EA042013B1 - METHOD FOR PRODUCING AMINOPYRIMIDINE AND ITS INTERMEDIATES - Google Patents

Description

Technical field

This document provides a method for obtaining aminopyrimidine and its salts. Also provided in this document is an intermediate product used in this method and its preparation.

State of the art

The cytoskeleton of skeletal and cardiac muscle cells is unique compared to the cytoskeleton of all other cells. It consists of an almost crystalline array of tightly packed cytoskeletal proteins called a sarcomere. The sarcomere is elegantly organized as an intertwining array of thin and thick filaments. Thick filaments are made up of myosin, a motor protein responsible for converting the chemical energy of ATP hydrolysis into force and directional movement. Thin filaments are made up of actin monomers arranged in a helical pattern. There are four regulatory proteins associated with actin filaments that allow calcium ions to modulate contraction. The intake of intracellular calcium initiates muscle contraction; thick and thin filaments slide against each other, which is due to the repeated interactions of myosin motor domains with thin actin filaments.

Of the thirteen different classes of myosin in human cells, class II myosin is responsible for skeletal, cardiac, and smooth muscle contraction. This class of myosin differs significantly in amino acid composition and general structure from myosin in the other twelve different classes. Myosin II forms homodimers, whereby the two globular domains of the head are linked by a long alpha helical helical tail, forming the core of the thick sarcomere filament. Globular heads have a catalytic domain in which myosin functions to bind actin and ATPase. After binding to the actin filament, phosphate release (see ADP inorganic phosphate in ADP) signals a change in the structural conformation of the catalytic domain, which in turn changes the orientation of the light chain-binding lever domain that extends from the globular head; this movement is called an effective hit. This change in the orientation of the myosin head with respect to actin causes the thick filament of which it is a part to move relative to the thin actin filament with which it is associated. Detachment of the globular head from the actin filament (regulated by Ca ²⁺ ), coupled with the return of the catalytic domain and light chain to their original conformation/orientation, completes the catalytic cycle responsible for intracellular movement and muscle contraction.

Tropomyosin and troponin mediate the effect of calcium on the interaction between actin and myosin. The troponin complex consists of three polypeptide chains: troponin C, which binds calcium ions; troponin I, which binds to actin; and troponin T, which binds to tropomyosin. The skeletal troponin-tropomyosin complex regulates myosin binding sites that span several actin units simultaneously.

Troponin, a complex of the three polypeptides described above, is an accessory protein that is closely associated with actin filaments in vertebrate muscles. The troponin complex acts in conjunction with the muscle form of tropomyosin to mediate the Ca ²⁺ -dependency of myosin ATPase activity and thereby regulate muscle contraction. Troponin polypeptides T, I, and C are named for their tropomyosin binding, inhibition, and calcium binding activities, respectively. Troponin T binds to tropomyosin and is believed to be responsible for the location of the troponin complex on the thin filament of muscle. Troponin I binds to actin, and the complex formed by troponins I and T and tropomyosin inhibits the interaction of actin and myosin. Skeletal troponin C is able to bind up to four calcium molecules. Research shows that when muscle calcium levels rise, troponin C exposes the troponin I binding site, recruiting it from actin. This causes the tropomyosin molecule to also shift its position, thereby exposing the myosin binding sites on actin and stimulating the activity of myosin ATPase.

U.S. Patent No. 8,962,632 discloses 1-(2-((((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)amino)pyrimidin-5-yl)-1H-pyrrol-3 β-carboxamide, a next generation fast skeletal muscle troponin activator (FSTA) as a potential treatment for people suffering from debilitating diseases and conditions associated with neuromuscular or non-neuromuscular dysfunction, muscle weakness and/or muscle fatigue.

There is a need for improved methods for producing such a compound at low cost and in high overall yield and purity.

Disclosure of invention

In one aspect, provided herein is a process for preparing a compound of formula (1)

- 1 042013 or its salts, including (i) the interaction of the compounds of formula (1A)

CN

MeO OMe(-|D) with 2-chloro-3-fluoropyridine to form a compound of formula (1B)

OMe (1B);

(ii) reacting a compound of formula (1B) with an aqueous acid solution to form a compound of formula (1C)

and (iii) converting a compound of formula (1C) to a compound of formula (1) or a salt thereof, wherein step (iii) comprises reacting a compound of formula (1C) with sodium borohydride to give a compound of formula (1G)

reacting a compound of formula (1G) with diethylaminosulfur trifluoride (DAST) to give a compound of formula (1H)

reaction of a compound of formula (1H) with hydrogen in the presence of Raney nickel to give a compound of formula (1I)

reaction of a compound of formula (1I) with where X is chlorine or fluorine, followed by reaction with di-tert-butyl dicarbonate in the presence of 4dimethylaminopyridine (DMAP) to give a compound of formula (1J)

where Z is a tert-butyloxycarbonyl (Boc) protecting group,

- 2 042013 reaction of a compound of formula (1J) with NC to form a compound of formula (1K)

reacting a compound of formula (1K) with hydrogen peroxide in the presence of potassium carbonate, followed by reacting with trifluoroacetic acid to form a compound of formula (1) or a salt thereof.

In some embodiments, the reaction of a compound of formula (1H) with hydrogen in the presence of Raney nickel to form a compound of formula (1I) is carried out in the presence of ammonia.

In some embodiments, the reaction of a compound of formula (1I) with /=M ^vg D/)-x where X is chlorine or fluorine is carried out in the presence of diisopropyl-N-ethylamine (DIPEA).

In some embodiments, a compound of formula (IA) is prepared by reacting 1,3-dibromo-2,2-dimethoxypropane with tert-butyl-2-cyanoacetate.

In some embodiments, the reaction of 1,3-dibromo-2,2-dimethoxypropane with tert-butyl-2-cyanoacetate is carried out in the presence of a base.

In some embodiments, the base is potassium tert-butoxide.

In some embodiments, a compound of formula (1A) is prepared by reacting a compound of formula (1D) ^Μ θθ OMe

CONH2 (1D) with trifluoroacetic anhydride.

In some embodiments, a compound of formula (1D) is prepared by reacting a compound of formula (1E)

MeO OMe

COOMe (1E) with ammonia.

In some embodiments, a compound of formula (1E) is prepared by reacting a compound of formula (1F)

Ocoon (1F) with trimethoxymethane in the presence of Amberlyst-15.

In some embodiments, step (i) is carried out in the presence of a base.

In some embodiments, the base is sodium bis(trimethylsilyl)amide.

In some embodiments, the aqueous solution of the acid of step (ii) is aqueous hydrochloric acid.

In another aspect of the invention, a compound of formula (1B) is provided.

- 3 042013

or its salt.

In yet another aspect of the invention, a process is provided for the preparation of a compound of formula (IB) ^NC x ^N

MeO OMe (1B), or its salts, including: interaction of the compound of formula (1A)

CN

MeO OMe(1D) with 2-chloro-3-fluoropyridine to form a compound of formula (1B).

In some embodiments, a compound of formula (IA) is prepared by reacting 1,3-dibromo-2,2-dimethoxypropane with tert-butyl-2-cyanoacetate.

In some embodiments, the reaction of 1,3-dibromo-2,2-dimethoxypropane with tert-butyl-2-cyanoacetate is carried out in the presence of a base.

In some embodiments, the base is potassium tert-butoxide.

In some embodiments, a compound of formula (1A) is prepared by reacting a compound of formula (1D)

meo ome

CONH2 (1D) with trifluoroacetic anhydride.

In some embodiments, a compound of formula (1D) is prepared by reacting a compound of formula (1E) ^MeO _h OMe

COOMe (1E) with ammonia.

In some embodiments, a compound of formula (1E) is prepared by reacting a compound of formula (1F)

ABOUT

COOH (1F) with trimethoxymethane in the presence of Amberlyst-15.

In some embodiments, the reaction of a compound of formula (IA) with 2-chloro-3-fluoropyridine is carried out in the presence of a base.

In some embodiments, the base is sodium bis(trimethylsilyl)amide.

