CN113912648A - Diaminopyrimidine compound and composition containing same - Google Patents

Diaminopyrimidine compound and composition containing same Download PDF

Info

Publication number
CN113912648A
CN113912648A CN202111097366.1A CN202111097366A CN113912648A CN 113912648 A CN113912648 A CN 113912648A CN 202111097366 A CN202111097366 A CN 202111097366A CN 113912648 A CN113912648 A CN 113912648A
Authority
CN
China
Prior art keywords
compound
deuterium
pharmaceutically acceptable
pharmaceutical composition
diaminopyrimidine compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202111097366.1A
Other languages
Chinese (zh)
Inventor
王义汉
李焕银
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shenzhen Targetrx Inc
Original Assignee
Shenzhen Targetrx Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shenzhen Targetrx Inc filed Critical Shenzhen Targetrx Inc
Publication of CN113912648A publication Critical patent/CN113912648A/en
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/004—Acyclic, carbocyclic or heterocyclic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen, sulfur, selenium or tellurium
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Abstract

The invention provides a diaminopyrimidine compound and a composition containing the same, and discloses the diaminopyrimidine compound shown as a formula (I) and a pharmaceutical composition containing the compound, or a crystal form, a pharmaceutically acceptable salt, a hydrate, a solvate, a stereoisomer, a prodrug or an isotopic variant of the compound. The diaminopyrimidine compound and the composition containing the same disclosed by the invention have excellent inhibition on protein kinase, have better pharmacokinetic parameter characteristics, and can improve the drug concentration of the compound in an animal body so as to improve the curative effect and safety of the drug.

Description

Diaminopyrimidine compound and composition containing same
The present application is a divisional application of an invention patent application having an application date of 2016, 22/7, an application number of 201810922557.9 and an invention name of "a diaminopyrimidine compound and a composition comprising the compound" (parent application number of 201610587472.0).
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a diaminopyrimidine compound and a composition containing the compound.
Background
In the last 30 years, the death rate of lung cancer rises by 465 percent, the morbidity increases by 26.9 percent every year, and the lung cancer becomes the leading cause of death of malignant tumors in China. Among them, non-small cell lung cancer (NSCLC) accounts for more than 80% of all lung cancers, only one third of NSCLC patients have the chance of surgical treatment, and about 70% of patients have local advanced stage or distant metastasis at the time of treatment, and the chance of surgery is lost, in which case, the drug treatment is particularly important. Anaplastic Lymphoma Kinase (ALK) gene fusion has recently become an important biomarker, providing assistance for the selection of patients of a particular subgroup of NSCLC for treatment with a corresponding inhibitor. The international association for lung cancer research (IASLC) recommends the use of an ALK fusion assay to guide patient screening and to select patients, whether gender, race, smoking history or other clinical risk factors, who may be eligible for treatment with an ALK inhibitor in advanced adenocarcinoma patients. Fluorescent In Situ Hybridization (FISH) assays using dual-labeled separation probes were used to select patients for treatment with ALK-TKI, and this diagnostic method was approved by the FDA in the United states and was used in the study of crizotinib to treat ALK rearrangement tumors. Crizotinib is an oral Adenosine Triphosphate (ATP) competitive inhibitor, and can inhibit ALK and MET tyrosine kinases, and also inhibit ROS1 and RON kinase activities.
However, crizotinib can exhibit the following side effects: visual disturbances, gastrointestinal side effects, and increased hepatic transaminase levels, grade 3-4, occur in 16% of cases. Furthermore, ALK-positive patients inevitably develop acquired resistance after an initial phase of sensitivity to crizotinib treatment. Therefore, there is a need to develop compounds with ALK kinase inhibitory activity and/or with better pharmacodynamic/pharmacokinetic properties.
Disclosure of Invention
In view of the above technical problems, the present invention discloses a diaminopyrimidine compound having a better ALK kinase inhibitory activity and/or having better pharmacodynamic/pharmacokinetic properties, and a composition comprising the same.
In contrast, the technical scheme adopted by the invention is as follows:
it is an object of the present invention to provide a novel class of compounds having ALK kinase inhibitory activity and/or having better pharmacodynamic/pharmacokinetic properties.
In a first aspect of the invention, a diaminopyrimidine compound represented by formula (I), or a crystalline form, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, is provided.
