CN114533733A - Isoquinoline-1, 3-diamine analogue pharmaceutical preparation and preparation method thereof - Google Patents

Isoquinoline-1, 3-diamine analogue pharmaceutical preparation and preparation method thereof Download PDF

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CN114533733A
CN114533733A CN202111675522.8A CN202111675522A CN114533733A CN 114533733 A CN114533733 A CN 114533733A CN 202111675522 A CN202111675522 A CN 202111675522A CN 114533733 A CN114533733 A CN 114533733A
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isoquinoline
diamine
reaction
compound
pharmaceutical formulation
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秦旭航
李玲
李砚明
戴信敏
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Beijing Xinkaiyuan Pharmaceuticals Co Ltd
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Beijing Xinkaiyuan Pharmaceuticals Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Abstract

The invention relates to the technical field of medicaments, and provides an isoquinoline-1, 3-diamine analogue medicinal preparation and a preparation method thereof, wherein the isoquinoline-1, 3-diamine analogue or pharmaceutically acceptable salt thereof, a filling agent, a disintegrating agent, a binding agent and a lubricating agent are contained. The isoquinoline-1, 3-diamine analogue has a structure shown in a formula I:
Figure DDA0003451844180000011
wherein R is1Represents R2CO or
Figure DDA0003451844180000012
When R is1Represents R2When CO, R2Is cyclopentyl, morpholin-4-yl, N-methylpiperazin-4-yl, 4-methylenecyclohexyl, 3-oxocyclopent-1-yl, cyclohexyl, 2-oxopiperidin-4-yl, 2-oxotetrahydro-2H-pyran-4-yl or 2-oxoazepan-4-yl; when R is1Represents
Figure DDA0003451844180000013
When R is3、R4With the nitrogen atom constituting pyrrol-1-yl, morpholin-4-yl, 4-methylpiperidin-1-yl, 4-methylenepiperidine, 3-oxopyrrol-1-yl, piperidin-1-yl or 3-oxopiperazin-1-yl. The isoquinoline-1, 3-diamine analogue medicinal preparation is used as a PDK1 inhibitor for treating cancers, and has the advantages of good activity, high selectivity, low toxicity, small side effect and the like. The isoquinoline-1, 3-diamine analogue medicinal preparation has high dissolution rate and good dissolution effect.

Description

Isoquinoline-1, 3-diamine analogue pharmaceutical preparation and preparation method thereof
Technical Field
The invention relates to an isoquinoline-1, 3-diamine analogue medicinal preparation and a preparation method thereof, belonging to the technical field of chemical medicine.
Background
PDKl (phosphoinositide-dependent protein kinase-1) is a protein serine/threonine kinase belonging to the AGC kinase family and plays an important role in the P13K/Akt growth pathway. Binding of various growth factors to receptor tyrosine kinases activates P13K, converting PIP2 to PIP3, PIP3 binds to Akt and PDKl, which phosphorylates threonine at position 308 of the Akt protein. Besides activating Akt, PDKl can also activate a series of AGC kinase family members by phosphorylating a conserved region T-loop region of AGC kinase; about 50 percent of all tumors including malignant diseases of a blood system have over-activation of PDKl, so that AGC kinase activates Akt and other AGC family proteins, and a series of downstream substrates are phosphorylated and activated, thereby causing tumor cell proliferation, inhibiting apoptosis, promoting angiogenesis and the like.
PDKl is overexpressed in most tumor tissues (e.g., breast cancer, pancreatic cancer, etc.), and about 50% of cancer (e.g., breast cancer, lung cancer, prostate cancer) cells have PDKl overexpressed. The main reason for breast cancer resistance to tamoxifen is also due to over-expression of PDK 1. Therefore, the discovery and research of new pharmaceutical preparations of PDK1 inhibitors with better activity, higher selectivity and lower toxicity have important significance.
Disclosure of Invention
The researchers of the invention find that the compound shown in the structural formula I has good PDK1 inhibitory activity and can be used for treating cancers. Therefore, the invention aims to provide an isoquinoline-1, 3-diamine analogue drug preparation with a structure shown in formula I and a preparation method thereof, wherein the compound represented by the formula I and various derivatives thereof have anti-tumor pharmacological activity, and the specific technical scheme is as follows:
the isoquinoline-1, 3-diamine analogue pharmaceutical preparation comprises isoquinoline-1, 3-diamine analogue or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers;
the isoquinoline-1, 3-diamine analogue has a structure shown in a formula I:
Figure BDA0003451844170000011
wherein R is1Represents R2CO or
Figure BDA0003451844170000012
When R is1Represents R2When CO, R2Is cyclopentyl, morpholin-4-yl, N-methylpiperazin-4-yl, 4-methylenecyclohexyl, 3-oxocyclopent-1-yl, cyclohexyl, 2-oxopiperidin-4-yl, 2-oxotetrahydro-2H-pyran-4-yl or 2-oxoazepan-4-yl;
when R is1Represents
Figure BDA0003451844170000021
When R is3、R4With the nitrogen atom constituting pyrrol-1-yl, morpholin-4-yl, 4-methylpiperidin-1-yl, 4-methylenepiperidine, 3-oxopyrrol-1-yl, piperidin-1-yl or 3-oxopiperazin-1-yl.
Further, R1The concrete structure is as follows:
Figure BDA0003451844170000022
the isoquinoline-1, 3-diamine analogue provided by the invention is selected from any one of the following compounds in the formulas 1 to 17, and the structural formula is as follows:
Figure BDA0003451844170000023
Figure BDA0003451844170000031
Figure BDA0003451844170000041
the isoquinoline-1, 3-diamine analogue medicinal preparation provided by the invention comprises the following components in parts by mass:
Figure BDA0003451844170000042
the sum of the above components is 100 parts.
