CN111362946A - Pharmaceutical compound and composition and application thereof - Google Patents

Pharmaceutical compound and composition and application thereof Download PDF

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CN111362946A
CN111362946A CN201811588121.7A CN201811588121A CN111362946A CN 111362946 A CN111362946 A CN 111362946A CN 201811588121 A CN201811588121 A CN 201811588121A CN 111362946 A CN111362946 A CN 111362946A
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杨欣
孔锐
袁哲东
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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Abstract

The novel compounds provided by the present invention exhibit biological activity and are useful as TRK kinase inhibitors, such as in the treatment and prevention of drug cancers, dermatitis, asthma, and the like, for the treatment of TRK mediated diseases or conditions.

Description

Pharmaceutical compound and composition and application thereof
Technical Field
The invention relates to the technical field of protein kinase TRK kinase inhibitors and methods for using the compounds.
Background
TRK kinases are a class of neurotrophic factor receptors, a family of which is encoded by highly homologous tropomyosin-related kinase a (TRK a), tropomyosin-related kinase b (TRK b), tropomyosin-related kinase c (TRK c), and the NTRK1, NTRK2, and NTRK3 genes, respectively. Studies have shown that the NTRK gene is expressed primarily in the nervous system, with it being expressed both during embryonic development and in adults. When activated by signal induction, TRK can be self-phosphorylated and activate downstream channels such as ERK, PLC gamma, P13K/AKT and the like, and cell proliferation, differentiation, metabolism and apoptosis are influenced. At present, overexpression of TRK protein is found in various cancers such as breast cancer, skin cancer (basal cell carcinoma), lung cancer, and neuroblastoma. Moreover, when the chromosome variation occurs the fusion of NTRK gene and other unrelated genes, the downstream signal channel of TRK kinase can be abnormally regulated, thereby causing the disease generation. The TRK kinase inhibitor can achieve the effect of treating diseases by inhibiting the catalytic activity of kinase.
Disclosure of Invention
The object of the present invention is to provide a novel compound and a pharmaceutical composition thereof, which are useful as a TRK kinase inhibitor.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
a compound 1 of the general formula, an optical isomer thereof or a mixture thereof, a salt thereof, a solvate thereof, an N-oxide thereof, or a prodrug thereof:
Figure BDA0001919611970000011
R1represents H, substituted or unsubstituted C1-C6R1Represents H, substituted or unsubstituted C1-C6Alkyl, alkenyl, alkynyl, substituted or unsubstituted C1-C6Heteroalkyl, alkenyl, alkynyl;
R2represents NRbRcSubstituted or unsubstituted C1-C6Alkyl, CF3Substituted or unsubstituted C1-C6Heteroalkyl, - (C)1-C6Alkyl) hetero Ar1,-(C1-C6Alkyl) NH2、-(C1-C6Alkyl) NH (C)1-C6Alkyl), - (C)1-C6Alkyl) N (C)1-C6Alkyl radical)2Hetero Ar2heteroCy, optionally substituted with NHSO2(C1-C6Alkyl) or phenyl optionally substituted by (C)1-C6Alkyl), CN, OH, OMe, NH2、NHMe、N(CH3)2、F、CF3、CO2(C1-C6Alkyl), CO2H、C(＝O)NReRfOR C (═ O) ORgSubstituted (C)3-C6) A cycloalkyl group;
Rbrepresents H, substituted or unsubstituted C1-C6An alkyl group;
RCrepresents H, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted adamantyl, substituted or unsubstituted C1-C6Heteroalkyl, hetero Ar3Or phenyl, wherein said phenyl is optionally independently selected from halogen, CN, CF3And O (C)1-C6Alkyl) with one or more substituents,
or NRbRcForm a 4-membered heterocyclic ring having a ring nitrogen atomWherein said heterocycle is optionally substituted with one or more substituents independently selected from the group consisting of: halogen, OH, (C)1-C6Alkyl group), (C)1-C6) Alkoxy, OC (═ O) (C)1-C6Alkyl), NH2、NHC(＝O)O(C1-C6Alkyl) and (C)1-C6) A hydroxyalkyl group,
or NRbRcForm a 5-to 6-membered heterocyclic ring having a ring heteroatom of nitrogen and optionally having a ring heteroatom selected from N, O and SO2Wherein the heterocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of: OH, halogen, CF3、C1-C6Alkyl, CO2(C1-C6Alkyl), CO2H、NH2、NHC(＝O)O(C1-C6Alkyl) and oxo.
Or NRbRcForming a 7-to 8-membered bridged heterocyclic ring having a ring nitrogen atom and optionally a second ring heteroatom selected from N and O, wherein the ring is optionally CO-bonded2(C1-C6Alkyl) substitution;
hetero Ar1Represents a 5-membered heteroaromatic ring having 1 to 3 ring nitrogen atoms;
hetero Ar2Represents a 5 to 6 membered heteroaromatic ring having at least one nitrogen ring atom and optionally having a second ring heteroatom independently selected from N and S, wherein the heteroaromatic ring is optionally independently selected from C1-C6Alkyl, halogen, (C)1-C6) Alkoxy and NH (C)1-C6Alkyl) with one or more substituents;
HeteroCy represents a carbon-linked 4-to 6-membered nitrogen heterocycle, optionally independently selected from (C)1-C6) Alkoxy, OC (═ O) (C)1-C6Alkyl) or is optionally substituted by one or more substituents selected from C1-C6A pyridone or pyridazinone ring substituted with a substituent of an alkyl group;
hetero Ar3Represents a 5-to 6-membered heteroaromatic ring having 1 to 2 ring heteroatoms independently selected from N and O and optionally being independently selected from C1-C6Alkyl substituted with one or more substituents;
Rerepresents H, substituted or unsubstituted C1-C6Alkyl radical
RfRepresents H, substituted or unsubstituted C1-C6Alkyl or (C)3-C6) A cycloalkyl group;
or NReRfForming a 4 to 6 membered nitrogen heterocycle optionally having other ring heteroatoms selected from N and O, wherein said nitrogen heterocycle is optionally substituted with OH;
Rgis H, substituted or unsubstituted C1-C6An alkyl group;
y represents phenyl, optionally independently selected from halogen, (C)1-C6) Alkoxy, CF3And CHF2Or represents a 5 to 6 membered heteroaryl ring having a ring heteroatom selected from N and S, wherein the heteroaryl ring is optionally substituted by one or more halogen atoms;
x is absent, or-CH2-、-CH2CH2-、-CH2O-or-CH2NRd-；
RdRepresents H, substituted or unsubstituted C1-C6An alkyl group;
R3represents H, substituted or unsubstituted C1-C6An alkyl group;
each R4Independently selected from halogen, (C)1-C6) Alkyl, OH, (C)1-C6) Alkoxy, NH2、NH(C1-C6Alkyl) and CH2OH；
n is 0, 1,2, 3, 4, 5 or 6.
A pharmaceutical composition comprising a compound of said formula, an optical isomer thereof or a mixture thereof, a salt thereof, a solvate thereof, an N-oxide thereof, or a prodrug thereof.
