WO2022053014A1

WO2022053014A1 - Process for preparing alkynyl-containing compound and intermediate thereof

Info

Publication number: WO2022053014A1
Application number: PCT/CN2021/117629
Authority: WO
Inventors: Jianfeng WEN; Jianpeng FENG; Tianzhu WU; Minmin CAI; Shangjun TENG
Original assignee: Guangzhou Healthquest Pharmaceuticals Co Ltd; Ascentage Pharma Suzhou Co Ltd; Ascentage Pharma Group Co Ltd
Current assignee: Guangzhou Healthquest Pharmaceuticals Co Ltd; Ascentage Pharma Suzhou Co Ltd; Ascentage Pharma Group Co Ltd
Priority date: 2020-09-10
Filing date: 2021-09-10
Publication date: 2022-03-17
Anticipated expiration: 2023-03-10
Also published as: CN114163434A; CN116514808A; CN114163434B

Abstract

Disclosed are processes for preparing alkylnyl-containing compounds of Formula (I) as shown below, intermediates and related compounds thereof. Pharmaceutical compositions comprising the compounds and methods of treating cancer thereof are also disclosed.

Description

[Title established by the ISA under Rule 37.2] PROCESS FOR PREPARING ALKYNYL-CONTAINING COMPOUND AND INTERMEDIATE THEREOF

The present invention claims the priority of the PCT/CN2020/114305, filed on September 10, 2020, and the priority of the PCT/CN2021/089740, filed on April 25, 2021, the contents of which are incorporated herein by its entirety.

Field of invention

Provided herein are methods for preparing compounds that contain an alkynyl moiety and methods of use thereof for treating cancer. Also provided are certain compounds related to the methods.

Prior arts

Cancer has a major impact on society across the world. Cancer is the second most common cause after cardiovascular disease responsible for human death. The National Cancer Institute estimates that in 2015, approximately 1, 658, 370 new cases of cancer will be diagnosed in the United States and 589, 430 people will die from the disease.

Chronic myeloid leukemia (CML) is a type of cancer that starts in certain blood forming cells of the bone marrow. CML cells contain an abnormal gene, BCR-ABL, causes CML cells to grow and reproduce out of control. BCR-ABL is a type of protein known as a tyrosine kinase. Drugs known as tyrosine kinase inhibitors (TKIs) that target BCR-ABL are the standard treatment for CML.

Imatinib

is the first drug to specifically target the BCR-ABL tyrosine kinase protein for treating CML. However, emerging acquired resistance to imatinib has become a major challenge for clinical management of CML. More than 100 resistance-related BCR-ABL mutants have been identified in the clinic, among which the “gatekeeper” T315I is most common mutation, as it accounts for approximately 15-20%of all clinically acquired mutants. Ren et al., J. Med Chem. 2013, 56, 879-894.

Great efforts have been devoted to identifying new BCR-ABL inhibitors to overcome imatinib resistance. Compound 6 is a novel oral bioavailable Bcr-Abl inhibitor that is effective against broad-spectrum expression of drug mutants including T3151. Compound 6 and its preparation are described in PCT publication, WO2012/000304. However, the method of preparing compound 6 disclosed in WO2012/000304 involves multiple synthetic steps, wide variety of chemical reagents, harsh reaction conditions including the use of pressure-resistant sealed tubes, high reaction temperature, and high performance liquid chromatography for purification at each synthetic step. Thus, the known method limits the large scale production.

Accordingly, there is a need for an efficient and cost effective route to prepare compound 6. The present invention provides a novel method for product compound 6, which uses mild reaction conditions and is capable of achieving higher yields for large-scale industrial production.

Content of the present invention

In certain embodiments, provided herein is a method for preparing a compound of Formula (I’) or a pharmaceutically acceptable salt thereof:

wherein the method comprises reacting a compound of Formula (II’) and a compound of Formula (III) to provide a compound of Formula (I’) , as shown in Scheme VI below:

Scheme VI:

wherein R ₁, R ₂, R ₃, R ₇, R ₈, R ₉, and R ₁₀ are as defined herein or elsewhere.

In certain embodiments, provided herein is a method for preparing a compound of Formula (I) or a pharmaceutically acceptable salt thereof:

wherein the method comprises reacting a compound of Formula (II) and a compound of Formula (III) to provide a compound of Formula (I) , as shown in Scheme I below:

Scheme I:

wherein R ₁, R ₂, and R ₃ are as defined herein or elsewhere.

In certain embodiments, provided herein is a method for preparing compound 6 that has the following structure:

wherein the method comprises reacting a compound of formula 4 and a compound of formula 5 to provide Compound 6 or a pharmaceutically acceptable salt as shown in Scheme V below:

Scheme V:

In some embodiments, the method described in Schemes I-VII is an amidation reaction, which is carried out under the protection of nitrogen or inert gas;

and/or, in the amidation reaction, the solvent comprises ether solvents, DMF, N, N-dimethylacetamide, DMSO, N-methylpyrrolidone, toluene or acetonitrile;

and/or, in the amidation reaction, the volume/mass ratio of the solvent to the compound of Formula (II’) or (II) or formula 4 is (about 5 to about 17) mL : 1 g;

and/or, in the amidation reaction, the base is an organic base and/or an inorganic base;

and/or, in the amidation reaction, the molar ratio of the base to the compound of Formula (II’) or (II) or formula 4 is (about 1.5 to about 10) : 1;

and/or, in the amidation reaction, the base is added to the mixture composed of the rest materials in batches;

and/or, in the amidation reaction, the molar ratio of the compound of Formula (III) or formula 5 to the compound of Formula (II’) or (II) or formula 4 is (about 0.8 to about 1.5) : 1;

and/or, in the amidation reaction, the reaction temperature of the amidation reaction is within a range from about -80℃ to about 10℃;

and/or, in the amidation reaction, optionally the post-treatment of the amidation reaction comprises washing the reaction solution with water and/or brine.

Detailed description

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

The term "about" is used herein to mean approximately, in the region of, roughly, or around. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term "about" is used herein to modify a numerical value above and below the stated value by a variance of 10%.

The term "comprises" refers to “includes, but is not limited to. "

As used herein, the terms "treatment, " "treat, " and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, including but not limited to therapeutic benefit. In some embodiments, treatment is administered after one or more symptoms have developed. In some embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a subject prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors) . Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

Therapeutic benefit includes eradication and/or amelioration of the underlying disorder being treated such as cancer; it also includes the eradication and/or amelioration of one or more of the symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. In some embodiments, "treatment" or "treating" includes one or more of the following: (a) inhibiting the disorder (for example, decreasing one or more symptoms resulting from the disorder, and/or diminishing the extent of the disorder) ; (b) slowing or arresting the development of one or more symptoms associated with the disorder (for example, stabilizing the disorder and/or delaying the worsening or progression of the disorder) ; and/or (c) relieving the disorder (for example, causing the regression of clinical symptoms, ameliorating the disorder, delaying the progression of the disorder, and/or increasing quality of life) .

As used herein, "administering" or "administration" of a compound provided herein, e.g., the compound of formula 6 or a pharmaceutically acceptable salt thereof, encompasses the delivery to a patient a compound or a pharmaceutically acceptable salt thereof, or a prodrug or other pharmaceutically acceptable derivative thereof, using any suitable formulation or route of administration, e.g., as described herein.

As used herein, the term "therapeutically effective amount" or "effective amount" refers to an amount that is effective to elicit the desired biological or medical response, including the amount of a compound that, when administered to a subject for treating a disorder, is sufficient to effect such treatment of the disorder. The effective amount will vary depending on the disorder, and its severity, and the age, weight, etc. of the subject to be treated. The effective amount may be in one or more doses (for example, a single dose or multiple doses may be required to achieve the desired treatment endpoint) . An effective amount may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved. Suitable doses of any co-administered compounds may optionally be lowered due to the combined action, additive or synergistic, of the compound.

As used herein, "patient" to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult) ) and/or other primates (e.g., cynomolgus monkeys, rhesus monkeys) .

As used herein, "pharmaceutically acceptable" or "physiologically acceptable" refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.

As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19. Pharmaceutically acceptable salts of Compound 6 include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Although pharmaceutically acceptable counter ions will be preferred for preparing pharmaceutical formulations, other anions are quite acceptable as synthetic intermediates. Thus it may be pharmaceutically undesirable anions, such as iodide, oxalate, trifluoromethanesulfonate and the like, when such salts are chemical intermediates.

In some embodiments, provided herein is a pharmaceutical composition comprising a compound provided herein (e.g., a compound of Formula (I’) or (I) ) , and a pharmaceutically acceptable excipient. In some embodiments, provided herein is a pharmaceutical composition comprising a compound of Formula (I) and optionally a pharmaceutically acceptable excipient. In some embodiments, provided herein is a pharmaceutical composition comprising compound 6 and optionally a pharmaceutically acceptable excipient.

In some embodiment, provided herein is a method for treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound provided herein (e.g., a compound of Formula (I’) or (I) ) or a pharmaceutical composition provided herein. In some embodiment, provided herein is a method for treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I) and optionally a pharmaceutically acceptable excipient. In some embodiment, provided herein is a method for treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising compound 6 and optionally a pharmaceutically acceptable excipient.

In some embodiments, provided herein is a medical use of a pharmaceutical composition comprising a compound of Formula (I’) or (I) and optionally a pharmaceutically acceptable excipient for manufacture of medicament for treating cancer. In some embodiments, provided herein is a medical use of a pharmaceutical composition comprising compound 6 and optionally a pharmaceutically acceptable excipient for manufacture of medicament for treating cancer.

In some embodiments, the cancer is hematological malignancy. In certain embodiments, the hematological malignancy is leukemia. In certain embodiments, the hematological malignancy is chronic myelogenous leukemia.

In certain embodiments, the patient has chronic myeloid leukemia that is resistant to current tyrosine kinase inhibitor therapies. In certain embodiments, the patient with chronic myeloid leukemia resistant to the current tyrosine kinase inhibitor therapies is caused by BCR-ABL mutations. In certain embodiments, BCR-ABL mutation is T315I, E255K/V, G250E, H396P, M351T, Q252H, Y253F/H, or BCR-ABL ^WT mutations. In certain embodiments, BCR-ABL mutation is T315I mutation.

In some embodiment, disclosed herein is a compound of Formula (I’) with high purity prepared by the method as shown in Scheme VI. In some embodiment, disclosed herein is a compound of Formula (I) with high purity prepared by the method as shown in Scheme I. In some embodiment, disclosed herein is compound 6 with high purity prepared by the method as shown in Scheme V.

In certain embodiments, the pharmaceutically composition comprising a compound of Formula (I’) or (I) is administered once every one, two, or three days during the treatment cycle. The said treatment cycle may be 20-40 days, preferably 25-35 days, more preferably 28-day treatment cycle. In certain embodiments, the pharmaceutically composition comprising compound 6 is administered once every one, two, or three days during the treatment cycle. The said treatment cycle may be 20-40 days, preferably 25-35 days, more preferably 28-day treatment cycle.

In certain embodiments, the pharmaceutical composition is administered once every other day, wherein the pharmaceutical composition comprising a compound of Formula (I’) or (I) in an amount of about 30 mg, about 40 mg, or about 45 mg. In certain embodiments, the pharmaceutical composition is administered once every other day, wherein the pharmaceutical composition comprising compound 6 in an amount of about 30 mg, about 40 mg, or about 45 mg.

In certain embodiments, pharmaceutical composition is administered once every other day, wherein the pharmaceutical composition comprising a compound of Formula (I’) or (I) in an amount of about 50 mg or about 60mg. In certain embodiments, pharmaceutical composition is administered once every other day, wherein the pharmaceutical composition comprising compound 6 in an amount of about 50 mg or about 60mg.

In certain embodiments, pharmaceutical composition is formulated into a dosage unit to be administered every day, or once every other day (QOD) , or once every three days, particularly once every other day.