Further, the filler is one or more of pregelatinized starch, microcrystalline cellulose, starch, lactose and mannitol.
Further, the disintegrating agent is one or more of sodium carboxymethyl starch, croscarmellose sodium, crospovidone and low-substituted hydroxypropyl cellulose.
Further, the adhesive is one or more of hypromellose, hydroxypropyl cellulose, povidone, and gelatin.
Further, the lubricant is one or more of magnesium stearate, sodium stearyl fumarate, superfine silica gel powder and talcum powder.
The preparation method of the isoquinoline-1, 3-diamine analogue pharmaceutical preparation comprises the following steps:
step 1, screening an isoquinoline-1, 3-diamine analogue raw material for later use;
step 2, weighing isoquinoline-1, 3-diamine analogues, a filling agent, a disintegrating agent and an adhesive, and putting the mixture into a three-dimensional mixer for mixing;
step 3, adding a lubricant into the uniformly mixed mixture in the three-dimensional mixer and mixing again;
step 4, pressing the mixed materials into tablets by adopting a rotary tablet press;
and 5, packaging the slices by adopting aluminum plastic.
The preparation method of the isoquinoline-1, 3-diamine analogue pharmaceutical preparation is characterized by comprising the following steps:
step 1, screening an isoquinoline-1, 3-diamine analogue raw material for later use; weighing the adhesive according to the prescription amount and preparing the adhesive and water into adhesive solution for later use;
step 2, weighing isoquinoline-1, 3-diamine analogues, a filler and a disintegrating agent, putting the mixture into a fluidized bed granulator for fluidization, adding an adhesive solution, and mixing to prepare wet granules;
step 3, drying the wet particles by adopting a fluidized bed until the moisture of the particles is 2-4%, and then finishing the particles;
step 4, adding a lubricant into the granules after finishing, and mixing by adopting a three-dimensional mixer;
and 5, preparing the mixed granules into tablets, granules or capsules.
Further, in the step 2, the air inlet temperature is controlled to be 50-70 ℃ and the air inlet quantity is controlled to be 30-100m in the fluidized bed granulator3After the adhesive solution is added, the rotating speed of a peristaltic pump is controlled to be 10-50rpm, the atomization pressure is controlled to be 0.5-1.5bar, and the material temperature is kept to be 30-40 ℃.
Further, in step 3, drying the wet granules by using a fluidized bed, controlling the air inlet temperature of the fluidized bed to be 50-70 ℃ and the air inlet amount to be 30-100m3H, keeping the temperature of the materials at 30-40 ℃.
The isoquinoline-1, 3-diamine analogue medicine preparation is prepared into an oral dosage form, such as a tablet.
The isoquinoline-1, 3-diamine analogue medicinal preparation is applied to preparing a medicament for treating or preventing cancer as a PDK1 inhibitor.
Further, the cancer is selected from skin cancer, bladder cancer, ovarian cancer, breast cancer, gastric cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, rectal cancer, esophageal cancer, tongue cancer, kidney cancer, cervical cancer, uterine corpus cancer, endometrial cancer, testicular cancer, urinary cancer, melanoma, astrocytic cancer, meningioma, hodgkin's lymphoma, non-hodgkin's lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic granulocytic leukemia, adult T-cell leukemia lymphoma, hepatocellular carcinoma, bronchial cancer, multiple myeloma, basal cell tumor, seminoma, chondrosarcoma, myosarcoma, fibrosarcoma.
Further, the invention provides a preparation method of the isoquinoline-1, 3-diamine analogue with the structure of the formula I, which comprises the following steps:
Figure BDA0003451844170000051
step one, synthesizing an intermediate IV: (the structural formula of the intermediate IV is shown as the formula IV, the structural formula of the compound II is shown as the formula II, and the rest can be analogized in the same way)
Reacting the compound II with the compound III in a reaction solvent under the action of alkali to obtain an intermediate IV; wherein the reaction temperature is 20-100 ℃; the alkali is at least one of cesium carbonate, potassium carbonate, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide and potassium hydroxide; the reaction solvent is at least one of N, N-Dimethylformamide (DMF), N-dimethylacetamide and dimethyl sulfoxide.
Step two, synthesis of intermediate VI
Reacting the intermediate IV with a compound V in a reaction solvent under the action of alkali and a catalyst (performing coupling reaction) to obtain an intermediate VI; wherein the reaction temperature is 40-120 ℃; the catalyst is palladium triphenylphosphine (Pd (PPh)3)4) Palladium acetate (Pd (OAc)2) Tris (dibenzylideneacetone) dipalladium (Pd)2(dba)3) 1,1' -bis (diphenylphosphino) ferrocene dichloropalladium (Pd) (dppf) Cl2) At least one of;the base is at least one of cesium carbonate, sodium tert-butoxide, potassium tert-butoxide and potassium carbonate; the reaction solvent is at least one of dioxane, N-Dimethylformamide (DMF) and toluene.
Step three, synthesis of intermediate VII
Reacting the intermediate VI in a reaction solvent under the action of acid to obtain an intermediate VII; wherein the reaction temperature is 0-60 ℃; the acid is at least one selected from trifluoroacetic acid, methanesulfonic acid, 4-methylbenzenesulfonic acid, ethanol solution of hydrogen chloride and ethyl acetate solution of hydrogen chloride; the reaction solvent is at least one of dichloromethane, ethyl acetate, toluene, methanol and ethanol.