Figure BDA0003269343280000021
In the formula:
wherein: r1a、R1b、R1c、R2a、R2b、R3a、R3b、R4a、R4b、R5a、R5b、R6、 R7a、R7b、R8a、R8b、R9a、R9b、R10a、R10b、R11、R12、R13、R14a、R14b、R14c、 R15、R16、R17a、R17b、R17c、R18a、R18b、R18c、R19、R20、R21And R22Each independently is hydrogen, deuterium, halogen or trifluoromethyl;
R16is hydrogen, deuterium, halogen, cyano, non-deuterated C1-C6Alkyl or C1-C6Alkoxy, mono-or multidutero or per-deuterated C1-C6Alkyl or C1-C6Alkoxy, or one or more halogen-substituted or perhalogen-substituted C1-C6Alkyl or C1-C6An alkoxy group;
with the proviso that R1a、R1b、R1c、R2a、R2b、R3a、R3b、R4a、R4b、R5a、R5b、 R6、R7a、R7b、R8a、R8b、R9a、R9b、R10a、R10b、R11、R12、R13、R14a、R14b、 R14c、R15、R16、R17a、R17b、R17c、R18a、R18b、R18c、R19、R20、R21And R22At least one of which is deuterated or deuterium.
Deuterium is essentially the same shape and volume as hydrogen in a drug molecule, and if hydrogen is selectively replaced by deuterium in a drug molecule, deuterated drugs will generally retain the original biological activity and selectivity. Meanwhile, the inventor proves that the combination of carbon and deuterium bonds is more stable than the combination of carbon and hydrogen bonds, and the absorption, distribution, metabolism, excretion and other properties of some medicines can be directly influenced, so that the curative effect, safety and tolerance of the medicines are improved.
In another preferred embodiment, the deuterium isotope content of deuterium at each deuterated position is at least greater than the natural deuterium isotope content (0.015%), preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, more preferably greater than 95%, more preferably greater than 99%.
Specifically, in the present invention R1a、R1b、R1c、R2a、R2b、R3a、R3b、R4a、R4b、 R5a、R5b、R6、R7a、R7b、R8a、R8b、R9a、R9b、R10a、R10b、R11、R12、R13、 R14a、R14b、R14c、R15、R16、R17a、R17b、R17c、R18a、R18b、R18c、R19、R20、 R21And R22The deuterium isotope content in each deuterated position is at least 5%, preferably greater than 10%, more preferably greater than 15%, more preferably greater than 20%, more preferably greater than 25%, more preferably greater than 30%, more preferably greater than 35%, more preferably greater than 40%, more preferably greater than 45%, more preferably greater than 50%, more preferably greater than 55%, more preferably greater than 60%, more preferably greater than 65%, more preferably greater than 70%, more preferably greater than 75%, more preferably greater than 80%, more preferably greater than 85%, more preferably greater than 90%, more preferably greater than 95%, more preferably greater than 99%.
In another preferred embodiment, the compound of formula (I) contains at least one deuterium atom, and the number of deuterium atoms may be any one of 1 to 38.
In another preferred embodiment, the compound of formula (I) contains at least one deuterium atom, and the number of deuterium atoms may be any one of 1 to 38.
In a further preferred embodiment of the method,r of the compound of formula (I)1a、R1b、R1c、R2a、R2b、R3a、 R3b、R4a、R4b、R5a、R5b、R6、R7a、R7b、R8a、R8b、R9a、R9b、R10a、R10b、 R11、R12、R13、R14a、R14b、R14c、R15、R16、R17a、R17b、R17c、R18a、R18b、 R18c、R19、R20、R21And R22Wherein at least one R contains deuterium, more preferably two R contains deuterium, more preferably three R contains deuterium, more preferably four R contains deuterium, more preferably five R contains deuterium, more preferably six R contains deuterium, more preferably seven R contains deuterium, more preferably eight R contains deuterium, more preferably nine R contains deuterium, more preferably ten R contains deuterium, more preferably eleven R contains deuterium, more preferably twelve R contains deuterium, more preferably thirteen R contains deuterium, more preferably fourteen R contains deuterium, more preferably fifteen R contains deuterium, more preferably sixteen R contains deuterium, more preferably seventeen R contains deuterium, more preferably eighteen R contains deuterium, more preferably nineteen R contains deuterium, more preferably twenty-one R contains deuterium, more preferably twenty-two R contains deuterium, more preferably twenty-three R contains deuterium, more preferably twenty-four R contains deuterium, more preferably twenty-five R contains deuterium, more preferably twenty-seven R contain deuterium, more preferably twenty-eight R contain deuterium, more preferably twenty-nine R contain deuterium, more preferably thirty-one R contain deuterium, more preferably thirty-two R contain deuterium, more preferably thirty-three R contain deuterium, more preferably thirty-four R contain deuterium, more preferably thirty-five R contain deuterium, more preferably thirty-six R contain deuterium, more preferably thirty-seven R contain deuterium, more preferably thirty-eight R contain deuterium.
In another preferred embodiment, R1a、R1bAnd R1cEach independently is deuterium or hydrogen.
In another preferred embodiment, R2a、R2b、R3a、R3b、R4a、R4b、R5aAnd R5bEach independently is deuterium or hydrogen.
In another preferred embodiment, R6Is deuterium or hydrogen.
In another preferred embodiment, R7a、R7b、R8a、R8b、R9a、R9b、R10aAnd R10bEach independently is deuterium or hydrogen.