The pharmaceutical composition provided herein for oral administration can be provided in solid, semisolid, or liquid dosage forms for oral administration. As used herein, oral administration also includes buccal, lingual, and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, fastmelts, chewable tablets, capsules, pills, strips, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, bulk powders, effervescent or non-effervescent powders or granules, oral mists, solutions, emulsions, suspensions, wafers, sprinkles, elixirs, and syrups. In addition to the active ingredient (s) , the pharmaceutical composition can contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, flavoring agents, emulsifying agents, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and sources of carbon dioxide.

Binders or granulators impart cohesiveness to a tablet to ensure the tablet remaining intact after compression. Suitable binders or granulators include, but are not limited to, starches, such as corn starch, potato starch, and pre-gelatinized starch (e.g., STARCH

) ; gelatin; sugars, such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums, such as acacia, alginic acid, alginates, extract of Irish moss, panwar gum, ghatti gum, mucilage of isabgol husks, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP) ,

larch arabogalactan, powdered tragacanth, and guar gum; celluloses, such as ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethylcellulose (HEC) , hydroxypropylcellulose (HPC) , hydroxypropyl methyl cellulose (HPMC) ; and microcrystalline celluloses, such as

PH-101,

PH-103,

PH-105, and

RC-581. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, and pre-gelatinized starch. The amount of a binder or filler in the pharmaceutical composition provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art. The binder or filler may be present from about 50 to about 99%by weight in the pharmaceutical composition provided herein.

Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar. Certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol, when present in sufficient quantity, can impart properties to some compressed tablets that permit disintegration in the mouth by chewing. Such compressed tablets can be used as chewable tablets. The amount of a diluent in the pharmaceutical composition provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art.

Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses, such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cation-exchange resins; alginic acid; gums, such as guar gum and

HV; citrus pulp; cross-linked celluloses, such as croscarmellose; cross-linked polymers, such as crospovidone; cross-linked starches; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; polacrilin potassium; starches, such as corn starch, potato starch, tapioca starch, and pre-gelatinized starch; clays; and algins. The amount of a disintegrant in the pharmaceutical composition provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art. The pharmaceutical composition provided herein may contain from about 0.5 to about 15%or from about 1 to about 5%by weight of a disintegrant.

Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols, such as glycerol behenate and polyethylene glycol (PEG) ; stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oil, such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laureate; agar; starch; lycopodium; and silica or silica gels, such as

200 and

The amount of a lubricant in the pharmaceutical composition provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art. The pharmaceutical compositions provided herein may contain about 0.1 to about 5%by weight of a lubricant.

Suitable glidants include, but are not limited to, colloidal silicon dioxide,

and asbestos-free talc. Suitable coloring agents include, but are not limited to, any of the approved, certified, water soluble FD&C dyes, and water insoluble FD&C dyes suspended on alumina hydrate, and color lakes. A color lake is a combination by adsorption of a water-soluble dye to a hydrous oxide of a heavy metal, resulting in an insoluble form of the dye. Suitable flavoring agents include, but are not limited to, natural flavors extracted from plants, such as fruits, and synthetic blends of compounds which produce a pleasant taste sensation, such as peppermint and methyl salicylate. Suitable sweetening agents include, but are not limited to, sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners, such as saccharin and aspartame. Suitable emulsifying agents include, but are not limited to, gelatin, acacia, tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitan monooleate (

20) , polyoxyethylene sorbitan monooleate 80 (

80) , and triethanolamine oleate. Suitable suspending and dispersing agents include, but are not limited to, sodium carboxymethylcellulose, pectin, tragacanth,

acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable preservatives include, but are not limited to, glycerin, methyl and propylparaben, benzoic add, and sodium benzoate and alcohol. Suitable wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Suitable solvents include, but are not limited to, glycerin, sorbitol, ethyl alcohol, and syrup. Suitable non-aqueous liquids utilized in emulsions include, but are not limited to, mineral oil and cottonseed oil. Suitable organic acids include, but are not limited to, citric and tartaric acid. Suitable sources of carbon dioxide include, but are not limited to, sodium bicarbonate and sodium carbonate.

It should be understood that many carriers and excipients may serve several functions, even within the same formulation.

The pharmaceutical composition provided herein for oral administration can be provided as compressed tablets, tablet triturates, chewable lozenges, rapidly dissolving tablets, multiple compressed tablets, or enteric-coating tablets, sugar-coated, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with substances that resist the action of stomach acid but dissolve or disintegrate in the intestine, thus protecting the active ingredient (s) from the acidic environment of the stomach. Enteric-coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial in covering up objectionable tastes or odors and in protecting the tablets from oxidation. Film-coated tablets are compressed tablets that are covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coating imparts the same general characteristics as sugar coating. Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets, and press-coated or dry-coated tablets.

The tablet dosage forms can be prepared from an active ingredient (s) in powdered, crystalline, or granular forms, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled-release polymers, lubricants, diluents, and/or colorants. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges.

The pharmaceutical composition provided herein for oral administration can be provided as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate. The hard gelatin capsule, also known as the dry-filled capsule (DFC) , consists of two sections, one slipping over the other, thus completely enclosing the active ingredient (s) . The soft elastic capsule (SEC) is a soft, globular shell, such as a gelatin shell, which is plasticized by the addition of glycerin, sorbitol, or a similar polyol. The soft gelatin shells may contain a preservative to prevent the growth of microorganisms. Suitable preservatives are those as described herein, including methyl-and propyl-parabens, and sorbic acid. The liquid, semisolid, and solid dosage forms provided herein may be encapsulated in a capsule. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239; and 4,410,545. The capsules may also be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient (s) .

The pharmaceutical composition provided herein for oral administration can be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. An emulsion is a two-phase system, in which one liquid is dispersed in the form of small globules throughout another liquid, which can be oil-in-water or water-in-oil. Emulsions may include a pharmaceutically acceptable non-aqueous liquid or solvent, emulsifying agent, and preservative. Suspensions may include a pharmaceutically acceptable suspending agent and preservative. Aqueous alcoholic solutions may include a pharmaceutically acceptable acetal, such as a di (lower alkyl) acetal of a lower alkyl aldehyde, e.g., acetaldehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened, and hydroalcoholic solutions. Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may also contain a preservative. For a liquid dosage form, for example, a solution in a polyethylene glycol may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be measured conveniently for administration.

Other useful liquid and semisolid dosage forms include, but are not limited to, those containing an active ingredient (s) , and a dialkylated mono-or poly-alkylene glycol, including, 1, 2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol. These dosage forms can further comprise one or more antioxidants, such as butylated hydroxytoluene (BHT) , butylated hydroxyanisole (BHA) , propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.

The pharmaceutical composition provided herein for oral administration can be provided as non-effervescent or effervescent, granules and powders, to be reconstituted into a liquid dosage form. Pharmaceutically acceptable carriers and excipients used in the non-effervescent granules or powders may include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders may include organic acids and a source of carbon dioxide.

Coloring and flavoring agents can be used in all of the dosage forms described herein.

The pharmaceutical composition provided herein for oral administration can be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms.

A process for preparing a compound of Formula (I’) or a pharmaceutically acceptable salt thereof:

comprising reacting a compound of Formula (II’) :

with a compound of Formula (III) :

in a solvent and in the presence of a base to provide the compound of Formula (I’) ,

wherein

R ₁ is H, C ₁-C ₄ alkyl, or -C (=O) O- (C ₁-C ₄ alkyl) ;

R ₂ is H or C ₁-C ₄ alkyl;

R ₃ is

-NH ₂, -NHC (=O) Me,

R ₇ is H or hydroxyl;

R ₈ is H or hydroxyl;

R ₉ is H or hydroxyl; and

R ₁₀ is H or hydroxyl.

In certain embodiments, provided herein is a process for preparing a compound of Formula (I) or a pharmaceutically acceptable salt thereof:

comprising reacting a compound of Formula (II) :

with a compound of Formula (III) :

in a solvent and in the presence of a base to provide the compound of Formula (I) ,

wherein R ₁ is H, C ₁-C ₄ alkyl, or -C (=O) O- (C ₁-C ₄ alkyl) , R ₂ is H or C ₁-C ₄ alkyl, and R ₃ is

-NH ₂, -NHC (=O) Me,

In one embodiment, the process is as shown in Scheme I below:

Scheme I:

In one embodiment, provided that the compound of Formula (I’) or (I) is not compound 6:

In one embodiment, the -CH ₂-R ₃ group is at para-position to the -NH-group.

In one embodiment, the compound of Formula (I) is a compound of Formula (I-A) :

In one embodiment, the -CH ₂-R ₃ group is at para-position to the -CF ₃ group.

In one embodiment, the compound of Formula (I) is a compound of Formula (I-B) :

In one embodiment, the compound of Formula (I) is a compound of Formula (I-C) :

In one embodiment, the compound of Formula (I’) is a compound of Formula (I-D) :

In one embodiment, R ₁ is H. In one embodiment, R ₁ is C ₁-C ₄ alkyl. In one embodiment, R ₁ is methyl. In one embodiment, R ₁ is t-butyl. In one embodiment, R ₁ is -C (=O) O- (C ₁-C ₄ alkyl) . In one embodiment, R ₁ is -C (=O) O- (C ₁-C ₄ alkyl) . In one embodiment, R ₁ is -C (=O) OMe. In one embodiment, R ₁ is -C (=O) O-t-butyl.

In one embodiment, R ₂ is H. In one embodiment, R ₂ is C ₁-C ₄ alkyl. In one embodiment, R ₂ is methyl.

Exemplary R ₁, R ₂, combination thereof, and corresponding compounds of Formula (II) are provided in Table 1.

Table 1

In one embodiment, instead of the methyl ester of Formula (II’) or (II) , a corresponding acid compound (e.g., Compound 39) can be used to react with the compound of Formula (III) to prepare a compound of Formula (I’) or (I) or a pharmaceutically acceptable salt thereof.

Exemplary R ₃ and corresponding compounds of Formula (III) are provided in Table 2.

Table 2

In one embodiment, provided herein is a compound of Formula (I-D) :

wherein:

R ₇ is H or hydroxyl;

R ₈ is H or hydroxyl;

R ₉ is H or hydroxyl;

R ₁₀ is H or hydroxyl; and

provided that at least one of R ₇, R ₈, R ₉, and R ₁₀ is hydroxyl;

or a pharmaceutically acceptable salt thereof.

In one embodiment, R ₇ is H. In one embodiment, R ₇ is hydroxyl.

In one embodiment, R ₈ is H. In one embodiment, R ₈ is hydroxyl.

In one embodiment, R ₉ is H. In one embodiment, R ₉ is hydroxyl.

In one embodiment, R ₁₀ is H. In one embodiment, R ₁₀ is hydroxyl.

In one embodiment, at least one of R ₇, R ₈, R ₉, and R ₁₀ is hydroxyl. In one embodiment, one of R ₇, R ₈, R ₉, and R ₁₀ is hydroxyl, and the other three of R ₇, R ₈, R ₉, and R ₁₀ are H.

In certain embodiments, provided herein is a method for preparing a compound of Formula (I-A) or a pharmaceutically acceptable salt thereof:

wherein the method comprises reacting a compound of Formula (II) and a compound of formula 5 to provide a compound of Formula (I-A) , as shown in Scheme II below.

Scheme II:

In certain embodiments, provided herein is a method for preparing a compound of Formula (I-B) or a pharmaceutically acceptable salt thereof:

wherein the method comprises reacting a compound of Formula (II) and a compound of formula 22 to provide a compound of Formula (I-B) , as shown in Scheme III below.

Scheme III:

In certain embodiments, provided herein is a method for preparing a compound of Formula (I-C) or a pharmaceutically acceptable salt thereof:

wherein the method comprises reacting a compound of formula 4 and a compound of Formula (III) to provide a compound of Formula (I-C) , as shown in Scheme IV below.

