CN115368366A - Pyrimidopyrazole compound and application thereof - Google Patents
Pyrimidopyrazole compound and application thereof Download PDFInfo
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- CN115368366A CN115368366A CN202210920243.1A CN202210920243A CN115368366A CN 115368366 A CN115368366 A CN 115368366A CN 202210920243 A CN202210920243 A CN 202210920243A CN 115368366 A CN115368366 A CN 115368366A
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- cancer
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- hydrogen
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- -1 Pyrimidopyrazole compound Chemical class 0.000 title claims description 28
- 150000001875 compounds Chemical class 0.000 claims abstract description 67
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- 239000003814 drug Substances 0.000 claims abstract description 19
- 108091000080 Phosphotransferase Proteins 0.000 claims abstract description 11
- 102000020233 phosphotransferase Human genes 0.000 claims abstract description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 57
- 229910052739 hydrogen Inorganic materials 0.000 claims description 52
- 239000001257 hydrogen Substances 0.000 claims description 52
- 150000002431 hydrogen Chemical class 0.000 claims description 50
- 125000003118 aryl group Chemical group 0.000 claims description 42
- 125000003545 alkoxy group Chemical group 0.000 claims description 32
- 238000002360 preparation method Methods 0.000 claims description 25
- 150000003839 salts Chemical group 0.000 claims description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 18
- 229910052805 deuterium Inorganic materials 0.000 claims description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
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- 125000001475 halogen functional group Chemical group 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 239000000651 prodrug Chemical group 0.000 claims description 11
- 229940002612 prodrug Drugs 0.000 claims description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 9
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- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 4
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- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical class [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 claims description 2
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims description 2
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- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 claims description 2
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 claims description 2
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
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- 125000002933 cyclohexyloxy group Chemical group C1(CCCCC1)O* 0.000 description 1
- XCIXKGXIYUWCLL-UHFFFAOYSA-N cyclopentanol Chemical compound OC1CCCC1 XCIXKGXIYUWCLL-UHFFFAOYSA-N 0.000 description 1
- 125000000131 cyclopropyloxy group Chemical group C1(CC1)O* 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
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- 239000002480 mineral oil Substances 0.000 description 1
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- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- Health & Medical Sciences (AREA)
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- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
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Abstract
The compounds have good inhibitory activity to bispecific kinase Mps1 (monopolar spindle 1, also called TTK)), can be used as Mps1 inhibitors, and can be used for preparing medicaments for preventing and/or treating diseases related to Mps1 overexpression mediation in organisms and medicaments related to angiogenesis or cancer metastasis.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a pyrimidopyrazole compound and application thereof in preparing medicines for preventing and/or treating diseases related to overexpression and mediation of bispecific kinase Mps1 (monopolar spindle 1, also called TTK) in organisms or medicines related to cancer metastasis.
Background
Breast cancer is one of the high-incidence malignant tumors of women worldwide. According to the international center for research on cancer (IARC) of the world health organization: in 2008, the number of new cases of breast cancer of women reaches 138 ten thousand worldwide, and accounts for 22.9 percent of all new cases of malignant tumors of women in the current year. About 45.8 million people die of breast cancer each year worldwide. The current worldwide breast cancer drug market is about $ 200 million, with a projected compound growth rate of about 11% in 2025, extending to $ 384 million. According to statistics, about 16.9 ten thousand women in China are diagnosed with breast cancer every year, and 4.5 ten thousand women die of breast cancer every year. The Chinese breast cancer has unique characteristics compared with European and American countries, wherein the incidence of the breast cancer accounts for more than half of the patients before menopause, the incidence peak is 40-70 years old, the whole breast cancer is higher than that of the European and American countries, and the proportion of triple-negative breast cancer (TNBC) is high. Triple negative breast cancer refers to breast cancer in which the cancer tissue immunohistochemical examination results show that Estrogen Receptor (ER), progesterone Receptor (PR) and human epidermal growth factor receptor (HER 2) are all negative. Triple negative breast cancer accounts for 20% of the pathological types of breast cancer, and 30% -40% of TNBC can develop into metastatic breast cancer, with multiple visceral metastasis, especially of the lung and brain, with poorer prognosis. The related kinases involved in the regulation of cell mitosis are expressed in many levels in common breast cancers, and the high expression of the kinases has a great relationship with the poor prognosis of tumors. In particular, the kinase Mps1 (monopolar spindle 1, also known as TTK), which is a dual-specificity kinase, is one of the major kinases involved in centromere localization and Spindle Assembly Checkpoint (SAC) and plays an important role in mitosis. Mps1 expression was associated with highly proliferating cells and tissues, as it was observed that Mps1 was overexpressed in many cancer cell lines and tumor types, especially significantly higher in TNBC patients, and strongly correlated with poor prognosis in TNBC patients. In certain species, silencing of Mps1 prevents mitotic arrest of cells due to spindle toxins, suggesting a fundamental function of Mps1 in spindle assembly signaling.
Thus, elimination of the mitotic checkpoint by drug inhibition of Mps1 kinase or other components of the mitotic checkpoint suggests a novel approach to the treatment of proliferative diseases, including solid tumors, such as carcinomas and sarcomas, as well as leukemias and lymphoid malignancies, or other diseases associated with uncontrolled cellular proliferation. In view of the important role played by Mps1 in breast cancer cells, especially TNBC, inhibition and invasion of TNBC cells are realized by inhibiting high expression of Mps1, so that the method has great research value, and development of an Mps1 inhibitor with a novel framework structure brings new selection and hope for treating TNBC patients.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a pyrimidopyrazole compound which has good inhibitory activity on Mps1 kinase, can be used as an Mps1 inhibitor and provides possibility for treating diseases mediated by Mps 1.
In order to achieve the above object, the present invention adopts the following technical means:
a compound of formula I or a pharmaceutically acceptable salt, prodrug, crystal form, stereoisomer, tautomer, hydrate or solvate thereof
In the formula I, the compound is shown in the specification,
x is selected from-CR 5 R 6 -、-NR 5 -, O or S, where R is 5 、R 6 Each independently represents hydrogen, deuterium, halogen, alkyl, aryl or Het;
y is selected from-NR 7 -, O or S, where R is 7 Each independently represents hydrogen, deuterium, halogen, alkyl, aryl or Het;
q is selected from-NR 8 CONR 9 -、-CONR 8 -、-NR 8 CO-、-CO-、-NR 8 SO 2 NR 9 -、-SO 2 NR 8 -、-NR 8 SO 2 -、-SO 2 -、-NR 8 -、-NR 8 (CH 2 ) n NR 9 -、-NR 8 (CH 2 ) n O-or-CR 8 R 9 Wherein n =1, 2,3, 4 or 5,R 8 、R 9 Each independently represents hydrogen, deuterium, alkyl, aryl or Het;
ring A is selected from 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl;
R 1 selected from hydrogen, halo, hydroxy, alkoxy, alkyl, aryl or Het;
R 2 selected from hydrogen, halo, hydroxy, alkoxy, alkyl, aryl or Het;
R 3 selected from hydrogen, halo, hydroxy, alkoxy, alkyl, aryl or Het;
R 4 selected from hydrogen, halo, hydroxy, alkoxy, alkyl, aryl or Het;
the alkyl is a straight chain or branched chain saturated hydrocarbon group with 1 to 6 carbon atoms, a cyclic saturated hydrocarbon group with 3 to 6 carbon atoms, or a cyclic saturated hydrocarbon group with 3 to 6 carbon atoms which is connected with the straight chain or branched chain saturated hydrocarbon group with 1 to 6 carbon atoms;
in the above groups, aryl is a carbocyclic ring selected from phenyl, naphthyl, acenaphthyl or tetrahydronaphthyl, each of which is optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from hydrogen, alkyl, cyano, halo, nitro, haloalkyl, hydroxy, mercapto, alkoxy, alkylthio, alkoxyalkyl, aralkyl, diarylalkyl, aryl or Het;
het is a monocyclic heterocycle selected from piperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; or a bicyclic heterocycle selected from quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2,3-dihydrobenzo [1,4] dioxinyl, or benzo [1,3] dioxolyl; each monocyclic or bicyclic heterocycle is optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from halo, haloalkyl, hydroxy, alkyl or alkoxy;
halogen is selected from fluorine, chlorine, bromine or iodine.