Detailed description

Definitions

In the context of this document, unless expressly stated or implied otherwise, the terms used in this document have the meanings defined below. Unless otherwise conflicted or implied, for example, by including mutually exclusive elements or variations, in these definitions and throughout this description, terms in the singular mean one or more, and the term or means and/or, when the context permits. Thus, as used herein and in the appended claims, the singular forms include the plural unless the context clearly dictates otherwise. At various places in the present description, for example, in any disclosed embodiments or in the claims, reference is made to compounds, compositions or methods that contain one or more of the specified components, elements

- 4 042013 or stages. Embodiments also specifically include those compounds, compositions, or methods which are, or which consist of, or which essentially consist of, the specified components, elements, or steps. The term contains is used interchangeably with the term containing and is indicated as equivalent terms. For example, disclosed compositions, devices, articles of manufacture, or methods that contain a component or step are open and include or are read by such compositions or methods that have plus additional component(s) or step(s). However, those terms do not cover non-listed items that may interfere with the functionality of the disclosed compositions, devices, articles, or methods for their intended purpose. Likewise, disclosed compositions, devices, articles of manufacture, or methods that consist of a component or step are proprietary and will not include or be read as compositions or methods having appreciable amounts of additional component(s) or step(s). In addition, the term essentially consisting of allows the inclusion of non-listed elements that do not significantly affect the functionality of the disclosed compositions, devices, articles of manufacture, or methods for their intended purpose, as further defined herein. The section headings used in this document are for organizational purposes only and should not be construed as limiting the subject matter of the description.

In the context of this document, the term approximately, when used in connection with a numerical value or range of values provided to describe a particular property of a compound or composition, indicates that the value or range of values may vary to an extent that is considered acceptable to a person skilled in the art. technique, but at the same time describes a specific property. Reasonable deviations include deviations that are within the error or accuracy of the instrument(s) used to measure, determine or obtain a particular property. In particular, the term about when used in this context indicates that a numerical value or range of values may vary between 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1 or 0.01% of the given value or range of values, e.g. 10 to 0.5% or 5 up to 1%, while at the same time describing a specific property.

Alkyl refers to and includes saturated linear and branched monovalent hydrocarbon structures, and combinations thereof, having the number of carbon atoms indicated (ie, C ₁ -C ₁₀ means from one to ten carbon atoms). Particular alkyl groups are those having from 1 to 20 carbon atoms (C ₁ -C ₂₀ alkyl). More specific alkyl groups are those having 1 to 8 carbon atoms (C ₁ -C ₈ alkyl), 3 to 8 carbon atoms (C ₃ -C ₈ alkyl), 1 to 6 carbon atoms (C ₁ -C ₆ alkyl), 1 to 5 carbon atoms (C ₁ -C ₅ alkyl) or 1 to 4 carbon atoms (C ₁ -C 4 alkyl). Examples of alkyl include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, homologs and isomers, for example, npentyl, n-hexyl, n -heptyl, n-octyl and the like.

Alkenyl, as used herein, refers to an unsaturated linear or branched monovalent hydrocarbon chain, or a combination thereof, having at least one site of olefinic unsaturation (i.e., having at least one C=C moiety) and having the designated number of carbon atoms (that is, C ₂ -C ₁₀ means from two to ten carbon atoms). The alkenyl group may be in cis or trans configurations, or alternatively in E or Z configurations. Particular alkenyl groups are those having 2 to 20 carbon atoms (C ₂ -C ₂₀ -alkenyl), having 2 to 8 carbon atoms (C ₂ -C ₈ -alkenyl), having 2 to 6 carbon atoms (C ₂ -C ₆ -alkenyl) or from 2 to 4 carbon atoms (C ₂ -C ₄ -alkenyl). Examples of alkenyl include, but are not limited to, groups such as ethenyl (or vinyl), prop-1-enyl, prop-1-en-2-yl, prop-2-enyl (or allyl), 2-methylprop-1 -enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3dienyl, their homologues and isomers, and the like.

Alkynyl, as used herein, refers to an unsaturated linear or branched monovalent hydrocarbon chain, or a combination thereof, having at least one site of acetylenic unsaturation (i.e., having at least one moiety of the formula C^C) and having the designated number of carbon atoms (that is, C ₂ -C ₁₀ means from two to ten carbon atoms). Particular alkynyl groups are those having 2 to 20 carbon atoms (C ₂ -C ₂₀ alkynyl), having 2 to 8 carbon atoms (C ₂ -C ₈ alkynyl), having 2 to 6 carbon atoms (C ₂ -C ₆ alkynyl) or from 2 to 4 carbon atoms (C ₂ -C ₄ alkynyl). Examples of alkynyl include, but are not limited to, groups such as ethynyl (or acetylenyl), prop-1-ynyl, prop-2-ynyl (or propargyl), but1-ynyl, but-2-ynyl, but-3-ynyl , its homologues and isomers, and the like.

Cycloalkyl, as used herein, refers to a C ₃ -C ₁₀ saturated or unsaturated non-aromatic hydrocarbon ring group. Cycloalkyl may be bridged. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl. Aryl, as used herein, refers to a C ₆ -C ₁₂ unsaturated aromatic hydrocarbon ring group. Aryl may be monocyclic or polycyclic (eg, bicyclic, tricyclic). Aryl may be ring fused (e.g. 1 to 3 rings) including but not limited to aryl, heteroaryl

- 5 042013 nye, cycloalkyl and/or heterocyclyl rings. In one embodiment, the aryl group contains from 6 to 14 ring carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, and the like.

Heteroaryl, as used herein, refers to unsaturated aromatic cyclic groups having from 1 to 10 ring carbon atoms and at least one ring heteroatom, including, but not limited to, heteroatoms such as nitrogen, oxygen, and sulfur, where the nitrogen atoms and sulfurs are optionally oxidized and nitrogen atom(s) are optionally quaternized(s). The heteroaryl group may be attached to the rest of the molecule at a ring carbon or a ring heteroatom. Heteroaryl may be ring-fused (eg, 1 to 3 rings) including, but not limited to, aryl, heteroaryl, cycloalkyl, and/or heterocyclyl rings. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrimidyl, thiophenyl, furanyl, thiazolyl, and the like.

Heterocycle, heterocyclyl or heterocycloalkyl refers to a saturated or unsaturated non-aromatic group having 1 to 10 ring carbon atoms and 1 to 4 ring heteroatoms such as nitrogen, sulfur or oxygen, and the like, where the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) is optionally quaternized(s). The heterocyclyl group may have one or more fused rings, but excludes heteroaryl groups. A heterocycle containing more than one ring may be fused, spiro or bridged, or any combination thereof. In fused ring systems, one or more fused rings may be aryl or heteroaryl. Examples of heterocyclyl groups include, but are not limited to, tetrahydropyranyl, dihydropyranyl, piperidinyl, piperazinyl, pyrrolidinyl, thiazolinyl, thiazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, 2,3-dihydrobenzo[b]thiophen-2-yl, 4-amino-2-oxopyrimidine 1( 2H)-yl and the like.

Halogen refers to fluorine, chlorine, bromine or iodine. In another embodiment, the halogen is fluorine. In another embodiment, the halogen is bromine.

Heteroalkyl refers to alkyl that is substituted with an alkoxy group. Examples of the heteroalkyl group include, but are not limited to, methoxymethyl, ethoxymethyl, and the like. Oxo belongs to the =O group.

Substituted, in the context of this document, means that any one or more hydrogen atoms in the specified atom or group is replaced by one or more substituents other than hydrogen, provided that the normal valence of the specified atom is not exceeded. One or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ether, cyano, guanidino, halogen, haloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof.