Scheme IV:

In some embodiments, provided herein is a method for preparing compound 6 via conducting an amidation reaction with a compound of formula 4 and a compound of formula 5 in a solvent and in the presence of a base as shown below:

In certain embodiments, provided herein is a method for preparing a compound of Formula (I-D) or a pharmaceutically acceptable salt thereof:

wherein the method comprises reacting a compound of Formula (II’-A) and a compound of formula 5 to provide a compound of Formula (I-D) , as shown in Scheme VII below.

Scheme VII:

In some embodiments, the amidation reaction (e.g., between compound 4 and compound 5, or between compound of Formula (II’) or (II) and compound of Formula (III) ) can be carried out under the protection of nitrogen or inert gas.

In some embodiments, the solvent in the amidation reaction is but not limited to an ether, DMF (N, N-dimethylformamide) , N, N-dimethylacetamide, DMSO (dimethyl sulfoxide) , N-methylpyrrolidone, toluene and acetonitrile, or a mixture thereof.

In some embodiments, the solvent in the amidation reaction is an ether, DMF, N, N-dimethylacetamide, N-methylpyrrolidone or toluene. In some embodiments, the solvent is an ether solvent.

In some embodiments, the ether solvent in the amidation reaction can be THF (tetrahydrofuran) , 2-methyltetrahydrofuran or dioxane. In some embodiments, the ether solvent is THF.

In some embodiments, the amount of solvent in the amidation reaction can be a conventional amount used in the amidation reaction in the art, or the amount of solvent is in a volume/mass ratio of the solvent to the compound of Formula (II’) or (II) or formula 4, for example, (about 5 to about 17) mL : 1g, or for example, (about 10 to about 15) mL : 1g, or (about 15) mL: 1 g.

In some embodiments, the base in the amidation reaction can be an organic base and/or an inorganic base.

In some embodiments, the organic base is but not limited to pyridine, an alkali metal salt of a C ₁-C ₄ alcohol and/or an amine such as –N (R ¹) (R ²) (R ³) , wherein each of R ¹, R ² and R ³ independently represents hydrogen or a C ₁-C ₄ alkyl.

In some embodiments, the alkali metal salt of the C ₁-C ₄ alcohol is but not limited to a conventional alkali metal salt of a C ₁-C ₄ alcohol used in the amidation reaction in the art, such as potassium tert-butoxide and/or sodium tert-butoxide.

In some embodiments, –N (R ¹) (R ²) (R ³) is Et ₃N, DIPEA, (i-Pr) ₂NH and Bu ₃N, such as Et ₃N or (i-Pr) ₂NH, typically, Et ₃N.

In some embodiments, the inorganic base is but not limited to an alkali metal carbonate and/or an alkali metal hydroxide.

In some embodiments, the alkali metal carbonate is, for example, K ₂CO ₃ and/or Cs ₂CO ₃.

In some embodiments, the alkali metal hydroxide is, for example, NaOH and/or KOH.

In some embodiments, the amount of the base used in the amidation reaction can be a conventional amount used in the amidation reaction in the art. In some embodiments, the molar ratio of a base to the compound of Formula (II’) or (II) or formula 4 is, for example, (about 1.5 to about 10) : 1, for example, (about 1.5 to about 8.0) : 1, for example, (about 1.5 to about 6) : 1, for example, (about 1.5 to about 5.0) : 1.

In some embodiments, in the amidation reaction, the base can be added to the mixture composed of the rest of the materials in batches.

In some embodiments, the molar ratio of the compound of Formula (III) or formula 5 to the compound of Formula (II’) or (II) or formula 4 is, for example, (about 0.8 to about 1.5) : 1, for example, (about 0.9 to about 1.3) : 1, for example (about 1.2 to about 1.3) : 1.

In some embodiments, the reaction temperature of the amidation reaction is, for example, within a range about from about -80℃ to about 10℃, such as about -65℃ to about -60℃, about -60℃ to about -40℃, about -30℃ to about -20℃, about -20℃ to –about 15℃, or about 0℃ to about 10℃.

In some embodiments, the process of the amidation reaction can be monitored by TLC, HPLC, and other methods known to a person skilled in the art. A person skilled in the art can assess the completion of the reaction according to the reaction scale, the conversion rate of raw materials, the efficiency of the reaction (i.e. the relationship between the yield and the reaction time) , the formation of impurities and so on to obtain the preferred yield and purity. The reaction time is within a range from about 2h to about 20h, for example, about 2h to about 12h. In some embodiments, the reaction time is about 2h to about 4h.

In some embodiments, the post-treatment of the amidation reaction can be a conventional post-treatment used in the amidation reaction in the art, which can comprise washing the reaction solution with water and saturated brine sequentially, removing the solvent, slurrying with water, filtering and drying.

In some embodiments, after post-treatment of the reaction mixture with saturated brine while before the removal of the solvent, the reaction mixture can immediately be mixed with an amino acid compound, followed by washed with saturated brine.

In some embodiments, the amino acid compound is cysteine, N-acetyl-L-cysteine, ethylenediaminetetraacetic acid, sodium edetate and dithiocarbamates, such as cysteine or N-acetyl-L-cysteine, typically, N-acetyl-L-cysteine.

In some embodiments, the molar ratio of the amino acid compound to the compound of Formula (II’) or (II) or formula 4 is about 0.7 to 1.0 : 1.

In some embodiments, the method for removing the solvent can be concentrated under reduced pressure.

In some embodiments, the amidation reaction is carried out under the protection of nitrogen or inert gas, the solvent comprises DMF and/or THF, the base comprises potassium tert-butoxide, sodium tert-butoxide, or Et ₃N, the molar ratio of the base to the compound of Formula (II’) or (II) or formula 4 is (about 1.5 to 6) : 1, the molar ratio of the compound of Formula (III) or formula 5 to the compound of Formula (II’) or (II) or formula 4 is (about 0.8 to 1.5) : 1, and the amidation reaction is conducted at from about -60℃ to about 10℃.

In some embodiments, the compound of formula 4 is prepared by deprotection of a compound of formula 3 in a solvent as shown below;

In some embodiments, the deprotection reaction can be carried out under the protection of nitrogen or inert gas.

In some embodiments, the deprotection reaction can be carried out in the presence of an acid. In some embodiments, the acid can be, but not limited to, hydrochloric acid, trifluoroacetic acid and p-toluenesulfonic acid.

When the deprotection reaction is carried out in the presence of the acid, the solvent can be a conventional solvent used in the deprotection reaction under this condition, and it can be a C ₁-C ₄ alcohol (e.g. methanol and/or ethanol, typically, methanol) , chloroalkane (s) , THF, or acetonitrile.

In some embodiments, the deprotection reaction can be carried out in the absence of an acid. For example, the raw materials of the deprotection reaction only consist of the solvent and the compound of formula 3.

When the deprotection reaction is carried out in the absence of the acid (for example that the raw materials of the deprotection reaction only consist of the solvent and the compound of formula 3) , the solvent can be a solvent conventionally used in the deprotection reaction under this condition. It can be, but not limited to, acetonitrile, a mixture solvent of acetonitrile and water, or a mixture solvent of a C ₁-C ₄ alcohol and water, wherein, the mass ratio of the C ₁-C ₄ alcohol to water is about, for example, 3 to 5 : 1; the C ₁-C ₄ alcohol comprises, for example, methanol, ethanol, isopropanol, or mixture thereof such as methanol and/or ethanol. In some embodiments, the solvent is methanol. In some embodiments, the mixed solvent of a C ₁-C ₄ alcohol and water is, for example, a mixed solvent of methanol and water with a mass ratio of 3: 1, typically a mixed solvent of a C ₁-C ₄ alcohol and water.

In some embodiments, in the deprotection reaction, the mass ratio of the solvent to the compound of formula 3 is, for example, (about 10 to about 15) : 1.

In some embodiments, the reaction temperature of the deprotection reaction is, for example, within a range from about 30℃ to about 80℃, such as about 60℃ to about 80℃, about 60℃ to about 70℃, or about 60℃ to about 65℃.

In some embodiments, the process of the deprotection reaction can be monitored by TLC, HPLC and other methods known to a person skilled in the art. A person skilled in the art can assess the completion of the reaction according to the reaction scale, the conversion rate of raw materials, the efficiency of the reaction (i.e. the relationship between the yield and the reaction time) , the formation of impurities and so on to obtain the preferred yield and purity. The reaction time is, for example, within a range from about 10h to about 36h, such as about 10h to about 18h.

In some embodiments, the post-treatment of the deprotection reaction can comprise cooling and filtering.

In some embodiments, the temperature to be achieved by cooling can be about 20℃ to about 25℃.

In some embodiments, the post-treatment can further comprise drying and recrystallizing immediately and subsequently after filtering, and it can also directly be subjected to recrystallizing without drying. The method for recrystallizing can be dissolving by heating and precipitating by cooling.

In some embodiments, the solvent used in the recrystallizing is, but not limited to for example, a C ₁-C ₄ alcohol, for further example, the solvent comprises methanol, ethanol, isopropanol, or mixture thereof. In some embodiments, the solvent is methanol or ethanol. In some embodiments, the solvent is methanol.

In some embodiments, the mass ratio of the solvent used in the recrystallizing to the compound of formula 4 can be (about 5 to about 15) : 1, such as (about 5 to about 10) : 1.

In some embodiments, in the method of dissolving by heating and precipitating by cooling, the temperature for dissolving is, for example within a range from about 50℃ to about 70℃, such as about 60℃to about 70℃.

In some embodiments, in the method of dissolving by heating and precipitating by cooling, the cooling can be slow cooling, rapid cooling or gradient cooling. In some embodiments, it can be gradient cooling. The temperature can be reduced by about 5℃ per 1h to 1.5h. The gradient cooling can be started at a temperature of about 40℃ to about 50℃.

A person skilled in the art can evaluate the completion of the reaction according to the precipitation conditions and so on to obtain a preferred yield and purity. The recrystallizing time is, for example within a range from about 8h to about 40h, such as about 8h to about 10h.

In some embodiments, the deprotection reaction can be carried out under the protection of nitrogen or inert gas, the raw materials of the deprotection reaction can only consist of the solvent and the compound of formula 3, the solvent is a mixture of a C ₁-C ₄ alcohol and water, the temperature of the deprotection reaction is within a range from about 60℃ to about 65℃.

In one embodiment, the compound of Formula (II) is prepared by a process comprising reacting Compound 1:

with a compound of Formula (IV) :

in a solvent and in the presence of a base, a catalyst and a catalyst ligand to provide the compound of Formula (II) .

In some embodiments, the compound of formula 3 can be prepared via a Sonogashira coupling reaction with a compound of formula 1 and a compound of formula 2 in a solvent and in the presence of a base, a catalyst and a catalyst ligand as shown below:

In one embodiment, the compound of Formula (II’) is prepared by a process comprising reacting a compound of Formula (V) :

wherein X is a halogen, with a compound of Formula (VI) :

in a solvent and in the presence of a base, a catalyst and a catalyst ligand to provide the compound of Formula (II’) .

In one embodiment, X is iodo. In one embodiment, X is bromo. In one embodiment, X is chloro.

In some embodiments, the Sonogashira reaction (e.g., between compound 1 and compound 2, or between compound 1 and compound of Formula (IV) , or between compound Formula (V) and compound of Formula (VI) ) can be carried out under the protection of nitrogen or inert gas.

In some embodiments, the solvent in the Sonogashira reaction, can be a conventional solvent used in the Sonogashira reaction in the art, for example that (1) comprises N-methylpyrrolidone, DMSO (dimethyl sulfoxide) , DMF (N, N-dimethylformamide) , N, N-dimethylacetamide, acetonitrile, toluene, dioxane and THF (tetrahydrofuran) , (2) N-methylpyrrolidone, DMSO (dimethyl sulfoxide) , DMF (N, N-dimethylformamide) , N, N-dimethyl acetamide or acetonitrile; or (3) N-methylpyrrolidone, DMF (N, N-dimethylformamide) or N, N-dimethylacetamide.