In another preferred embodiment, R11、R12And R13Each independently is deuterium or hydrogen.
In another preferred embodiment, R14a、R14bAnd R14cEach independently is deuterium or hydrogen.
In another preferred embodiment, R17a、R17bAnd R17cEach independently is deuterium or hydrogen.
In another preferred embodiment, R18a、R18bAnd R18cEach independently is deuterium or hydrogen.
In another preferred embodiment, R19、R20、R21And R22Each independently is deuterium or hydrogen.
In another preferred embodiment, R16Each independently selected from halogen, trifluoromethyl, cyano, alkyl and alkoxy which is deuterated one or more times.
In another preferred embodiment, R is16Is chlorine.
In another preferred embodiment, R is1a、R1b、R1cIs deuterium.
In another preferred embodiment, R is2a、R2b、R5a、R5bIs deuterium.
In another preferred embodiment, R is3a、R3b、R4a、R4bIs deuterium.
In another preferred embodiment, R2a、R2b、R3a、R3b、R4a、R4b、R5a、R5bIs deuterium.
In another preferred embodiment, R6Is deuterium.
In another preferred embodiment, R7a、R7b、R10a、R10bIs deuterium.
In another preferred embodiment, R8a、R8b、R9a、R9bIs deuterium.
In another preferred embodiment, R7a、R7b、R8a、R8b、R9a、R9b、R10a、R10bIs deuterium.
In another preferred embodiment, R11、R13Is deuterium.
In another preferred embodiment, R11、R12、R13Is deuterium.
In another preferred embodiment, R14a、R14b、R14cIs deuterium.
In another preferred embodiment, R17a、R17b、R17c、R18a、R18b、R18cIs deuterium.
In another preferred embodiment, R20、R22Is deuterium.
In another preferred embodiment, R19、R20、R21、R22Is deuterium.
In another preferred embodiment, the compound is selected from the group consisting of:
5-chloro-N4- [2- (dimethylphosphoryl) phenyl group]-N2- {2-d 3-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl]Phenyl } pyrimidine-2, 4-diamine, the structural formula is shown as formula (2);
Figure BDA0003269343280000051
5-chloro-N4- [2- (dimethylphosphoryl) phenyl group]-N2- { 2-methoxy-4- [4- (4-d 3-methylpiperazin-1-yl) piperidin-1-yl]Phenyl } pyrimidine-2, 4-diamine, the structural formula is shown as formula (3);
Figure BDA0003269343280000052
5-chloro-N4- [2- (dimethylphosphoryl) phenyl group]-N2- { 2-methoxy-4- [4- (4-methyl-piperazin-1-yl) -4-d-piperidin-1-yl]Phenyl } pyrimidine-2, 4-diamine, the structural formula is shown as formula (4);
Figure 1
Figure BDA0003269343280000061
5-chloro-N4- [2- (dimethylphosphoryl) phenyl group]-N2- { 2-methoxy-4- [4- (4-methyl-3, 3,5,5-d 4-piperazin-1-yl) piperidin-1-yl]Phenyl } pyrimidine-2, 4-diamine, the structural formula is shown as formula (5);
Figure BDA0003269343280000062
in another preferred embodiment, the compound is selected from the group consisting of:
Figure BDA0003269343280000063
Figure BDA0003269343280000071
Figure BDA0003269343280000081
in another preferred embodiment, the compound does not include non-deuterated compounds.
In another preferred embodiment, the non-deuterated compound is 5-chloro-N4- (2- (dimethylphosphinyl) phenyl) -N2- (2-methoxy-4- (4- (4-methylpiperazin-1-yl) -piperidin-1-yl) phenyl) pyrimidine-2, 4-diamine.
In a second aspect of the present invention, there is provided a method of preparing a pharmaceutical composition comprising the steps of: mixing a pharmaceutically acceptable carrier with a compound described in the first aspect of the invention, or a crystalline form, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, to form a pharmaceutical composition.
In a third aspect of the invention, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the first aspect of the invention, or a crystalline form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof.
In another preferred embodiment, the pharmaceutical composition is an injection, a capsule, a tablet, a pill, a powder or a granule.
In another preferred embodiment, the pharmaceutical composition further comprises an additional therapeutic agent, wherein the additional therapeutic agent is an agent for cancer, cardiovascular disease, inflammation, infection, immune disease, cell proliferative disease, viral disease, metabolic disease, or organ transplantation.
In a fourth aspect of the present invention, there is provided the use of a compound described in the first aspect of the present invention, or a crystalline form, a pharmaceutically acceptable salt, a prodrug, a stereoisomer, an isotopic variant, a hydrate or a solvate thereof, for the preparation of a pharmaceutical composition for inhibiting a protease.