Optionally substituted, as used herein, means that a group may be unsubstituted or substituted with one or more (eg, 1, 2, 3, 4, or 5) substituents listed for that group in which the substituents may be the same or different. In one embodiment, the optionally substituted group has one substituent. In another embodiment, the optionally substituted group has two substituents. In another embodiment, the optionally substituted group has three substituents. In another embodiment, the optionally substituted group has four substituents. In some embodiments, an optionally substituted group has 1 to 2, 2 to 5, 3 to 5, 2 to 3, 2 to 4, 3 to 4, 1 to 3, 1 to 4, or 1 up to 5 deputies. It is understood that when a chemical moiety herein is optionally substituted, the description includes embodiments in which the moiety is substituted and embodiments in which the moiety is unsubstituted. A protecting group, as used herein, unless expressly stated or implied otherwise, refers to a moiety that prevents or substantially reduces the ability of the atom or functional group to which it is associated to participate in undesired reactions. Typical protecting groups for atoms or functional groups are given in Greene (2014), Protective groups in organic synthesis, ^5th ed., Wiley Interscience. Protecting groups for heteroatoms such as oxygen, sulfur and nitrogen are sometimes used to minimize or prevent their unwanted reactions with electrophilic compounds. In other cases, a protecting group is used to reduce or eliminate the nucleophilicity and/or basicity of an unprotected heteroatom. Non-limiting examples of protected oxygen are given as -OR ^P R, where R ^pr is a protecting group for hydroxyl, where in some embodiments, the hydroxyl is protected as an ester (eg, acetate, propionate, or benzoate). Other protecting groups for hydroxyl avoid its effect on the nucleophilicity of organometallic reagents or other highly basic reagents, whereby in some embodiments, the hydroxyl is protected as an ether, including, without limitation, alkyl or heterocyclyl ethers (e.g., methyl or tetrahydropyranyl ethers), alkoxymethyl ethers (e.g., , methoxymethyl or ethoxymethyl ethers), optionally substituted aryl ethers and silyl ethers (e.g. trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldiphenylsilyl (TBDPS), tert

- 6 042013 butyldimethylsilylsilyl (TBS/TBDPS), triisopropylsilyl (TIPS) and [2-(trimethylsilyl)ethoxy]methylsilyl (SEM)). Nitrogen protecting groups include groups for primary or secondary amines such as -NHRPR or -N(R ^pr ) ₂ where at least one of R ^pr is a nitrogen atom protecting group or both RPRs together define a nitrogen atom protecting group .

A protecting group is suitable for protection when it is capable of preventing or substantially preventing unwanted side reactions and/or premature loss of the protecting group under the reaction conditions required to effect the desired chemical transformation(s) in other parts of the molecule and during the purification of the newly formed molecule, if necessary. , and can be removed under conditions that do not adversely affect the structure or stereochemical integrity of the newly formed molecule. In some aspects, suitable protecting groups are those previously described for protecting functional groups. For example, a suitable protecting group for the basic nitrogen atom of an acyclic or cyclic basic group is an acid-labile carbamate protecting group such as tert-butyloxycarbonyl (Boc).

Each compound disclosed herein may be in the form of a salt. The compound may contain at least one amino group, and accordingly acid addition salts may be formed with this amino group. Representative salts include, without limitation, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, hydrogen phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e. 1,1'-methylene-bis-(2hydroxy-3- naphthoate)).

The salt may include the addition of another molecule such as an acetate ion, a succinate ion, or another counterion. The counterion can be any organic or inorganic moiety that stabilizes the charge of the parent compound. In addition, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Examples where multiple charged atoms are part of a pharmaceutically acceptable salt may have multiple counterions. Therefore, a salt may have one or more charged atoms and/or one or more counterions.

A pharmaceutically acceptable salt refers to salts that have toxicity profiles within a range that is useful in pharmaceutical applications. In some embodiments, the pharmaceutically acceptable salt is selected from those described in P. H. Stahl and C. G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim/Zurich: WileyVCH/VHCA, 2002. The choice of salt depends on properties to be exhibited by the medicinal product, including adequate solubility in water at different pH values, depending on the intended route(s) of administration, crystallinity with flow characteristics and low hygroscopicity (i.e. water absorption depending on relative humidity) suitable for processing , and the desired shelf life by determining chemical and solid state stability under accelerated conditions (ie, to determine degradation or change in solid state when stored at 40°C and 75% relative humidity).

Ways

In one aspect, provided herein is a process for preparing a compound of formula (1)

or a salt thereof, comprising (i) reacting a compound of formula (1A)

CN

MeO OMe(-|D) with 2-chloro-3-fluoropyridine to form a compound of formula (1B) ^NC x ^N

MeO OMe (1B);

(ii) reacting a compound of formula (1B) with an aqueous acid solution to form a compound of formula (1C)

- 7 042013

and (iii) converting a compound of formula (1C) to a compound of formula (1) or a salt thereof.

In some embodiments, step (i) is performed in the presence of a base. In some embodiments, the base is inorganic. Examples of inorganic bases include, without limitation, potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, magnesium hydroxide, lithium hydroxide, sodium t-butoxide, potassium carbonate, sodium bis(trimethylsilyl)amide, and the like. In some embodiments, the base is organic. Examples of organic bases include, without limitation, N,Ndiisopropylethylamine, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N,Ndimethylethanolamine, tris(hydroxymethyl)aminomethane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine and N-methylglucamine. In some embodiments, the base is sodium bis(trimethylsilyl)amide.

In some embodiments, step (i) is performed in an organic solvent. Examples of organic solvents include, without limitation, hexane, pentane, cyclopentane, cyclohexane, benzene, toluene, 1,4-dioxane, dichloromethane (DCM), chloroform, ethyl acetate, tetrahydrofuran (THF), dichloromethane, acetone, acetonitrile (MeCN), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1,3dimethyl-2-imidazolidinone (DMI), acetic acid, n-butanol, isopropanol, n-propanol, ethanol and methanol, and the like. In some embodiments, the organic solvent is any compatible mixture of organic solvents, such as those exemplified herein. In some embodiments, the organic solvent does not contain water. In some embodiments, the organic solvent contains water. In some embodiments, step (i) is carried out in toluene. It is understood that each description of an organic solvent can be combined with each description of the base in the same way as if each and every combination were specifically and individually listed. For example, in some embodiments, step (i) is carried out in toluene in the presence of sodium bis(trimethylsilyl)amide.

In some embodiments, step (i) is carried out at a temperature of about 100°C, about 90°C, about 80°C, about 70°C, about 60°C, about 50°C, about 40°C, about 30°C , approximately 20°C, approximately 10°C, approximately 0°C, approximately minus 10°C, approximately minus 20°C, approximately minus 30°C, approximately minus 40°C, approximately minus 50°C or approximately minus 60° C. In some embodiments, step (i) is conducted at a temperature of less than about 100°C, about 90°C, about 80°C, about 70°C, about 60°C, about 50°C, about 40°C, about 30°C, approximately 20°C, approximately 10°C, approximately 0°C, approximately -10°C, approximately -20°C, approximately -30°C, approximately -40°C, approximately -50°C or approximately minus 60°C. In some embodiments, step (i) is carried out at a temperature of at least about 100°C, about 90°C, about 80°C, about 70°C, about 60°C, about 50°C, about 40°C, about 30°C, approximately 20°C, approximately 10°C, approximately 0°C, approximately -10°C, approximately -20°C, approximately -30°C, approximately -40°C, approximately -50°C or approximately minus 60°C. In some embodiments, step (i) is carried out at a temperature between about 10°C and about minus 60°C, between about 0°C and about minus 60°C, between about minus 10°C and about minus 60°C, between about 10°C and approximately minus 40°C, between approximately 0°C and approximately minus 40°C, between approximately minus 10°C and approximately minus 40°C, between approximately 10°C and approximately minus 30°C, between approximately 0 °C and approximately minus 30°C or between approximately minus 10°C and approximately minus 30°C. In some embodiments, step (i) is carried out at a temperature of approximately minus 20°C. It is understood that each description of the temperature can be combined with each description of the base and/or organic solvent in the same way as if each and every combination were specifically and individually listed. For example, in some embodiments, step (i) is carried out in toluene in the presence of sodium bis(trimethylsilyl)amide at a temperature of approximately minus 20°C.

In some embodiments, the aqueous acid of step (ii) is an inorganic acid. Examples of inorganic acids include, without limitation, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like. In some embodiments, the aqueous acid of step (ii) is an organic acid. Examples of organic acids include acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, pyranosidilic acid and the like. In some embodiments, the aqueous acid is any compatible mixture of acids, such as those exemplified herein. In some embodiments, the aqueous acid of step (ii) is hydrochloric acid.

In some embodiments, step (ii) is carried out at a temperature of about 100°C, about 90°C, about 80°C, about 70°C, about 60°C, about 50°C, about 40°C, about 30°C , approximately 20°C, approximately 10°C or approximately 0°C. In some embodiments, step (i) is conducted at a temperature of less than about 100°C, about 90°C, about 80°C, about 70°C, about 60°C, about 50°C, about 40°C, about 30°C, approximately 20°C or approximately 10°C. In some embodiments, step (i) is carried out at a temperature of at least about 90°C, about 80°C, about 70°C, about 60°C, about 50°C, about 40°C, about 30°C, about 20°C, approximately 10°C or approximately 0°C. In some embodiments, step (ii) is carried out at a temperature of approximately 50°C. It is understood that each temperature description can be combined with each aqueous acid description just as if each and every combination were specifically and individually listed. For example, in some embodiments, step (ii) is carried out in the presence of hydrochloric acid at a temperature of approximately 50°C.