In some embodiments, the volume/mass ratio of the solvent to the compound of formula (IV) or formula 2 is, for example, (about 5 to about 10) mL: 1g, such as (about 7 to about 10) mL: 1g.

In some embodiments, in the Sonogashira reaction, the catalyst can be a conventional catalyst used in the Sonogashira reaction in the art, such as a palladium catalyst. The palladium catalyst can comprise PdCl ₂ (PPh ₃) ₂, Pd (dppf) ₂Cl ₂, Pd (dppf) ₂Cl ₂ and/or palladium carbon. In some embodiments, the catalyst is PdCl ₂ (PPh ₃) ₂ or Pd (dppf) ₂Cl _2.

In some embodiments, the molar ratio of the catalyst to the compound of formula (IV) or formula 2 is, for example, (about 0.01 to about 0.05) : 1, such as (about 0.01 to about 0.03) : 1.

In some embodiments, a catalyst ligand used in the Sonogashira reaction comprises, for example, a copper compound and/or triphenylphosphine. In some embodiments, the copper compound can be , for example, CuI, CuBr, Cu ₂O, CuO and/or Cupric acetate. In some embodiments, the catalyst ligand is CuI or CuBr.

In some embodiments, the molar ratio of the catalyst ligand to the catalyst is, for example, (about 0.8 to about 1.2) : 1. In some embodiments, the molar ratio of the catalyst ligand to the catalyst is1: 1.

In some embodiments, in the Sonogashira reaction, the base can be, for example an organic base and/or an inorganic base.

In some embodiments, the organic base can be a conventional organic base used in the Sonogashira reaction in the art, for example that it comprises pyridine, an alkali metal salt of a C ₁-C ₄ alcohol, and/or –N (R ⁴) (R ⁵) (R ⁶) , wherein each of R ⁴, R ⁵ and R ⁶ independently represents hydrogen or a C ₁-C ₄ alkyl.

In some embodiments, the alkali metal salt of the C ₁-C ₄ alcohol can be, but not limited to potassium tert-butoxide and/or sodium tert-butoxide.

In some embodiments, the –N (R ⁴) (R ⁵) (R ⁶) , for example, comprises Et ₃N, DIPEA, (i-Pr) ₂NH and/or Bu ₃N. In some embodiments, the –N (R ⁴) (R ⁵) (R ⁶) is Et ₃N or DIPEA. In some embodiments, the –N (R ⁴) (R ⁵) (R ⁶) is Et ₃N.

In some embodiments, the inorganic base can be a conventional inorganic base used in the Sonogashira reaction in the art, for example, it comprises an alkali metal carbonate and/or an alkali metal hydroxide.

In some embodiments, in the Sonogashira reaction, the molar ratio of the base to the compound of formula (IV) or formula 2 is, for example, (about 1.0 to about 1.5) : 1. In some embodiments, the molar ration is , (about 1.2 to about 1.3) : 1.

In some embodiments, in the amidation reaction, the molar ratio of the compound of formula 1 to the compound of formula (IV) or formula 2 is, for example, (about 0.95 to about 2.0) : 1, such as (about 1.2 to about 1.5) : 1. In some embodiments, the molar ration is (about 1.2 to about 1.3) : 1.

In some embodiments, the reaction temperature of the Sonogashira reaction is, for example, about 40℃ to about 80℃, such as about 65℃ to about 75℃, typically, about 65℃ to about 70℃.

The process of the Sonogashira reaction can be monitored by TLC, HPLC and other methods known to a person skilled in the art. A person skilled in the art can evaluate the completion of the reaction according to the reaction scale, the conversion rate of raw materials, the efficiency of the reaction (i.e. the relationship between the yield and the reaction time) , the formation of impurities and so on to obtain the preferred yield and purity. The reaction time is, for example, within a range from about 2h to about 12h, such as about 2h to about 5h. In some embodiments, it is about 2h to about 3h.

In some embodiments, the post-treatment of the Sonogashira reaction can be a conventional post-treatment used in the amidation reaction in the art, which comprise mixing with water and filtering.

In some embodiments, the post-treatment of the Sonogashira reaction can further comprise mixing with an amino acid compound before mixing with water.

In some embodiments, the amino acid compound used for removing heavy metals comprises but not limited to, for example, cysteine, N-acetyl-L-cysteine, ethylenediaminetetraacetic acid, sodium edetate and/or dithiocarbamates. In some embodiments, the amino acid compound is cysteine or N-acetyl-L-cysteine. In some embodiments, the amino acid compound is N-acetyl-L-cysteine.

In some embodiments, the molar ratio of the amino acid compound to the compound of formula (IV) or formula 2 is, for example, (about 0.1 to about 0.5) : 1.

In some embodiments, the temperature subjected to mixing with an amino acid compound can be within a range from about 35℃ to about 45℃.

In some embodiments, the mixing time subjected to mixing with an amino acid compound can be about 4h to about 5h.

In some embodiments, the mixing temperature subjected to mixing with water can be within a range from about 20℃ to about 25℃.

In some embodiments, the process of filtering can further comprise washing with water.

In some embodiments, the post-treatment of the Sonogashira reaction can further comprise slurrying right after filtering.

In some embodiments, the solvent used for slurrying can be, but not limited to, ethyl acetate and n-heptane. The volume ratio of the ethyl acetate to the n-heptane can be about 1: 1.

In some embodiments, the volume/mass ratio of the solvent to the crude filter cake used in the slurrying can be (about 5 to about 7) mL: 1 g.

In some embodiments, the Sonogashira reaction can be carried out under the protection of nitrogen or inert gas, the solvent is N-methylpyrrolidone, DMF or acetonitrile, the catalyst is PdCl ₂ (PPh ₃) ₂ or Pd (dppf) ₂Cl ₂, the molar ratio of the catalyst to the compound of formula (IV) or formula 2 is (about 0.01 to about 0.05) : 1, the catalyst ligand is CuI or CuBr, the molar ratio of the catalyst ligand to the catalyst is (about 0.8 to about 1.2) : 1, the base is Et ₃N, the molar ratio of the base to the compound of formula (IV) or formula 2 is, for example, (about 1.0 to about 1.5) : 1, the molar ratio of the compound of formula 1 to the compound of formula (IV) or formula 2 is, for example, (about 0.95 to about 1.3) : 1, the temperature of the Sonogashira reaction is about 65℃ to about 75℃.

In some embodiments, a compound of formula 4 can be prepared via a deprotection reaction of the compound of formula 3 in a solvent as shown below:

the reaction conditions of the deprotection reaction can refer to those as described above.

the conditions of the Sonogashira reaction can refer to those as described above.

In some embodiments, the present invention also provides a compound of formula 3 or a compound of formula 4,

Without violating the common knowledge in the art, embodiments in the present invention may be combined.

The reagents and raw materials employed in the present invention are commercially available.

In some embodiments, the present invention provides a compound of Formula (I’) or (I) or formula 6 prepared by the methods described herein.

Without being limited by a particular theory, the advantageous effects achieved by the processes provided herein include the following:

i. The present invention adopts a new design route. According to the structural characteristics of compound 6, the present invention selects inexpensive and readily available reaction raw materials, utilizes convenient operation and mild reaction conditions, avoids the use of harsh reaction equipment such as sealed tube, simplify the post-treatment with the only requirement of recrystallization and prevent multiple column chromatography, and can meet the requirements of industrial production.

ii. The present invention has novel design route and shorter reaction route. It only requires three steps of the reaction to obtain the target product. Compared with the existing route, the present invention has shortened reaction route, reduced expensive and complex raw materials, and achieves advantages such as high yield, good purity and controllable cost, etc. The present invention utilizes multiple in-process control in the reaction process, which can effectively ensure the quality of the intermediates and the subsequent final product. iii. During the early stage of the present invention, amino acids are added for several times in process of the coupling and amidation reaction in order to prevent the excess of the heavy metal, which is environment friendly and effectively ensures that the heavy metal contained in the active pharmaceutical ingredient meets the standard of the pharmacopoeia.

iv. The present invention adopts a new design route to obtain two new intermediates which are the compound of formula 3 and the compound of formula 4.

In some embodiments, provided are compounds listed in Table 3.

Table 3

Detailed description of the preferred embodiment

The following examples further illustrate, but not limit to, the present invention. It should be noted that, a person skilled in the art, without departing from the inventive concept of the present invention, may make several modifications and improvements, which all include to the protection scope of the present invention.

The specific conditions that haven’t been disclosed in the experimental methods of the following examples may be selected according to conventional methods and conditions, or according to product specifications.

Unless otherwise specified, "room temperature" in the following examples refers to 20℃ to 25℃. The term “h” used herein refers to hour or hours.

Example 1

Step 1:

Under the protection of nitrogen, N-methylpyrrolidone (137.6g) was heated to 30 to 35 ℃, and a compound of formula 1 (14.4g, 1.3eq) , a compound of formula 2 (19.14g, 1eq) , bis (triphenylphosphate) palladium dichloride (0.46g, 0.01eq) and cuprous iodide (0.113g, 0.01eq) were added sequentially thereto, and then triethylamine (9.45g, 1.5eq) was added thereto under the protection of nitrogen. The reaction mixture was heated to 65 to 75℃ and kept at this temperature for 2 hours. In-process control of the reaction was performed by liquid phase detection . When the content of the compound of formula 2 was ≤ 0.1%, the reaction was terminated. After the reaction was terminated, the reaction solution was cooled to 35 to 45℃, and N-acetyl-L-cysteine (1g, 0.1eq) was added thereto directly. The reaction was performed under stirring for 4 to 5h. The resultant product was cooled to room temperature, precipitated by adding water, centrifuged, and washed with purified water to obtain a crude filter cake. After the crude filter cake was dried under vacuum, a mixture of ethyl acetate and n-heptane (wherein the volume ratio of ethyl acetate to n-heptane was 1: 1, and 5 mL of the mixed solvent of ethyl acetate and n-heptane was used per gram of the crude filter cake) was added to the crude filter cake and slurried. The obtained slurry was dried under vacuum to give a compound of formula 3 with a yield of 85.97%and a purity of 98.2%.

The NMR data of the compound of formula 3 is ¹HNMR (400MHz, d-DMSO) : δ ppm: 8.93 (1H, d, J=2.0 Hz) ; 8.63 (1H, d, J=2.0 Hz) ; 8.49 (1H, s) ; 8.11 (1H, d, J=2.0 Hz) ; 7.92 (1H, dd, J1=1.6 Hz; J2=8.0 Hz) ; 7.52 (1H, d, J=8.0 Hz) ; 3.88 (3H, s) ; 2.59 (3H, s) ; 1.65 (9H, s) .

Step 2:

Under the protection of nitrogen, methanol (160g) and water (50g) were added to a compound of formula 3 (20g, 1.0eq) sequentially, the reaction system was stirred under reflux for 18 hours and in-process control thereof was performed. The resultant product was cooled to room temperature, and filtered to obtain a filter cake (without oven-drying) . Methanol with a mass of 10 times that of the filter cake was added thereto for recrystallization, the obtained mixture was stirred at 60 to 70℃ for 8 to 10h, then cooled to 40 to 50℃, and subjected to a gradient cooling process with a cooling rate of 5℃ per 1 to 1.5h to generate a solid precipitate slowly. The obtained mixture was filtered and the filter cake was washed with methanol and dried under vacuum to obtain a compound of formula 4, with a yield of 91%and a purity of 99.7%.