The compound I with the general formula, the optical isomer or the mixture, the salt, the solvate, the N-oxide or the prodrug thereof is used for treating TRK kinase related diseases or symptoms.
In certain embodiments of such uses, the disease or disorder is cancer, a proliferative disease, a pain disease, a skin disease, a metabolic disease, a muscle disease, a neurodegenerative disease, a neurological disease, an immunodeficiency disease, an immune-mediated disease, an autoimmune-mediated disease, a bone disease, an inflammatory disease, fibrosis, an eye disease, an infectious disease, a viral disease, wound repair, a respiratory disease, a pulmonary disease, a renal disease, a liver disease, a cardiovascular disease, a vascular disease, a heart disease, cell death, and a proliferative inflammatory disease.
In certain embodiments of such uses, the disease or disorder is asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, ulcerative colitis, crohn's disease, bronchitis, dermatitis, allergic rhinitis, psoriasis, scleroderma, urticaria, rheumatoid arthritis, multiple sclerosis, lymphoma, metastasis, anaplastic large cell lymphoma, osteosarcoma, fibroma, melanoma, breast cancer, renal cancer, brain cancer, prostate cancer, colorectal cancer, thyroid cancer, ovarian cancer, pancreatic cancer, neuronal cancer, neuroblastoma, lung cancer, uterine cancer, gastrointestinal cancer, HIV or lupus.
In certain embodiments of such pharmaceutical compositions, such pharmaceutical compositions are formulated for intravenous, oral, rectal, inhalation, intranasal, topical, intraocular, or otic administration. In certain embodiments of such pharmaceutical compositions, the pharmaceutical composition is a tablet, pill, capsule, liquid formulation, inhalant, nasal spray solution, suppository, solution, emulsion, ointment, eye drop, or ear drop.
In the present invention, the halogen atom means fluorine, chlorine, bromine and iodine.
In the present invention, C1-C6Alkyl means a straight or branched C group such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl and the like1-C6An alkyl group.
In the present invention, C1-C6Alkylene radicalThe term "methylene", "ethylene", "propylene", "butylene" and isomers thereof. In the present invention, C1-C6Alkoxy means straight or branched chain C such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, etcl-C4An alkoxy group.
In the present invention, unless otherwise specified, all isomers are also included, for example, alkyl includes straight-chain alkyl and branched-chain alkyl, further, geometric isomers (E-form, Z-form, cis-form, trans-form) in double bond, ring, condensed ring, optical isomers (R, S-form, α, β -form, enantiomer, diastereomer) resulting from the presence of asymmetric carbon atom and the like, optically active forms (D, L, D, L-form) having optical activity, polar forms (high polar form, low polar form) by chromatographic separation, equilibrium compounds, rotational isomers, mixtures thereof in any proportion, and racemic mixtures are included in the present invention, and in the present invention, all isomers resulting from tautomers are also included.
In addition, the optical isomers in the present invention include not only 100% pure but also less than 50% of other optical isomers.
In the present invention, unless otherwise specified, symbols known to those skilled in the art are used
Figure BDA0001919611970000041
Indicating bonding to the side facing the paper (i.e. α configuration),
Figure BDA0001919611970000042
indicating the front of the viewer's eye bonded to the paper (i.e. the β configuration),
Figure BDA0001919611970000043
representing α configuration, β configuration or a mixture of the configurations in any proportion.
The compound represented by formula 1 can be converted into a corresponding salt by a known method. The salt is preferably water soluble. Suitable salts include salts of alkali metals (potassium, sodium, etc.), salts of alkaline earth metals (calcium, magnesium, etc.), ammonium salts, salts of pharmaceutically acceptable organic bases (tetramethylammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) aminomethane, lysine, arginine, N-methyl-D-glucamine, etc.), acid adduct salts (inorganic acid salts (hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, etc.), organic acid salts (acetate, trifluoroacetate, lactate, tartrate, oxalate, fumarate, maleate, benzoate, citrate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, gluconate, etc.), etc.;
the compound represented by formula 1 and its salt may also be converted into a solvate. The solvate is preferably low in toxicity and water-soluble. Examples of suitable solvates include solvates of water and alcohol solvents (e.g., ethanol).
The prodrug of the compound represented by the general formula I is a compound that can be converted into the compound represented by the general formula I by reacting with an enzyme and/or gastric acid in a living body. Examples of the prodrug of the compound represented by the general formula I include compounds in which the hydroxyl group is acylated, alkylated, phosphorylated, and boronated when the compound represented by the general formula I has a hydroxyl group.
The terms "co-administration" or "combined administration" and the like as used herein are meant to encompass the administration of a selected therapeutic agent to a single patient, which shall include treatment regimens in which the agents need not be administered by the same route of administration or at the same time.
The term "pharmaceutical composition" as used herein refers to a mixture of a compound described herein with other chemical ingredients, such as carriers, stabilizers, release agents, dispersing agents, suspending agents, thickening agents, or excipients.
The term "cancer" as used herein refers to an abnormal growth of cells that has a tendency to proliferate in an uncontrolled manner, and in some cases, to metastasize (spread). Types of cancer include, but are not limited to, solid tumors (e.g., bladder, bowel, brain, breast, endometrial, heart, kidney, lung tumors), lymphoid (lymphoma), ovarian, pancreatic or other endocrine organs (thyroid), prostate, skin (melanoma), or hematological tumors (e.g., leukemia).
Such cancers and proliferative diseases include, but are not limited to, hematopoietic disorders, hematopoietic malignancies, non-hematopoietic malignancies, benign or malignant tumors, head and neck tumors, brain cancer, kidney cancer, liver cancer, adrenal cancer, neuronal cancer, neuroblastoma, bladder cancer, breast cancer, secretory breast cancer, stomach cancer, gastric tumors, ovarian cancer, uterine cancer, colon cancer, rectal cancer, colorectal adenoma, prostate cancer, kidney cancer, brain cancer, endometrial cancer, pancreatic cancer, lung cancer, non-small cell lung cancer, human adenoid cystic cancer, vaginal cancer, thyroid cancer, papillary thyroid cancer, sarcoma, congenital fibroma, osteosarcoma, fibrosarcoma, myeloma, tumor metastasis to bone, congenital mesoblastic nephroma, glioblastoma, melanoma, multiple myeloma, gastrointestinal cancer, gastrointestinal stromal tumor, mastocytosis, neuroblastoma, melanoma, multiple myeloma, and myeloblastosis, Fibrotic cancer, tumor metastatic growth, epidermal hyperproliferation, psoriasis, metastasis, prostatic hyperplasia, neoplasia, epithelioid neoplasia, lymphoma, diffuse large B-cell lymphoma, breast cancer, nephroblastoma, hamartoma syndrome, diffuse ganglioneuroma of the cerebellum cortex, and Bannayan-Zonana syndrome.
Such hematological malignancies include, but are not limited to, leukemia, myeloid leukemia, hairy cell leukemia, lymphoma (non-hodgkin lymphoma), hodgkin's disease (also known as hodgkin lymphoma), and myeloma, including, but not limited to, acute lymphocytic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic neutrophilic leukemia, acute undifferentiated leukemia, anaplastic large cell lymphoma, hematopoietic stem cell leukemia, juvenile myelomonocytic leukemia, adult T-cell acute lymphocytic leukemia, acute myelogenous leukemia with myelotriplastic hematopoietic, mixed lineage leukemia, myelodysplastic syndrome, myeloproliferative disorders, multiple myeloma, myelosarcoma, and acute promyelocytic leukemia.