In some embodiments, step (iii) comprises converting a compound of formula (1C) to a compound of formula (1G) he f NC VN \=/ (IS), and converting a compound of formula (1G) to a compound of formula (1) or a salt thereof. In some embodiments, the conversion of a compound of formula (1C) to a compound of formula (1G) is carried out in a mixture of DCM and methanol. In some embodiments, the conversion of a compound of formula (1C) to a compound of formula (1G) is carried out in the presence of NaBH ₄ . In some embodiments, the conversion of a compound of formula (1C) to a compound of formula (1G) is carried out at a temperature of approximately minus 78°C.

In some embodiments, step (iii) further comprises converting a compound of formula (1G) to a compound of formula (1H)

and converting the compound of formula (1H) into a compound of formula (1) or a salt thereof. In some embodiments, the conversion of a compound of formula (1G) to a compound of formula (1H) is carried out in DCM. In some embodiments, the conversion of a compound of formula (1G) to a compound of formula (1H) is carried out in the presence of diethylaminosulfur trifluoride (DAST). In some embodiments, the conversion of a compound of formula (1G) to a compound of formula (1H) is carried out at a temperature between about 0°C and about 10°C.

In some embodiments, step (iii) further comprises converting a compound of formula (1H) to a compound of formula (1I)

and converting the compound of formula (1I) into a compound of formula (1) or a salt thereof. In some embodiments, the conversion of a compound of formula (1H) to a compound of formula (1I) is carried out in methanol. In some embodiments, the conversion of a compound of formula (1H) to a compound of formula (1I) is carried out in the presence of Raney nickel. In some embodiments, the conversion of a compound of formula (1H) to a compound of formula (1I) is carried out in the presence of ammonia. In some embodiments, step (iii) further comprises reacting a compound of formula (1I) with

- 9 042013

where X is chlorine or fluorine to form a compound of formula (1J)

where Z is a protecting group or hydrogen, and the conversion of a compound of formula (1J) into a compound of formula (1) or a salt thereof. In some embodiments, X is chlorine. In some embodiments, X is fluoro. In some embodiments, Z is Boc. In some embodiments, Z is hydrogen. In some embodiments, the conversion of a compound of formula (1I) to a compound of formula (1J) is carried out in the presence of NMP. In some embodiments, the conversion of a compound of formula (1I) to a compound of formula (1J) is carried out in the presence of DIPEA. In some embodiments, the conversion of a compound of formula (1I) to a compound of formula (1J) is carried out in the presence of DMAP. In some embodiments, the conversion of a compound of formula (1I) to a compound of formula (1J) is carried out in the presence of Boc ₂ O. In some embodiments, the conversion of a compound of formula (1I) to a compound of formula (1J) is carried out in the presence of THF. In some embodiments, the conversion of a compound of formula (1I) to a compound of formula (1J) is carried out at a temperature of approximately 60°C. In some embodiments, step (iii) is added

significantly includes reacting a compound of formula (1J) with NC of formula (1K) to form a compound

where Z is a protecting group or hydrogen, and converting a compound of formula (1K) to a compound of formula (1) or a salt thereof. In some embodiments, Z is Boc. In some embodiments, Z is coH

fight hydrogen. In some embodiments, the reaction of a compound of formula (1J) with ^NC is carried out in toluene. In some embodiments, the reaction of a compound of formula (1J) with ^NC is carried out in the presence of copper iodide. In some embodiments, the reaction of a compound of formula (1J) with

H

NC

carried out in the presence of potassium phosphate. In some embodiments, the reaction of a compound of formula (1J) with ^NC

carried out in the presence of trans-N,N'-dimethylcyclohexane-1,2-diamine. In some embodiments, the reaction of a compound of formula (1J) with a temperature of approximately 100°C.

carried out at tempera In some embodiments, step (iii) comprises isolating a compound of formula (1) or a salt thereof.

In some embodiments, a method for preparing a compound of formula (1) or a salt thereof further comprises preparing a compound of formula (1A) by reacting a compound of formula (2A)

MeO OMe ^X VX^ ^x2 ₍ 2A),

- 10 042013 where X ¹ and X ² each independently represents a substitutable group, with a compound of formula (2B)

O NCL A .R O (2B), where R is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, or an optionally substituted heteroaryl, to form a compound of formula (1A).

In some embodiments, X ¹ and X ² are independently halogen, triflate, tosylate, mesylate, or acetoxy. In some embodiments, X ¹ and X ² are independently halogen. In some embodiments, X ¹ and X ² are both fluoro. In some embodiments, X ¹ and X ² are both chlorine. In some embodiments, X ¹ and X ² are both bromine. In some embodiments, X ¹ and X ² are both iodine. In some embodiments, X ¹ and X ² are different. In some embodiments, X ¹ is fluoro. In some embodiments, X ¹ is chlorine. In some embodiments, X ¹ is bromine. In some embodiments, X ¹ is iodine. In some embodiments, X ² is fluoro. In some embodiments, X ² is chlorine. In some embodiments, X ² is bromine. In some embodiments, X ² is iodine. It is understood that each description of X ¹ can be combined with each description of X ² in the same way as if each and every combination were specifically and individually listed. In some embodiments, R is an optionally substituted alkyl. In some embodiments, R is unsubstituted alkyl. In some embodiments, R is an optionally substituted linear alkyl. In some embodiments, R is an optionally substituted branched alkyl. In some embodiments, R is an optionally substituted C ₁ -C ₆ alkyl. In some embodiments, R is an optionally substituted linear C ₁ -C ₆ alkyl. In some embodiments, R is an optionally substituted C ₁ -C ₆ branched alkyl. In some embodiments, R is t-butyl.

It is understood that each description of X ¹ and/or X ² can be combined with each description of R in the same way as if each and every combination were specifically and individually listed. In some embodiments, the compound of formula (2A) is 1,3-dibromo-2,2-dimethoxypropane and the compound of formula (2B) is t-butyl 2-cyanoacetate.

In some embodiments, the reaction of a compound of formula (2A) (eg, 1,3-dibromo-2,2dimethoxypropane) with a compound of formula (2B) (eg, t-butyl 2-cyanoacetate) is carried out in the presence of a base. In some embodiments, the base is an inorganic base. Examples of inorganic bases include, without limitation, potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, magnesium hydroxide, lithium hydroxide, sodium t-butoxide, potassium carbonate, sodium bis(trimethylsilyl)amide, and the like. In some embodiments, the base is an organic base. Examples of organic bases include, without limitation, N,N-diisopropylethylamine, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N,N-dimethylethanolamine, tris(hydroxymethyl)aminomethane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine and N-methylglucamine. In some embodiments, the base is any compatible mixture of bases, such as those exemplified herein. In some embodiments, the base is potassium tert-butoxide. It is understood that each description of the base can be combined with each description of X ¹ , X ² and/or R in the same way as if each and every combination were specifically and individually listed. For example, in some embodiments, the compound of formula (2A) is 1,3dibromo-2,2-dimethoxypropane; the compound of formula (2B) is t-butyl 2-cyanoacetate; and the base is potassium tert-butoxide.

In some embodiments, the reaction of a compound of formula (2A) (eg, 1,3-dibromo-2,2dimethoxypropane) with a compound of formula (2B) (eg, t-butyl 2-cyanoacetate) is carried out in an organic solvent. Examples of organic solvents include, without limitation, hexane, pentane, cyclopentane, cyclohexane, benzene, toluene, 1,4-dioxane, chloroform, ethyl acetate, tetrahydrofuran (THF), dichloromethane, acetone, dimethylacetamide (DMAc), acetonitrile (MeCN) dimethylformamide ( DMF), dimethyl sulfoxide (DMSO), 1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidone (NMP), acetic acid, n-butanol, isopropanol, n-propanol, ethanol and methanol, and the like. In some embodiments, the organic solvent is any compatible mixture of organic solvents, such as those exemplified herein. In some embodiments, the organic solvent does not contain water. In some

- 11 042013 In some embodiments, the organic solvent contains water. In some embodiments, the organic solvent is selected from the group consisting of DMI, DMAc, DMSO, and NMP. In some embodiments, the organic solvent is DMY. In some embodiments, the organic solvent is DMAc. In some embodiments, the organic solvent is DMSO. In some embodiments, the organic solvent is NMP. It is understood that each description of an organic solvent can be combined with each description of X ¹ , X ² , R and/or base, just as if each and every combination were specifically and individually listed. For example, in some embodiments, the compound of formula (2A) is 1,3-dibromo-2,2-dimethoxypropane; the compound of formula (2B) is t-butyl 2-cyanoacetate; and the base is potassium t-butoxide and the organic solvent is DMI.