Further, in the formula I,
x is-NR 5 Or O, wherein R 5 Selected from hydrogen, deuterium, halogen, alkyl, aryl or Het;
y is selected from-NR 7 Or O, wherein R 7 Each independently represents hydrogen, deuterium, halogen, alkyl, aryl or Het;
q is selected from-NR 8 CONR 9 -、-CONR 8 -、-NR 8 CO-、-CO-、-NR 8 SO 2 NR 9 -、-SO 2 NR 8 -、-NR 8 SO 2 -、-NR 8 (CH 2 ) n NR 9 -、-SO 2 -or-CR 8 R 9 Wherein n =1, 2,3, 4 or 5,R 8 、R 9 Each independently represents hydrogen, deuterium, alkyl, aryl or Het;
ring A is selected from 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl;
R 1 selected from hydrogen, alkoxy, alkyl, aryl or Het;
R 2 selected from hydrogen, halo, hydroxy, alkoxy, alkyl, aryl or Het;
R 3 selected from hydrogen, halo, alkoxy, alkyl, aryl or Het;
R 4 selected from hydrogen, hydroxy, alkoxy, alkyl, aryl or Het.
Further, in the formula I,
x is-NR 5 -, wherein R 5 Selected from hydrogen, deuterium or alkyl;
y is selected from O;
q is selected from-NR 8 CONR 9 -、-NR 8 CO-、-NR 8 SO 2 NR 9 -、-NR 8 (CH 2 ) n NR 9 -、-NR 8 SO 2 -or-CR 8 R 9 Wherein n =1, 2,3, 4 or 5,R 8 、R 9 Each independently represents hydrogen, deuterium, alkyl, aryl or Het;
ring A is selected from 6-10 membered aryl;
R 1 selected from hydrogen, alkoxy, alkyl or aryl;
R 2 selected from hydrogen, halogen, hydroxy, alkoxy or alkyl;
R 3 selected from hydrogen, alkoxy or alkyl;
R 4 selected from hydrogen, alkoxy, alkyl, aryl or Het.
Further, in the formula I,
x is-NH-;
y is selected from O;
q is selected from-NR 8 (CH 2 ) n R 9 N-or-N (CH) 2 ) n N-, wherein N =1 or 2,R 8 、R 9 Each independently represents hydrogen, deuterium, alkyl, aryl or Het;
R 1 is hydrogen or alkyl;
R 2 selected from hydrogen, halogen or alkyl;
R 3 selected from hydrogen, alkoxy or alkyl;
R 4 selected from hydrogen, alkoxy, alkyl, aryl or Het.
Further, the pharmaceutically acceptable salts include acid addition salts of the compounds of formula I with the following acids: hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, benzenesulfonic, p-toluenesulfonic, naphthalenesulfonic, citric, tartaric, lactic, pyruvic, acetic, maleic or succinic acid, fumaric, salicylic, phenylacetic, mandelic acid; also included are acid salts of compounds of formula I with inorganic bases.
Further, the pharmaceutically acceptable salts include alkali metal cation salts, alkaline earth metal cation salts, and ammonium cation salts.
Further, the compound of the general formula I is one of the following compounds:
a pharmaceutical composition, comprising the above compound or a pharmaceutically acceptable salt, prodrug, crystal form, stereoisomer, tautomer, hydrate or solvate thereof, and a pharmaceutically acceptable carrier or excipient.
The application of the compound in preparing the medicine for preventing and/or treating the diseases related to the Mps 1.
Further, the Mps 1-associated disease is selected from, but not limited to, hyperlipidemia or cancer; the cancer includes lung cancer, squamous cell carcinoma, bladder cancer, stomach cancer, ovarian cancer, peritoneal cancer, breast cancer, ductal carcinoma of the breast, head and neck cancer, endometrial cancer, corpus uteri cancer, rectal cancer, liver cancer, kidney cancer, renal pelvis cancer, esophageal adenocarcinoma, glioma, prostate cancer, thyroid cancer, cancer of the female reproductive system, carcinoma in situ, lymphoma, neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, oral cancer, pharyngeal cancer, multiple myeloma, leukemia, non-hodgkin's lymphoma, villous adenoma of the large intestine, melanoma, cell tumors, and sarcoma, and myelodysplastic syndrome.
Has the advantages that: the compound of the general formula I and pharmaceutically acceptable salts, prodrugs, crystal forms, stereoisomers, tautomers, hydrates or solvates thereof provided by the invention are used as receptor tyrosine kinase inhibitors, and especially have excellent inhibitory activity on Mps1 kinase. Thus, the above compounds may be used for the preparation of a medicament for the treatment of clinical conditions associated with Mps1, such as: the use thereof for producing a medicament for preventing and/or treating diseases associated with abnormal cell proliferation, morphological changes, hyperkinesia, and the like associated with Mps1 in a living body, and a disease associated with angiogenesis or cancer metastasis.
Detailed Description
The present invention provides compounds of formula I:
pharmacological test results show that the compound has good inhibitory activity on Mps1, can be used as a novel Mps1 inhibitor, and provides possibility for treatment of diseases mediated by Mps 1.
In the present invention, the compounds of formula I may also exist in the form of their salts, hydrates, solvates, which are converted in vivo to the compounds of formula I. For example, within the scope of the present invention, the compounds of the present invention are converted into pharmaceutically acceptable salt forms according to procedures known in the art, and they are used in salt form.
Also, the compounds of formula I may exist in polycrystalline or amorphous form.
In addition, the compounds of formula I may also exist in specific geometric or stereoisomeric forms. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups, and all such isomers and mixtures thereof are included within the scope of the present invention.
As used herein, "prodrug" refers to any covalently bound carrier that releases the active parent drug when administered to a mammalian patient. Prodrugs can be prepared by modifying functional groups present in the compound in such a way that they are cleaved, either by routine manipulation or in vivo, to the parent compound. Prodrugs include, when administered to a mammalian patient, for example: compounds in which a hydroxyl, amino, thiol or carboxyl group is linked to any group and is decomposed to form a free hydroxyl, amino, thiol or carboxyl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohols or amine functional methylamine, ethylamine derivatives in the compounds of the invention.
The pharmaceutical composition provided by the invention comprises a compound of a general formula I or pharmaceutically acceptable salt, prodrug, crystal form, stereoisomer, tautomer, hydrate or solvate thereof and a pharmaceutically acceptable carrier or excipient.
The pharmaceutical compositions of the invention may be administered in various known ways, for example orally, parenterally, by inhalation spray or via an implanted depot. The pharmaceutical composition can be independently administered or combined with other antitumor drugs. Oral compositions may be any orally acceptable dosage form, including, but not limited to, tablets, capsules, emulsions, and suspensions, dispersions, and solutions. Commonly used pharmaceutically acceptable carriers or excipients include stabilizers, diluents, surfactants, lubricants, antioxidants, binders, colorants, fillers, emulsifiers, and the like.