In another preferred embodiment, the pharmaceutical composition is used for treating and preventing the following diseases: cancer, cell proliferative disorders, inflammation, infection, immunological disorders, organ transplantation, viral disorders, cardiovascular disorders or metabolic disorders.
In another preferred embodiment, the cancer includes, but is not limited to: lung cancer, head and neck cancer, breast cancer, prostate cancer, esophageal cancer, rectal cancer, colon cancer, nasopharyngeal cancer, uterine cancer, pancreatic cancer, lymphoma, leukemia, osteosarcoma, melanoma, renal cancer, gastric cancer, liver cancer, bladder cancer, thyroid cancer or carcinoma of large intestine.
In another preferred embodiment, the immune or inflammatory disease includes, but is not limited to: rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gout, asthma, bronchitis, rhinitis, chronic obstructive pulmonary disease, cystic fibrosis.
In another preferred embodiment, the cell proliferative disease is lung cancer, head and neck cancer, breast cancer, prostate cancer, esophageal cancer, rectal cancer, colon cancer, nasopharyngeal cancer, uterine cancer, pancreatic cancer, lymphoma, leukemia, osteosarcoma, melanoma, renal cancer, gastric cancer, liver cancer, bladder cancer, thyroid cancer or colorectal cancer.
In another preferred embodiment, the cancer is non-small cell lung cancer.
In a fifth aspect of the present invention, there is provided a method of inhibiting a protein kinase (e.g., ALK kinase) or a method of treating a disease (e.g., cancer, cell proliferative disorder, inflammation, infection, immunological disorder, organ transplantation, viral disease, cardiovascular disease or metabolic disease) comprising the steps of: administering a compound as described in the first aspect of the invention, or a crystalline form, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, or administering a pharmaceutical composition as described in the third aspect of the invention, to a subject in need of treatment.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
The invention also includes isotopically-labeled compounds, equivalent to those disclosed herein as the original compound. Examples of isotopes that can be listed as compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, respectively2H，3H，13C，14C，15N，17O，18O，31P，32P，35S，18F and36and (4) Cl. The compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solventsCompounds containing isotopes or other isotopic atoms of the above compounds are within the scope of the present invention. Certain isotopically-labelled compounds of the invention, e.g.3H and14among these, the radioactive isotope of C is useful in tissue distribution experiments of drugs and substrates. Tritium, i.e.3H and carbon-14, i.e.14C, their preparation and detection are relatively easy, and are the first choice among isotopes. In addition, heavier isotopes such as deuterium, i.e.2H, due to its good metabolic stability, may be advantageous in certain therapies, such as increased half-life in vivo or reduced dose, and therefore, may be preferred in certain circumstances. Isotopically labeled compounds can be prepared by conventional methods by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents using the protocols set forth in the examples.
Herein, "halogen" means F, Cl, Br, and I, unless otherwise specified. More preferably, the halogen atom is selected from F, Cl and Br.
Herein, "C" is not specifically defined1-C6Alkyl "means a straight or branched chain alkyl group including 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, or the like.
Herein, "deuterated", unless otherwise specified, means that one or more hydrogens of a compound or group are replaced with deuterium; deuterium can be mono-, di-, poly-, or fully substituted. The terms "deuterated one or more" and "deuterated one or more" are used interchangeably.
Herein, unless otherwise specified, "non-deuterated compound" means a compound containing deuterium at an atomic ratio of deuterium not higher than the natural deuterium isotope content (0.015%).
In the present invention, the pharmaceutically acceptable salts include inorganic salts and organic salts. One preferred class of salts is that formed by reacting a compound of the present invention with an acid. Suitable acids for forming the salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, and the like; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid and the like; and amino acids such as proline, phenylalanine, aspartic acid, glutamic acid, etc. Another preferred class of salts are those of the compounds of the invention with bases, for example alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., magnesium or calcium salts), ammonium salts (e.g., lower alkanolammonium salts and other pharmaceutically acceptable amine salts), for example methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, triethanolamine salts, and amine salts formed from morpholine, piperazine, lysine, respectively.
The term "solvate" refers to a complex of a compound of the present invention coordinated to solvent molecules in a specific ratio. "hydrate" refers to a complex formed by the coordination of a compound of the present invention with water.
Compared with the prior art, the invention has the beneficial effects that:
(1) the compounds of the present invention have excellent inhibitory activity against protein kinases (kinases), such as ALK kinase.
(2) The deuteration technology changes the metabolism of the compound in organisms, so that the compound has better pharmacokinetic parameter characteristics. In this case, the dosage can be varied and a long acting formulation formed, improving the applicability.
(3) Deuterium is used for replacing hydrogen atoms in the compound, and due to the deuterium isotope effect, the medicine concentration of the compound in an animal body can be improved, so that the medicine curative effect is improved.
(4) Replacement of hydrogen atoms in compounds with deuterium may increase the safety of the compounds as certain metabolites are inhibited.