Step four, synthesis of compound I
Reacting the intermediate VII and the compound VIII in a reaction solvent under the action of a condensing agent and alkali to obtain a compound I; wherein, when the compound VIII is R2When COOH is used, the reaction temperature is 0-100 ℃, the condensing agent is at least one of 1-ethyl-3 (3-dimethylpropylamine) carbodiimide (EDCI), Dicyclohexylcarbodiimide (DCC), 6-chlorobenzotriazole-1, 1,3, 3-tetramethylurea Hexafluorophosphate (HCTU), 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) and bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (BopCl), the base is at least one of potassium carbonate, triethylamine and N, N-diisopropylethylamine, and the reaction solvent is at least one of dichloromethane, dioxane, tetrahydrofuran, N, N-Dimethylformamide (DMF) and acetonitrile;
when the compound VIII is R3R4NH, the reaction temperature is 0-100 ℃, and the condensing agent is at least one of N, N' -Carbonyldiimidazole (CDI) and triphosgene; the base is at least one of pyridine, triethylamine and N, N-Diisopropylethylamine (DIEA); the reaction solvent is at least one of dichloromethane, dioxane, tetrahydrofuran, toluene and acetonitrile.
The synthetic method of the isoquinoline-1, 3-diamine analogue with the structure of the formula I, provided by the invention, has the advantages of few byproducts, high yield and great application value in the synthetic reaction process.
The pharmaceutical formulation provided by the invention comprises an isoquinoline-1, 3-diamine analogue with a structure shown in a formula I or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or diluents.
The pharmaceutical preparation provided by the invention can be prepared into various common dosage forms, such as tablets, pills, capsules, granules, oral solutions, oral suspensions, oral emulsions, injections and the like, according to conventional preparation methods in the pharmaceutical field. It is convenient to provide the patient with clinical use by administering to the patient by various common modes of administration, such as oral or parenteral administration (by intravenous, intramuscular, topical or subcutaneous routes).
Some of the terms involved in the expression of the present invention are defined as follows:
"pharmaceutically acceptable salts" refers to those salts that retain the biological effectiveness and properties of the parent compound. The salt comprises: acid addition salts obtained by reaction of the free base of the parent compound with an inorganic acid or with an organic acid; such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, sulfuric acid, perchloric acid, and the like; such as acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, benzenesulfonic acid (benzenesulfonate), benzoic acid, camphorsulfonic acid, citric acid, fumaric acid, gluconic acid, glutamic acid, isethionic acid, lactic acid, maleic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, succinic acid, tartaric acid, malonic acid, or the like; preferably hydrochloric acid or (L) -malic acid; or when the acid proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion, or coordinated with an organic base, a salt is formed; such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.
The compounds of the invention may have one or more asymmetric centers; the compounds can thus be prepared as individual (R) -stereoisomers or (S) -stereoisomers or as mixtures thereof. Unless otherwise indicated, the description or designation of a particular compound in the specification and claims is intended to include the individual enantiomers as well as racemic or other mixtures thereof. Methods for determining stereochemical configuration and separating stereoisomers are well known in the art (see the discussion in chapter 4 of "Advanced Organic Chemistry", 4 th edition, j. march, John Wiley and Sons, New York, 1992). Thus, the present invention also encompasses any stereoisomeric form, its corresponding enantiomers (d-and l-or (+) and (-) isomers) and its diastereoisomers and mixtures thereof having PDK1 inhibitory activity and is not limited to any one stereoisomeric form.
The invention has the beneficial effects that:
(1) the isoquinoline-1, 3-diamine analogue medicinal preparation can be used as a PDK1 inhibitor for treating cancers, and has the advantages of good activity, high selectivity, low toxicity, small side effect and the like.
(2) The isoquinoline-1, 3-diamine analogue medicinal preparation has high dissolution rate and good dissolution effect.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
A compound of formula 1: n- (3- ((1- ((4- (1H-pyrazol-4-yl) phenyl) amino) isoquinolin-3-yl) amino) phenyl) pyrrolidine-1-carboxamide; the synthesis reaction formula is as follows:
Figure BDA0003451844170000081
the first step is as follows: compound 1a (39.4g, 200.0mmol), compound 1b (31.8g, 200.0mmol), and cesium carbonate (129.6g, 400.0mmol) were dissolved in N, N-dimethylformamide (300mL), the temperature was raised to 80 ℃, the reaction was monitored by TLC, after completion of the reaction, water (300mL) was added to quench the reaction, extraction was performed with ethyl acetate (300mL × 2), the organic layers were combined, dried, concentrated, and column chromatography was performed to give 43.5g of a pale yellow solid (intermediate 1 c). Wherein, the structural formula of the compound 1a is shown as the formula 1a, and the rest can be analogized.
The second step is that: intermediate 1c (43.0g, 134.4mmol), compound 1d (28.0g, 134.4mmol), potassium carbonate (37.1g, 268.8mmol), Pd (dppf) Cl2(7.3g, 10mmol) was dissolved in DMF (500mL), heated to 80 ℃ and stirred for reaction for 12 hours, the reaction was monitored by TLC, after completion of the reaction, water was added to quench the reaction, which was extracted with ethyl acetate (500 mL. times.2), the organic layer was concentrated and separated by column chromatography to give 42.7g of off-white solid (intermediate 1e) with a yield of 64.6%.
The third step: intermediate 1e (41.1g, 83.4mmol) was dissolved in ethyl acetate (300mL), an ethyl acetate solution of hydrogen chloride (200mL) was added at room temperature, the reaction was stirred at room temperature for 6 hours, the reaction was monitored by TLC, after completion of the reaction, the mixture was washed with a saturated sodium bicarbonate solution, and the ethyl acetate layer was concentrated and separated by column chromatography to give 30.2g of a white solid (intermediate 1f) with a yield of 92.3%.
The fourth step: intermediate 1f (392mg, 1.0mmol), compound 1g (71mg, 1.0mmol), DIEA (258mg, 2.0mmol) were dissolved in dichloromethane (50mL), CDI (194mg, 1.2mmol) was added at room temperature, the reaction was stirred at room temperature, TLC monitored, after completion of the reaction, water (50mL) was added to quench the reaction, the organic layer was dried, concentrated, and column chromatography gave 256mg of an off-white solid (compound 1) with a yield of 52.3% and ESI (+) m/z of 490.2.