The NMR data of the compound of formula 4 is ¹HNMR (400MHz, d-DMSO) : δ ppm: 8.73 (1H, d, J=2.0 Hz) ; 8.52 (1H, t, J=2.0 Hz) ; 8.21 (1H, d, J=2.0 Hz) ; 8.06 (1H, s) ; 7.86 (1H, dd, J1=2.0 Hz; J2=8.0 Hz) ; 7.49 (1H, dd, J1=1.6 Hz; J2=7.6 Hz) ; 3.86 (3H, s) ; 2.56 (3H, s) .

Step 3:

Under the protection of nitrogen, THF (448mL) , a compound of formula 4 (29.1g, 1eq) and a compound of formula 5 (24.6g, 0.9eq) were added, and the mixture was cooled under stirring to -65℃ to -60℃. At this temperature, potassium tert-butoxide (19g×3) was added at intervals of 0.5h in batches. In-process control of the reaction was performed by liquid phase detection. After 2 hours, the temperature of the reaction was raised to -5 to 0℃. The reaction solution was washed with purified water, stirred for 0.5 to 1 hour, washed with brine, and partitioned to obtain an organic phase. The organic phase was added with N-acetyl-L-cysteine (11.41g, 0.7eq) , stirred, washed with brine to neutralization, and concentrated under reduced pressure. The resultant filter cake was washed with purified water, and slurried. The resultant product was washed with purified water again and dried under vacuum to obtain a compound of formula 6, with a yield of 88.2%and a purity of 98.6%.

The NMR data of the compound of formula 6 is ¹H NMR (400MHz, d-DMSO) : δ ppm: 10.53 (1H, s) ; 8.75 (d, J=2.0) ; 8.53 (d, J=2.4) ; 8.24 (1H, s) ; 8.23 (d, J=2.4) ; 8.21 (d, J=1.6) ; 8.09 (dd, J1=1.6; J2=8.4) ; 7.94 (dd, J1=2.0; J2=8.0) ; 7.71 (d, J=8.8) ; 7.53 (d, J=8.0) ; 3.56 (2H, s) ; 2.59 (3H, s) ; 2.34-2.35 (8H, m) , 2.16 (3H, s) .

The carbon spectrum data thereof is ¹³C NMR (100MHz, d-DMSO) : δ ppm: 20.38, 45.65, 52.64, 54.67, 57.41, 88.26, 91.86, 111.76, 113.98, 117.19, 122.14, 123.43, 127.35 (q) , 124.30 (q) , 128.10, 129.89, 130.49, 131.15, 132.02, 132.13, 132.93, 133.66, 138.15, 143.65, 150.55, 164.64.

Example 2

The Sonogashira reaction was carried out with reference to the reaction parameters in each row of Table 4 (the other parameters are the same as those in the first step of embodiment 1) , the yield calculated according to the compound of formula 2 is shown in the last column of Table 4.

Table 4

Example 3

The amidation reaction was carried out with reference to the reaction parameters in each row of Table 5 (the other parameters are the same as those in the third step of embodiment 1) , the yield calculated on the basis of the compound of formula 4 or 5 which is with a smaller molar amount is shown in the last column of Table 5.

Table 5

Example 4: Preparation of Compound 8

A mixture of 5-bromo-2-fluoro-4-methylpyridine (25.02g, 131.7mmol, 1.0eq) , NBS (46.93g, 263.3mmol, 2.0eq) , AIBN (4.52g, 26.3mmol, 0.2eq) , HOAC (1.61g) in CAN (300mL) was heated to reflux reaction for 8 hours, the organic phase was concentrated to dry, and purified via column chromatography (n-heptane: EA = 50: 1) to provide orange oil (30.15g) .

A mixture of the oil product obtained in the previous step (20.53 g, 76 mmol, 1.0 eq) , calcium carbonate (40.15 g, 400 mmol, 5.3 eq) , in 1, 4-dioxane (200mL) and water (200mL) was heated to 100 ℃ and reacted overnight. The reaction solution was cooled to room temperature and filtered. The filter product was washed with ethyl acetate, ethyl acetate (200mL) and water (200mL) were added to the filtrate. The liquid was separated and the organic phase was collected. The aqueous phase was extracted with ethyl acetate, and the organic phase was combined, concentrated to dry, and column chromatography (DCM: MeOH=150: 1-100: 1-50: 1) 3.27g.

Under nitrogen, a mixture of the product obtained in the previous step (3.22g, 15.6 mmol, 1.0 eq) , DMP (9.93 g, 23.4 mmol, 1.5eq) in DCM (100mL) was heated to 25 ℃ and reacted for 1.5h. After the reaction was finished, sodium thiosulfate solution (100mL) and sodium bicarbonate solution (100mL) were added. The aqueous phase was extracted with ethyl acetate, and the organic phase was combined, and concentrated to dry to provide light yellow oil (3.11g) .

Under nitrogen, a mixture of the oil product obtained in the previous step (3.02g, 14.8mmol, 1.0eq) and hydrazine hydrate (80%) (0.92 g, 14.7 mmol, 1.0 eq) was dissolved in 12 mL anhydrous ethanol, and slowly dropped in several portions. After 3 hours of reaction at 25℃, the reaction mixture was filtered and dried to provide compound 8 (2.08 g) .

¹H NMR (400 MHz, DMSO-d ₆) δ 8.33 (s, 1H) , 8.24 (s, 2H) , 7.81 (d, J = 2.1 Hz, 1H) , 7.28 (d, J = 1.5 Hz, 1H) . LC-MS: 219.90, 217.90.

Example 5: Preparation of Compound 10

Under nitrogen, to a mixture of LDA (15ml, 34.81mmol, 1.5eq) and THF (20ml) , 2-fluoro-5-bromopyridine (4.02g, 23.01mmol, 1.0eq) tetrahydrofuran solution was added at -60 ℃ to -70 ℃. The mixture was stirred for 15 min at -60 ℃ to -70 ℃ and ethyl formate (2.51g, 34.81mmol, 1.5eq) was added and stirred at -60 ℃ to -70 ℃ for 20min. Under -60 ℃ or below, 40 mL of 10%tetrahydrofuran citrate solution was added and then 30 mL water was added. After the reaction was finished, the aqueous phase was extracted with ethyl acetate, and the organic phase was combined, and concentrated to dry to provide 2-fluoro-5-bromopyridine-3-formaldehyde (4.21g) .

Under nitrogen, to a mixture of LDA (3.8ml, 8.70mmol, 1.5eq) and 5ml THF, 2-fluoro-5-bromopyridine (1.02g, 5.80mmol, 1.0eq) tetrahydrofuran solution was added at -60 ℃ to -70 ℃. The mixture was stirred for 15 min at -60 ℃ to -70 ℃ and the product obtained in the previous step (1.41g, 6.95mmol, 1.2eq) and 15ml THF were slowly added in several portions at -60 ℃ to -70 ℃. After the reaction was stirred at -60 ℃ to -70 ℃ for 15min, the temperature was controlled below -60 ℃. 10ml of 10%tetrahydrofuran citrate solution was added and then 10mL water was added. The organic phase was washed with water and sodium chloride solution, dried with anhydrous magnesium sulfate, concentrated to dry, providing brown red oil, which was purified by thin-layer chromatography to provide compound 10 as light yellow oil (0.12g) .

¹H NMR (400 MHz, DMSO-d ₆) 8.35 (d, J = 2.5 Hz, 2H) , 8.33 –8.24 (m, 2H) , 6.76 (d, J = 4.5 Hz, 1H) , 6.00 (d, J = 4.4 Hz, 1H) . LC-MS: 382.90, 381.85, 380.80, 378.90.

Example 6: Preparation of Compound 12

Under nitrogen, to a mixture of LDA (15ml, 34.81mmol, 1.5eq) and THF (20ml) , 2-fluoro-5-bromopyridine (4.02g, 23.01mmol, 1.0eq) tetrahydrofuran solution was added at -60 ℃ to -70 ℃. The mixture was stirred for 15 min at -60 ℃ to -70 ℃, and ethyl formate (2.51g, 34.81mmol, 1.5eq) was added and stirred at -60 ℃ to -70 ℃ for 20min. Under -60 ℃ or below, 40 ml of 10%tetrahydrofuran citrate solution was added and then 30 ml water was added. After the reaction was finished, the aqueous phase was extracted with ethyl acetate, and the organic phase was combined, and concentrated to dry to provide 2-fluoro-5-bromopyridine-3-formaldehyde (4.21g) .

Under nitrogen, to a mixture of the 2-fluoro-5-bromopyridine-3-formaldehyde (1.57g, 7.34mmol, 1.0eq) of and 15ml anhydrous ethanol, anhydrous ethanol solution of 80%hydrazine hydrate (0.24g, 3.67mmol, 0.5eq) was slowly dropped in several portions. The reaction was carried out overnight at 25℃, and filtered and dried to provide compound 12 (0.46g) .

¹H NMR (400 MHz, Chloroform-d) δ 8.76 (d, J = 1.0 Hz, 2H) , 8.70 –8.60 (m, 2H) , 8.41 (dt, J = 2.4, 1.2 Hz, 2H) . LC-MS: 406.90, 405.85, 404.90, 402.90.

Example 7: Preparation of Compound 19

To a mixture of compound 19-1 (2.0g) in tetrahydrofuran (19ml) , 1N borane tetrahydrofuran solution (33ml) was slowly added. The reaction mixture was then heated under reflux, and cooled to the room temperature and 2N HCl (6ml) was added. The mixture was refluxed for 1h, cooled to the room temperature, and concentrated to provide a solid. The solid was slurried in the mixed solution of DCM (100ml) and EtOAc (50ml) , and filtered to provide a solid. The solid was dried under vacuum to provide compound 19-2 (2.14g) .

A mixture of compound 19-2 (0.5g) and trimethylamine in dichloromethane (20ml) was cooled to 0 ℃, and dichloromethane solution of acetyl chloride was added by drops. After dropping, the reaction mixture was warmed to room temperature. The organic phase was washed with sodium bicarbonate solution, and then the organic phase was dried with anhydrous magnesium sulfate, filtered, concentrated, and purified by silica gel column to provide compound 19.

¹H NMR (400 MHz, DMSO-d ₆) δ 8.13 (t, J = 5.2, 1H) , 7.13 (d, J=8.0, 1H) , 6.88 (d, J = 2.4, 1H) , 6.76 (dd, J1=8.4, J2=2.0, 1H, 5.48 (br, 1H) , 4.22 (d, J=5.2, 2H) , 1.85 (s, 3H) . MS: M+H+=233.00.

Example 8: Preparation of Compound 23

Under nitrogen, to a mixture of the compound 23-1 (20.11g, 108.04mmol, 1.0eq) and THF (200ml) , after the temperature was cooled to -20 ℃ to -30 ℃, DIBAL-H toluene solution (216ml, 1.5mol/l, 324.13mmol, 3.0eq) and slowly added in several portions. The temperature was kept at from -20 ℃ to -30 ℃for 30min, then increased to 25 to 30 ℃ for reaction for 4-5 hours. The temperature was cooled to 0 ℃, isopropanol (20ml) , saturated sodium potassium tartrate solution (500 ml) and ethyl acetate (500 ml) were added. The aqueous phase was extracted with ethyl acetate (200 ml) , and the organic phase was combined, and concentrated to dry to provide compound 23-2 (21.7g) .

To a mixture of the compound 23-2 (4.0g, 21.16mmol, 1.0eq) , ethyl acetate (40ml) and toluene (4.0g) , 1M HCl solution (20ml) was added and stirred for 10min. Sodium hydroxide solution (16ml 1M) was added and stirred. The organic phase was washed with sodium chloride solution (50ml) . To the separated organic phase, p-toluenesulfonic acid (0.44g 2.33mmol, 0.11eq) , piperazine (1.82g, 21.16mmol, 1.0eq) , and ethyl acetate (10ml) were added. The temperature was cooled to 50 ℃ and sodium triacetoxyborohydride (9.64g, 45.49mmol, 15 eq) was added. The reaction time was 1.5 hours. After reaction was completed; the saturated sodium bicarbonate solution was added to the reaction system until no bubbles were released. The solution was separated, and the organic phase was concentrated to dry to provide compound 23 crude product. The crude product was purified by column chromatography, and 0.50g compound 23 was provided by preparative chromatography.