Detailed Description
The following describes more specifically the processes for the preparation of the compounds of formula (I) according to the invention, but these particular processes do not constitute any limitation of the invention. 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 preparation of the non-deuterated diaminopyrimidine compounds used according to the invention and their physiologically compatible salts is known. The corresponding deuterated diaminopyrimidine compounds can be prepared starting from the corresponding deuterated starting compounds by the same route. For example, the compounds of formula (I) according to the invention can be prepared according to the preparation method described in WO2012061299, with the difference that deuterated starting materials are used in the reaction instead of non-deuterated starting materials.
In general, in the preparative schemes, each reaction is usually carried out in an inert solvent at a temperature ranging from room temperature to reflux temperature (e.g., from 0 ℃ to 100 ℃, preferably from 0 ℃ to 80 ℃). The reaction time is usually 0.1 to 60 hours, preferably 0.5 to 24 hours.
The following general preparative routes may be used to synthesize the compounds of the formula (I) of the present invention. The synthetic route is as follows:
Figure BDA0003269343280000121
Figure BDA0003269343280000131
the synthesis of piperazine substituted piperidinamines is shown below:
Figure BDA0003269343280000132
the following examples are given for illustrative purposes.
Example 1
Preparation of 5-chloro-N according to the following synthetic route4- [2- (dimethylphosphoryl) phenyl group]-N2- {2-d 3-methoxy-4- [4- (4-methylpiperazin-1-yl) -piperidin-1-yl]Phenyl } pyrimidine-2, 4-diamine (compound 9 in the following synthetic route):
Figure BDA0003269343280000141
the preparation method comprises the following steps:
(1) preparation of compound 2:
30mL of acetone was added to a 100mL single-neck flask, and 5-fluoro-2-nitrophenol (2.0g, 12.7mmol), anhydrous potassium carbonate (3.5g, 25.4mmol), and deuterated iodomethane (2.4 g, 16.5mmol) were added in this order with stirring, and the mixture was heated to 60 ℃ and stirred for 2 hours while maintaining the temperature. Cool to room temperature, rotary evaporate off acetone, add 20mL water to the residue, extract with ethyl acetate (30mL x 3), combine the organic layers, dry over anhydrous sodium sulfate, filter, concentrate the filtrate to give 2.0g of a white solid in 90% yield.
1H NMR(300MHz,CDCl3)(δ/ppm)8.00-7.95(m,1H),6.83-6.71(m,2H)， LC-MS(APCI):m/z＝175.2(M+1)+,95％。
(2) Preparation of compound 4:
into a 25mL single-neck flask was added N, N-dimethylformamide (4mL), followed by stirring 4-fluoro-2-d 3-methoxynitrobenzene (0.4g, 2.3mmol), 1-methyl-4- (piperidin-4-yl) piperazine hydrochloride (0.7g, 3.2mmol) and anhydrous potassium carbonate (0.95g, 6.9mmol), and the reaction mixture was heated to 80 ℃ and N2The reaction was carried out overnight under an atmosphere. Cooled to room temperature, poured into ice water (80mL), precipitated a large amount of yellow solid, filtered, dissolved in DCM (40mL), dried over anhydrous sodium sulfate, filtered and the filtrate concentrated to give 0.55g of yellow solid in 70.9% yield.
LC-MS(APCI):m/z＝338.2(M+1)+；1H NMR(300MHz,CDCl3)(δ/ppm) 8.01(d,J＝9.3Hz,1H),6.43(dd,J＝9.6Hz,J＝2.7Hz,1H),6.31(d,J＝2.4Hz, 1H),3.98-3.94(m,2H),3.03-2.94(m,2H),2.65-2.62(m,4H),2.54-2.46(m,5H), 2.32(s,3H),2.01-1.96(m,2H),1.65-1.60(m,2H)。
(3) Preparation of compound 5:
6mL of ethanol and 2mL of water were put into a 25mL single-neck flask, and 1- (1- (3-d 3-methoxy-4-nitrophenyl) piperidin-4-yl) -4-methylpiperazine (0.2g, 0.59mmol), reduced iron powder (0.20g, 3.55mmol), ammonium chloride (16mg, 0.30mmol) and a reaction mixture N were added successively under stirring2Heating to 85 deg.C under atmosphereAnd reacting for 1h under the condition of heat preservation and stirring. Cooled to room temperature, the solid material was filtered off, the filtrate was concentrated, saturated sodium bicarbonate (5mL) was added to the residue, extracted with dichloromethane (15mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give an off-white solid 0.15g, yield 79.6%, which was directly put to the next step.