In some embodiments, the reaction of a compound of formula (2A) (e.g., 1,3-dibromo-2,2dimethoxypropane) with a compound of formula (2B) (e.g., t-butyl 2-cyanoacetate) is carried out at a temperature of about 200°C, about 190° C, approximately 180°C, approximately 170°C, approximately 160°C, approximately 150°C, approximately 140°C, approximately 130°C, approximately 120°C, approximately 110°C, approximately 100°C, approximately 90° C, approximately 80°C, approximately 70°C, approximately 60°C, approximately 50°C, approximately 40°C, approximately 30°C, approximately 20°C, approximately 10°C, approximately 0°C, approximately minus 10 °C, approximately minus 20°C or approximately minus 30°C. In some embodiments, the reaction of a compound of formula (2A) (e.g., 1,3-dibromo-2,2-dimethoxypropane) with a compound of formula (2B) (e.g., t-butyl 2-cyanoacetate) is carried out at a temperature of less than about 200° C, approximately 190°C, approximately 180°C, approximately 170°C, approximately 160°C, approximately 150°C, approximately 140°C, approximately 130°C, approximately 120°C, approximately 110°C, approximately 100° C, approximately 90°C, approximately 80°C, approximately 70°C, approximately 60°C, approximately 50°C, approximately 40°C, approximately 30°C, approximately 20°C, approximately 10°C, approximately 0° C, approximately minus 10°C, approximately minus 20°C or approximately minus 30°C. In some embodiments, the reaction of a compound of formula (2A) (e.g., 1,3-dibromo-2,2-dimethoxypropane) with a compound of formula (2B) (e.g., t-butyl 2-cyanoacetate) is carried out at a temperature of at least about 200° C, approximately 190°C, approximately 180°C, approximately 170°C, approximately 160°C, approximately 150°C, approximately 140°C, approximately 130°C, approximately 120°C, approximately 110°C, approximately 100° C, approximately 90°C, approximately 80°C, approximately 70°C, approximately 60°C, approximately 50°C, approximately 40°C, approximately 30°C, approximately 20°C, approximately 10°C, approximately 0° C, approximately minus 10°C, approximately minus 20°C or approximately minus 30°C. In some embodiments, the reaction of a compound of formula (2A) (e.g., 1,3-dibromo-2,2-dimethoxypropane) with a compound of formula (2B) (e.g., t-butyl 2-cyanoacetate) is carried out at a temperature between about 200°C and between about 100°C, between about 200°C and about 110°C, between about 200°C and about 120°C, between about 200°C and about 130°C, between about 200°C and about 140°C, between between about 180°C and about 100°C, between about 180°C and about 110°C, between about 180°C and about 120°C, between about 180°C and about 130°C, between about 180°C and about 140°C, between approximately 160°C and approximately 100°C, between approximately 160°C and approximately 110°C, between approximately 160°C and approximately 120°C, between approximately 190°C and approximately 130°C, or between approximately 160°C and approximately 140°C. In some embodiments, the reaction of a compound of formula (2A) (eg, 1,3-dibromo-2,2-dimethoxypropane) with a compound of formula (2B) (eg, t-butyl 2-cyanoacetate) is carried out at a temperature of about 150°C. In some embodiments, the reaction of a compound of formula (2A) (eg, 1,3-dibromo-2,2dimethoxypropane) with a compound of formula (2B) (eg, t-butyl 2-cyanoacetate) is carried out at a temperature of approximately 160°C. It is understood that each description of temperature can be combined with each description of X ¹ , X ² , R, base and/or organic solvent, just as if each and every combination were specifically and individually listed. For example, in some embodiments, the compound of formula (2A) is 1,3-dibromo-2,2-dimethoxypropane; the compound of formula (2B) is t-butyl-2-cyanoacetate; the base is potassium tert-butoxide; the base is DMI; and the reaction of 1,3-dibromo-2,2-dimethoxypropane and tert-butyl-2-cyanoacetate is carried out at a temperature of approximately 150°C.

In some embodiments, a compound of formula (2A) (eg, 1,3-dibromo-2,2dimethoxypropane), a compound of formula (2B) (eg, t-butyl 2-cyanoacetate), and a base are added sequentially to the organic solvent. In some embodiments, a compound of formula (2A) (eg, 1,3-dibromo-2,2-dimethoxypropane), a base, and a compound of formula (2B) (eg, t-butyl 2-cyanoacetate) are added sequentially to an organic solvent. In some embodiments, a compound of formula (2B) (e.g., tert-butyl 2-cyanoacetate), compound

- 12 042013 formula (2A) (for example, 1,3-dibromo-2,2-dimethoxypropane) and the base are added successively to the organic solvent. In some embodiments, a compound of formula (2B) (eg, tert-butyl 2-cyanoacetate), a base, and a compound of formula (2A) (eg, 1,3-dibromo-2,2-dimethoxypropane) are added sequentially to an organic solvent. In some embodiments, a base, a compound of formula (2A) (eg, 1,3-dibromo-2,2-dimethoxypropane), and a compound of formula (2B) (eg, t-butyl 2-cyanoacetate) are added sequentially to the organic solvent. In some embodiments, a base, a compound of formula (2B) (eg, tert-butyl 2-cyanoacetate), and a compound of formula (2A) (eg, 1,3-dibromo-2,2dimethoxypropane) are added sequentially to the organic solvent. In some embodiments, a compound of formula (2A) (eg, 1,3-dibromo-2,2-dimethoxypropane), a compound of formula (2B) (eg, t-butyl 2-cyanoacetate), and a base are simultaneously added to the organic solvent.

In some embodiments, the reaction product of a compound of formula (2A) (eg, 1,3dibromo-2,2-dimethoxypropane) with a compound of formula (2B) (eg, t-butyl 2-cyanoacetate) is distilled prior to use in step (i). In some embodiments, a method for making a compound of formula (1) or a salt thereof further comprises making a compound of formula (1A) by converting a compound of formula (1D)

MeO OMe

CONH2 (1D) to a compound of formula (1A). In some embodiments, the conversion of a compound of formula (1D) to a compound of formula (1A) is carried out in toluene. In some embodiments, the conversion of a compound of formula (1D) to a compound of formula (1A) is carried out in the presence of TEA. In some embodiments, the conversion of a compound of formula (1D) to a compound of formula (1A) is carried out in the presence of TFAA. In some embodiments, the conversion of a compound of formula (1D) to a compound of formula (1A) is carried out at a temperature of approximately 0°C.

In some embodiments, the method further comprises obtaining a compound of formula (1D) by converting a compound of formula (1E)

Meo ome

COOMe (1E) to a compound of formula (1D). In some embodiments, the conversion of a compound of formula (1E) to a compound of formula (1D) is carried out in methanol. In some embodiments, the conversion of a compound of formula (1E) to a compound of formula (1D) is carried out in the presence of ammonia. In some embodiments, the conversion of a compound of formula (1E) to a compound of formula (1D) is carried out at a temperature of approximately 40°C.

In some embodiments, the method further comprises obtaining a compound of formula (1E) by converting a compound of formula (1F)

ABOUT

COOH(1F) to a compound of formula (1E). In some embodiments, the conversion of a compound of formula (1F) to a compound of formula (1E) is carried out in methanol. In some embodiments, the conversion of a compound of formula (1F) to a compound of formula (1E) is carried out in the presence of Amberlyst-15. In some embodiments, the conversion of a compound of formula (1F) to a compound of formula (1E) is carried out in the presence of trimethoxymethane. In some embodiments, the conversion of a compound of formula (1F) to a compound of formula (1E) is carried out at a temperature of approximately 55°C.

In another aspect, provided herein is a compound of formula (1B)

or its salt.

In another aspect, provided herein is a process for preparing a compound of formula

- 13 042013 (1B) or its salts, where the method is as described in this document.

In another aspect, provided herein is a compound of formula (1D) MeO OMe

CONH2 (1D), or its salt.