¹H NMR (400 MHz, Chloroform-d) δ 7.53 (d, J = 8.3 Hz, 2H) , 6.93 (d, J = 2.5 Hz, 2H) , 6.81 (dd, J = 8.3, 2.5 Hz, 2H) , 3.76 (s, 4H) , 3.55 (d, J = 1.7 Hz, 4H) , 2.48 (s, 8H) . LC-MS: 433.05.

Example 9: Preparation of Compound 24

Compound 24-1 (15.0g, 80.60mmol, 1.0eq) and THF (150ml) were mixed. After the temperature was reduced to -30 ℃ to -40 ℃, DIBAL-H (161.2ml, 1.5m toluene solution, 241.81mmol, 3.0eq) was added slowly in several portions. The temperature was kept at -30 ℃ to -40 ℃ for 30min, then at 25 ℃ to 30 ℃for 3-4 hours. The reaction mixture was cooled down to 0 to 10 ℃. Isopropanol (100ml) was added for quenching reaction, and sodium potassium tartrate solution was added. The mixture was extracted with ethyl acetate (400ml) , dried and concentrated to provide compound 24-2 (15.19g) .

Under nitrogen, to the mixture of compound 24-1 (15.0g, 80.60mmol, 1.0eq) , 1.5g of 10%Pd/C and anhydrous methanol (120ml) , dripped a few drops of concentrated hydrochloric acid. The reaction mixture was connected to hydrogen. The reaction was carried out for three hours at room temperature. After filtration, the filtrate was spin dried to provide compound 24-3 (14.9g) .

Under nitrogen, compound 24-2 (15.19g, 80.35mmol, 1.0eq) and compound 24-3 (14.9g, 78.35mol, 0.97eq) , sodium triacetoxyborohydride (36.61g, 172.76mmol, 2.15eq) , ethyl acetate (150ml) were mixed, heated to 30 ℃ and reacted for 5-6 hours. The reaction solution was quenched with sodium bicarbonate solution. The solution was separated, and the organic phase was concentrated to dry. Compound 24 (2.0 g) was obtained by column chromatography.

¹H NMR (400 MHz, DMSO-d ₆) δ 7.15 (t, J = 7.9 Hz, 2H) , 6.94 (dd, J = 8.1, 1.2 Hz, 2H) , 6.86 (dd, J = 7.7, 1.2 Hz, 2H) , 5.57 (s, 4H) , 3.77 (s, 4H) . LC-MS: 364.00.

Example 10: Preparation of Compound 29

To a mixture of the sulfuric acid, iodine (0.88eq) , and sodium periodate (0.44eq) , p-toluenoic acid (1.0eq) was added. The reaction was maintained at room temperature for 2-3 hours, then the reaction solution was pour into ice water, stirred, and filtered. The filter cake was recrystallized with ethanol to provide compound 29-1.

Compound 29-1 was dissolved in methanol and sulfuric acid, heated and refluxed. The reaction solution was concentrated to dryness and then dissolved in ethyl acetate. The organic phase was washed with sodium bicarbonate solution, stratified, dried, filtered and concentrated to provide compound 29-2.

Compound 29-2 (1.0eq) was dissolved in ethyl acetate, and then trimethylsilylene (3.0eq) , bis (triphenylphosphine) palladium dichloride (0.02eq) , cuprous iodide (0.02eq) , triethylamine (6.0eq) were added into the reaction solution. The organic phase was washed with water and saturated salt water, stratified, dried, filtered and concentrated to provide compound 29-3.

Compound 29-3 was dissolved in methanol, cooled, and then potassium carbonate was added. The reaction was completed at room temperature. Cold water was added to the reaction solution, and dichloromethane was extracted. After stratification, the organic phase was dried with, filtered, concentrated, and purified by column chromatography to provide compound 29.

¹H NMR (400 MHz, DMSO-d ₆) δ 7.92 (s, 2H) , 4.60 (s, 2H) , 3.86 (s, 3H) , 2.55 (s, 3H) . MS: M+H ⁺=199.10.

Example 11: Preparation of Compound 33 and Compound 34

Under nitrogen, to a mixture of the compound 33-1 (10 g) and acetonitrile (76 g) , bis (triphenylphosphine) palladium dichloride (0.31 g) , cuprous iodide (84 mg) , and triethylamine (6.71 g) were added. The reaction mixture was controlled at 60-70℃ and stirred for 20 hours, then filtered directly through silica gel to provide the dark green liquid. The dark green liquid was concentrated, beat with n-heptane for 20 hours, and filtered to provide compound 33.

Compound 33: ¹H NMR (400 MHz, DMSO-d ₆) : δ7.92 (d, J=9.2, 2H) , 7.86 (d, J=7.6, 2H) , 7.45 (m, 2H) , 6.06 (s, 1H) , 5.78 (s, 1H) , 3.84 (s, J=6.0, 1H) , 2.42 (s, 3H) . MS: M+H ⁺=349.20.

Compound 34 can be isolated from the preparation of Compound 33 or from a process described herein.

Compound 34: ¹H NMR (400 MHz, DMSO-d ₆) : δ 8.77 (s, 1H) , 8.09 (s, 1H) , 7.88～7.99 (m, 4H) , 6.47 (s, 1H) , 6.27 (s, 1H) , 5.39 (s, 1H) , 3.93～3.98 (m, 6H) , 3.84 (d, J=9.2, 3H) , 2.47 (s, 3H) , 2.40 (s, 3H) , 2.14 (s, 3H) .

Example 12: Preparation of Compound 35

Compound 35 can be prepared in analogous fashion to the procedures described in International Publication No. WO2009/143404 (for example, on pages 107-108) and International Publication No. WO2010/124047 (for example, on page 50) , the content of each of which is incorporated herein by reference in its entirety.

Compound 35 can also be isolated from a process described herein.

¹H NMR (400 MHz, DMSO-d ₆) : δ 8.76 (s, 1H) , 8.63 (s, 1H) , 8.49 (s, 1H) , 8.09 (s, 1H) , 7.89 (d, J=8.4, 1H) , 7.51 (d, J=7.6, 1H) , 3.88 (3H, s) , 2, 58 (s, 3H) , 1.71 (s, 9H) .

Example 13: Preparation of Compound 36

Compound 4 (2g) and anhydrous tetrahydrofuran (50mL) was mixed, cooled to 0 ℃, to which sodium hydrogen (328 mg) was added. The reaction mixture was then stirred at 0 ℃ for 1 hour, and then methyl chloroformate (777 mg) was added. After dropping, the temperature was increased to 20 ℃ and the mixture was stirred for 48 hours. Water (20 mL) was added to stop the reaction. The mixture was stirred and filtered to provide compound 36 as a white solid.

¹H NMR (400 MHz, DMSO-d ₆) δ 8.95 (d, J=2.0, 1H) , 8.64 (d, J=2.0, 1H) , 8.55 (s, 1H) , 8.11 (s, 1H) , 7.91 (d, J=7.6, 1H) , 7.53 (d, J=8.0, 1H) , 4.06 (3H, s) , 3.87 (3H, s) , 2, 59 (s, 3H) . MS: M+H ⁺=350.1.

Example 14: Preparation of Compound 37

To a mixture of Compound 4 (2g) and anhydrous tetrahydrofuran (50mL) , sodium hydrogen (329mg) was added at 20 ℃. The reaction mixture was stirred for 1 hour at 25 ℃. Iodomethane (1.95g) was added by dropping, after which, the reaction mixture was stirred at 20 ℃ for 17 hours, and then filtered to provide the crude product. The crude product was slurried in tetrahydrofuran, filtered to provide compound 37.

¹H NMR (400 MHz, DMSO-d ₆) δ 8.79 (s, 1H) , 8.52 (s, 2H) , 8.07 (s, 1H) , 7.88 (d, J=7.6, 1H) , 7.51 (d, J=7.2, 1H) , 4.. 22 (3H, s) , 3.86 (3H, s) , 2, 50 (s, 3H) . MS: M+H ⁺=306.2.

Example 15: Preparation of Compound 38

Compound 38-1 (561mg) , compound 4 (921mg) and 52ml THF were mixed and cooled to -66 ℃, to which potassium tert butyl alcohol (2.73g) was added. The reaction mixture was stirred for 3 hours at -66 ℃ to -70 ℃. When the temperature was raised to room temperature, 1ml of water was added to stop the reaction. 20ml of 15%salt water was added to stir for 1 hour. After stratification, the organic layer was washed twice with 15%salt water. After stratification, yellow solution was provided. After adding 20ml water, the mixture was concentrated to 30ml, to which 10ml ethanol was added. After stirring for 1 hour, the mixture was filtered to provide white solid compound 38.

¹H NMR (400 MHz, DMSO-d ₆) δ 13.9 (br, 2H) , 10.55 (s, 2H) , 8.74 (s, 2H) , 8.54 (s, 2H) , 8.21 (m, 6H) , 8.11 (d, J=8.0, 2H) , 7.93 (t, J=8.0, 2H) , 7.83 (d, J=8.4, 2H) , 7.53 (d, J=8.4, 2H) , 3.87 (4H, s) , 2.59 (3H, s) , 2, 53 (s, 3H) . MS: M+ H ⁺=882.4.

Example 16: Preparation of Compound 39

Sodium hydroxide (6.4g) was dissolved in 40 ml of water, compound 3 (5g) and 40 ml of tetrahydrofuran were added. The reaction mixture was stirred at room temperature for 41 hours. After filtration, the filtrate was dried in 40 ℃ to provide a white solid compound 39.

¹H NMR (400 MHz, DMSO-d ₆) δ 13.9 (br, 1H) , 10.55 (s, 2H) , 8.73 (s, 1H) , 8.53 (s, 1H) , 8.21 (s, 1H) , 8.06 (d, J=1.6, 1H) , 7.85 (m, 1H) , 7.47 (d, J=8.0, 2H) , 2.56 (3H, s) .

Example 17: Preparation of Compound 40

Compound 40-1 (294mg) was dissolved in tetrahydrofuran (7ml) , to which compound 4 (250mg) was added, and then the reaction solution was cooled to -77 ℃. 520mg potassium tert-butyl alcohol was added, and the reaction was stirred at -77 ℃ for 5 hours. The reaction solution was directly purified through the column to provide 60mg compound 40.

¹H NMR (400 MHz, DMSO-d ₆) δ 13.96 (br, 1H) , 10.57 (s, 1H) , 8.74 (s, 1H) , 8.54 (s, 1H) , 8.27 (m, 3H) , 8.11 (s, J=8.0, 1H) , 7.91 (t, J=8.0, 1H) , 7.58 (m, 2H) , 7.36 (d, J=8.4, 1H) , 6.79～6.84 (m, 3H) , 4.43 (s, 2H) , 3.60 (s, 2H) , 2.16～2.67 (m, 14H) . MS: M+H ⁺=706.3.

Example 18: Preparation of Compound 41

Preparation of compound 41-1: 20.00g compound 2, 158mL NMP, 41.80g trimethylsilylacetylene, 2.35g Pd (PPh ₃) ₂Cl ₂, 0.6380g CuI, 13.00g DIPEA were added sequentially. The reaction mixture was protected under nitrogen, heated to 60-70℃ and stirred for 5 hours. After the reaction was complete, the reaction mixture was cooled down to 5℃, and EtOAc and water were added. The mixture was stirred, separated, extracted, the organic phases were combined, concentrated, and purified by column chromatography to provide 15.40 g of compound 41-1 (yield: 72.8%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 8.74 (d, J = 2.1 Hz, 1H) , 8.48 (d, J = 2.1 Hz, 1H) , 8.43 (s, 1H) , 1.63 (s, 9H) , 0.27 (s, 9H) .