The term "skin disease" as used herein refers to a skin disease. Such skin diseases include, but are not limited to, proliferative or inflammatory diseases of the skin such as atopic dermatitis, vesiculosis, collagen diseases, contact dermatitis, eczema, Kawasaki disease, rosacea, Sjogren-Larsso syndrome, and urticaria.
The term "fibrosis" or "fibrotic disease" as used herein refers to a disease following acute or chronic inflammation associated with abnormal accumulation of cells and/or collagen, including but not limited to fibrosis of organs or tissues of thousands of individuals, such as the heart, kidney
Fibrosis of the viscera, joints, lungs or skin, including, for example, idiopathic pulmonary fibrosis and cryptogenic fibrotic alveolitis.
The term inhibiting, as used herein, refers to alleviating or inhibiting a given symptom, disorder or disease, or significantly reducing the baseline activity of a biological activity or process.
The term "inflammatory disease" as used herein refers to those diseases or conditions characterized by having one or more of the following symptoms: pain (pain caused by noxious substances and nerve stimulation), heat (heat caused by vasodilation), redness (redness of the skin caused by vasodilation and increased blood flow), swelling (tumors, caused by excessive or limited inflow or outflow of body fluids), and loss of function (loss of function, possibly partial or total, temporary or permanent). There are various forms of inflammation, including but not limited to one or more of the following: acute, adhesive, atrophic, catarrhal, chronic, sclerosing, diffusible, infiltrative, exudative, fibrous, focal, granulomatous, proliferative, hypertrophic, interstitial, metastatic, necrotic, occlusive, substantive, proliferative, pseudomembranous, purulent, serofibrinous, serous, simple, specific, subacute, purulent, toxic, traumatic and/or ulcerative inflammation. Inflammatory diseases also include, but are not limited to, those affecting the following tissues: blood vessels (polyarteritis, giant cell arteritis); joints (arthritis: crystalline, bone-, psoriatic, reactive, rheumatoid, Reiter's); gastrointestinal tract (disease); skin (dermatitis); or multiple organs and tissues (systemic lupus erythematosus).
The term "neurodegenerative disease" or "neurological disease" as used herein refers to a condition that alters the structure or function of the brain, spinal cord or peripheral nervous system, including but not limited to, alzheimer's disease, cerebral edema, cerebral ischemia, multiple sclerosis, neuropathy, parkinson's disease, diseases found after blunt or surgical trauma (including post-surgical cognitive disorders and spinal cord or brainstem injuries), and neurological aspects of the disease, such as degenerative risk diseases and sciatica.
The term "respiratory disease" as used herein refers to a disease affecting respiratory-related organs such as the nose, throat, larynx, trachea, bronchi and lungs. Respiratory tract disorders include, but are not limited to, asthma, adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, hyperventilation with carbon dioxide, childhood asthma, adult-onset asthma, cough-variant asthma, occupational asthma, hormone-resistant asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease (including chronic bronchitis or emphysema), pulmonary hypertension, interstitial pulmonary fibrosis and/or respiratory inflammation, and cystic fibrosis and hypoxia.
Detailed Description
The position of separation by chromatography and the solvent in parentheses indicated by TLC indicate the elution solvent or developing solvent used, and the ratio indicates the volume ratio.
The names of the compounds used in the present specification are generally named using a computer program named based on IUPAC rules, ACD/Name (registered trademark) of Advanced Chemistry Development, or named according to IUPAC nomenclature.
Example 1: (R, E) -N- (2, 5-difluorobenzylidene) -2-methylpropane-2-sulfinamide
Figure BDA0001919611970000071
2, 5-Difluorobenzaldehyde (24g, 168.89mmol) was dissolved in dichloromethane (100mL), and (R) - (+) -tert-butylsulfinamide (21.59g, 177.33mmol) and cesium carbonate (38.52g, 59.11mmol) were added and reacted at room temperature for 3h to complete the reaction. Filtering, washing a filter cake by dichloromethane (100mL), combining filtrates, and carrying out rotary drying to obtain a crude product of 40.1g, wherein the yield is 96.8%, and the crude product is directly put into the next reaction.
Example 2: (R) -N- ((R) -1- (2, 5-difluorophenyl) -3- (1, 3-dioxane-2-) propyl) -2-methylpropane-2-sulfinamide
Figure BDA0001919611970000072
Magnesium strips (5.95g, 0.245mol) and iodine (catalytic amount) are suspended in tetrahydrofuran (50mL), 2- (2-bromoethyl) -1, 3-dioxane (4.43g, 0.0245mol) tetrahydrofuran solution (20mL) is added dropwise to the suspension, the temperature of the reaction solution is raised to about 65 ℃, after the solution is cooled to room temperature, 2- (2-bromoethyl) -1, 3-dioxane (39.87g, 0.221mol) tetrahydrofuran solution (180mL) is added dropwise, the reaction solution is cooled to room temperature for 30min, the reaction solution is reduced to-40 ℃, the temperature is maintained to be not more than-35 ℃ during the addition process, the reaction is carried out at-40 ℃ overnight after the completion of the dropwise addition, saturated ammonium chloride solution (200mL) is added for quenching, the liquid is separated, the aqueous phase is extracted with dichloromethane (2 × 200mL), the crude phase is combined, and dried, the crude phase is dried, and the yield of the compound is 2.34.5 g.
Example 3: r-2- (2, 5-difluorophenyl) pyrrolidine
Figure BDA0001919611970000073
The compound of example 2 (30g, 0.083mol) was dissolved in trifluoroacetic acid/water (4:1, 75mL) and reacted for 1h, trifluoroacetic acid (225mL) and triethylsilane (28.95g, 0.25mol) were added and stirring was continued for 20h after the end of the reaction and TFA was removed by distillation under reduced pressure, water (200mL) and methyl tert-butyl ether (200mL) were added and diluted, the organic layer was separated, extracted with 1N hydrochloric acid (200mL), the aqueous layer was combined, the aqueous layer was adjusted to pH 13 with 40% sodium hydroxide solution and extracted with dichloromethane (3 × 200mL), the combined organic layers were dried over anhydrous sodium sulfate and then lyophilized to give 10.2g of the compound of example 3 in 64.5% yield.
Example 4: r-5- (2- (2, 5-difluorophenyl) pyrrolidin-1-yl) -3-nitropyrazolo [1,5-a ] pyrimidine
Figure BDA0001919611970000081
The compound of example 3 (5.04g, 27.5mmol), 5-chloro-3-nitropyrazolo [1,5-a ] pyrimidine (5.2g,26.19mmol) was dissolved in ethanol/tetrahydrofuran (4:1, 50 mL). Triethylamine (12.74mL, 91.66mol) was added, the mixture was heated to 50 ℃ and reacted for 3 hours, after completion of the reaction, the reaction mixture was cooled to room temperature and filtered to obtain 8.2g of the compound of example 4 with a yield of 90.7%.