Sterile injectable compositions can be formulated according to the techniques known in the art using suitable dispersing or wetting agents and suspending agents. Pharmaceutically acceptable carriers and solvents that may be used include water, mannitol, sodium chloride solution and the like.
The topical compositions may be formulated as oils, lotions, creams and the like. Carriers for the composition include vegetable or mineral oils, animal fats, high molecular weight alcohols, and the like. Pharmaceutically acceptable carriers are carriers in which the active ingredient is soluble.
The actual dosage level of the active ingredient in the pharmaceutical compositions of the invention can be varied to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition and mode of administration, and which is non-toxic to the patient. The selected dosage level depends on a variety of factors including the activity of the particular compound of the invention or salt thereof employed, the route of administration, the time of administration, the rate of excretion of the particular composition employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular composition employed, the age, sex, body weight, general health and past medical history of the patient being treated, and like factors well known in the medical arts.
The invention also provides application of the compound shown in the formula I or pharmaceutically acceptable salt, prodrug, crystal form, stereoisomer, tautomer, hydrate or solvate thereof in preparing a medicament for preventing and/or treating Mps1 related diseases. Such as: the use thereof for producing a medicament for preventing and/or treating diseases associated with abnormal cell proliferation, morphological changes, hyperkinesia, and the like associated with Mps1 in a living body, and a disease associated with angiogenesis or cancer metastasis.
Said Mps1 related diseases are selected from, but not limited to, hyperlipidemia or cancer; the cancer comprises lung cancer, squamous cell carcinoma, bladder cancer, stomach cancer, ovarian cancer, peritoneal cancer, breast cancer, ductal carcinoma of the breast, head and neck cancer, endometrial cancer, corpus uteri cancer, rectal cancer, liver cancer, kidney cancer, renal pelvis cancer, esophageal adenocarcinoma, glioma, prostate cancer, thyroid cancer, female reproductive system cancer, carcinoma in situ, lymphoma, neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, oral cancer, pharyngeal cancer, multiple myeloma, leukemia, non-Hodgkin's lymphoma, villous adenoma of the large intestine, melanoma, cytoma and sarcoma, myelodysplastic syndrome.
The process for the preparation of the compounds of formula I according to the invention is described below with reference to specific examples, which are not intended to limit the invention in any way. The compounds of the present invention may also be conveniently prepared by optionally combining various synthetic methods described in the present specification or known in the art, and such combinations may be readily carried out by those skilled in the art to which the present invention pertains.
The starting materials, reaction reagents and the like used in the examples of the present invention are commercially available. The present invention may be prepared in salified form by salification methods commonly used in the art.
Example 1
3- (3,4-dimethoxyphenyl) -4- (cyclopentyloxy) -N- [ (2-methoxy-4-morpholinyl) phenyl ] -1H-pyrazolo [3,4-d ] pyrimidin-6-amine (I-1)
The synthetic route is as follows:
synthesis of Compound I-1-1:
into a 100mL single-necked flask was added 4,6-dichloro-1H-pyrazolo [3,4-d]Pyrimidine (2.00g, 11mmol), N-iodosuccinimide (3.57g, 11mmol), 1,4-dioxane 20mL and DMF 5mL, reacted at 90 ℃ for 8h, TLC monitored for reaction completion. Pouring the reaction solution into 25mL of ice water, extracting with EA (50mL x 3) until no product exists in the water layer, stopping extraction, concentrating to obtain a crude product, and purifying by column chromatography (PE: EA = 8:1) to obtain 1.5g of white solid with yield of 38%, MS m/z:315.2[ M ] +H ],] + 。
synthesis of Compound I-1-2:
to a 100mL single-necked flask was added compound I-1-1 (1.25g, 4.00mmol), CH 2 Cl 2 20mL and DMF 2mL, cooling to 0 ℃, adding sodium hydrogen (0.19g, 4.80mmol), reacting for 20min at 0 ℃, slowly dropping trimethylsilyl ethoxymethyl chloride 0.8mL, reacting for 0.5h at 0 ℃, monitoring the reaction completion by TLC (PE: EA = 4:1), pouring the reaction liquid into 10mL of ice water, EA (30mL × 3) extracting, drying with sodium sulfate, and performing column chromatography (PE: EA = 10) to obtain 1.26g of yellow oily substance with yield of 72%, MS m/z: 446.2M + H] + 。
Synthesis of Compounds I-1-3:
adding compound I-1-2 (1.26g, 2.80mmol), 1,4-dioxane 6mL into a 50mL single-neck flask, cooling to 0 ℃, adding sodium hydrogen (0.34g, 8.50mmol), reacting at 0 ℃ for 30min, slowly dropping cyclopentanol 0.6mL, heating to room temperature for reacting for 4h, monitoring the reaction by TLC (PE: EA = 4:1), pouring the reaction solution into 5mL of ice water, EA (10mL × 3) extracting, drying sodium sulfate, concentrating to dryness, and performing column chromatography (PE: EA = 10) to obtain 1.23g of yellow oily matter, yield 88%, MS m/z: 495.4M H [ H ]] + 。