In another aspect, provided herein is a process for preparing a compound of formula (1D) or a salt thereof, wherein the process is as described herein.

Synthesis schemes

Certain methods provided herein are described with reference to the illustrative synthesis schemes shown below and the specific examples that follow. Certain reactions and transformations described herein can be carried out using methods known in the art. For example, US Pat. No. 8,962,632, WO 2011/133920, WO 2011/133888, and WO 2011/133882 describe methods and reagents that can be used to synthesize certain compounds described herein. Those of skill in the art will appreciate that in order to prepare the various compounds provided herein, the starting materials may be appropriately selected such that the final desired substituents will be carried through the reaction scheme, with or without protection, as appropriate, to obtain the desired product. Alternatively, it may be necessary or desirable to use, in place of the final desired substituent, a suitable group that can be carried around in the reaction scheme and replaced, if necessary, with the desired substituent. In addition, one skilled in the art will appreciate that protecting groups can be used to protect certain functional groups (amino, carboxy, or side chains) from reaction conditions and that such groups are removed under standard conditions when necessary.

Where it is desired to obtain a particular enantiomer of a compound, this may be done from the appropriate mixture of enantiomers using any suitable conventional procedure for isolating or separating enantiomers. Thus, for example, diastereomeric derivatives can be prepared by reacting a mixture of enantiomers, such as a racemate, and the corresponding chiral compound. The diastereomers can then be separated by any convenient means, such as crystallization, and the desired enantiomer can be obtained. In another isolation method, the racemate can be separated using chiral high performance liquid chromatography. Alternatively, if desired, a particular enantiomer can be obtained using an appropriate chiral intermediate in one of the methods described.

Chromatography, recrystallization, and other conventional separation techniques may also be used with intermediates or end products when it is desired to obtain a particular isomer of a compound or otherwise purify a reaction product.

The abbreviations used in this document are explained in the following table.

Abbreviations.

Reduction Meaning DIPEA Ν,Ν-diisopropyl-M-ethylamine DMF Ν,Ν-dimethylformamide tBuOK potassium tert-butoxide DMI 1,3-dimethyl-2-imidazolidinone NaHMDS sodium bis(trimethylsilyl)amide NS(OMe) ₃ trimethylorthoformate Meon methanol Me methyl Et ₃ N triethylamine NMP N-methylpyrrolidone Vos ₂ O di-tert-butyl dicarbonate □MAP 4-dimethylaminopyridine

- 14 042013

THF tetrahydrofuran TFK trifluoroacetic acid AC2O acetic anhydride NaOMe sodium methoxide DMSO dimethyl sulfoxide Tos-CI 4-toluenesulfonyl chloride DAST diethylaminosulfur trifluoride k.t. room temperature us. saturated EtOAc ethyl acetate MTVE methyl tert-butyl ether TFAA trifluoroacetic anhydride TEA triethanolamine RE petroleum ether DXM dichloromethane

Scheme 1.

Scheme 1 illustrates a scheme for the synthesis of the compound of formula (1C).

Meo ome

Bg^X^Br ⁺

1ViOK, DMI 150°С

Scheme 2.

Scheme 2 illustrates an alternative synthesis scheme for the compound of formula (1C). O

HC (OMe) _{3 MeO OMe} NH ₃ (g)

Amberlyst-15X

MeO. OME

TFAA

Et ₃ N

MeOH 65°C

Meo Oh

MeO. OME

CI

Meon

NaHMDS, toluene

-20°C

_H2N ^O

CN toluene

25°C

- 15 042013

Scheme 3.

Scheme 3 illustrates a scheme for converting a compound of formula (1C) to a compound of formula (11).

Scheme 4.

Scheme 4 illustrates a scheme for converting a compound of formula (1I) to a compound of formula (1).

Examples

Example 1 Synthesis of 3,3-dimethoxycyclobutane-1-carbonitrile.

MeO. OMe vg<X^.vg

1ViOK, DMI 150°C

Meo ome

CN

N-methylpyrrolidone (30 ml), tert-butylcyanoacetate (8.08 g) was added to the flask at room temperature. Potassium tert-butoxide (7.71 g), 1,3-dibromo-2,2-dimethoxypropane (5.00 g) was added to the resulting solution at 0°C. Potassium iodide (158 mg), 2,6-di-tert-butyl-cresol (42 mg), N-methylpyrrolidone (25 ml) were added to another flask at room temperature, and then the resulting solution was heated to 165°C. To this solution, the pre-mixture was added dropwise at 140-165°C, then stirred for 2 hours at 165°C. Water (65 ml) was added to the reaction mixture. The resulting solution was extracted with toluene (40 ml, three times) and then the combined organic layer was washed with water (20 ml, three times) and 1N. aqueous NaOH (20 ml). The resulting organic layer was concentrated below 50°C under reduced pressure to give 3,3dimethoxycyclobutane-1-carbonitrile (66% yield, GC analysis) as a toluene solution. 1H NMR (CDCl ₃ , 400 MHz) δ 3.17 (s, 3H), 3.15 (s, 3H), 2.93-2.84 (m, 1H), 2.63-2.57 (m , 2H), 2.52-2.45 (m, 2H).

- 16 042013

Example 2 Synthesis of methyl 3,3-dimethoxycyclobutane-1-carboxylate.

The reactor was evacuated to 0.02 MPa or less, and then nitrogen was introduced into the atmosphere three times. MeOH (339.00 kg), 3-oxocyclobutanecarboxylic acid (85.19 kg, 746.6 mol, 1.0 eq.), Amberlyst-15 ion exchange resin (8.90 kg, 10% w/w) and trimethoxymethane (196.00 kg, 1847.3 mol, 2.5 eq.) was charged into the reactor and the resulting mixture was heated to 55±5° C. and reacted for 6 hours to give a solution of methyl 3,3-dimethoxycyclobutane-1 -carboxylate to MeOH. 1H NMR (CDCl ₃ , 400 MHz) δ 3.70 (s, 3H), 3.17 (s, 3H), 3.15 (s, 3H), 2.94-2.85 (m, 1H), 2.47-2.36 (m, 4H).

Example 3 Synthesis of 3,3-dimethoxycyclobutane-1-carboxamide.

A solution of methyl 3,3-dimethoxycyclobutane-1-carboxylate in MeOH, prepared as described in Example 2, was cooled to below 25° C. and centrifuged. The filter cake was washed with MeOH (7.00 kg) and the filtrate was pumped into the reactor. The solution was concentrated in vacuo below 55° C. until the system had no more than 2 volumes. MeOH (139.40 kg) was loaded into the reactor and the solution was concentrated in vacuo below 55° C. until the system had no more than 2 volumes. MeOH (130.00 kg) was loaded into the reactor and the solution was concentrated in vacuo below 55° C. until the system had no more than 2 volumes. Half of the resulting solution was diluted with MeOH (435.00 kg) and cooled to a temperature below 30°C. NH ₃ gas (133.80 kg) was introduced into the reactor at a temperature below 35°C for 24 hours. The mixture was stirred at 40±5°C for 72 hours. The resulting solution was concentrated in vacuo at a temperature below 50°C until until the system had no more than 2 volumes. MTBE (181.00 kg) was loaded into the reactor. The resulting solution was concentrated in vacuo below 50° C. until the system had no more than 2 volumes. PE (318.00 kg) was loaded into the reactor. The resulting mixture was cooled to 5±5°C, stirred for 4 h at 5±5°C and centrifuged. The filter cake was washed with PE (42.00 kg) and the wet filter cake was placed in a vacuum oven. The filter cake was dried at 30±5° C. for at least 8 hours to give 3,3-dimethoxycyclobutane-1-carboxamide as an off-white solid (112.63 kg, 94.7% yield). ¹ H NMR (CDCl ₃ , 400 MHz) δ 5.76 (bs, 1H), 5.64 (bs, 1H), 3.18 (s, 3H), 3.17 (s, 3H), 2.84 -2.76 (m, 1H), 2.45-2.38 (m, 4H).

Example 4 Synthesis of 3,3-dimethoxycyclobutane-1-carbonitrile.