Example 5: r-5- (2- (2, 5-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-amine
Figure BDA0001919611970000082
The compound of example 4 (8.0g, 23.17mmol) was dissolved in methanol (50mL) and 10 wt% palladium on carbon (0.8g) was added. The reaction was carried out under hydrogen atmosphere at 50 ℃ under normal pressure overnight. Filtration and spin-drying of the solvent gave 6.7g of the compound from example 5 in 86.8% yield.
Example 6: r-5- (2- (2, 5-difluorophenyl) pyrrolidin-1-yl) -3-isothiocyanatopyrazolo [1,5-a ] pyrimidine
Figure BDA0001919611970000083
Example 5 the compound (2.0g, 6.34mmol) was dissolved in dichloromethane (20mL), potassium carbonate (1.75g, 12.69mL) and thiophosgene (0.88g, 0.6mL) were added and allowed to react overnight at room temperature after the reaction was completed, water was added to quench the reaction, the aqueous layer was extracted with dichloromethane (3 × 20mL), the organic phases were combined, dried over anhydrous sodium sulfate and spun dry, and the crude product was isolated and purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 3: 1) to give 1.7g of the compound of example 6 in 79.4% yield.
Example 7: (S) -N- (5-R- (2- (2, 5-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) -3-hydroxypyrrolidine-1-thioamide
Figure BDA0001919611970000091
The compound of example 6 (50mg, 0.14mmol) was dissolved in dichloromethane (5mL), and (S) -3-hydroxypyrrolidine hydrochloride (20.8mg, 0.17mmol) and triethylamine (28.3mg, 0.28mmol) were added and reacted for 1h, after the reaction was completed, 1N hydrochloric acid was added, and the organic phase was washed with water, dried over anhydrous sodium sulfate, filtered and dried to give the compound of example 7.
Example 8: (R) -1- (5- (2- (2, 5-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) -3- (tetrahydrofuran-4-yl) thiourea
Figure BDA0001919611970000092
Prepared according to the procedure for the preparation of the compound of example 7, substituting 4-aminotetrahydrofuran for (S) -3-hydroxypyrrolidine hydrochloride.
Example 9: (R) -1-benzyl-3- (5- (2- (2, 5-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) thiourea
Figure BDA0001919611970000093
Prepared according to the procedure for the preparation of the compound of example 7, substituting benzylamine for (S) -3-hydroxypyrrolidine hydrochloride.
Example 10: 1- (5- ((R) -2- (2, 5-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) -3- ((1R,4R) -4-hydroxycyclohexyl) thiourea
Figure BDA0001919611970000101
Prepared according to the procedure for the preparation of the compound of example 7, substituting trans-p-aminocyclohexanol for (S) -3-hydroxypyrrolidine hydrochloride.
Example 11: (R) -1- (cyclohexylmethyl) -3- (5- (2- (2, 5-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) thiourea
Figure BDA0001919611970000102
Prepared according to the procedure for the preparation of the compound of example 7, substituting cyclohexylmethylamine for (S) -3-hydroxypyrrolidine hydrochloride.
Example 12: (R) -1-cyclohexyl-3- (5- (2- (2, 5-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) thiourea
Figure BDA0001919611970000103
Prepared according to the procedure for the preparation of the compound of example 7, substituting cyclohexylamine for (S) -3-hydroxypyrrolidine hydrochloride.
Example 13: (R) -N- (5- (2- (2, 5-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) -3-hydroxyazetidinyl-1-thioamide
Figure BDA0001919611970000104
Prepared according to the procedure for the preparation of the compound of example 7, replacing (S) -3-hydroxypyrrolidine hydrochloride with 3-hydroxyazetidine.
Example 14: (R) -1- (5- (2- (2, 5-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) -3- (2-hydroxyethyl) thiourea
Figure BDA0001919611970000111
Prepared according to the procedure for the preparation of the compound of example 7, substituting ethanolamine for (S) -3-hydroxypyrrolidine hydrochloride.
Example 15: (R) -3- (5- (2- (2, 5-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) -1, 1-bis (2-hydroxyethyl) thiourea
Figure BDA0001919611970000112
Prepared according to the procedure for the preparation of the compound of example 7, replacing (S) -3-hydroxypyrrolidine hydrochloride with diethanolamine.
Example 16: (R) -1- (5- (2- (2, 5-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) -3- (3-methoxypropyl) thiourea
Figure BDA0001919611970000113
Prepared according to the procedure for the preparation of the compound of example 7, substituting 3-methoxypropylamine for (S) -3-hydroxypyrrolidine hydrochloride.
Example 17: (R) -1- (5- (2- (2, 5-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) -3- (2-methoxyethyl) thiourea
Figure BDA0001919611970000114
Prepared according to the procedure for the preparation of the compound of example 7, substituting 2-methoxyethylamine for (S) -3-hydroxypyrrolidine hydrochloride.
Example 18: (R) -1- (5- (2- (2, 5-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) -3- (2, 2-dimethoxyethyl) thiourea
Figure BDA0001919611970000121
Prepared according to the method for preparing the compound of example 7, replacing (S) -3-hydroxypyrrolidine hydrochloride with aminoacetaldehyde dimethyl acetal.
Example 19: (S) -3-amino-N- (5- ((R) -2- (2, 5-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyrrolidine-1-thioamide
Figure BDA0001919611970000122
Step 1: (S) -3-tert-butoxycarbonylamino-N- (5- ((R) -2- (2, 5-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyrrolidine-1-thioamide was prepared according to the method for preparing the compound of example 7 by substituting (S) -3-tert-butoxycarbonylaminopyrrolidine for (S) -3-hydroxypyrrolidine hydrochloride.
Step 2: (S) -3-tert-Butoxycarbonylamino-N- (5- ((R) -2- (2, 5-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyrrolidine-1-thioamide was dissolved in dichloromethane/trifluoroacetic acid (4:1,2.5mL), stirred at room temperature for 30min and spin-dried to give the compound of example 19.
Example 20: (R) -3-amino-N- (5- ((R) -2- (2, 5-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyrrolidine-1-thioamide
Figure BDA0001919611970000123
Prepared according to the procedure for the preparation of the compound of example 19, substituting (R) -3-tert-butoxycarbonylaminopyrrolidine for (S) -3-tert-butoxycarbonylaminopyrrolidine.
Example 21: (R) -1- (5- (2- (2, 5-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) -3- (2,2, 2-trifluoroethyl) thiourea
Figure BDA0001919611970000131
Prepared according to the procedure for the preparation of the compound of example 7, substituting trifluromethanamide for (S) -3-hydroxypyrrolidine hydrochloride.
Example 22: (R) -1- (5- (2- (2, 5-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) -3- (3-hydroxyadamantyl) thiourea
Figure BDA0001919611970000132
Prepared according to the procedure for the preparation of the compound of example 7, substituting 3-hydroxy-1-adamantanamine for (S) -3-hydroxypyrrolidine hydrochloride.