Example 2
A compound of formula 2: n- (3- ((1- ((4- (1H-pyrazol-4-yl) phenyl) amino) isoquinolin-3-yl) amino) phenyl) morpholine-4-carboxamide; the synthesis reaction formula is as follows:
Figure BDA0003451844170000091
intermediate 1f (392mg, 1.0mmol), compound 2a (87mg, 1.0mmol), DIEA (258mg, 2.0mmol) were dissolved in dichloromethane (50mL), CDI (194mg, 1.2mmol) was added at room temperature, the reaction was stirred at room temperature, monitored by TLC, after completion of the reaction, the reaction was quenched by addition of water (50mL), the organic layer was dried, concentrated, and isolated by column chromatography to give 335mg of an off-white solid (compound 2) in 66.3% yield and ESI (+) m/z 506.2.
Example 3
A compound of formula 3: n- (3- ((1- ((4- (1H-pyrazol-4-yl) phenyl) amino) isoquinolin-3-yl) amino) phenyl) -4-methylpiperazine-1-carboxamide; the synthesis reaction formula is as follows:
Figure BDA0003451844170000092
intermediate 1f (392mg, 1.0mmol), compound 3a (100mg, 1.0mmol), DIEA (258mg, 2.0mmol) were dissolved in dichloromethane (50mL), CDI (194mg, 1.2mmol) was added at room temperature, the reaction was stirred at room temperature, monitored by TLC, after completion of the reaction, the reaction was quenched with water (50mL), the organic layer was dried, concentrated, and isolated by column chromatography to give 289mg of an off-white solid (compound 3), 55.8% yield, ESI (+) m/z ═ 519.2.
Example 4
A compound represented by formula 4: n- (3- ((1- ((4- (1H-pyrazol-4-yl) phenyl) amino) isoquinolin-3-yl) amino) phenyl) -4-methylenepiperidine-1-carboxamide; the synthesis reaction formula is as follows:
Figure BDA0003451844170000101
intermediate 1f (392mg, 1.0mmol), compound 4a (97mg, 1.0mmol), DIEA (258mg, 2.0mmol) were dissolved in dichloromethane (50mL), CDI (194mg, 1.2mmol) was added at room temperature, the reaction was stirred at room temperature, monitored by TLC, after completion of the reaction, the reaction was quenched with water (50mL), the organic layer was dried, concentrated, and isolated by column chromatography to give 221mg of an off-white solid (compound 4) in 42.9% yield and ESI (+) m/z 516.2.
Example 5
A compound of formula 5: n- (3- ((1- ((4- (1H-pyrazol-4-yl) phenyl) amino) isoquinolin-3-yl) amino) phenyl) -3-oxopyrrolidine-1-carboxamide; the synthesis reaction formula is as follows:
Figure BDA0003451844170000103
intermediate 1f (392mg, 1.0mmol), compound 5a (85mg, 1.0mmol), DIEA (258mg, 2.0mmol) were dissolved in dichloromethane (50mL), CDI (194mg, 1.2mmol) was added at room temperature, the reaction was stirred at room temperature, monitored by TLC, after completion of the reaction, the reaction was quenched with water (50mL), the organic layer was dried, concentrated, and isolated by column chromatography to give 285mg of an off-white solid (compound 5) in 56.6% yield, ESI (+) m/z 504.2.
Example 6
A compound of formula 6: n- (3- ((1- ((4- (1H-pyrazol-4-yl) phenyl) amino) isoquinolin-3-yl) amino) phenyl) piperidine-1-carboxamide; the synthesis reaction formula is as follows:
Figure BDA0003451844170000102
intermediate 1f (392mg, 1.0mmol), compound 6a (85mg, 1.0mmol), DIEA (258mg, 2.0mmol) were dissolved in dichloromethane (50mL), CDI (194mg, 1.2mmol) was added at room temperature, the reaction was stirred at room temperature, monitored by TLC, after completion of the reaction, water (50mL) was added to quench the reaction, the organic layer was dried, concentrated, and isolated by column chromatography to give 332mg of off-white solid (compound 6) at 66.0% yield ESI (+) m/z 504.2.
Example 7
A compound of formula 7: n- (3- ((1- ((4- (1H-pyrazol-4-yl) phenyl) amino) isoquinolin-3-yl) amino) phenyl) -3-oxopiperazine-1-carboxamide; the synthesis reaction formula is as follows:
Figure BDA0003451844170000111
intermediate 1f (392mg, 1.0mmol), compound 7a (100mg, 1.0mmol), DIEA (258mg, 2.0mmol) were dissolved in dichloromethane (50mL), CDI (194mg, 1.2mmol) was added at room temperature, the reaction was stirred at room temperature, the reaction was monitored by TLC, after completion of the reaction, water (50mL) was added to quench the reaction, the organic layer was dried, concentrated, and column chromatography gave an off-white solid (compound 7)351mg, yield 67.8%, ESI (+) m/z ═ 519.2.
Example 8
A compound represented by formula 8: n- (3- ((1- ((4- (1H-pyrazol-4-yl) phenyl) amino) isoquinolin-3-yl) amino) phenyl) -2-oxomorpholin-4-carboxamide; the synthesis reaction formula is as follows:
Figure BDA0003451844170000112
intermediate 1f (392mg, 1.0mmol), compound 8a (101mg, 1.0mmol), DIEA (258mg, 2.0mmol) were dissolved in dichloromethane (50mL), CDI (194mg, 1.2mmol) was added at room temperature, the reaction was stirred at room temperature, monitored by TLC, after completion of the reaction, the reaction was quenched with water (50mL), the organic layer was dried, concentrated, and isolated by column chromatography to give an off-white solid (compound 8)365mg in 70.3% yield and ESI (+) m/z 520.2.