The reactor was evacuated to 0.02 MPa or less, and then nitrogen was introduced into the atmosphere three times. Toluene (500.00 kg), 3,3-dimethoxycyclobutane-1-carboxamide (112.54 kg, 706.9 mol, 1.0 eq) and TEA (158.00 kg, 1561.3 mol, 2.20 equiv.) was loaded into the reactor and the resulting mixture was cooled to 0±5°C. TFAA (164.00 kg, 781 mol, 1.10 eq.) was added dropwise at 0±5°C. The resulting mixture was stirred for 10 hours at 20±5°C and cooled to a temperature below 5±5°C. H ₂ O (110.00 kg) was loaded into the reactor at a temperature below 15°C. The resulting mixture was stirred for 30 minutes and the aqueous phase was separated. The aqueous phase was extracted twice with toluene (190.00 kg). The organic phases were combined and washed with water (111.00 kg). H ₂ O was removed by azeotrope until the water content was no more than 0.03%. The resulting solution was cooled to below 20°C to give a solution of 3,3-dimethoxycyclobutane-1carbonitrile in toluene (492.00 kg with 17.83% assay, 87.9% yield).

Example 5 Synthesis of 1-(3-fluoropyridin-2-yl)-3,3-dimethoxycyclobutane-1-carbonitrile.

The reactor was evacuated to 0.02 MPa or less, and then nitrogen was introduced into the atmosphere three times. A solution of 3,3-dimethoxycyclobutane-1-carbonitrile in toluene prepared as described in Example 4 (246.00 kg

- 17 042013

17.8% solution of 3,3-dimethoxycyclobutane-1-carbonitrile in toluene, 1.05 eq.) and 2-chloro-3fluoropyridine (39.17 kg, 297.9 mol, 1.00 eq.) were loaded into reactor. The reactor was evacuated to 0.02 MPa or less, and then nitrogen was introduced into the atmosphere three times. The mixture was slowly cooled to minus 20±5°C. NaHDMS (2 M in THF) (165.71 kg, 1.20 eq.) was added dropwise at minus 20±5°C. The resulting mixture was stirred at minus 15±5°C for 1 hour, the Mixture was stirred until the content of 2chloro-3-fluoropyridine was not more than 2% according to HPLC. Soft water (16.00 kg) was added dropwise at a temperature below 0° C. while maintaining the temperature of the reactor. The resulting solution was transferred to another reactor. Water NH4C1 (10% w/w, 88.60 kg) was added dropwise below 0° C. while maintaining the reactor temperature. Soft water (112.00 kg) was charged to the reactor and the aqueous phase was separated and collected. The aqueous phase was extracted with ethyl acetate (70.00 kg) and the organic phase was collected. The organic phase was washed with us. NaCl (106.00 kg) and collected. The above steps were repeated to obtain another batch of the organic phase. Two batches of the organic phase were concentrated in vacuo below 70° C. until the system had no more than 2 volumes. The resulting solution was cooled to a temperature below 30°C, obtaining a solution of 1-(3-fluoropyridin-2-yl)-3,3dimethoxycyclobutane-1-carbonitrile. 1H NMR (CDCl ₃ , 400 MHz) δ 8.42-8.38 (m, 1H), 7.50-7.45 (m, 1H), 7.38-7.33 (m, 1H), 3 .28 (s, 3H), 3.13 (s, 3H), 3.09-3.05 (m, 4H).

Example 6 Synthesis of 1-(3-fluoropyridin-2-yl)-3-oxocyclobutanecarbonitrile.

The reactor was evacuated to 0.02 MPa or less, and then nitrogen was introduced into the atmosphere three times. Water (603.00 kg) was added to the reactor and stirred. Concentrated HCl (157.30 kg) was loaded into the reactor at a temperature below 35°C. A solution of 1-(3-fluoropyridin-2-yl)-3,3-dimethoxycyclobutane-1carbonitrile prepared as described in Example 5 (206.00 kg) was charged into the reactor and the resulting mixture was heated to 50±5°C and the reaction was carried out for 3 hours at 50±5°C. The mixture was reacted until the content of 1-(3-fluoropyridin-2-yl)-3,3-dimethoxycyclobutane-1-carbonitrile was not more than 2.0% as measured by HPLC. The reaction mixture was cooled to below 30° C. and extracted with ethyl acetate (771.00 kg). The aqueous phase was collected and extracted with ethyl acetate (770.00 kg). The organic phases were combined and the combined organic phase was washed with soft water (290.00 kg) and brine (385.30 kg). The organic phase was concentrated in vacuo below 60° C. until the system had no more than 2 volumes. Propan-2-ol (218.00 kg) was loaded into the reactor. The organic phase was concentrated in vacuo below 60°C until the system had no more than 1 volume. PE (191.00 kg) was loaded into the reactor at 40±5°C, and the resulting mixture was heated to 60±5°C and stirred for 1 hour at 60±5°C. The mixture was then slowly cooled to 5±5°C and stirred for 5 hours at 5±5°C. The mixture was centrifuged and the filter cake was washed with PE (48.00 kg) and the wet filter cake was collected. In this order, water (80.00 kg), concentrated HCl (2.20 kg), propan-2-ol (65.00 kg) and wet filter cake were loaded into the drum. The resulting mixture was stirred for 10 minutes at 20±5°C. The mixture was centrifuged and the filter cake was washed with a mixture containing 18.00 kg of propan-2-ol, 22.50 kg of soft water and 0.60 kg of concentrated HCl. The filter cake was placed in a vacuum oven and dried at 30±5° C. for at least 10 h. as an off-white solid (77.15 kg, 68.0% yield). 1H NMR (CDCI3, 400 MHz) δ 8.45-8.42 (m, 1H), 7.60-7.54 (m, 1H), 7.47-7.41 (m, 1H), 4.184, 09 (m, 2H), 4.02-3.94 (m, 2H).

Example 7 Synthesis of 1-(3-fluoropyridin-2-yl)-3-hydroxycyclobutanecarbonitrile.

OH OH

To a solution of 1-(3-fluoropyridin-2-yl)-3-oxocyclobutanecarbonitrile (231 g, 1.22 mol) in a mixture of DCM (2 L) and MeOH (200 ml) NaBH ₄ was added in portions at minus 78°C. The reaction mixture was stirred at minus 78°C for 1 h and quenched with a mixture of methanol and water (1:1). The organic layer was washed with water (500 mlx3), dried over Na ₂ SO ₄ and concentrated. The residue was purified on silica gel (50% EtOAc/hexanes) to give the title compound as an amber oil (185.8 g, 77.5%). Low Resolution Mass Spectrometry (LRMS) (M+H) mass/charge 193.2.

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Example 8 Synthesis of (1s,3s)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutane-1-carbonitrile

To a solution of 1-(3-fluoropyridin-2-yl)-3-hydroxycyclobutanecarbonitrile (185 g, 0.96 mol) in DCM (1 L) was added DAST portionwise at 0-10°C. Upon completion of the addition, the reaction mixture was refluxed for 6 hours. The reaction mixture was cooled to room temperature and poured into us. NaHCO ₃ solution. The mixture was separated and the organic layer was washed with water, dried over Na ₂ SO ₄ and concentrated. The residue was purified on silica gel (100% DCM) to give the title compound as a brown oil (116 g) in an 8:1 trans-cis mixture. The above brown oil (107 g) was dissolved in toluene (110 ml) and hexane (330 ml) at 70°C. The solution was cooled to 0°C and stirred at 0°C overnight. The precipitate was filtered off and washed with hexane to give the trans isomer as a white solid (87.3 g). MSNR (M+H) mass/charge 195.1.

Example 9 Synthesis of ((1r,3r)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methanamine.

A mixture of (1s,3s)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutan-1-carbonitrile (71 g, 0.37 mol) and Raney nickel (~7 g) in 7N ammonia in methanol ( 700 ml) was loaded with hydrogen (60 psi) for 2 days. The reaction mixture was filtered through a pad of celite and washed with methanol. The filtrate was concentrated under high vacuum to give the title compound as a light green oil (70 g, 97.6%). MSNR (M+H) mass/charge 199.2.

Example 10 Synthesis of tert-butyl-5-bromopyrimidin-2-yl((trans-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate.