Example 23: (S) -N- (5- ((R) -2- (2, 5-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) -3- (3, 3-dimethylureido) pyrrolidine-1-thioamide
Figure BDA0001919611970000133
The compound of example 19 was dissolved in dichloromethane, and dimethylformamide (1.2eq) and triethylamine (2.5eq) were added to react at room temperature for 1 hour, followed by separation and purification by silica gel column chromatography (petroleum ether: ethyl acetate ═ 3: 1) to obtain the compound of example 23.
Example 24: (R) -N- (5- ((R) -2- (2, 5-difluorophenyl) pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) -3- (3, 3-dimethylureido) pyrrolidine-1-thioamide
Figure BDA0001919611970000141
Prepared according to the procedure for the preparation of the compound of example 23, substituting the compound of example 20 for the compound of example 19.
Example 25: (R) -N- ((R) -1- (2, 5-difluorophenyl) but-3-en-1-yl) -2-methylpropane-2-sulfinamide
Figure BDA0001919611970000142
Example 1 the compound (21.2g,86.43mmol) was dissolved in HMPA (100mL) and H was added sequentially2O (1.63g,90.75mmol), zinc powder (8.48g, 129.64mmol) and allyl bromide (15.68g, 129.64 mmol). The reaction was complete after the mixed solution was stirred at room temperature for 1.5 h. Water (250mL), methyl tert-butyl ether (250mL) was added portionwise in an ice bath,10% citric acid (200 mL.) the organic layer was separated and washed successively with saturated brine (200mL +10mL 10% citric acid), water (2 × 200mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a white solid, slurried with n-heptane (200mL), filtered to give 19.8g of a white solid in 80% yield.
Example 26: n- ((1R) -1- (2, 5-difluorophenyl) -2- (oxiranyl-2-yl) ethyl) -2-methylpropane-2-sulfinamide
Figure BDA0001919611970000143
The compound of example 25 (18.0g, 62.64mmol) was dissolved in dichloromethane (200mL) and mCPBA (27.02g, 156.59mmol) was added portionwise under ice-bath maintaining the reaction temperature around 0 ℃. After 20 minutes of reaction, the temperature was raised to room temperature for 40 hours. The reaction mixture was cooled to 10 ℃ or lower, and water (200mL) and a saturated sodium carbonate solution (100mL) were added. The organic layer was separated, washed with a mixed solution of 10% sodium hydrogensulfite (100mL), saturated brine (100mL) and saturated sodium hydrogencarbonate solution (100mL) and 10% sodium hydrogencarbonate solution (100mL) in this order, and dried over anhydrous sodium sulfate.
Filtration and spin-drying gave a colorless oil (solidified on a lima-horse), slurried with n-hexane (50mL), and filtered to give 17.2g of a white solid with a yield of 86%.
Example 27: (3R,5R) -1- (tert-Butylsulfonyl) -5- (2, 5-difluorophenyl) -3-hydroxypyrrolidine
Figure BDA0001919611970000151
Example 26 the compound (8.7g,27.24mmol) was dissolved in DMF (80mL), potassium iodide (4.52g,27.24mmol) and potassium carbonate (11.29g,81.72mmol) were added, the temperature was raised to 80 deg.C and after 0.5h reaction the starting material reacted completely the reaction solution was cooled to room temperature, water (150mL) was added, isopropyl acetate (2 × 100mL) was extracted, the organic phases were combined, the organic phase was washed successively with water (2 × 150mL) and brine (150mL), dried over anhydrous sodium sulfate, filtered, spun dried to give a light brown solid, recrystallized twice with ethyl acetate: n-heptane (1:1)80mL, the filtrates were taken twice and finally the filtrate was spun dried to give a solid 3.7g, 43% yield.
Example 28: (2R,4S) -1- (tert-Butylsulfonyl) -2- (2, 5-difluorophenyl) -4-fluoro-pyrrolidine
Figure BDA0001919611970000152
The compound of example 27 (3.7g,11.59mmol) was dissolved in dichloromethane (50mL), the reaction was cooled to-40 ℃ and DAST (4.67mL,34.76mmol) was added dropwise. After reacting at-40 ℃ for 20min, the reaction mixture was warmed to room temperature and reacted overnight. After completion of the reaction, a saturated sodium bicarbonate solution (30mL) was added to quench the reaction, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate and then spin dried to give a light brown solid. The crude product was extracted with ethyl acetate: recrystallization from n-hexane (35mL, 1:5) and filtration gave 2.1g of an off-white solid with a yield of 56.4%.
Example 29: (2R,4S) -2- (2, 5-difluorophenyl) -4-fluoro-pyrrolidine
Figure BDA0001919611970000161
Example 28 the compound (1.0g, 3.11mmol) was dissolved in dichloromethane (10mL), trifluoromethanesulfonic acid (1.38mL, 15.56mmol) and triethylsilane (0.5g, 4.67mmol) were added, the reaction was allowed to react at room temperature for 2h, the reaction was completed, 40% sodium hydroxide solution was added to the reaction solution to adjust the pH to about 13, the organic layer was separated, the aqueous layer was extracted with dichloromethane (3 × 10mL), the organic layers were combined, dried over anhydrous sodium sulfate, and spun to give 0.58g of a light brown oil in 93% yield.
Example 30: 5- ((2R,4S) -2- (2, 5-difluorophenyl) -4-fluoro-pyrrolidin-1-yl) -3-nitropyrazolo [1,5-a ] pyrimidine
Figure BDA0001919611970000162
Prepared according to the procedure for the preparation of the compound of example 4, substituting (2R,4S) -2- (2, 5-difluorophenyl) -4-fluoro-pyrrolidine for R-2- (2, 5-difluorophenyl) pyrrolidine.
Example 31: 5- ((2R,4S) -2- (2, 5-difluorophenyl) -4-fluoro-pyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-amine
Figure BDA0001919611970000163
The compound of example 4 was replaced by the compound of example 30 according to the procedure for the preparation of the compound of example 5.
Example 32: 5- ((2R,4S) -2- (2, 5-difluorophenyl) -4-fluoro-pyrrolidin-1-yl) -3-isothiocyanatopyrazolo [1,5-a ] pyrimidine
Figure BDA0001919611970000171
The compound of example 5 was replaced by the compound of example 32 according to the procedure for the preparation of the compound of example 6.
Example 33: (S) -N- (5- ((2R.4S) -2- (2, 5-difluorophenyl) -4-fluoropyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) -3-hydroxypyrrolidine-1-thioamide
Figure BDA0001919611970000172
The compound of example 5 was replaced by the compound of example 32 according to the procedure for the preparation of the compound of example 7.
Example 34: (R) -1- (5- ((2R.4S) -2- (2, 5-difluorophenyl) -4-fluoropyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) -3- (tetrahydrofuran-4-yl) thiourea
Figure BDA0001919611970000173
Prepared according to the procedure for the preparation of the compound of example 33, substituting 4-aminotetrahydrofuran for (S) -3-hydroxypyrrolidine hydrochloride.
Example 35: (R) -1-benzyl-3- (5- ((2R.4S) -2- (2, 5-difluorophenyl) -4-fluoropyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) thiourea
Figure BDA0001919611970000181
Prepared according to the procedure for the preparation of the compound of example 33 substituting benzylamine for (S) -3-hydroxypyrrolidine hydrochloride.