Synthesis of Compounds I-1-4:
a50 mL single-neck flask was charged with I-1-3 (1.23g, 2.40mmol), 3,5-dimethoxyphenylboronic acid (0.50g, 2.70mmol), na 2 CO 3 (0.66g, 6.20mmol), 1,4-dioxane 15mL and water 5mL, pd (dppf) Cl was added under a nitrogen atmosphere 2 (0.18g, 0.24mmol), nitrogen substitution 3 times, heating to 70 ℃ for reaction for 5h, TLC (PE: EA = 4:1) monitoring the completion of the reaction, cooling the reaction liquid to room temperature, adding ice water 5mL to the reaction liquid, EA (5mL. Multidot.3) extraction, whereinThe organic phase is dried and concentrated, and a yellow solid is obtained by column chromatography (PE: EA = 5:1) with the yield of 0.73g and the MS m/z of 506.1[ M ] +H] + 。
Synthesis of Compounds I-1-5:
a50 mL single-neck bottle was charged with I-1-4 (0.37g, 0.73mmol), 4-morphinyl-2-methoxyaniline (0.23g, 1.00mmol), cs 2 CO 3 (0.70g, 2.20mmol) and 1,4-dioxane (7 mL) were added Pd under a nitrogen atmosphere 2 (dba) 3 (0.04g, 0.07mmol) and BINAP (0.04g, 0.07mmol), replacing with nitrogen for 3 times, heating to 120 ℃ for reaction for 9h, monitoring the reaction by TLC (PE: EA = 1:1), cooling the reaction liquid to room temperature, adding ice water for 5mL into the reaction liquid, EA (5mL x 3) for extraction, drying and concentrating the organic phase, and performing column chromatography (PE: EA = 1:1) to obtain 0.31g of yellow solid, the yield is 63%, and MS m/z: 677.1M + H + is obtained at 63% yield] + . Synthesis of Compound I-1:
to a 50mL single neck flask were added I-1-5 (0.31g, 0.45mmol) and CH 2 Cl 2 20mL, cool to 0 ℃, add trifluoroacetic acid 5mL,0 ℃ reaction 4h, TLC (DCM: meOH = 10) to monitor completion of the reaction, pour the reaction into 10mL of ice water, CH 2 Cl 2 (20mL × 3), drying with sodium sulfate, and performing column chromatography (DCM: meOH =30] + 。
1 H-NMR(400MHz,DMSO-d 6 )δ(ppm):13.15(s,1H),8.06-7.81(m,3H),7.64(ddd,J＝8.4,5.0,2.0Hz,1H),7.51(dd,J＝3.5,2.0Hz,1H),7.02(t,J＝8.1Hz,1H),6.67(dd,J＝4.3,2.5Hz,2H),6.53(td,J＝9.2,2.5Hz,1H),5.70-5.53(m,2H),3.89-3.79(m,12H),3.76(t,J＝4.8Hz,6H),3.11(t,J＝4.8Hz,5H),1.99(ddd,J＝13.6,9.0,4.1Hz,3H),1.88-1.57(m,5H)。
Example 2
3- (3,4-dimethoxyphenyl) -4- (cyclopentyloxy) -N- [ (2-methoxy-4- (N-methylpiperazine)) phenyl ] -1H-pyrazolo [3,4-d ] pyrimidin-6-amine (I-2)
The preparation method is referred to example 1,4,6-dichloro-1H-pyrazolo [3,4-d]Pyrimidine is used as starting material to obtain yellow solid 150mg with yield of 53%, MS m/z:560.2[ M ] +H] + 。
1 H-NMR(400MHz,DMSO-d 6 )δ(ppm):13.16(s,1H),7.87(t,J＝4.3Hz,2H),7.63(dd,J＝8.4,2.0Hz,1H),7.51(d,J＝2.0Hz,1H),7.01(d,J＝8.5Hz,1H),6.66(d,J＝2.5Hz,1H),6.52(dd,J＝8.8,2.5Hz,1H),3.89-3.76(m,9H),3.17(t,J＝4.7Hz,4H),2.67-2.54(m,4H),2.32(s,3H),2.07-1.91(m,2H),1.86-1.56(m,5H)。
Example 3
3- (3,4-dimethoxyphenyl) -4- (cyclopentyloxy) -N- [ (2-methoxy-4- (N-acetylpiperazine)) phenyl ] -1H-pyrazolo [3,4-d ] pyrimidin-6-amine (I-3)
Preparation method referring to example 1, with 4,6-dichloro-1H-pyrazolo [3,4-d]Pyrimidine is used as starting material to obtain yellow solid 130mg with yield 45%, MS m/z 588.3[ M ] +H] + 。
1 H-NMR(400MHz,DMSO-d 6 )δ(ppm):13.14(s,1H),8.09-7.81(m,2H),7.64(ddd,J＝8.2,5.4,2.0Hz,1H),7.51(d,J＝2.2Hz,1H),7.02(t,J＝8.3Hz,2H),6.76-6.67(m,2H),6.56(td,J＝9.4,9.0,2.6Hz,2H),3.93-3.75(m,14H),3.60(q,J＝6.1Hz,7H),3.12(dt,J＝23.9,5.2Hz,6H),2.06(s,5H),2.04-1.95(m,1H),1.86-1.57(m,2H)。
Example 4
3- (3,4-dimethoxyphenyl) -4- (cyclohexyloxy) -N- [ (2-methoxy-4- (N, N-dimethylaminopiperidine)) phenyl ] -1H-pyrazolo [3,4-d ] pyrimidin-6-amine (I-4)
Preparation method referring to example 1, with 4,6-dichloro-1H-pyrazolo [3,4-d]Pyrimidine is used as starting material to obtain yellow solid 80mg with yield of 54%, MS m/z 602.1[ m ] +H] + 。
1 H-NMR(400MHz,CDCl 3 )δ(ppm):13.13(s,1H),7.90(s,1H),7.79(d,J＝8.7Hz,1H),7.65(dd,J＝8.4,2.0Hz,1H),7.52(d,J＝2.1Hz,1H),7.02(d,J＝8.4Hz,1H),6.66(d,J＝2.6Hz,1H),6.52(dd,J＝8.8,2.5Hz,1H),3.82(d,J＝6.5Hz,10H),2.82(s,1H),2.73-2.59(m,2H),2.09-1.94(m,5H),1.70(ddd,J＝23.8,10.6,6.3Hz,3H),1.61-1.48(m,3H)。
Example 5
3- (3,4-dimethoxyphenyl) -4- (cyclopropyloxy) -N- [ (2-methoxy-4- (N, N-dimethylaminopiperidine)) phenyl ] -1H-pyrazolo [3,4-d ] pyrimidin-6-amine (I-5)
Preparation method referring to example 1, with 4,6-dichloro-1H-pyrazolo [3,4-d]Pyrimidine is used as starting material to obtain yellow solid 65mg with yield 28%, MS m/z 560.3[ M ] +H] + 。
1 H-NMR(400MHz,CDCl 3 )δ(ppm):13.18(s,1H),10.05(s,1H),8.01-7.88(m,2H),7.50(d,J＝7.0Hz,1H),7.03(d,J＝8.5Hz,1H),6.69(d,J＝2.4Hz,1H),6.56(dd,J＝8.8,2.5Hz,1H),4.66-4.43(m,1H),3.86-3.79(m,10H),3.17(s,1H),2.79(d,J＝3.0Hz,6H),2.68(t,J＝12.1Hz,2H),2.07(d,J＝11.9Hz,2H),1.72(dd,J＝12.1,4.0Hz,2H),1.22(s,2H),0.84(dt,J＝13.9,4.4Hz,4H)。
Example 6
3- (3-methoxyphenyl) -4- (cyclopentyloxy) -N- [ (2-methoxy-4- (N, N-dimethylaminopiperidine)) phenyl ] -1H-pyrazolo [3,4-d ] pyrimidin-6-amine (I-6)
Preparation method referring to example 1, with 4,6-dichloro-1H-pyrazolo [3,4-d]Pyrimidine is used as starting material to obtain yellow solid 220mg, yield is 73%, MS m/z is 558.3[ M ] +H ]] + 。