Mixture of ((1g,3g)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methanamine (37.6g, 190mmol), 5-bromo2-fluoropyrimidine (32.0g, 181mmol) , DIPEA (71 ml, 407 mmol) and NMP (200 ml) were stirred at room temperature overnight. The reaction mixture was then diluted with EtOAc (1500 ml) and washed with saturated sodium bicarbonate (500 ml). The organic layer was separated, dried over Na ₂ SO ₄ and concentrated. The resulting solid was dissolved in THF (600 ml) followed by slow addition of DMAP (14 g, 90 mmol) and Boc ₂ O (117.3 g, 542 mmol). The reaction mixture was heated to 60° C. and stirred for 3 h. The reaction mixture was then concentrated and purified by silica gel chromatography (EtOAc/hexane) to give 59.7 g of tert-butyl 5-bromopyrimidin-2-yl((trans-3- fluoro-1-(3fluoropyridin-2-yl)cyclobutyl)methyl)carbamate as a white solid.

Example 11 Synthesis of tert-butyl 5-(3-cyano-1H-pyrrol-1-yl)pyrimidin-2-yl(((trans)-3-fluoro-1-(3fluoropyridin-2-yl)cyclobutyl)methyl) carbamate.

To a solution of tert-butyl-5-bromopyrimidin-2-yl((trans-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methyl) carbamate (1.0 g, 2.8 mmol) in 15 ml of toluene (degassed with nitrogen) were added copper iodide (100 mg, 0.6 mmol), potassium phosphate (1.31 g, 6.2 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (320 mg , 2.2 mmol) and 3-cyanopyrrole (310 mg, 3.6 mmol). The reaction mixture was heated to 100° C. and stirred for 2 hours. The reaction mixture was then concentrated and purified by silica gel chromatography (EtOAc/hexanes) to give 1.1 g of tert-butyl 5-(3-cyano-1H-pyrrole-1- yl)pyrimidin-2-yl(((trans)-3fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate as a clear oil.

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Claims (22)

Example 12 Synthesis of 1-(2-((((trans)-3-fluoro-1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)amino)pyrimidin-5-yl)-1H-pyrrol-3 -carboxamide. To a solution of tert-butyl-5-(3-cyano-1H-pyrrol-1-yl)pyrimidin-2-yl(((trans)-3-fluoro-1-(3-fluoropyridin2-yl)cyclobutyl)methyl)carbamate (1.1 g, 3.1 mmol) in DMSO (10 ml) was added potassium carbonate (1.3 g, 9.3 mmol). The mixture was cooled to 0° C. and hydrogen peroxide (3 ml) was added slowly. The reaction mixture was warmed to room temperature and stirred for 90 minutes. The reaction mixture was diluted with EtOAc (75 ml) and washed three times with brine (50 ml). The organic layer was then dried over Na ₂ SO ₄ , filtered and concentrated to give a crude solid which was purified by silica gel chromatography (10% MeOH/CH ₂ Cl ₂ ) to give 1.07 g of a white solid. This compound was dissolved in 25% TFA/CH2CI2 and stirred for 1 hour. The reaction mixture was then concentrated, dissolved in ethyl acetate (75 ml) and washed three times with saturated potassium carbonate solution. The organic layer was then dried over Na ₂ SO ₄ , filtered and concentrated to give a crude solid which was triturated with 75% ethyl acetate/hexanes. The resulting suspension was sonicated and filtered to give 500 mg of 1-(2-((((trans)-3-fluoro-1-(3fluoropyridin-2-yl)cyclobutyl)methyl)amino)pyrimidin-5-yl)-1H- pyrrole-3-carboxamide as a white solid. MSNR (M+H=385). While the foregoing written description of the methods, compounds, and compositions provided herein allows one of skill in the art to make and use the methods, compounds, and compositions described herein, those skilled in the art will understand and appreciate the possibility of variations, combinations, and equivalents. specific embodiment, method, schemes and examples in this document. The methods, compounds, and compositions provided herein are not to be limited to the embodiments, methods, schemes, or examples described above, but rather encompass all embodiments and methods within the scope and spirit of the methods, compounds, and compositions provided herein. Each reference disclosed herein is incorporated by reference in its entirety. CLAIM 1. Process for preparing the compound of formula (1) or a salt thereof, comprising (i) reacting a compound of formula (1A) CN MeO OMe(1D) with 2-chloro-3-fluoropyridine to form a compound of formula (1B) OMe (1B); (ii) reacting a compound of formula (1B) with an aqueous acid solution to form a compound of formula (1C) - 20 042013 (iii) converting a compound of formula (1C) to a compound of formula (1) or a salt thereof, wherein step (iii) comprises reacting a compound of formula (1C) with sodium borohydride to give a compound of formula (1G) reacting a compound of formula (1G) with diethylaminosulfur trifluoride (DAST) to give a compound of formula (1H) reaction of a compound of formula (1H) with hydrogen in the presence of Raney nickel to give a compound of formula (1I) reaction of a compound of formula (1I) with where X is chlorine or fluorine, followed by reaction with di-tert-butyl dicarbonate in the presence of 4-dimethylaminopyridine (DMAP) to give a compound of formula (1J) Vg ^F (U) where Z is a tert-butyloxycarbonyl (Boc) protecting group, H reacting a compound of formula (1J) with NC to form a compound of formula (1K) reacting a compound of formula (1K) with hydrogen peroxide in the presence of potassium carbonate followed by reacting with trifluoroacetic acid to form a compound of formula (1) or a salt thereof. 2. The method according to claim 1, where the reaction of the compound of formula (1H) with hydrogen in the presence of nickel Raney to obtain compounds of formula (1I) is carried out in the presence of ammonia. Z \u003d N ^{Br - x} 3. The process according to claim 1 or 2, wherein the reaction of a compound of formula (1I) with X is chlorine or fluorine is carried out in the presence of diisopropyl-N-ethylamine (DIPEA). - 21 042013 4. Process according to any one of claims 1 to 3, characterized in that the compound of formula (1A) is obtained by reacting 1,3-dibromo-2,2-dimethoxypropane with tert-butyl-2-cyanoacetate. 5. The method according to claim 4, characterized in that the reaction of 1,3-dibromo-2,2-dimethoxypropane with tert-butyl2-cyanoacetate is carried out in the presence of a base. 6. The method according to claim 5, characterized in that the base is potassium tert-butoxide. 7. The method according to any one of claims 1 to 3, characterized in that the compound of formula (1A) is obtained by reacting the compound of formula (1D) Meo ome ΌΝΗ2 (1D) with trifluoroacetic anhydride. 8. The method according to claim 7, characterized in that the compound of formula (1D) is obtained by reacting the compound of formula (1E) MeO _h oMe OOMe (1E) with ammonia. 9. The method according to claim 8, characterized in that the compound of formula (1E) is obtained by reacting the compound of formula (1F) ABOUT COOH(1F) with trimethoxymethane in the presence of Amberlyst-15. 10. Process according to any one of claims 1 to 9, characterized in that step (i) is carried out in the presence of a base. 11. The method according to p. 10, characterized in that the base is sodium bis(trimethylsilyl)amide. 12. The method according to any one of claims 1 to 11, characterized in that the aqueous acid solution of step (ii) is aqueous hydrochloric acid. 13. Compound of formula (1B) MeO OMe (1B), or its salt. 14. Process for the preparation of a compound of formula (1B) ^NC x ^N MeO OMe (1B), or a salt thereof, comprising reacting a compound of formula (1A) CN f MeO > OMe(1D) with 2-chloro-3-fluoropyridine to form a compound of formula (1B). 15. The method according to claim 14, characterized in that the compound of formula (1A) is obtained by reacting 1,3-dibromo-2,2-dimethoxypropane with tert-butyl-2-cyanoacetate. 16. The method according to claim 15, characterized in that the reaction of 1,3-dibromo-2,2-dimethoxypropane with tert-butyl-2-cyanoacetate is carried out in the presence of a base. 17. The method according to claim 16, wherein the base is potassium tert-butoxide. 18. The method according to claim 14, characterized in that the compound of formula (1A) is obtained by reacting the compound of formula (1D) - 22 042013 Meo ome CONH2 (1D) with trifluoroacetic anhydride. 19. Method according to and. 18, characterized in that the compound of formula (1D) is obtained by reacting the compound of formula (1E) MeO OMe OOMe (1E) with ammonia. 20. The method according to claim 19, characterized in that the compound of formula (1E) is obtained by reacting the compound of formula (1F) ABOUT COOH (1F) with trimethoxymethane in the presence of Amberlyst-15. 21. Method according to any of pi. 14-20, characterized in that the reaction of the compound of formula (1A) with 2chloro-3-fluoropyridine is carried out in the presence of a base. 22. The method according to claim 21, wherein the base is sodium bis(trimethylsilyl)amide. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2