Example 36: 1- (5- ((2R.4S) -2- (2, 5-difluorophenyl) -4-fluoropyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) -3- ((1R,4R) -4-hydroxycyclohexyl) thiourea
Figure BDA0001919611970000182
Prepared according to the procedure for the preparation of the compound of example 33 substituting trans-p-aminocyclohexanol for (S) -3-hydroxypyrrolidine hydrochloride.
Example 37: (R) -1- (cyclohexylmethyl) -3- (5- ((2R.4S) -2- (2, 5-difluorophenyl) -4-fluoropyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) thiourea
Figure BDA0001919611970000183
Prepared according to the procedure for the preparation of the compound of example 33, substituting cyclohexylmethylamine for (S) -3-hydroxypyrrolidine hydrochloride.
Example 38: (R) -1-cyclohexyl-3- (5- ((2R.4S) -2- (2, 5-difluorophenyl) -4-fluoropyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) thiourea
Figure BDA0001919611970000191
Prepared according to the procedure for the preparation of the compound of example 33, substituting cyclohexylamine for (S) -3-hydroxypyrrolidine hydrochloride.
Example 39: (R) -N- (5- ((2R.4S) -2- (2, 5-difluorophenyl) -4-fluoropyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) -3-hydroxyazetidinyl-1-thioamide
Figure BDA0001919611970000192
Prepared according to the procedure for the preparation of the compound of example 33, substituting 3-hydroxyazetidine for (S) -3-hydroxypyrrolidine hydrochloride.
Example 40: (R) -1- (5- ((2R.4S) -2- (2, 5-difluorophenyl) -4-fluoropyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) -3- (2-hydroxyethyl) thiourea
Figure BDA0001919611970000193
Prepared according to the procedure for the preparation of the compound of example 33, substituting ethanolamine for (S) -3-hydroxypyrrolidine hydrochloride.
Example 41: (R) -3- (5- ((2R.4S) -2- (2, 5-difluorophenyl) -4-fluoropyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) -1, 1-bis (2-hydroxyethyl) thiourea
Figure BDA0001919611970000201
Prepared according to the procedure for the preparation of the compound of example 33, substituting diethanolamine for (S) -3-hydroxypyrrolidine hydrochloride.
Example 42: (R) -1- (5- ((2R.4S) -2- (2, 5-difluorophenyl) -4-fluoropyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) -3- (3-methoxypropyl) thiourea
Figure BDA0001919611970000202
Prepared according to the procedure for the preparation of the compound of example 33, substituting 3-methoxypropylamine for (S) -3-hydroxypyrrolidine hydrochloride.
Example 43: (R) -1- (5- ((2R.4S) -2- (2, 5-difluorophenyl) -4-fluoropyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) -3- (2-methoxyethyl) thiourea
Figure BDA0001919611970000203
Prepared according to the procedure for the preparation of the compound of example 33, substituting 2-methoxyethylamine for (S) -3-hydroxypyrrolidine hydrochloride.
Example 44: (R) -1- (5- ((2R.4S) -2- (2, 5-difluorophenyl) -4-fluoropyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) -3- (2, 2-dimethoxyethyl) thiourea
Figure BDA0001919611970000211
Prepared according to the procedure for the preparation of the compound of example 33, replacing (S) -3-hydroxypyrrolidine hydrochloride with aminoacetaldehyde dimethyl acetal.
Example 45: (S) -3-amino-N- (5- ((2R.4S) -2- (2, 5-difluorophenyl) -4-fluoropyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyrrolidine-1-thioamide
Figure BDA0001919611970000212
Step 1: (S) -3-tert-Butoxycarbonylamino-N- (5- ((2R.4S) -2- (2, 5-difluorophenyl) -4-fluoropyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyrrolidine-1-thioamide was prepared according to the procedure for the preparation of the compound of example 33 substituting (S) -3-hydroxypyrrolidine for (S) -3-hydroxypyrrolidine hydrochloride.
Step 2: (S) -3-tert-Butoxycarbonylamino-N- (5- ((2R.4S) -2- (2, 5-difluorophenyl) -4-fluoropyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyrrolidine-1-thioamide was dissolved in dichloromethane/trifluoroacetic acid (4:1,2.5mL), stirred at room temperature for 30min, and spin-dried to give the compound of example 45.
Example 46: (R) -3-amino-N- (5- ((2R.4S) -2- (2, 5-difluorophenyl) -4-fluoropyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) pyrrolidine-1-thioamide
Figure BDA0001919611970000213
Prepared according to the procedure for the preparation of the compound of example 45 substituting (R) -3-tert-butoxycarbonylaminopyrrolidine for (S) -3-tert-butoxycarbonylaminopyrrolidine.
Example 47: (R) -1- (5- ((2R.4S) -2- (2, 5-difluorophenyl) -4-fluoropyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) -3- (2,2, 2-trifluoroethyl) thiourea
Figure BDA0001919611970000221
Prepared according to the procedure for the preparation of the compound of example 33, substituting trifluoromethanesulfonamide for (S) -3-hydroxypyrrolidine hydrochloride.
Example 49: (R) -1- (5- ((2R.4S) -2- (2, 5-difluorophenyl) -4-fluoropyrrolidin-1-yl) pyrazolo [1,5-a ] pyrimidin-3-yl) -3- (3-hydroxyadamantyl) thiourea
Figure BDA0001919611970000222
Prepared according to the procedure for the preparation of the compound of example 33, substituting 3-hydroxy-1-adamantanamine for (S) -3-hydroxypyrrolidine hydrochloride.
List of target compounds:
Figure BDA0001919611970000223
Figure BDA0001919611970000231
Figure BDA0001919611970000241
Figure BDA0001919611970000251
Figure BDA0001919611970000261
Figure BDA0001919611970000271
Figure BDA0001919611970000281
biological experimental example 1:
determination of TRK A enzyme inhibitory Activity
Kinase reaction:
buffer 50mM Hepes,0.1mM Orthovonatate, 5mM MgCl2,0.01％BSA,1nm DTT；
0.5nM TRKA；
0.3μM TK-peptide,20mM ATP,50nM SEB；
Reacting 90minutes at 23 ℃;
and (3) color development reaction:
color buffer 50mM Hepes,0.8M KF,20mM EDTA, 0.01% BSA;
0.67nM TK-Antibody,50nM XL665；
reacting at 23 ℃ for 60 minutes;
the detection device comprises:
Envision(PerkinElmer#2104)
from the inhibition curves based on the inhibition rates at the respective concentrations of the test compounds, the 50% inhibition rate value (IC) of the test compound was calculated50Value).
IC for the target Compounds of the invention50Values, as shown in the following table:
Figure BDA0001919611970000301
Figure BDA0001919611970000311
biological experimental example 2:
investigation of the Effect of active Compounds on inhibiting in vitro tumor cell proliferation
1. Cell line and culture method
Cell lines Tumor type Growth characteristics Culture method
KM-12 Cancer of colon Wall-attached type DMEM+FBS10％
2. Culture medium and reagent
Culture medium and reagent Manufacturer of the product Goods number
DMEM GIBCO 11995-065
Dulbecco's PBS Thermo SH30028.02B
FBS Hyclone SH30084.03
Antibiotic-antimycotic GIBCO 15240-062
DMSO SIGMA D2650
L-glutamine Invitrogen 25030164
3. Reagent and instrument for cell activity experiment
(1) Promega CellTiter-Glo luminescence cell activity assay kit (Promega-G7573).