Example 9
A compound of formula 9: n- (3- ((1- ((4- (1H-pyrazol-4-yl) phenyl) amino) isoquinolin-3-yl) amino) phenyl) cyclopentanecarboxamide; the synthesis reaction formula is as follows:
Figure BDA0003451844170000113
intermediate 1f (392mg, 1.0mmol), compound 9a (114mg, 1.0mmol), and DIEA (258mg, 2.0mmol) were dissolved in N, N-dimethylformamide (50mL), HATU (570mg, 1.5mmol) was added at room temperature, the reaction was stirred at room temperature, monitored by TLC, quenched with water (50mL) after completion of the reaction, extracted with ethyl acetate (50mL × 2), the organic layer was dried, concentrated, and isolated by column chromatography to give 386mg of an off-white solid (compound 9), yield 79.1%, ESI (+) m/z ═ 489.2.
Example 10
A compound according to formula 10: n- (3- ((1- ((4- (1H-pyrazol-4-yl) phenyl) amino) isoquinolin-3-yl) amino) phenyl) tetrahydro-2H-pyran-4-carboxamide; the synthesis reaction formula is as follows:
Figure BDA0003451844170000121
intermediate 1f (392mg, 1.0mmol), compound 10a (130mg, 1.0mmol), and DIEA (258mg, 2.0mmol) were dissolved in N, N-dimethylformamide (50mL), HATU (570mg, 1.5mmol) was added at room temperature, the reaction was stirred at room temperature, monitored by TLC, quenched with water (50mL) after completion of the reaction, extracted with ethyl acetate (50mL × 2), the organic layer was dried, concentrated, and isolated by column chromatography to give 288mg of an off-white solid (compound 10), yield 57.1%, ESI (+) m/z ═ 505.2.
Example 11
A compound of formula 11: n- (3- ((1- ((4- (1H-pyrazol-4-yl) phenyl) amino) isoquinolin-3-yl) amino) phenyl) -1-methylpiperidine-4-carboxamide; the synthesis reaction formula is as follows:
Figure BDA0003451844170000122
intermediate 1f (392mg, 1.0mmol), compound 11a (143mg, 1.0mmol), and DIEA (258mg, 2.0mmol) were dissolved in N, N-dimethylformamide (50mL), HATU (570mg, 1.5mmol) was added at room temperature, the reaction was stirred at room temperature, monitored by TLC, quenched with water (50mL) after completion of the reaction, extracted with ethyl acetate (50mL × 2), the organic layer was dried, concentrated, and column chromatography was performed to obtain 318mg of an off-white solid (compound 11), yield was 61.5%, and ESI (+) m/z was 518.2.
Example 12
A compound of formula 12: n- (3- ((1- ((4- (1H-pyrazol-4-yl) phenyl) amino) isoquinolin-3-yl) amino) phenyl) -4-methylenecyclohexane-1-carboxamide; the synthesis reaction formula is as follows:
Figure BDA0003451844170000131
intermediate 1f (392mg, 1.0mmol), compound 12a (140mg, 1.0mmol), and DIEA (258mg, 2.0mmol) were dissolved in N, N-dimethylformamide (50mL), HATU (570mg, 1.5mmol) was added at room temperature, the reaction was stirred at room temperature, monitored by TLC, quenched with water (50mL) after completion of the reaction, extracted with ethyl acetate (50mL × 2), the organic layer was dried, concentrated, and column chromatography was performed to give 354mg of an off-white solid (compound 12), yield was 68.9%, and ESI (+) m/z was 515.5.
Example 13
A compound of formula 13: n- (3- ((1- ((4- (1H-pyrazol-4-yl) phenyl) amino) isoquinolin-3-yl) amino) phenyl) -3-oxocyclopropane-1-carboxamide; the synthesis reaction formula is as follows:
Figure BDA0003451844170000132
intermediate 1f (392mg, 1.0mmol), compound 13a (128mg, 1.0mmol), and DIEA (258mg, 2.0mmol) were dissolved in N, N-dimethylformamide (50mL), HATU (570mg, 1.5mmol) was added at room temperature, the reaction was stirred at room temperature, monitored by TLC, quenched with water (50mL) after completion of the reaction, extracted with ethyl acetate (50mL × 2), the organic layer was dried, concentrated, and isolated by column chromatography to give 304mg of an off-white solid (compound 13), yield 60.6%, and ESI (+) m/z ═ 503.2.
Example 14
A compound of formula 14: n- (3- ((1- ((4- (1H-pyrazol-4-yl) phenyl) amino) isoquinolin-3-yl) amino) phenyl) cyclohexanecarboxamide; the synthesis reaction formula is as follows:
Figure BDA0003451844170000141
intermediate 1f (392mg, 1.0mmol), compound 14a (128mg, 1.0mmol), and DIEA (258mg, 2.0mmol) were dissolved in N, N-dimethylformamide (50mL), HATU (570mg, 1.5mmol) was added at room temperature, the reaction was stirred at room temperature, monitored by TLC, quenched with water (50mL) after completion of the reaction, extracted with ethyl acetate (50mL × 2), the organic layer was dried, concentrated, and isolated by column chromatography to give 331mg of an off-white solid (compound 14), yield 65.9%, ESI (+) m/z ═ 503.2.