Preparation of compound 41: 14.86g of compound 41-1 and 150ml methanol were added in turn, cooled to 0-5℃, 9.76g potassium carbonate was added to the reaction in batches. After the addition, the mixture was naturally warmed up to 10-15℃, reacted for 30-45min, and the reaction was complete, Water was slowly added to precipitate solids, kept for 30-45min, and filtered. The filter cake was washed with water to pH 7～8, and dried to provide 6.50g powder solid of compound 41 (yield: 96.4%) .

Example 19: Preparation of Compound 42

Preparation of compound 42-2: Compound 42-1 (3.00g) , carbon tetrachloride (50ml) , NBS (2.89g) , AIBN (356mg) , potassium carbonate (1.65g) were added in sequence, heated to 60-70℃ overnight and stirred for 15-19 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, concentrated to dryness under reduced pressure, dissolved in ethyl acetate, washed with water, and the organic phase was concentrated to dryness under reduced pressure to provide the crude product of compound 42-2 (4.35g) . MS: [M+H] ⁺=356.9.

Preparation of compound 42-3: Compound 42-2 (4.35g) , sodium formate (3.17g) , ethanol (180ml) , water (48ml) were added successively, heated to 80-90℃ overnight and stirred for 15-20 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. Ethyl acetate was added, stirred, and separated. The organic phase was concentrated to dryness under reduced pressure to provide the crude product of Compound 42-3 (3.52g) . The crude product was purified by silica gel column to obtain the pure product of Compound 42-3 (1.20g) , yield 33%. MS: [M+H] ⁺=293.0.

Preparation of compound 42-4: Compound 42-3 (1.70g) , compound 41 (833mg) , Pd (PPh ₃) ₂Cl ₂ (327mg) , CuI (89mg) , DIPEA (1.13g) , and NMP (50ml) were added, heated to 60-65℃ under nitrogen, and stirred overnight for 10-15 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, 2-methyltetrahydrofuran and water were added and stirred. The layers were separated, the organic phase was washed with water, concentrated to dryness under reduced pressure, and purified through a silica gel column to provide compound 42-4 (0.96g) , yield 54%. MS: [M+H] ⁺=308.10.

¹H NMR (400 MHz, DMSO-d ₆) δ 13.94 (s, 1H) , 8.74 (q, J = 2.4, 1.7 Hz, 1H) , 8.54 (t, J = 1.7 Hz, 1H) , 8.23 (s, 1H) , 8.07 (s, 1H) , 8.01 (d, J = 8.0 Hz, 1H) , 7.74 (d, J = 8.1 Hz, 1H) , 5.58 (t, J = 5.6 Hz, 1H) , 4.84 (d, J = 5.4 Hz, 2H) , 3.88 (s, 3H) .

Preparation of compound 42: t-BuOK (1790 mg) was dissolved in THF (14ml) for later use. Compound 42-4 (700mg) , compound 5 (623mg) , and THF (30ml) were added, and the temperature was reduced to -60℃ under nitrogen, then the THF solution of t-BuOK was slowly added dropwise, and the temperature was controlled at -60℃. After the addition was completed, the temperature was kept at -60℃and stirred for 1 hour. After the reaction was completed, the temperature was raised to -10℃, water and ethyl acetate were added, stirred, and the layers were separated. The organic phase was concentrated and dried under reduced pressure. After purification by silica gel column, 490mg crude product was obtained. The crude product and absolute ethanol were heated to reflux, stirred for 30 minutes, then cooled to room temperature, stirred for 1 hour, filtered, and the filter cake was placed in a vacuum drying oven at 40℃ for 10-13 hours to provide white solid compound 42 (270mg) , yield 20%. MS: [M+H] ⁺=549.10.

¹H NMR (400 MHz, DMSO-d ₆) δ 13.95 (s, 1H) , 10.58 (s, 1H) , 8.74 (t, J = 1.6 Hz, 1H) , 8.54 (t, J = 1.6 Hz, 1H) , 8.27 –8.16 (m, 3H) , 8.06 (dd, J = 15.4, 8.3 Hz, 2H) , 7.73 (dd, J = 10.9, 8.3 Hz, 2H) , 5.54 (t, J = 5.7 Hz, 1H) , 4.86 (d, J = 5.5 Hz, 2H) , 3.57 (s, 2H) , 2.37 (d, J = 24.3 Hz, 8H) , 2.16 (s, 3H) .

Example 20: Preparation of Compound 43

Preparation of compound 43-2: 30ml concentrated sulfuric acid was added, the temperature was reduce to 5～10℃, 10.00g methyl 3-iodo-4-methylbenzoate (compound 42-1) was added under nitrogen protection, stirred at 5～10℃ for 20min, then a mixture of fuming nitric acid and concentrated sulfuric acid (4.57g fuming nitric acid was dissolved in 10ml concentrated sulfuric acid, the temperature was controlled at 5～10℃) was added dropwise. After the addition, the reaction mixture was warmed to room temperature, poured into water, and DCM was added. The layers were separated, the organic phase was collected and extracted. The combined organic phase was washed with water, concentrated to dryness, and the crude product was purified by column chromatography to provide 2.00 g of compound 43-2 (yield: 17.2%) . ¹H NMR (400 MHz, DMSO-d ₆) δ 8.57 (d, J = 1.8 Hz, 1H) , 8.32 (d, J = 1.7 Hz, 1H) , 3.90 (s, 3H) , 2.56 (s, 3H) .

Preparation of compound 43-3: 1.78g compound 43-2, 20ml ethanol, 1.39g iron powder, 0.3110g ammonium chloride and 4.19g aqueous solution, were added sequentially under nitrogen protection. The reaction mixture was stirred, heated up to 80-90℃, and reacted for about 1-1.5 hours. When the reaction was completed, the reaction mixture was cooled to room temperature, diluted by addition of DCM, saturated sodium bicarbonate aqueous solution was added, and the pH of the aqueous phase was about 8. The mixture was stirred, filtered, separated, and extracted. The combined organic phase was washed with water, and concentrated to provide 1.60 g compound 43-3 (yield: 99.1%) , which was used directly to the next step.

Preparation of compound 43-4: 15ml of water was added and cooled to -5℃-5℃, then 1.37g concentrated sulfuric acid, 1.00g compound 43-3, and 15ml ethanol were added sequentially under nitrogen protection. Sodium nitrite aqueous solution (0.0618g sodium nitrite dissolved in 200ul of water) was slowly added at 0-5℃ with stirring and the temperature was maintained. The reaction mixture was heated to 80-90℃ for refluxing, reacted for 30-45min. After the reaction was completed, the reaction mixture was diluted by addition of DCM, the layers were separated and extracted. The combined organic phase was washed with alkali, washed with water, concentrated and purified by column chromatography to provide 0.77 g solid compound 43-4.

Preparation of compound 43-5: Compound 43-4 (0.715g) , NMP (20ml) , compound 41 (0.876g) , Pd (dppf) Cl ₂ (0.358g) , CuI (93mg) and DIPEA (3.16g) were added in sequence under nitrogen protection. The reaction mixture was heated to 90-95℃, and reacted for 5-7 hours. After the reaction was completed, the reaction mixture was cooled to 20℃, quenched by water, and extracted with 2-methyltetrahydrofuran. The combined organic phase was concentrated to dryness, and purified by column chromatography to obtain the crude product. The crude product was washed with EtOAc, cooled to room temperature, n-heptane was added dropwise, stirring, filtered, and dried to provide compound 43-5 (0.62 g) with a purity of 83%and a yield of 82%.

Preparation of compound 43: Compound 43-5 (0.60g) , compound 5 (0.53g) , and THF (15ml) were added successively under nitrogen protection. The temperature was reduced to -55℃, and 1.0M potassium tert-butoxide in THF (23.4ml) was slowly added dropwise. After the addition was completed, the reaction continued for 10-15 hours. After the reaction was completed, 14%potassium dihydrogen phosphate solution was added until pH 8-9, extracted with EtOAc, the organic phase was washed with water, the layers were separated, the organic phase was washed, and purified by column chromatographic to provide crude product. The crude product was stirred with THF (9ml) , petroleum ether (15ml) was added dropwise, stirring was continued for 20-30 minutes, filtered, and dried to provide compound 43 (0.334g) with a purity of 99%and yield 32%. ¹H NMR (400 MHz, DMSO-d ₆) δ 13.94 (s, 1H) , 10.50 (s, 1H) , 10.08 (s, 1H) , 8.72 (d, J = 2.0 Hz, 1H) , 8.52 (d, J = 1.9 Hz, 1H) , 8.25 –8.18 (m, 2H) , 8.07 (dd, J = 8.6, 2.1 Hz, 1H) , 7.75 –7.67 (m, 2H) , 7.44 (d, J = 1.7 Hz, 1H) , 3.58 (s, 2H) , 2.42 (s, 10H) , 2.22 (s, 3H) . MS: [M+H] ⁺=549.10.

Example 21: Preparation of Compound 44 and Compound 45

Methyl 2-hydroxy-4-methylbenzoate (15.25g) and DCM (100ml) were added in sequence under nitrogen protection, cooled to 0-5℃, NIS (19.82g) was added. After the addition, the reaction mixture was warmed up to 20-25℃, stirred and reacted for 20-22 hours. After the reaction was completed, water and DCM were added, and the layers were separated. The organic phase was washed with water, concentrated to dryness, and purified by column chromatography to provide 15.10 g of product (amixture of methyl 2-hydroxy-4-methylbenzoate, compound 44-1, and compound 45-1) .

5.10g of compound 45-1 mixture, NMP (30ml) , compound 41 (1.0g) , PdCl ₂ (PPh ₃) ₂ (0.39g) , CuI (0.11g) and DIPEA (1.36g) were sequentially added. Under nitrogen protection, the reaction mixture was heated to 60-66℃ and reacted for 3-5 hours. After the reaction was completed, the reaction mixture was cooled to 20-25℃, poured into water, extracted with 2-methyltetrahydrofuran (200ml) and EtOAc (300ml) . The organic phase was concentrated to dryness and purified by column chromatography to provide compound 45-2 (1.26g) , yield 59%.

Compound 45-2 (0.6g) was dissolved in THF (8ml) to prepare a THF solution of compound 45-2 for use later. A mixture of compound 5 (0.56g) and 1.0M potassium tert-butoxide in THF solution (23.5ml) was cool to -55℃, and compound 45-2 in THF solution was added dropwise. After the addition was completed, the reaction mixture was stirred for 15-20 hours while the temperature was maintained. The temperature was then raised to -30℃, and the reaction mixture was stirred for 4-5 hours. After the reaction was completed, water was added, and 1M hydrochloric acid was added dropwise to pH 7-8, and the mixture was extracted with EtOAc. The organic phases were combined, concentrated to dryness, and purified by column chromatography to obtain a crude product. The crude product was refluxed with ethanol, cooled to room temperature, filtered, and dried to provide compound 45 (70 mg) with a purity of 78%and a yield of 6.5%. MS: [M+H] ⁺=549.10.

¹H NMR (400 MHz, DMSO-d ₆) δ 13.88 (s, 1H) , 11.71 (s, 1H) , 8.67 (d, J = 2.0 Hz, 1H) , 8.43 (d, J = 2.0 Hz, 1H) , 8.23 –8.15 (m, 2H) , 8.13 (s, 1H) , 7.93 (dd, J = 8.5, 2.2 Hz, 1H) , 7.71 (d, J = 8.5 Hz, 1H) , 6.84 (s, 1H) , 3.60 (s, 2H) , 2.55 (s, 3H) , 2.46 (s, 7H) , 2.32 (s, 3H) .