(2) 2104EnVision plate reader, PerkinElmer
4. Experimental methods and procedures
4.1 cell culture
Tumor cell lines were cultured at 37 ℃ in 5% CO under the respective conditions2The incubator of (2) for cultivation. Cells in logarithmic growth phase were taken for plating after regular passage.
4.1.1 cell plating
1) Cell staining was performed with trypan blue and viable cells were counted.
2) The cell concentration was adjusted to an appropriate concentration.
3) 90 μ L of cell suspension was added to each well of the plate and cell-free medium was added to the blank air.
4) Plates were incubated at 37 ℃ with 5% CO2And overnight in an incubator at 100% relative humidity.
4.2 Compound memory plate preparation
Preparation of 400X compound storage plates: compounds were diluted from highest concentration gradient to lowest concentration with DMSO.
4.310X compound working solution preparation and compound treatment cell
1) Preparation of 10X compound working solution: add 76. mu.L of cell culture to the V-bottom 96-well plate and aspirate 4. mu.L of compound from the 400 Xcompound storage plate into the 96-well plate. Add 4 μ L DMSO to vehicle control and blank control. Adding compound or DMSO, blowing with a discharge gun, and mixing.
2) Adding medicine: 10 μ L of 10 Xcompound working solution was added to the cell culture plate. To the vehicle control and blank control, 10 μ L of DMSO-cell culture broth was added. The final concentration of DMSO is 0.50%.
3) The 96-well cell plate was returned to the incubator for 72 h.
4.4CellTiter-Glo luminescence method for detecting cell activity
The following procedure was performed according to the instructions of Promega CellTiter-Glo luminescence cell activity assay kit (Promega-G7573).
1) CellTiter-Glo buffer was thawed and left to stand at room temperature.
2) The CellTiter-Glo substrate was allowed to stand at room temperature.
3) CellTiter-Glo buffer was added to a flask of CellTiter-Glo substrate to dissolve the substrate, thereby preparing CellTiter-Glo working solution.
4) Vortex slowly to dissolve sufficiently.
5) The cell culture plate was removed and allowed to equilibrate to room temperature for 30 minutes.
6) 50 μ L (equal to half the volume of cell culture medium in each well) of CellTiter-Glo working solution was added to each well. The cell plates were wrapped in aluminum foil paper to protect from light.
7) The plates were shaken on an orbital shaker for 2 minutes to induce cell lysis.
8) The plate was left at room temperature for 10 minutes to stabilize the luminescence signal.
9) The luminescence signal was detected on 2104EnVision plate reader.
5. Data analysis
The Inhibition Rate (IR) of the test compound was calculated by the following formula: IR (%) ═ 100% (1- (RLU compound-RLU blank)/(RLU vehicle control-RLU blank)). The inhibition rate of the compound at different concentrations was calculated in Excel, and then GraphPad Prism software was used to make inhibition curves and calculate relevant parameters.
Compound 33 and Larotrectinib (LOXO-101)
Inhibition of in vitro tumor cell proliferation
Figure BDA0001919611970000331
Pharmaceutical formulation example 1:
blends were produced according to the formulations presented in the table below, and these blends were available as tablet formulations based on direct compression or roller compaction. First, the API, microcrystalline cellulose and lactose were added to the mixer and mixed for 3min at 25 rpm. Then, the remaining diluent, disintegrant, glidant, lubricant were mixed into the mixer at 25rpm for an additional 3 min.
Components Purpose(s) to Percentage of
API Pharmaceutical substance 50
Microcrystalline cellulose Diluent 30.3
Lactose Diluent 15.2
Croscarmellose sodium Disintegrating agent 3
Silicon dioxide Glidants 1
Magnesium stearate Lubricant agent 0.5
Finally, it should be noted that: although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (18)

1. A compound of the general formula 1, an optical isomer thereof or a mixture thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, an N-oxide thereof, or a prodrug thereof:
Figure FDA0001919611960000011
R1represents H, substituted or unsubstituted C1-C6R1Represents H, substituted or unsubstituted C1-C6Alkyl, alkenyl, alkynyl, substituted or unsubstituted C1-C6HeteroalkanesAlkyl, alkenyl, alkynyl;
R2represents NRbRcSubstituted or unsubstituted C1-C6Alkyl, CF3Substituted or unsubstituted C1-C6Heteroalkyl, - (C)1-C6Alkyl) hetero Ar1,-(C1-C6Alkyl) NH2、-(C1-C6Alkyl) NH (C)1-C6Alkyl), - (C)1-C6Alkyl) N (C)1-C6Alkyl radical)2Hetero Ar2heteroCy, optionally substituted with NHSO2(C1-C6Alkyl) or phenyl optionally substituted by (C)1-C6Alkyl), CN, OH, OMe, NH2、NHMe、N(CH3)2、F、CF3、CO2(C1-C6Alkyl), CO2H、C(＝O)NReRfOR C (═ O) ORgSubstituted (C)3-C6) A cycloalkyl group;
Rbrepresents H, substituted or unsubstituted C1-C6An alkyl group;
RCrepresents H, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted adamantyl, substituted or unsubstituted C1-C6Heteroalkyl, hetero Ar3Or phenyl, wherein said phenyl is optionally independently selected from halogen, CN, CF3And O (C)1-C6Alkyl) with one or more substituents,
or NRbRcForming a 4-membered heterocyclic ring having a ring nitrogen atom, wherein the heterocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of: halogen, OH, (C)1-C6Alkyl group), (C)1-C6) Alkoxy, OC (═ O) (C)1-C6Alkyl), NH2、NHC(＝O)O(C1-C6Alkyl) and (C)1-C6) A hydroxyalkyl group,
or NRbRcForm a 5-to 6-membered heterocyclic ring having a ring heteroatom of nitrogen and optionally having a ring heteroatom selected from N, O and SO2Second of (2)A ring heteroatom or group, wherein the heterocyclic ring is optionally substituted with one or more substituents independently selected from: OH, halogen, CF3、C1-C6Alkyl, CO2(C1-C6Alkyl), CO2H、NH2、NHC(＝O)O(C1-C6Alkyl) and oxo.