Example 15
A compound according to formula 15: n- (3- ((1- ((4- (1H-pyrazol-4-yl) phenyl) amino) isoquinolin-3-yl) amino) phenyl) -2-oxopiperidine-4-carboxamide; the synthesis reaction formula is as follows:
Figure BDA0003451844170000142
intermediate 1f (392mg, 1.0mmol), compound 15a (143mg, 1.0mmol), DIEA (258mg, 2.0mmol) were dissolved in N, N-dimethylformamide (50mL), HATU (570mg, 1.5mmol) was added at room temperature, the reaction was stirred at room temperature, the reaction was monitored by TLC, after completion of the reaction, the reaction was quenched with water (50mL), extracted with ethyl acetate (50mL × 2), the organic layer was dried, concentrated, and column chromatography was performed to give 297mg of an off-white solid (compound 15), yield 57.4%, and ESI (+) m/z ═ 518.2.
Example 16
A compound according to formula 16: n- (3- ((1- ((4- (1H-pyrazol-4-yl) phenyl) amino) isoquinolin-3-yl) amino) phenyl) -2-oxotetrahydro-2H-pyran-4-carboxamide; the synthesis reaction formula is as follows:
Figure BDA0003451844170000143
intermediate 1f (392mg, 1.0mmol), compound 16a (144mg, 1.0mmol), and DIEA (258mg, 2.0mmol) were dissolved in N, N-dimethylformamide (50mL), HATU (570mg, 1.5mmol) was added at room temperature, the reaction was stirred at room temperature, monitored by TLC, quenched with water (50mL) after completion of the reaction, extracted with ethyl acetate (50mL × 2), the organic layer was dried, concentrated, and isolated by column chromatography to give 337mg of an off-white solid (compound 16), yield 65.1%, ESI (+) m/z ═ 519.2.
Example 17
A compound according to formula 17: n- (3- ((1- ((4- (1H-pyrazol-4-yl) phenyl) amino) isoquinolin-3-yl) amino) phenyl) -2-oxoazaheptane-4-carboxamide; the synthesis reaction formula is as follows:
Figure BDA0003451844170000151
intermediate 1f (392mg, 1.0mmol), compound 17a (157mg, 1.0mmol), and DIEA (258mg, 2.0mmol) were dissolved in N, N-dimethylformamide (50mL), HATU (570mg, 1.5mmol) was added at room temperature, the reaction was stirred at room temperature, monitored by TLC, quenched with water (50mL) after completion of the reaction, extracted with ethyl acetate (50mL × 2), the organic layer was dried, concentrated, and isolated by column chromatography to give 309mg of an off-white solid (compound 17), yield 58.2%, and ESI (+) m/z ═ 532.2.
Biological evaluation
Biological evaluation, i.e. determination of kinase activity, of the corresponding compounds 1 to 17 in examples 1 to 17 was carried out:
1. reagents were prepared, SKOV3 cells were collected, lysed and quantified.
2. Samples (one of compounds 1-17) were diluted with dimethyl sulfoxide (DMSO) to 10 sample solutions of different concentrations for use.
3. The quantified protein was then added to a 96-well plate, incubated at room temperature for 2 hours, pipetted off, washed 2 times, and inverted onto clean paper to remove residual liquid after the last pipette off.
4. Add 25mL wash buffer, MgCl, to a clean centrifuge tube2(1mM), ATP (2mM), PDK1 was added, incubation was carried out at 30 ℃ for 1 hour, sample solutions of different concentrations were added to 96-well plates, 200. mu.L/well, 3 auxiliary wells per group, incubation was carried out at 30 ℃ for 10 minutes, the liquid was aspirated off, and washing was carried out 2 times.
5. Add 50 u L Detector antibody, room temperature incubation for 1 hours, centrifugal, suction liquid, washing 2 times.
6. Adding 50 μ L of 1 × HRP labeled secondary antibody, incubating at room temperature for 1 hr, centrifuging, removing liquid, washing for 2 times, adding 100 μ L of TMB to obtain blue, adding diluted hydrochloric acid to brown, terminating the reaction, detecting OD (450nm), and calculating to obtain IC of the sample (target compound)50. The test results are shown in table 1:
TABLE 1
Compound (I) IC50(PDK1)(nM) Compound (I) IC50(PDK1)(nM)
1 16.0 10 2.4
2 19.5 11 8.9
3 5.4 12 13.6
4 27.6 13 10.5
5 30.6 14 54.4
6 3.5 15 65.3
7 58.0 16 32.4
8 72.5 17 5.7
9 36.8 BX517 10.0
Wherein BX517 is a conventional PDK1 inhibitor.
As can be seen from Table 1, compounds 1 to 17 all have certain inhibitory effects on PDK1 kinase, wherein compounds 3, 6, 10 to 11 and 17 have IC (integrated Circuit) on PDK150Values were less than 10 nM.
Example 18
Formulation 1 (Components in wt%)
Figure BDA0003451844170000161
The isoquinoline-1, 3-diamine analogs described in this example select the product of example 3: n- (3- ((1- ((4- (1H-pyrazol-4-yl) phenyl) amino) isoquinolin-3-yl) amino) phenyl) -4-methylpiperazine-1-carboxamide as PDK1 inhibitor.
The preparation method of the isoquinoline-1, 3-diamine analogue drug tablet comprises the following steps:
step 1, screening isoquinoline-1, 3-diamine analogue raw materials for later use.
And 2, weighing isoquinoline-1, 3-diamine analogue, pregelatinized starch, sodium carboxymethyl starch and hydroxypropyl methylcellulose, and putting into a three-dimensional mixer to mix for 20min at a speed of 15 r/min.
And 3, adding magnesium stearate into the mixed material, and mixing for 5min at 15r/min by using a three-dimensional mixer.
And 4, pressing the mixed materials into tablets by adopting a rotary tablet press.
And 5, packaging the slices by adopting aluminum plastic.
Example 19
Formulation 2 (Components in wt%)
Figure BDA0003451844170000171
The isoquinoline-1, 3-diamine analogs described in this example were selected from the product of example 6: n- (3- ((1- ((4- (1H-pyrazol-4-yl) phenyl) amino) isoquinolin-3-yl) amino) phenyl) piperidine-1-carboxamide as a PDK1 inhibitor.