1 H-NMR(400MHz,CDCl 3 )δ(ppm):10.30(s,1H),7.98(d,J＝15.0Hz,1H),7.89(d,J＝8.7Hz,1H),7.60(d,J＝7.7Hz,1H),7.54(t,J＝1.9Hz,1H),7.36(q,J＝7.7Hz,1H),6.97(dd,J＝8.2,2.5Hz,1H),6.72(d,J＝2.6Hz,1H),6.58(dd,J＝8.9,2.4Hz,1H),5.62(d,J＝39.5Hz,1H),3.85(d,J＝7.5Hz,3H),3.81(d,J＝2.0Hz,3H),3.31(d,J＝4.3Hz,1H),3.17(s,3H),2.80(d,J＝4.5Hz,6H),2.72(s,1H),2.09(d,J＝10.9Hz,2H),2.04-1.89(m,2H),1.86–1.69(m,5H),1.67-1.58(m,2H),1.28-1.19(m,1H)。
Example 7
3- (3,5-dimethoxyphenyl) -4- (cyclopentyloxy) -N- [ (2-methoxy-4- (N, N-dimethylaminopiperidine)) phenyl ] -1H-pyrazolo [3,4-d ] pyrimidin-6-amine (I-7)
Preparation method referring to example 1, with 4,6-dichloro-1H-pyrazolo [3,4-d]Pyrimidine is used as a starting material to obtain 62mg of yellow solid, the yield is 25%, MS m/z is 589.3[ M ] +H] + 。
1 H-NMR(400MHz,CDCl 3 )δ(ppm):10.16(s,1H),7.89(d,J＝9.1Hz,1H),7.16(d,J＝2.1Hz,1H),7.04(d,J＝2.2Hz,1H),6.87(d,J＝2.2Hz,1H),6.73(d,J＝5.0Hz,1H),6.63(d,J＝10.6Hz,2H),5.63(s,1H),5.40(s,1H),3.91-3.79(m,9H),3.51(s,1H),3.34(s,1H),3.17(s,3H),2.80(d,J＝4.3Hz,6H),2.10(d,J＝11.9Hz,2H),1.97(d,J＝9.6Hz,2H),1.88-1.52(m,8H),1.22(s,1H)。
Example 8
3- (4-methoxyphenyl) -4- (cyclopentyloxy) -N- [ (2-methoxy-4- (N, N-dimethylaminopiperidine)) phenyl ] -1H-pyrazolo [3,4-d ] pyrimidin-6-amine (I-8)
Preparation method referring to example 1, with 4,6-dichloro-1H-pyrazolo [3,4-d]Pyrimidine is used as starting material to obtain yellow solid 210mg, yield 81%, MS m/z 558.2[ M ] +H] + 。
1 H-NMR(400MHz,CDCl 3 )δ(ppm):10.20(s,1H),7.91(dd,J＝12.4,8.4Hz,3H),6.99(d,J＝8.2Hz,2H),6.72(s,1H),6.59(d,J＝8.8Hz,1H),5.65(s,1H),4.51(d,J＝7.1Hz,4H),3.83(s,3H),3.80(s,3H),3.39-3.27(m,1H),3.16(s,2H),2.83-2.69(m,6H),2.17-1.88(m,3H),1.88-1.55(m,6H),1.38-1.16(m,2H)。
Example 9
4- [ (3- ((2,6-dimethyl) carbamoyl) pyrrolyl ] -N- [ (2-methoxy-4- (N-methylpiperazine)) phenyl ] -1H-pyrazolo [3,4-d ] pyrimidin-6-amine (I-9)
Preparation method referring to example 1, with 4,6-dichloro-1H-pyrazolo [3,4-d]Pyrimidine is used as starting material to obtain yellow solid 36mg with yield of 22%, MS m/z of 552.1[ m ] +H] + 。
1 H-NMR(400MHz,CDCl 3 )δ(ppm):13.52(s,1H),9.73(s,1H),8.62(d,J＝6.2Hz,2H),8.32(s,1H),7.94(s,1H),7.76(d,J＝8.7Hz,1H),7.12(s,3H),6.94(d,J＝3.3Hz,1H),6.67(d,J＝2.5Hz,1H),6.54(dd,J＝8.7,2.5Hz,1H),3.82(s,3H),3.19(t,J＝4.9Hz,4H),2.56(t,J＝5.0Hz,4H),2.29(s,3H),2.21(s,6H)。
Example 10
4- [ (3- ((2,6-diethyl) carbamoyl) pyrrolyl ] -N- [ (2-methoxy-4- (N-methylpiperazine)) phenyl ] -1H-pyrazolo [3,4-d ] pyrimidin-6-amine (I-10)
Preparation method referring to example 1, with 4,6-dichloro-1H-pyrazolo [3,4-d]Pyrimidine is used as starting material to obtain yellow solid 24mg with yield 23%, MS m/z 580.2[ M ] +H] + 。
1 H-NMR(400MHz,CDCl 3 )δ(ppm):13.55(s,1H),9.78(s,1H),8.65(d,J＝4.8Hz,2H),8.34(s,1H),7.94(s,1H),7.76(d,J＝8.5Hz,1H),7.26-7.19(m,1H),7.14(d,J＝7.5Hz,2H),6.95(d,J＝3.3Hz,1H),6.67(d,J＝2.5Hz,1H),6.53(dd,J＝8.8,2.5Hz,1H),3.82(s,3H),3.19(t,J＝5.0Hz,4H),2.57(t,J＝7.3Hz,8H),2.29(s,3H),1.12(t,J＝7.6Hz,6H)。
Example 11
4- [ (3- ((2,6-dimethyl) carbamoyl) pyrrolyl ] -N- [ (2-methoxy-4- (N-acetylpiperazine)) phenyl ] -1H-pyrazolo [3,4-d ] pyrimidin-6-amine (I-11)
Preparation method referring to example 1, with 4,6-dichloro-1H-pyrazolo [3,4-d]Pyrimidine is used as starting material to obtain yellow solid 60mg, yield 48%, MS m/z 580.3[ M ] +H] + 。
1 H-NMR(400MHz,CDCl 3 )δ(ppm):13.51(s,1H),9.58(s,1H),8.55(d,J＝12.6Hz,2H),8.36(s,1H),7.95(t,J＝2.7Hz,1H),7.79(d,J＝8.7Hz,1H),7.13(s,3H),6.94(dd,J＝3.3,1.6Hz,1H),6.71(d,J＝2.5Hz,1H),6.56(dd,J＝8.8,2.5Hz,1H),3.83(s,3H),3.60(dt,J＝10.8,5.4Hz,4H),3.14(dt,J＝23.2,5.2Hz,4H),2.22(s,6H),2.06(s,3H)。
Example 12
4- [ (3- ((2,6-diethyl) carbamoyl) pyrrolyl ] -N- [ (2-methoxy-4- (N-acetylpiperazine)) phenyl ] -1H-pyrazolo [3,4-d ] pyrimidin-6-amine (I-12)
Preparation method referring to example 1, with 4,6-dichloro-1H-pyrazolo [3,4-d]Pyrimidine is used as starting material to obtain yellow solid 30mg, yield 22%, MS m/z 608.2[ M ] +H] + 。
1 H-NMR(400MHz,CDCl 3 )δ(ppm):13.50(s,1H),9.54(s,1H),8.54(d,J＝12.8Hz,2H),8.35(s,1H),7.94(t,J＝2.7Hz,1H),7.79(d,J＝8.7Hz,1H),7.24(dd,J＝8.4,6.6Hz,1H),7.16(d,J＝7.5Hz,2H),6.94(dd,J＝3.3,1.6Hz,1H),6.71(d,J＝2.5Hz,1H),6.56(dd,J＝8.7,2.5Hz,1H),3.83(s,3H),3.60(q,J＝5.6Hz,4H),3.14(dt,J＝24.1,5.2Hz,4H),2.58(q,J＝7.6Hz,4H),2.06(s,3H),1.13(t,J＝7.6Hz,6H)。
Example 13
3- (3,4-dimethoxyphenyl) -4- (cyclopentyloxy) -N- [ (2-methoxy-4-piperazine) phenyl ] -1H-pyrazolo [3,4-d ] pyrimidin-6-amine (I-13)
Preparation method referring to example 1, with 4,6-dichloro-1H-pyrazolo [3,4-d]Pyrimidine is used as starting material to obtain yellow solid 50mg, yield 20%, MS m/z:546.3[ M ] +H] + 。
1 H-NMR(400MHz,CDCl 3 )δ(ppm):13.19(s,1H),7.92(t,J＝4.4Hz,2H),7.63(dd,J＝8.3,1.9Hz,1H),7.51(d,J＝2.0Hz,1H),7.01(d,J＝8.4Hz,1H),6.71(d,J＝2.5Hz,1H),6.56(dd,J＝8.9,2.4Hz,1H),3.91-3.77(m,10H),3.32(d,J＝5.7Hz,5H),3.17(d,J＝5.2Hz,5H),1.99(dt,J＝13.3,5.7Hz,2H),1.87-1.58(m,6H),1.30-1.20(m,1H)。
Example 14
3-cyano-4- (cyclopentyloxy) -N- [ (2-methoxy-4- (N, N-dimethylaminopiperidine)) phenyl ] -1H-pyrazolo [3,4-d ] pyrimidin-6-amine (I-14)