(4) Preparation of compound 8:
DMF (3mL) was added to a 25mL single-neck flask, and 2,5, 6-trichloropyrimidine (0.72 g, 3.9mmol), 2- (dimethylphosphinyl oxide) aniline (0.5g, 3mmol), and anhydrous potassium carbonate (0.62g, 4.5mmol) were added sequentially with stirring, warmed to 60 ℃ and stirred for 4h with incubation. Cooling to room temperature, adding ethyl acetate (30mL) and water (30mL) in turn, shaking for layering, extracting the water layer with ethyl acetate (30mL x 2), combining the organic phases, washing with water (60mL x 2), drying the organic layer with anhydrous sodium sulfate, filtering, concentrating, passing the residue through silica gel column to obtain light yellow solid 0.8g, and obtaining yield 84.6%.
LC-MS(APCI):m/z＝175.2(M+1)+；1H NMR(CDCl3,300MHz)(δ/ppm) 8.00-7.95(m,1H),6.83-6.71(m,2H)。
(5) Preparation of compound 9:
2mL of ethylene glycol monomethyl ether was added to a 25mL single-neck flask, and 2, 5-dichloro-N- (2- (dimethylphosphite) phenyl) pyrimidin-4-amine (60mg, 0.19mmol), 1- (1- (3-d 3-methoxy-4-aminophenyl) piperidin-4-yl) -4-methylpiperazine (60mg, 0.2mmol), concentrated hydrochloric acid (two drops) and the reaction mixture N were added in this order with stirring2The temperature is raised to 100 ℃ under the atmosphere, and the reaction is kept under the temperature and stirred overnight. Cooling to room temperature, adding saturated sodium bicarbonate water solution (10mL), extracting with dichloromethane (15mL × 3), mixing organic phases, drying with anhydrous sodium sulfate, filtering, concentrating, passing through silica gel column to obtain white solid 60mg with yield of 50.1%;
LC-MS(APCI):m/z＝587.2(M+1)+；1H NMR(300MHz,DMSO-d6)(δ/ppm) 11.18(s,1H),8.51-8.47(m,1H),0.08-8.07(m,2H),7.57-7.50(m,1H), 7.40-7.32(m,2H),7.12-7.07(m,1H),6.62(d,J＝2.4Hz,1H),6.47(dd,J＝9.0 Hz,2.4Hz,1H),3.77-3.72(m,2H),2.82-2.61(m,11H),2.48-2.34(m,3H), 1.91-1.85(m,2H),1.79(s,3H),1.74(s,3H),1.59-1.52(m,2H)。
example 2
Preparation of 5-chloro-N according to the following synthetic route4- [2- (dimethylphosphoryl) phenyl group]-N2- { 2-methoxy-4- [4- (4-d 3-methylpiperazin-1-yl) -piperidin-1-yl]Phenyl } pyrimidine-2, 4-diamine (compound 15 in the following synthetic route):
Figure BDA0003269343280000161
the method comprises the following steps:
(1) preparation of compound 10:
n, N-dimethylformamide (10mL) was added to a 100mL single-neck flask, 4-fluoro-2-methoxynitrobenzene (2g, 11.8mmol), piperidin-4-one hydrochloride (2.23g, 16.5mmol) and anhydrous potassium carbonate (4.88g, 35.4mmol) were added in this order with stirring, and the reaction mixture was heated to 80 ℃ to N2The reaction was carried out overnight under an atmosphere. Cooled to room temperature, poured into ice water (80mL), precipitated a large amount of yellow solid, filtered, dissolved in DCM (100mL), dried over anhydrous sodium sulfate, filtered and the filtrate concentrated to give 2.2g of yellow solid in 74.6% yield.
LC-MS(APCI):m/z＝251.2(M+1)+；1H NMR(300MHz,DMSO-d6) (δ/ppm)7.93(d,J＝9.6Hz,1H),6.62(dd,J＝9.6Hz,2.4Hz,1H),6.53(d,J＝ 2.4Hz,1H),3.94(s,3H),3.84(t,J＝6.3Hz,4H),2.50(t,J＝6.3Hz,4H)。
(2) Preparation of compound 11:
20mL of toluene was placed in a 100mL single-neck flask, and 1- (3-methoxy-4-nitrophenyl) piperidin-4-one (0.53g, 2.1mmol), triethylamine (0.8mL), N-Boc piperazine (0.85g, 4.5mmol), N-Boc piperazine (N-Boc piperazine) and the mixture were added in this order with stirring2Stirring and reacting for 30min under the atmosphere, adding sodium borohydride acetate (0.4g, 1.92mmol) at one time, stirring for 30min, supplementing 1.2g of sodium borohydride acetate again for three times, and completely reacting. Adding saturated sodium bicarbonate water solution (30mL), separating organic layer, extracting water layer with ethyl acetate (30mL x 2), combining organic phase, drying with anhydrous sodium sulfate, filtering, concentrating, passing residue through silica gel column to obtain light yellow solid 0.58g, yield 65.7%.