Or NRbRcForming a 7-to 8-membered bridged heterocyclic ring having a ring nitrogen atom and optionally a second ring heteroatom selected from N and O, wherein the ring is optionally CO-bonded2(C1-C6Alkyl) substitution;
hetero Ar1Represents a 5-membered heteroaromatic ring having 1 to 3 ring nitrogen atoms;
hetero Ar2Represents a 5 to 6 membered heteroaromatic ring having at least one nitrogen ring atom and optionally having a second ring heteroatom independently selected from N and S, wherein the heteroaromatic ring is optionally independently selected from C1-C6Alkyl, halogen, (C)1-C6) Alkoxy and NH (C)1-C6Alkyl) with one or more substituents;
HeteroCy represents a carbon-linked 4-to 6-membered nitrogen heterocycle, optionally independently selected from (C)1-C6) Alkoxy, OC (═ O) (C)1-C6Alkyl) or is optionally substituted by one or more substituents selected from C1-C6A pyridone or pyridazinone ring substituted with a substituent of an alkyl group;
hetero Ar3Represents a 5-to 6-membered heteroaromatic ring having 1 to 2 ring heteroatoms independently selected from N and O and optionally being independently selected from C1-C6Alkyl substituted with one or more substituents;
Rerepresents H, substituted or unsubstituted C1-C6Alkyl radical
RfRepresents H, substituted or unsubstituted C1-C6Alkyl or (C)3-C6) A cycloalkyl group;
or NReRfForming a 4 to 6 membered nitrogen heterocycle optionally having other ring heteroatoms selected from N and O, wherein said nitrogen heterocycle is optionally substituted with OH;
Rgis H, substituted or unsubstituted C1-C6An alkyl group;
y represents phenyl, optionally independently selected from halogen, (C)1-C6) Alkoxy, CF3And CHF2Or represents a 5 to 6 membered heteroaryl ring having a ring heteroatom selected from N and S, wherein the heteroaryl ring is optionally substituted by one or more halogen atoms;
x is absent, or-CH2-、-CH2CH2-、-CH2O-or-CH2NRd-；
RdRepresents H, substituted or unsubstituted C1-C6An alkyl group;
R3represents H, substituted or unsubstituted C1-C6An alkyl group;
each R4Independently selected from halogen, (C)1-C6) Alkyl, OH, (C)1-C6) Alkoxy, NH2、NH(C1-C6Alkyl) and CH2OH；
n is 0, 1,2, 3, 4, 5 or 6.
2. Compound 1 of the general formula 1, its optical isomers or their mixtures, its pharmaceutically acceptable salts, its solvates, its N-oxides, or their prodrugs according to claim 1, characterized in that: said R2Represents NRbRcSubstituted or unsubstituted C1-C6Alkyl, CF3Substituted or unsubstituted C1-C6Heteroalkyl, - (C)1-C6Alkyl) hetero Ar1、-(C1-C6Alkyl) NH2、-(C1-C6Alkyl) NH (C)1-C6Alkyl), - (C)1-C6Alkyl) N (C)1-C6Alkyl radical)2Hetero Ar2heteroCy, optionally NHSO2(C1-C6Alkyl) or optionally (C) substituted phenyl1-C6Alkyl), CN, OH, OMe, NH2、NHMe、N(CH3)2、F、CF3、-CO2(C1-C6 alkyl), -CO2H substituted (C)3-C6) Cycloalkyl, C (═ O) NReRfOR C (═ O) ORg。
3. Compound 1 of the general formula, its optical isomers or their mixtures, its pharmaceutically acceptable salts, its solvates, its N-oxides, or their prodrugs according to claim 2, characterized in that: said R2Represents NRbRc。
4. A compound 1 according to any one of claims 1 to 3 of the general formula: the NR describedbRcForming a 4-membered heterocyclic ring having a ring nitrogen atom, wherein the heterocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of: halogen, OH, (C1-C6 alkyl), (C1-C6) alkoxy, -OC (═ O) (C1-C6 alkyl), NH2, -NHC (═ O) O (C1-C6 alkyl), and (C1-C6) hydroxyalkyl, or NRbRc forms a 5 to 6 membered heterocyclic ring having a ring heteroatom which is nitrogen and optionally having a second ring heteroatom or group selected from N, O and SO2, wherein said heterocyclic ring is optionally substituted with one or more substituents independently selected from: OH, halogen, CF3, C1-C6 alkyl, -OC (═ O) (C1-C6 alkyl), CO2H, NH2, -NHC (═ O) O (C1-C6 alkyl), and oxo.
5. A compound 1 according to any one of claims 1 to 3 of the general formula: rcIs H, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted adamantyl, substituted or unsubstituted C1-C6Heteroalkyl, hetero Ar3Or phenyl, wherein said phenyl is optionally independently selected from halogen, CN, CF3and-O (C)1-C6Alkyl) with one or more substituents.
6. A compound 1 according to any one of claims 1 to 3 of the general formula: wherein X is absent, or-CH2-or-CH2CH2-。
7. Compound 1 of the general formula, its optical isomers or their mixtures, its pharmaceutically acceptable salts, its solvates, its N-oxides, or their prodrugs according to claim 6, characterized in that: x is-CH2-。
8. A compound 1 according to any one of claims 1 to 3 of the general formula: y is optionally independently selected from halogen, (C)1-C6) Alkoxy, CF3And CHF2Phenyl substituted with one or more substituents of (1).
9. Compound 1 of the general formula, its optical isomers or their mixtures, its pharmaceutically acceptable salts, its solvates, its N-oxides, or their prodrugs according to claim 8, characterized in that: wherein Y is 2, 5-difluorophenyl.
10. A compound 1 according to any one of claims 1 to 3 of the general formula: y has the following configuration 1a
Figure FDA0001919611960000031
11. Such asA compound 1 of the general formula according to any one of claims 1 to 3, its optical isomers or mixtures thereof, its pharmaceutically acceptable salts, its solvates, its N-oxides, or prodrugs thereof, characterized in that: wherein R is3Is H.
12. A compound 1 according to any one of claims 1 to 3 of the general formula: each R4Independently selected from halogen, (C)1-C6) Alkyl, OH, (C)1-C6) Alkoxy, NH2、NH(C1-C6Alkyl) and CH2OH; n is 0, 1 or 2.
13. Compound 1 of formula 1, its optical isomers or their mixtures, its pharmaceutically acceptable salts, its solvates, its N-oxides, or their prodrugs according to claim 12, characterized in that: r4Is fluorine and n is 0 or 1.
14. A pharmaceutical composition characterized by: the pharmaceutical composition comprises a therapeutically effective amount of compound 1 of the general formula, an optical isomer thereof, or a mixture thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, an N-oxide thereof, or a prodrug thereof according to any one of claims 1 to 13, and a pharmaceutically acceptable carrier.
15. Use of compound 1 of general formula (la), an optical isomer thereof, or a mixture thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, an N-oxide thereof, or a prodrug thereof according to any one of claims 1 to 13, in the manufacture of a medicament for treating a TRK-mediated disease or disorder, wherein the disease or disorder is cancer, dermatitis, or asthma.
16. Use of compound 1 of general formula (la), an optical isomer thereof or a mixture thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, an N-oxide thereof, or a prodrug thereof according to any one of claims 1 to 13 for the manufacture of a medicament for the treatment of TRK-mediated pain or cachexia.
17. Use of a compound of general formula 1, an optical isomer thereof or a mixture thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, an N-oxide thereof, or a prodrug thereof according to any one of claims 1 to 13 in the manufacture of a medicament for the treatment of a disease in which TRK kinase activity is implicated, wherein the disease is selected from cancer, dermatitis and asthma.
18. Use of a compound of general formula 1, an optical isomer thereof or a mixture thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, an N-oxide thereof, or a prodrug thereof according to any one of claims 1 to 13 in the manufacture of a medicament for the treatment of pain or cachexia wherein IRK kinase activity is involved.
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