The preparation method of the isoquinoline-1, 3-diamine analogue drug tablet comprises the following steps:
step 1, screening an isoquinoline-1, 3-diamine analogue raw material for later use; weighing the hydroxypropyl methylcellulose according to the prescription amount of the formula 2, and preparing the hydroxypropyl methylcellulose and purified water into a hydroxypropyl methylcellulose solution for later use.
Step 2, weighing isoquinoline-1, 3-diamine analogue, pregelatinized starch and sodium carboxymethyl starch, and putting into a fluidized bed granulator, wherein the air inlet temperature is 50-70 ℃, and the air inlet air volume is 30-100m3H, fluidizing for 5min, adding hydroxypropyl methylcellulose solution, rotating at peristaltic pump speed of 10-50rpm and atomizing pressure of 0.5-1.5bar, maintaining material temperature at 30-40 deg.C, and making into wet granule.
Step 3, drying the wet particles by adopting a fluidized bed, wherein the air inlet temperature of the fluidized bed is 50-70 ℃, and the air inlet amount is 30-100m3And h, keeping the temperature of the material at 30-40 ℃, drying until the water content of the particles is 2-4%, and finishing the particles by adopting a 18-mesh sieve.
And 4, adding magnesium stearate into the granules after finishing, and mixing for 5min at 15r/min by using a three-dimensional mixer.
And 5, pressing the mixed materials into plain tablets by adopting a rotary tablet press.
And 6, putting the pressed plain tablets into a high-efficiency coating machine for coating, and preparing coating liquid with solid content of 10% by adopting Opadry series gastric-soluble film coating powder of Carekon company for coating, wherein the weight of the coating is controlled to be increased by 2-4%.
And 7, packaging the slices by adopting aluminum plastic.
Example 20
Formulation 3 (Components in wt%)
Figure BDA0003451844170000172
The isoquinoline-1, 3-diamine analog described in this example was selected from the product of example 10: n- (3- ((1- ((4- (1H-pyrazol-4-yl) phenyl) amino) isoquinolin-3-yl) amino) phenyl) tetrahydro-2H-pyran-4-carboxamide as PDK1 inhibitor.
The preparation method of the isoquinoline-1, 3-diamine analogue drug tablet comprises the following steps:
step 1, screening an isoquinoline-1, 3-diamine analogue raw material for later use; weighing the hydroxypropyl cellulose according to the prescription amount of the formula 3, and preparing the hydroxypropyl cellulose and purified water into a hydroxypropyl cellulose solution for later use.
Step 2, weighing isoquinoline-1, 3-diamine analogue, microcrystalline cellulose and croscarmellose sodium, putting into a fluidized bed granulator, wherein the air inlet temperature is 50-70 ℃, and the air inlet air quantity is 30-100m3H, fluidizing for 5min, adding hydroxypropyl cellulose solution, rotating at speed of peristaltic pump of 10-50rpm and atomizing pressure of 0.5-1.5bar, maintaining material temperature at 30-40 deg.C, and making into wet granule.
Step 3, drying the wet particles by adopting a fluidized bed, wherein the air inlet temperature of the fluidized bed is 50-70 ℃, and the air inlet amount is 30-100m3And h, keeping the temperature of the material at 30-40 ℃, drying until the water content of the particles is 2-4%, and finishing the particles by adopting a 18-mesh sieve.
And 4, adding the whole granules into sodium stearyl fumarate, and mixing for 5min at a speed of 15r/min by using a three-dimensional mixer.
And 5, pressing the mixed materials into plain tablets by adopting a rotary tablet press.
And 6, putting the pressed plain tablets into a high-efficiency coating machine for coating, and preparing coating liquid with solid content of 10% by adopting Opadry series gastric-soluble film coating powder of Carekon company for coating, wherein the weight of the coating is controlled to be increased by 2-4%.
And 7, packaging the slices by adopting aluminum plastic.
Example 21
Formulation 4 (Components in wt%)
Figure BDA0003451844170000181
The isoquinoline-1, 3-diamine analog described in this example was selected from the product of example 15: n- (3- ((1- ((4- (1H-pyrazol-4-yl) phenyl) amino) isoquinolin-3-yl) amino) phenyl) -2-oxopiperidine-4-carboxamide as PDK1 inhibitor.
The preparation method of the isoquinoline-1, 3-diamine analogue drug tablet comprises the following steps:
step 1, screening an isoquinoline-1, 3-diamine analogue raw material for later use; weighing the povidone according to the prescription amount of the formula 4, and preparing the povidone and the purified water into povidone solution for later use.
Step 2, weighing isoquinoline-1, 3-diamine analogue, starch and crospovidone, putting into a fluidized bed granulator, wherein the inlet air temperature is 50-70 ℃, and the inlet air volume is 30-100m3And h, fluidizing for 5min, adding povidone solution, rotating the peristaltic pump at the speed of 10-50rpm and the atomization pressure of 0.5-1.5bar, keeping the temperature of the materials at 30-40 ℃, and preparing wet particles.
Step 3, drying the wet particles by adopting a fluidized bed, wherein the inlet air temperature of the fluidized bed is 50-70 ℃, and the inlet air quantity is 30-100m3And/h, keeping the temperature of the material at 30-40 ℃, drying until the moisture of the particles is 2-4%, and grading the particles by adopting a 18-mesh sieve.
And 4, adding the sized particles into the superfine silica gel powder, and mixing for 5min at the speed of 15r/min by using a three-dimensional mixer.
And 5, pressing the mixed materials into plain tablets by adopting a rotary tablet press.