LC-MS(APCI):m/z＝421.2(M+1)+；1H NMR(300MHz,CDCl3)(δ/ppm) 8.01(d,J＝9.3Hz,1H),6.43(dd,J＝9.6Hz,2.7Hz,1H),6.31(d,J＝2.4Hz, 1H),3.94(s,3H),3.03-2.94(m,2H),2.65-2.62(m,4H),2.54-2.46(m,5H),2.32 (s,3H),2.01-1.96(m,2H),1.65-1.60(m,2H),1.51(s，9H)。
(3) Preparation of compound 12:
20mL of methylene chloride was placed in a 100mL single-neck flask, and 4- (1- (3-methoxy-4-nitrophenyl) piperidin-4-yl) piperazin-1-t-butyl ester (0.58g, 1.4mmol), trifluoroacetic acid (2mL), N2Stirring at normal temperature under atmosphere for 1h, concentrating the reaction solution to dryness, adding saturated sodium bicarbonate water solution (10mL), extracting the mixture with dichloromethane (20mL x 3), drying with anhydrous sodium sulfate, filtering, concentrating to obtain yellow solid 0.45g with yield of 100%, LC-MS (APCI) with M/z of 321.2(M +1)+。
(4) Preparation of compound 13:
in a 25mL single-neck flask, 5mL of acetonitrile is added, 4- (1- (3-methoxy-4-nitrophenyl) piperidin-4-yl) piperazine (0.32g, 1mmol) and triethylamine (0.12g, 1.2mmol) are sequentially added with stirring, the mixture is cooled in an ice water bath, deuterated iodomethane (0.16g, 1.1mmol) is slowly added dropwise, the mixture is stirred and reacted for 30min in an ice water bath, the mixture is concentrated to dryness under reduced pressure, and the residue is passed through a silica gel column to obtain 0.15g of yellow solid with the yield of 44.5%.
LC-MS(APCI):m/z＝338.2(M+1)+；1H NMR(300MHz,CDCl3)(δ/ppm) 8.01(d,J＝9.3Hz,1H),6.43(dd,J＝9.6Hz,2.7Hz,1H),6.31(d,J＝2.4Hz, 1H),3.98-3.94(m,2H),3.92(s,3H),3.03-2.94(m,2H),2.65-2.62(m,4H), 2.54-2.46(m,5H),2.01-1.96(m,2H),1.65-1.60(m,2H)。
(5) Compound 14 was prepared in accordance with the preparation of compound 5, except that 1- (1- (3-d 3-methoxy-4-nitrophenyl) piperidin-4-yl) -4-d 3-methylpiperazine was used in place of 1- (1- (3-d 3-methoxy-4-nitrophenyl) piperidin-4-yl) -4-methylpiperazine.
(6) Preparation of 5-chloro-N4- [2- (Dimethylphosphinyl) phenyl group]-N2- { 2-methoxy-4- [4- (4-d 3-methylpiperazin-1-yl) -piperidin-1-yl]Phenyl } pyrimidine-2, 4-diamines (compound 14), process for their preparation and process for preparation of compound 9The preparation process was identical except that 1- (1- (3-methoxy-4-aminophenyl) piperidin-4-yl) -4-d 3-methylpiperazine was used instead of 1- (1- (3-d 3-methoxy-4-aminophenyl) piperidin-4-yl) -4-methylpiperazine.
LC-MS(APCI):m/z＝587.2(M+1)+；1H NMR(300MHz,DMSO-d6) (δ/ppm)11.18(s,1H),8.51-8.47(m,1H),0.08-8.07(m,2H),7.57-7.50(m,1H), 7.40-7.32(m,2H),7.12-7.07(m,1H),6.62(d,J＝2.4Hz,1H),6.47(dd,J＝9.0 Hz,2.4Hz,1H),3.76-3.71(m,6H),2.82-2.61(m,11H),2.48-2.34(m,3H), 1.91-1.85(m,2H),1.79(s,3H),1.74(s,3H),1.59-1.52(m,2H)。
Example 3
Preparation of 5-chloro-N according to the following synthetic route4- [2- (dimethylphosphoryl) phenyl group]-N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) -4-d-piperidin-1-yl]Phenyl } pyrimidine-2, 4-diamine (compound 20 in the following synthetic route):
Figure BDA0003269343280000181
the method comprises the following steps:
(1) preparation of compound 16:
adding 10mL of deuterated methanol into a 50mL single-neck flask, adding 1- (3-methoxy-4-nitrophenyl) piperidin-4-one (0.25g, 1mmol) under the stirring of an ice-water bath, slowly adding deuterated sodium borohydride (42mg, 1mmol) after complete dissolution and clarification, and performing N-water bath2The reaction was stirred under an atmosphere for 5min, followed by addition of heavy water (2mL) to quench the reaction, stirring at room temperature for 30min, addition of water (30mL) and ethyl acetate (30mL) in that order, separation of the organic layer, extraction of the aqueous layer with ethyl acetate (30mL x 2), concentration, redissolving of the residue in ethyl acetate (50mL), washing with saturated brine (20mL x 1), drying of the organic phase over anhydrous sodium sulfate, filtration, and concentration to give a yellow solid in 0.25g, 96% yield.