Preparation method referring to example 1, with 4,6-dichloro-1H-pyrazolo [3,4-d]Pyrimidine is used as a starting material to obtain yellow solid 18mg with yield of 46%, MS m/z:477.3[ M ] +H] + 。
1 H-NMR(400MHz,CDCl 3 )δ(ppm):14.19(s,1H),10.01(s,1H),8.41(s,1H),7.61(d,J＝8.6Hz,1H),6.69(d,J＝4.9Hz,1H),6.57(t,J＝9.4Hz,1H),3.87(s,1H),3.81(d,J＝8.8Hz,3H),2.78(d,J＝4.8Hz,6H),2.69(d,J＝11.6Hz,2H),2.09(d,J＝11.8Hz,2H),1.97(s,2H),1.79(dd,J＝23.2,13.6Hz,6H),1.64(s,2H),1.24(s,2H)。
Example 15
3- (3,4-dimethoxyphenyl) -4- (cyclopentyloxy) -N- [ (2-methoxy-4-piperidine) phenyl ] -1H-pyrazolo [3,4-d ] pyrimidin-6-amine (I-15)
Preparation method referring to example 1, with 4,6-dichloro-1H-pyrazolo [3,4-d]Pyrimidine is used as starting material to obtain yellow solid 60mg, yield 20%, MS m/z:545.2[ M ] +H] + 。
1 H-NMR(400MHz,CDCl 3 )δ(ppm):13.14(s,1H),8.04-7.78(m,3H),7.64(ddd,J＝8.1,5.5,2.0Hz,1H),7.51(t,J＝2.5Hz,1H),7.02(t,J＝8.4Hz,1H),6.58(d,J＝47.0Hz,3H),3.86-3.78(m,13H),3.12(t,J＝5.3Hz,5H),2.06-1.91(m,2H),1.88-1.47(m,18H)。
Example 16
3- (3,4-dimethoxyphenyl) -4- (cyclopentyloxy) -N- [ (2-methoxy-4- (N, N-dimethylaminopiperidine)) phenyl ] -1H-pyrazolo [3,4-d ] pyrimidin-6-amine (I-16)
Preparation method referring to example 1, with 4,6-dichloro-1H-pyrazolo [3,4-d]Pyrimidine is used as a starting material to obtain 37mg of yellow solid, the yield is 9 percent, and MS m/z is 588.2[ M ] +H] + 。
1 H-NMR(400MHz,CDCl 3 )δ(ppm):13.11(s,1H),7.92(s,1H),7.78(d,J＝8.6Hz,1H),7.64(dd,J＝8.6,2.0Hz,1H),7.52(d,J＝2.0Hz,1H),7.03(d,J＝8.6Hz,1H),6.68(d,J＝2.6Hz,1H),6.52(dd,J＝8.8,2.5Hz,1H),3.81(d,J＝6.5Hz,10H),2.80(s,1H),2.73-2.56(m,2H),2.09-1.94(m,4H),1.72(ddd,J＝23.8,10.6,6.3Hz,3H),1.61-1.48(m,2H)。
Example 17
3- (3,5-dimethoxyphenyl) -N- [ (2-propionylamino) phenyl ] -1H-pyrazolo [3,4-d ] pyrimidin-6-amine (I-17)
Preparation method referring to example 1, with 4,6-dichloro-1H-pyrazolo [3,4-d]Pyrimidine is used as starting material to obtain yellow solid 10mg, yield is 8%, MS m/z is 417.2[ M ] +H ]] + 。
1 H-NMR(400MHz,CDCl 3 )δ(ppm):9.16(s,1H),7.99(d,J＝9.1Hz,1H),7.53(d,J＝2.1Hz,1H),7.42-7.27(m,5H),6.79-6.50(m,3H),5.63(s,1H),5.40(s,1H),3.88(s,6H)。
Example 18
3-chloro-4- (cyclopentyloxy) -N- [ (2-methoxy-4- (N, N-dimethylaminopiperidine)) phenyl ] -1H-pyrazolo [3,4-d ] pyrimidin-6-amine (I-18)
Preparation method referring to example 1, with 4,6-dichloro-1H-pyrazolo [3,4-d]Pyrimidine is used as a starting material to obtain yellow solid 18mg, the yield is 15 percent, and MS m/z is 487.2[ M ] +H ]] + 。
1 H-NMR(400MHz,CDCl 3 )δ(ppm):14.17(s,1H),10.01(s,1H),8.40(s,1H),7.61(d,J＝8.6Hz,1H),6.70(d,J＝4.8Hz,1H),6.57(t,J＝9.4Hz,1H),3.88(s,1H),3.81(d,J＝8.6Hz,3H),2.78(d,J＝4.8Hz,6H),2.67(d,J＝11.6Hz,2H),2.08(d,J＝11.8Hz,2H),1.97(s,2H),1.79(dd,J＝23.2,13.6Hz,6H),1.64(s,2H),1.23(s,2H)。
Example 19
3-bromo-4- (cyclopentyloxy) -N- [ (2-methoxy-4- (N, N-dimethylaminopiperidine)) phenyl ] -1H-pyrazolo [3,4-d ] pyrimidin-6-amine (I-19)
Preparation method referring to example 1, with 4,6-dichloro-1H-pyrazolo [3,4-d]Pyrimidine is used as starting material to obtain yellow solid 8mg, yield is 4%, MS m/z is 531.2[ M ] +H] + 。
1 H-NMR(400MHz,CDCl 3 )δ(ppm):14.18(s,1H),10.03(s,1H),8.44(s,1H),7.63(d,J＝8.6Hz,1H),6.71(d,J＝4.8Hz,1H),6.57(t,J＝9.2Hz,1H),3.88(s,1H),3.83(d,J＝8.6Hz,3H),2.77(d,J＝4.8Hz,6H),2.66(d,J＝11.4Hz,2H),2.08(d,J＝11.4Hz,2H),1.97(s,2H),1.78(dd,J＝23.2,13.6Hz,6H),1.66(s,2H),1.24(s,2H)。
Example 20
3- (3,4-dimethoxyphenyl) -4- (cyclopentylsulfanyl) -N- [ (2-methoxy-4-morpholinyl) phenyl ] -1H-pyrazolo [3,4-d ] pyrimidin-6-amine (I-20)
Preparation method referring to example 1, with 4,6-dichloro-1H-pyrazolo [3,4-d]Pyrimidine is used as a starting material to obtain 78mg of yellow solid, the yield is 56 percent, MS m/z:563.2[ M + H ]] + 。
1 H-NMR(400MHz,CDCl 3 )δ(ppm):13.16(s,1H),8.06-7.80(m,3H),7.66(dd,J＝8.4,5.0,1H),7.50(dd,J＝3.5,2.0Hz,1H),7.04(t,J＝8.1Hz,1H),6.67(dd,J＝4.3,2.5Hz,2H),6.52(td,J＝9.2,2.5Hz,1H),5.70-5.54(m,2H),3.89-3.78(m,12H),3.76(t,J＝4.8Hz,6H),3.11(t,J＝4.8Hz,5H),1.99(ddd,J＝13.6,9.0,4.1Hz,3H),1.88-1.56(m,5H)。
Example 21
3- (3,4-dimethoxyphenyl) -4- (cyclopentylamino) -N- [ (2-methoxy-4-morpholinyl) phenyl ] -1H-pyrazolo [3,4-d ] pyrimidin-6-amine (I-21)
Preparation method referring to example 1, with 4,6-dichloro-1H-pyrazolo [3,4-d]Pyrimidine is used as starting material to obtain yellow solid 70mg with yield of 55%, MS m/z:546.2[ M ] +H] + 。
1 H-NMR(400MHz,DMSO-d 6 )δ(ppm):13.16(s,1H),8.06-7.77(m,4H),7.65(dd,J＝8.4,5.0,1H),7.51(dd,J＝3.5,2.0Hz,1H),7.05(t,J＝8.1Hz,1H),6.66(dd,J＝4.3,2.5Hz,2H),6.50(td,J＝9.2,2.5Hz,1H),5.70-5.53(m,2H),3.89-3.78(m,12H),3.74(t,J＝4.8Hz,6H),3.11(t,J＝4.8Hz,5H),1.98(ddd,J＝13.6,9.0,4.1Hz,3H),1.88-1.55(m,5H)。
Example 22
3- (3,4-dimethoxyphenyl) -4- (cyclopentyloxy) -N- [ (2-methoxy-4-morpholinyl) phenyl ] -1H-pyrazolo [3,4-d ] pyrimidin-6-amine hydrochloride (I-22)
Preparation method referring to example 1, with 4,6-dichloro-1H-pyrazolo [3,4-d]Pyrimidine is used as starting material to obtain white solid 90mg with yield 89%, MS m/z:547.2[ M ] +H] + 。
1 H-NMR(400MHz,DMSO-d 6 )δ(ppm):13.75(s,1H),13.16(s,1H),8.06-7.81(m,3H),7.64(ddd,J＝8.4,5.0,2.0Hz,1H),7.51(dd,J＝3.5,2.0Hz,1H),7.02(t,J＝8.1Hz,1H),6.67(dd,J＝4.3,2.5Hz,2H),6.53(td,J＝9.2,2.5Hz,1H),5.70-5.53(m,2H),3.89-3.79(m,12H),3.76(t,J＝4.8Hz,6H),3.11(t,J＝4.8Hz,5H),1.99(ddd,J＝13.6,9.0,4.1Hz,3H),1.88-1.57(m,5H)。