And 6, putting the pressed plain tablets into a high-efficiency coating machine for coating, and preparing coating liquid with solid content of 10% by adopting Opadry series gastric-soluble film coating powder of Carekon company for coating, wherein the weight of the coating is controlled to be increased by 2-4%.
And 7, packaging the slices by adopting aluminum plastic.
Dissolution testing experiment
Dissolution testing experiments were performed on the pharmaceutical formulations provided in examples 18-21.
Dissolution is determined by reference to dissolution and release determination methods (second method 0931 of the four general rules of the chinese pharmacopoeia 2020 edition).
The instrument comprises the following steps: ultraviolet spectrophotometer and dissolution rate tester.
Dissolution medium: pH 6.8 phosphate buffered solution.
Volume of dissolution medium: 900mL, rotation speed: 50 r/min.
Sampling time: 5min, 10min, 15min, 20min, 30min, 45 min.
The corresponding preparations of examples 18 to 21 were measured for dissolution and release according to the method (0931 second method of the four ministry of general regulations in the 2020 edition of Chinese pharmacopoeia) using a hydrochloric acid solution having a pH of 6.8 as a dissolution medium and a rotation speed of 50 rotations per minute, and the solutions were sampled and measured according to the sampling time.
The results of the dissolution profiles of examples 18-21 and the reference formulation in phosphate buffered saline at pH 6.8 are shown in table 2.
TABLE 2
Time (min) 5 10 15 30 45
Example 18 From preparation (%) 19.5 44.5 60.2 87.6 97.5
Example 19 From preparation (%) 20.5 45.1 63.1 90.2 97.6
Example 20 From preparation (%) 25.1 47.3 70.2 93.2 99.5
Example 21 From (a) preparation (％) 12.1 30.1 55.2 85.5 95.2
As shown in Table 2, the pharmaceutical preparation of isoquinoline-1, 3-diamine analogues has excellent dissolution effect when being prepared into tablets, the in vitro dissolution can reach more than 85% in 30min, the in vitro dissolution can reach more than 90% in 45min, and the dissolution rate is high.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.

Claims (10)

1. An isoquinoline-1, 3-diamine analog pharmaceutical formulation, characterized by: comprising a pharmaceutically acceptable salt of an isoquinoline-1, 3-diamine analog, and one or more pharmaceutically acceptable carriers;
the isoquinoline-1, 3-diamine analogue is selected from any one of the following formulas 1 to 17, and has the following structural formula:
Figure FDA0003451844160000011
Figure FDA0003451844160000021
Figure FDA0003451844160000031
2. the isoquinoline-1, 3-diamine analog pharmaceutical formulation according to claim 1, comprising the following components in parts by mass:
Figure FDA0003451844160000032
the sum of the above components is 100 parts.
3. The isoquinoline-1, 3-diamine analog pharmaceutical formulation of claim 2, wherein the filler is one or more of pregelatinized starch, microcrystalline cellulose, starch, lactose, mannitol.
4. The isoquinoline-1, 3-diamine analog pharmaceutical formulation of claim 2, wherein the disintegrant is one or more of sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low substituted hydroxypropyl cellulose.
5. The isoquinoline-1, 3-diamine analog pharmaceutical formulation of claim 2, wherein the binder is one or more of hypromellose, hydroxypropyl cellulose, povidone, gelatin.
6. The isoquinoline-1, 3-diamine analog pharmaceutical formulation of claim 2, wherein the lubricant is one or more of magnesium stearate, sodium stearyl fumarate, aerosil, talc.
7. The method of preparing an isoquinoline-1, 3-diamine analog pharmaceutical formulation according to claims 1 to 6, comprising the steps of:
step 1, screening an isoquinoline-1, 3-diamine analogue raw material for later use;
step 2, weighing isoquinoline-1, 3-diamine analogues, a filling agent, a disintegrating agent and an adhesive, and putting the mixture into a three-dimensional mixer for mixing;
step 3, adding a lubricant into the uniformly mixed mixture in the three-dimensional mixer and mixing again;
step 4, pressing the mixed materials into tablets by adopting a rotary tablet press;
and 5, packaging the slices by adopting aluminum plastic.
8. The method of preparing an isoquinoline-1, 3-diamine analog pharmaceutical formulation according to claims 1 to 6, comprising the steps of:
step 1, screening an isoquinoline-1, 3-diamine analogue raw material for later use; weighing the adhesive according to the prescription amount and preparing the adhesive and water into adhesive solution for later use;
step 2, weighing isoquinoline-1, 3-diamine analogues, a filler and a disintegrating agent, putting the mixture into a fluidized bed granulator for fluidization, adding an adhesive solution, and mixing to prepare wet granules;
step 3, drying the wet particles by adopting a fluidized bed until the water content of the particles is 2-4%, and then finishing the particles;
step 4, adding a lubricant into the granules after finishing, and mixing by adopting a three-dimensional mixer;
and 5, preparing the mixed granules into tablets, granules or capsules.
9. The method for preparing an isoquinoline-1, 3-diamine analog pharmaceutical preparation according to claim 8, wherein in step 2, the temperature of the inlet air is controlled in a fluidized bed granulator to be 50 to 70 ℃ and the inlet air volume is controlled to be 30 to 100m3After the adhesive solution is added, controlling the rotating speed of a peristaltic pump to be 10-50rpm, the atomization pressure to be 0.5-1.5bar and keeping the material temperature to be 30-40 ℃; in step 3, drying the wet granules by using a fluidized bed, controlling the air inlet temperature of the fluidized bed to be 50-70 ℃ and the air inlet amount to be 30-100m3H, keeping the temperature of the materials at 30-40 ℃.
10. Use of an isoquinoline-1, 3-diamine analog pharmaceutical formulation according to any one of claims 1 to 2 as a PDK1 inhibitor in the manufacture of a medicament for the treatment or prevention of cancer.
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