2.5g of compound 44-1 mixture, NMP (20ml) , compound 41 (1.395g) , Pd (dppf) Cl ₂ (1.424g) , CuI (0.372g) and DIPEA (5.53g) were added in sequence. Under nitrogen protection, the reaction mixture was heated to 90-95℃, and reacted for 16-18 hours. After the reaction was completed, the temperature was lowered to 20℃, water was added, and extracted with 2-methyltetrahydrofuran. The organic phase was concentrated to dryness and purified by column chromatography to provide compound 44-2 (1.44g) with a purity of 86.8%and a yield of 55%.

Compound 44-2 (0.50g) was dissolved in THF (8ml) to prepare a THF solution of compound 44-2 for later use. A mixture of compound 5 (0.467g) and 1.0M potassium tert-butoxide in THF solution (19.5ml) was cooled to -55℃, and compound 44-2 in THF solution was slowly added dropwise. After the addition was completed, the reaction mixture was stirred for 15-20 hours while the temperature was maintained. After the completion of the reaction, water was added, 1M hydrochloric acid was added dropwise to pH 7-8, extracted with EtOAc, the organic phases were combined, concentrated to dryness, and purified by column chromatography to provide a crude product. The crude product was washed with DCM, filtered, and dried to provide compound 44 (80 mg) with a purity of 99%and a yield of 9%. MS: [M+H] ⁺=549.10.

¹H NMR (400 MHz, DMSO-d ₆) δ 13.91 (s, 1H) , 10.62 (s, 1H) , 9.20 (s, 1H) , 8.74 (s, 1H) , 8.41 –8.18 (m, 2H) , 8.06 (d, J = 8.5 Hz, 1H) , 7.89 –7.73 (m, 2H) , 7.68 (dd, J = 7.7, 1.4 Hz, 1H) , 7.25 (d, J = 7.7 Hz, 1H) , 3.60 (s, 2H) , 2.62 (s, 3H) , 2.39 (d, J = 26.4 Hz, 7H) , 2.17 (d, J = 1.4 Hz, 3H) .

Example 23: Anti-proliferation activity of selected compounds in K562 cells

K562/Ku812/MEG-01 cells were seeded to 96-well plate and treated with various concentrations of selected compounds for 72 hours. cell viability was determined by CTG assay and IC50s were calculated using GraphPad Prism 8. Data points were shown as mean + SEM. The results are listed in the following table.

NA = not available

Claims

A process for preparing a compound of Formula (I’) or a pharmaceutically acceptable salt thereof:

comprising reacting a compound of Formula (II’) :

with a compound of Formula (III) :

in a solvent and in the presence of a base to provide the compound of Formula (I’) ,

wherein

R ₁ is H, C ₁-C ₄ alkyl, or -C (=O) O- (C ₁-C ₄ alkyl) ;

R ₂ is H or C ₁-C ₄ alkyl;

R ₃ is
-NH ₂, -NHC (=O) Me,

R ₇ is H or hydroxyl;

R ₈ is H or hydroxyl;

R ₉ is H or hydroxyl;

R ₁₀ is H or hydroxyl; and

provided that the compound of Formula (I’) is not compound 6:
A process for preparing a compound of Formula (I) :

comprising reacting a compound of Formula (II) :

with a compound of Formula (III) :

in a solvent and in the presence of a base to provide the compound of Formula (I) ,

wherein R ₁ is H, C ₁-C ₄ alkyl, or -C (=O) O- (C ₁-C ₄ alkyl) , R ₂ is H or C ₁-C ₄ alkyl, and R ₃ is
-NH ₂, -NHC (=O) Me,
and

provided that the compound of Formula (I) is not compound 6:
The process of claim 1 or 2, wherein the -CH ₂-R ₃ group is at para-position to the -NH-group.
The process of claim 3, wherein the compound of Formula (I) is a compound of Formula (I-A) :
The process of claim 1 or 2, wherein the -CH ₂-R ₃ group is at para-position to the -CF ₃ group.
The process of claim 5, wherein the compound of Formula (I) is a compound of Formula (I-B) :
The process of any one of claims 1 to 6, wherein R ₁ is H, t-butyl, -C (=O) OMe, or methyl.
The process of any one of claims 1 to 7, wherein R ₂ is H or methyl.
The process of claim 2, wherein the compound of Formula (I) is a compound of Formula (I-C) :
The process of claim 1, wherein the compound of Formula (I’) is a compound of Formula (I-D) :
The process of any one of claims 1 to 10, wherein the compound of Formula (II) is prepared by a process comprising reacting Compound 1:

with a compound of Formula (IV) :

in a solvent and in the presence of a base, a catalyst and a catalyst ligand to provide the compound of Formula (II) .
The process of any one of claims 1 to 10, wherein the compound of Formula (II’) is prepared by a process comprising reacting a compound of Formula (V) :

wherein X is a halogen, with a compound of Formula (VI) :

in a solvent and in the presence of a base, a catalyst and a catalyst ligand to provide the compound of Formula (II’) .
The process of claim 11 or 12, wherein the reaction between Compound 1 and the compound of Formula (IV) or the reaction between the compound of Formula (V) and the compound of Formula (VI) is carried out under the protection of nitrogen or inert gas;

and/or, the solvent comprises N-methylpyrrolidone, DMSO, DMF, N, N-dimethylacetamide, acetonitrile, toluene, dioxane and THF;

and/or, the volume/mass ratio of the solvent to the compound of Formula (IV) is (about 5 to about 10) mL : 1g;

and/or, the catalyst is a palladium catalyst;

and/or, the molar ratio of the catalyst to the compound of Formula (IV) is (about 0.01 to about 0.05) : 1;

and/or, the catalyst ligand is a copper compound and/or triphenylphosphine;

and/or, the molar ratio of the catalyst ligand to the catalyst is (about 0.8 to about 1.2) : 1;

and/or, the base is an organic base and/or an inorganic base;

and/or, the molar ratio of the base to the compound of Formula (IV) is (about 1.0 to about 1.5) : 1;

and/or, the molar ratio of Compound 1 to the compound of Formula (IV) is (about 0.95 to about 2.0) : 1;

and/or, the reaction temperature is about 40℃ to about 80℃;

and/or, the post-treatment of the reaction comprises mixing with water and filtering.
The process of claim 13, wherein in the reaction between Compound 1 and the compound of Formula (IV) or the reaction between the compound of Formula (V) and the compound of Formula (VI) , the solvent is N-methylpyrrolidone, DMSO, DMF, N, N-dimethylacetamide or acetonitrile;

and/or, the volume/mass ratio of the solvent to the compound of Formula (IV) is (about 7 to about 10) mL : 1g;

and/or, when the catalyst is a palladium catalyst, the palladium catalyst is selected from the group consisting of PdCl ₂ (PPh ₃) ₂, Pd (dppf) ₂Cl ₂, Pd (OAc) ₂ and palladium carbon;

and/or, the molar ratio of the catalyst to the compound of Formula (IV) is (about 0.01 to about 0.03) : 1;

and/or, when the catalyst ligand includes a copper compound, the copper compound is selected from the group consisting of CuI, CuBr, Cu ₂O, CuO and Cupric acetate;

and/or, the molar ratio of the catalyst ligand to the catalyst is 1: 1;

and/or, when the base includes an organic base, the organic base comprises pyridine, an alkali metal salt of a C ₁-C ₄ alcohol, or –N (R ⁴) (R ⁵) (R ⁶) , wherein each of R ⁴, R ⁵ and R ⁶ independently represents hydrogen or a C ₁-C ₄ alkyl;

and/or, when the base includes an inorganic base, the inorganic base is an alkali metal carbonate and/or an alkali metal hydroxide;

and/or, the molar ratio of the base to the compound of Formula (IV) is (about 1.2 to about 1.3) : 1;

and/or, the molar ratio of Compound 1 to the compound of Formula (IV) is (about 1.2 to about 1.5) : 1;

and/or, the reaction temperature is about 60℃ to 75℃;

and/or, when the post-treatment of the reaction comprises mixing with water and filtering, it further comprises mixing with an amino acid compound before mixing with water;

and/or, when the post-treatment of the reaction comprises mixing with water and filtering, the mixing temperature in the mixing with water step is about 20℃ to about 25℃;

and/or, when the post-treatment of the reaction comprises mixing with water and filtering, the filtering further comprises washing with water;

and/or, when the post-treatment of the reaction comprises mixing with water and filtering, it further comprises slurrying after filtering.
The process of claim 14, wherein in the reaction between Compound 1 and the compound of Formula (IV) or the reaction between the compound of Formula (V) and the compound of Formula (VI) , the solvent is N-methylpyrrolidone, DMSO, DMF or N, N-dimethylacetamide;

and/or, when the catalyst is a palladium catalyst, the palladium catalyst is PdCl ₂ (PPh ₃) ₂ or Pd (dppf) ₂Cl ₂;

and/or, when the catalyst ligand includes a copper compound, the copper compound is CuI or CuBr;

and/or, when the base includes an organic base and the organic base includes an alkali metal salt of a C ₁-C ₄ alcohol, the alkali metal salt of the C ₁-C ₄ alcohol is potassium tert-butoxide and/or sodium tert-butoxide;

and/or, when the base includes an organic base and the organic base includes or –N (R ⁴) (R ⁵) (R ⁶) , the –N (R ⁴) (R ⁵) (R ⁶) comprises Et ₃N, DIPEA, (i-Pr) ₂NH and Bu ₃N;

and/or, when the base includes an inorganic base and the inorganic base includes an alkali metal carbonate, the alkali metal carbonate is K ₂CO ₃ and/or Cs ₂CO ₃;

and/or, when the base includes an inorganic base, the inorganic base includes an alkali metal hydroxide, the alkali metal hydroxide is NaOH and/or KOH;

and/or, the molar ratio of Compound 1 to the compound of Formula (IV) is (about 1.2 to about 1.3) : 1;

and/or, the reaction temperature is about 65℃ to about 70℃;

and/or, when the post-treatment of the reaction comprises mixing with water and filtering and further comprises mixing with an amino acid compound before mixing with water, the amino acid compound is selected from the group consisting of cysteine, N-acetyl-L-cysteine, ethylenediaminetetraacetic acid, sodium edetate and dithiocarbamates;

and/or, when the post-treatment of the reaction comprises mixing with water and filtering and further comprises mixing with an amino acid compound before mixing with water, the molar ratio of the amino acid compound to the compound of Formula (IV) is (about 0.1 to about 0.5) : 1;

and/or, when the post-treatment of the reaction comprises mixing with water and filtering and further comprises mixing with an amino acid compound before mixing with water, the mixing temperature upon mixing with an amino acid compound is about 35℃ to about 45℃;

and/or, when the post-treatment of the reaction comprises mixing with water and filtering and further comprises mixing with an amino acid compound before mixing with water, the mixing time for mixing with an amino acid compound is about 4h to 5h;

and/or, when the post-treatment of the reaction comprises mixing with water, filtering and further comprises slurrying immediately after filtering, the solvent used for slurrying is a mixed solvent of ethyl acetate and n-heptane with a volume ratio of 1: 1;

and/or, when the post-treatment of the reaction comprises mixing with water, filtering and further comprises slurrying immediately after filtering, the volume/mass ratio of the solvent to the crude filter cake used for slurrying is (about 5 to about 7) mL: 1g.
A compound, which is:
A compound of Formula (I-D) :

wherein:

R ₇ is H or hydroxyl;

R ₈ is H or hydroxyl;

R ₉ is H or hydroxyl;

R ₁₀ is H or hydroxyl; and

provided that at least one of R ₇, R ₈, R ₉, and R ₁₀ is hydroxyl;

or a pharmaceutically acceptable salt thereof.
The compound of claim 17, which is:

or a pharmaceutically acceptable salt thereof.
A pharmaceutical composition comprising a compound of any one of claims 16 to 18, and a pharmaceutically acceptable excipient.
A method for treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 16 to 18 or a pharmaceutical composition of claim 19.