Example 23: biological activity
1. Mps1 inhibitory Activity assay of target Compounds
The synthesized compounds were tested for Mps1 inhibitory activity by Fluorescence Resonance Energy Transfer (FRET) (for specific examples: lebakken CS, kang HC, vogel KW, A fluorescence lifetime-based binding assay to biological enzyme inhibitors J Biomol Screen 2007.12 (6): 828-841.), and compounds with better activity were selected as compared with positive controls. Mps1 was obtained by direct purchase of the kit.
2. MDA-MB-468 and MDA-MB-231 cytostatic activity assays of target compounds
a. Recovering the cells, and culturing the cells to a logarithmic growth phase; b. preparing a compound: dissolving the test sample in DMSO at a concentration of 30mM, and diluting at a ratio of 1: 3 in gradient manner for 10 gradients; c. 4 to 6 x 10 4 Cells at a density of one ml were plated in 384-well plates, 25. Mu.L of each well,adding a compound to a final concentration of 30, 10,3.33,1.11,0.37,0.123,0.041,0.014,0.005,0.002mM; c. the compounds were incubated with the cells for 72h and the activity of the cells was measured by the CTG method.
The following table shows the results of in vitro Mps1 kinase activity and in vitro cancer cell activity assays for some of the compounds:
(the compound symbols in the table correspond to the preceding compound symbols)
From the above table, it can be seen that: the compound and the medically acceptable salt thereof have an Mps1 inhibiting effect, and can provide a basis for preparing a medicament for treating/preventing diseases related to Mps 1.
Pharmacological test results show that the pyrimidopyrimidinone has good Mps1 kinase, MDA-MB-468 cell and MDA-MB-231 cell inhibitory activity, and part of compounds IC 50 The value is equivalent to BAY 1161909 or better than a positive control, and can be used for preventing or treating clinical diseases related to the Mps1 kinase inhibitor.
The compounds and pharmaceutically acceptable salts thereof of the present invention have an Mps1 inhibitory action and are useful as active ingredients in pharmaceuticals. Therefore, drugs containing the above compounds as active ingredients can be used for the preparation of drugs for the treatment of clinical disorders associated with Mps1, such as: the use thereof for producing a medicament for preventing and/or treating diseases associated with abnormal cell proliferation, morphological changes, hyperkinesia, and the like associated with Mps1 in a living body, and a disease associated with angiogenesis or cancer metastasis.
As noted above, while the present invention has been shown and described with reference to certain preferred embodiments, it is not to be construed as limited thereto. Various changes in form and detail may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (10)
1. A compound of formula I or a pharmaceutically acceptable salt, prodrug, crystal form, stereoisomer, tautomer, hydrate, or solvate thereof:
in the formula I, the raw materials are mixed,
x is selected from-CR 5 R 6 -、-NR 5 -, O or S, where R is 5 、R 6 Each independently represents hydrogen, deuterium, halogen, alkyl, aryl or Het;
y is selected from-NR 7 -, O or S, where R is 7 Each independently represents hydrogen, deuterium, halogen, alkyl, aryl or Het;
q is selected from-NR 8 CONR 9 -、-CONR 8 -、-NR 8 CO-、-CO-、-NR 8 SO 2 NR 9 -、-SO 2 NR 8 -、-NR 8 SO 2 -、-SO 2 -、-NR 8 -、-NR 8 (CH 2 ) n NR 9 -、-NR 8 (CH 2 ) n O-or-CR 8 R 9 Wherein n =1, 2,3, 4 or 5,R 8 、R 9 Each independently represents hydrogen, deuterium, alkyl, aryl or Het;
ring A is selected from 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl;
R 1 selected from hydrogen, halo, hydroxy, alkoxy, alkyl, aryl or Het;
R 2 selected from hydrogen, halo, hydroxy, alkoxy, alkyl, aryl or Het;
R 3 selected from hydrogen, halo, hydroxy, alkoxy, alkyl, aryl or Het;
R 4 selected from hydrogen, halo, hydroxy, alkoxy, alkyl, aryl or Het;
the alkyl is a straight chain or branched chain saturated hydrocarbon group with 1 to 6 carbon atoms, a cyclic saturated hydrocarbon group with 3 to 6 carbon atoms, or a cyclic saturated hydrocarbon group with 3 to 6 carbon atoms which is connected with the straight chain or branched chain saturated hydrocarbon group with 1 to 6 carbon atoms;
in the above groups, aryl is a carbocyclic ring selected from phenyl, naphthyl, acenaphthyl or tetrahydronaphthyl, each of which is optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from hydrogen, alkyl, cyano, halo, nitro, haloalkyl, hydroxy, mercapto, alkoxy, alkylthio, alkoxyalkyl, aralkyl, diarylalkyl, aryl or Het;
het is a monocyclic heterocycle selected from piperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; or a bicyclic heterocycle selected from quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2,3-dihydrobenzo [1,4] dioxinyl or benzo [1,3] dioxolyl; each monocyclic or bicyclic heterocycle is optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from halo, haloalkyl, hydroxy, alkyl or alkoxy;
halogen is selected from fluorine, chlorine, bromine or iodine.
