OH) ２ The method according to claim 57, selected from ).

59. The method according to claim 58, wherein the base is lithium hydroxide (LiOH) or sodium hydroxide (NaOH).

60. The method according to any one of claims 56 to 59, wherein at least one solvent is water.

61. The method according to any one of claims 56 to 60, wherein the compound of formula (B-4) is hydrolyzed in water and a polar aprotic solvent.

62. The method according to claim 61, wherein the polar aprotic solvent is selected from dimethylacetamide (DMAC), 2-methyltetrahydrofuran (2-MeTHF), tetrahydrofuran (THF), dimethylformamide (DMF), acetonitrile (ACN), and dimethyl sulfoxide (DMSO), or any combination thereof.

63. The method according to claim 62, wherein the polar aprotic solvent is THF.

64. The compound of formula (B-4) is the compound of formula (B-3): 【Chemistry 105】 of, The method according to any one of claims 56 to 63, which is prepared by reacting with an oxidizing agent in at least one solvent to form a compound of formula (B-4).

65. The oxidizing agent is hydrogen peroxide and sodium tungstate (Na ２ WO ４ The method according to claim 64, which is as follows.

66. The method according to claims 63 to 65, wherein at least one solvent is a nonpolar solvent.

67. The method according to claim 66, wherein at least one nonpolar solvent is selected from dichloromethane, toluene, chlorobenzene, dichlorobenzene, and xylene, or any combination thereof.

68. The method according to claim 67, wherein the nonpolar solvent is chlorobenzene.

69. The method according to any one of claims 63 to 68, further comprising at least one phase transfer catalyst.

70. The method according to claim 69, wherein the interphase transfer catalyst is methyltrioctylammonium hydrogen sulfate.

71. The method according to any one of claims 63 to 70, further comprising at least one acid.

72. The method according to claim 71, wherein the acid is phenylphosphonic acid.

73. The compound of formula (B-3) is the compound of formula (B-2): 【Chemistry 106】 of, Phosphorus oxychloride (POCl ３ The method according to any one of claims 63 to 72, which is prepared by reacting with dimethylformamide (DMF) and one or more solvents to form a compound of formula (B-3).

74. The method according to claim 73, wherein one of the solvents is a nonpolar solvent.

75. The method according to claim 74, wherein the nonpolar solvent is selected from toluene, chlorobenzene, dichlorobenzene, and xylene, or any combination thereof.

76. The method according to claim 75, wherein the nonpolar solvent is chlorobenzene.

77. R １ However, C １ -C ６ Alkyl or C １ -C ６ The method according to any one of claims 47 to 76, wherein the material is a haloalkyl.

78. R １ However, C １ -C ６ The method according to any one of claims 47 to 77, wherein the alkyl group is alkyl.

79. R １ The method according to any one of claims 47 to 78, wherein the substance is methyl.

80. R ２ The method according to any one of claims 56 to 79, wherein the substance is ethyl.

81. R ４ However, Halo and C １ -C ６ The method according to any one of claims 56 to 80, wherein the aryl group is a 6 to 12-membered group optionally substituted with 1 to 3 groups selected from alkyl groups.

82. R ４ The method according to any one of claims 56 to 81, wherein the substance is 4-methylbenzene.

83. L is C １ -C ６ The method according to any one of claims 49 to 82, wherein the material is alkylene.

84. L is -CH ２ - The method according to any one of claims 49 to 83.

85. Q is a 6- to 12-membered aryl or a 5- to 14-membered heteroaryl, and each of these is a halo, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, hydroxyl, C １ -C ６ Aminoalkyl, -NH ２ ,-NH(C １ -C ６ Alkyl), N (C １ -C ６ Alkyl) ２ -CN, and -NO ２ The method according to any one of claims 49 to 84, wherein the base is optionally replaced with one to three bases selected from the above.

86. Q is -NH ２ The method according to any one of claims 49 to 85, wherein the substituted 5 to 7 member heteroaryl is a method according to any one of claims 49 to 85.

87. The compound of formula (B-1) is 【Chemistry 107】 The method according to any one of claims 49 to 86:

88. The compound of formula (B-2) is 【Chemistry 108】 The method according to any one of claims 73 to 87.

89. The compound of formula (B-3) is 【Chemistry 109】 The method according to any one of claims 64 to 88.

90. The compound of formula (B-4) is 【Chemical 110】 The method according to any one of claims 56 to 89.

91. The compound of formula (B-5) is 【Chemistry 111】 The method according to any one of claims 49 to 90.

92. The compound of formula (A-2) or a salt thereof, 【Chemistry 112】 The method according to any one of claims 49 to 91.

93. Compounds having the following structure: 【Chemistry 113】 or its salts, tautomers, or hydrates.

94. Compounds having the following structure: 【Chemical 114】 or its salts, tautomers, or hydrates.

95. Compounds having the following structure: 【Chemical 115】 or its salts, tautomers, or hydrates.

96. Compounds having the following structure: 【Chemistry 116】 or its salts, tautomers, or hydrates.

97. Compounds having the following structure: 【Chemistry 117】 or its salts, tautomers, or hydrates.

98. Compounds having the following structure: 【Chemistry 118】 or its salts, tautomers, or hydrates.

99. Compounds having the following structure: 【Chemical 119】 or its salts, tautomers, or hydrates.

100. Compounds having the following structure: 【Chemical 120】 or its bisate.

101. Compounds having the following structure: 【Chemistry 121】 or its tautomer or hydrate.

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