2. The compound of claim 1, wherein: in the formula I, the compound is shown in the specification,
x is-NR 5 Or O, wherein R 5 Selected from hydrogen, deuterium, halogen, alkyl, aryl or Het;
y is selected from-NR 7 Or O, wherein R 7 Each independently represents hydrogen, deuterium, halogen, alkyl, aryl or Het;
q is selected from-NR 8 CONR 9 -、-CONR 8 -、-NR 8 CO-、-CO-、-NR 8 SO 2 NR 9 -、-SO 2 NR 8 -、-NR 8 SO 2 -、-NR 8 (CH 2 ) n NR 9 -、-SO 2 -or-CR 8 R 9 Wherein n =1, 2,3, 4 or 5,R 8 、R 9 Each independently represents hydrogen, deuterium, alkyl, aryl or Het;
ring A is selected from 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl;
R 1 selected from hydrogen, alkoxy, alkyl, aryl or Het;
R 2 selected from hydrogen, halo, hydroxy, alkoxy, alkyl, aryl or Het;
R 3 selected from hydrogen, halo, alkoxy, alkyl, aryl or Het;
R 4 selected from hydrogen, hydroxy, alkoxy, alkyl, aryl or Het.
3. The compound of claim 1, wherein: in the formula I, the compound is shown in the specification,
x is-NR 5 -, wherein R 5 Selected from hydrogen, deuterium or alkyl;
y is selected from O;
q is selected from-NR 8 CONR 9 -、-NR 8 CO-、-NR 8 SO 2 NR 9 -、-NR 8 (CH 2 ) n NR 9 -、-NR 8 SO 2 -or-CR 8 R 9 Wherein n =1, 2,3, 4 or 5,R 8 、R 9 Each independently represents hydrogen, deuterium, alkyl, aryl or Het;
ring A is selected from 6-10 membered aryl;
R 1 selected from hydrogen, alkoxy, alkyl or aryl;
R 2 selected from hydrogen, halogen, hydroxy, alkoxy or alkyl;
R 3 selected from hydrogen, alkoxy or alkyl;
R 4 selected from hydrogen, alkoxy, alkyl, aryl or Het.
4. The compound of claim 1, wherein: in the formula I, the compound is shown in the specification,
x is-NH-;
y is selected from O;
q is selected from-NR 8 (CH 2 ) n R 9 N-or-N (CH) 2 ) n N-, wherein N =1 or 2,R 8 、R 9 Each independently represents hydrogen, deuterium, alkyl, aryl or Het;
R 1 is hydrogen or alkyl;
R 2 selected from hydrogen, halogen or alkyl;
R 3 selected from hydrogen, alkoxy or alkyl;
R 4 selected from hydrogen, alkoxy, alkyl, aryl or Het.
5. The compound of claim 1, wherein: the pharmaceutically acceptable salts include acid addition salts of the compounds of formula I with the following acids: hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, benzenesulfonic, p-toluenesulfonic, naphthalenesulfonic, citric, tartaric, lactic, pyruvic, acetic, maleic or succinic, fumaric, salicylic, phenylacetic, mandelic; also included are acid salts of the compounds of formula I with inorganic bases.
6. The compound of claim 5, wherein: the pharmaceutically acceptable salts include basic metal cation salts, alkaline earth metal cation salts, and ammonium cation salts.
7. The compound of claim 1, wherein: the compound of formula I is one of the following compounds:
8. a pharmaceutical composition characterized by: comprising a compound of claim 1, or a pharmaceutically acceptable salt, prodrug, crystal form, stereoisomer, tautomer, hydrate, or solvate thereof, and a pharmaceutically acceptable carrier or excipient.
9. Use of a compound according to claim 1 for the preparation of a medicament for the prevention and/or treatment of a disease associated with kinase Mps 1.
10. Use according to claim 9, characterized in that: the kinase Mps1 related disease is selected from, but not limited to, hyperlipidemia or cancer; the cancer includes lung cancer, squamous cell carcinoma, bladder cancer, stomach cancer, ovarian cancer, peritoneal cancer, breast cancer, ductal carcinoma of the breast, head and neck cancer, endometrial cancer, uterine corpus cancer, rectal cancer, liver cancer, kidney cancer, renal pelvis cancer, esophageal adenocarcinoma, glioma, prostate cancer, thyroid cancer, cancer of the female reproductive system, carcinoma in situ, lymphoma, neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, oral cancer, pharyngeal cancer, multiple myeloma, leukemia, non-hodgkin's lymphoma, villous adenoma of the large intestine, melanoma, cell tumor, and sarcoma, and myelodysplastic syndrome.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009032694A1 (en) * | 2007-08-28 | 2009-03-12 | Dana Farber Cancer Institute | Amino substituted pyrimidine, pyrollopyridine and pyrazolopyrimidine derivatives useful as kinase inhibitors and in treating proliferative disorders and diseases associated with angiogenesis |
| CN101611035A (en) * | 2006-12-28 | 2009-12-23 | 大正制药株式会社 | Pyrazolopyrimidine compound |
| CN103641833A (en) * | 2006-12-08 | 2014-03-19 | Irm责任有限公司 | Compounds and compositions as protein kinase inhibitors |
| CN105566329A (en) * | 2014-11-07 | 2016-05-11 | 温州医科大学 | Parazole [5,6-d]pyrimidine type EGFR inhibitor and anti-tumor activity thereof |
| KR20180137057A (en) * | 2017-06-15 | 2018-12-27 | 한국화학연구원 | Fused-pyrimidine derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating Bruton's tyrosine kinase activity related diseases containing the same as an active ingredient |
| CN109311896A (en) * | 2016-06-30 | 2019-02-05 | 株式会社大熊制药 | Pyrazolopyrimidine derivative is as kinase inhibitor |
-
2022
- 2022-08-02 CN CN202210920243.1A patent/CN115368366A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103641833A (en) * | 2006-12-08 | 2014-03-19 | Irm责任有限公司 | Compounds and compositions as protein kinase inhibitors |
| CN103641816A (en) * | 2006-12-08 | 2014-03-19 | Irm责任有限公司 | Compounds and compositions as protein kinase inhibitors |
| CN101611035A (en) * | 2006-12-28 | 2009-12-23 | 大正制药株式会社 | Pyrazolopyrimidine compound |
| WO2009032694A1 (en) * | 2007-08-28 | 2009-03-12 | Dana Farber Cancer Institute | Amino substituted pyrimidine, pyrollopyridine and pyrazolopyrimidine derivatives useful as kinase inhibitors and in treating proliferative disorders and diseases associated with angiogenesis |
| CN105566329A (en) * | 2014-11-07 | 2016-05-11 | 温州医科大学 | Parazole [5,6-d]pyrimidine type EGFR inhibitor and anti-tumor activity thereof |
| CN109311896A (en) * | 2016-06-30 | 2019-02-05 | 株式会社大熊制药 | Pyrazolopyrimidine derivative is as kinase inhibitor |
| KR20180137057A (en) * | 2017-06-15 | 2018-12-27 | 한국화학연구원 | Fused-pyrimidine derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating Bruton's tyrosine kinase activity related diseases containing the same as an active ingredient |
Non-Patent Citations (1)
| Title |
|---|
| QIAOMEI JIN 等: "Pyrrolo[2,3-b]pyridine-3-one derivatives as novel fibroblast growth factor receptor 4 inhibitors for the treatment of hepatocellular carcinoma", 《BIOORGANIC & MEDICINAL CHEMISTRY》, vol. 29, pages 2 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023128708A1 (en) * | 2021-12-30 | 2023-07-06 | 한국화학연구원 | Pyrazolopyrimidine derivative and anticancer pharmaceutical composition containing same as active ingredient |
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