LC-MS(ESI):m/z＝254.2(M+1)+；1H NMR(300MHz,DMSO-d6)(δ/ppm) 7.88(d,J＝9.3Hz,1H),6.58(dd,J＝9.3Hz,2.4Hz,1H),6.49(d,J＝2.4Hz, 1H),4.75(s,1H),3.90(s,3H),3.83-3.77(m,2H),3.23-3.14(s,2H),1.84-1.76 (m,2H),1.45-1.37(m,2H)。
(2) Preparation of compound 17:
in a 50mL single-neck flask was added dichloromethane (15mL), 1- (3-methyl-4-nitrophenyl) -4-d-piperidin-4-ol (0.25g, 1mmol) was added under ice-water bath, triethylamine (0.18g, 1.8mmol) was added with stirring, methanesulfonyl chloride (0.17g, 1.5mmol) was slowly added dropwise, N was added at room temperature2The reaction was stirred for 1h under an atmosphere. Water (20mL) was added, the organic layer was separated by shaking, the aqueous layer was extracted with dichloromethane (20mL x 2), the organic layers were combined, dried over anhydrous sodium sulfate with 0.5M aqueous HCl (20mL x 1), saturated aqueous sodium bicarbonate (15mL x 1), saturated brine (15mL x 1), filtered, and concentrated to dryness to give 0.3g of a yellow solid in 90.9% yield, which was used directly in the next step.
(3) Preparation of compound 18:
DMF (3mL) was charged in a 25mL single-neck flask, and 1- (3-methyl-4-nitrophenyl) -4-d-piperidine-4-methylsulfonate (0.3g, 0.9mmol), 1-methylpiperazine (0.36g, 3.6mmol), and anhydrous potassium carbonate (0.62g, 4.5mmol) were added in this order with stirring, and the mixture was heated to 100 ℃ under stirring, N2The reaction was stirred overnight with heat preservation under atmosphere. After cooling to room temperature, water (30mL) and ethyl acetate (30mL) were added, the organic layer was separated, the aqueous layer was extracted with ethyl acetate (20mL x 2), the organic phases were combined, washed with water (40mL x 3), the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was passed through a silica gel column to give 100 mg of a yellow solid in 33.1% yield.
LC-MS(APCI):m/z＝339.2(M+1)+；1H NMR(300MHz,CDCl3)(δ/ppm) 8.01(d,J＝9.3Hz,1H),6.43(dd,J＝9.6Hz,2.7Hz,1H),6.31(d,J＝2.4Hz, 1H),3.98-3.94(m,2H),3.03-2.94(m,2H),2.65-2.62(m,4H),2.54-2.46(m,5H), 2.32(s,3H),2.01-1.96(m,2H),1.65-1.60(m,2H)。
(4) Preparation of 1- [1- (3-methoxy-4-aminophenyl) -4-d-piperidin-4-yl ] -4-methylpiperazine (compound 19) in accordance with the preparation of compound 5 except that 1- [1- (3-methoxy-4-nitrophenyl) -4-d-piperidin-4-yl ] -4-methylpiperazine was used instead of 1- [1- (3-d 3-methoxy-4-nitrophenyl) piperidin-4-yl ] -4-methylpiperazine.
(5) Preparation of 5-chloro-N4- [2- (dimethylphosphoryl) benzeneBase of]-N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) -4-d-piperidin-1-yl]Phenyl } pyrimidine-2, 4-diamine (Compound 20) prepared in accordance with Compound 9, except that 1- [1- (3-methoxy-4-aminophenyl) -4-d-piperidin-4-yl ] -is used]-4-methylpiperazine instead of 1- [1- (3-d 3-methoxy-4-aminophenyl) piperidin-4-yl]-4-methylpiperazine.
LC-MS(APCI):m/z＝587.2(M+1)+；1H NMR(300MHz,DMSO-d6)δ (ppm):11.18(s,1H),8.51-8.47(m,1H),0.08-8.07(m,2H),7.57-7.50(m,1H), 7.40-7.32(m,2H),7.12-7.07(m,1H),6.62(d,J＝2.4Hz,1H),6.47(dd,J＝9.0 Hz,2.4Hz,1H),3.76-3.71(m,6H),2.82-2.61(m,10H),2.48-2.34(m,3H), 1.91-1.85(m,2H),1.79(s,3H),1.74(s,3H),1.59-1.52(m,2H)。
Example 4
Preparation of 5-chloro-N4- [2- (dimethylphosphoryl) phenyl group]-N2- { 2-methoxy-4- [4- (4-methyl-3, 3,5,5-d 4-piperazin-1-yl) -piperidin-1-yl]Phenyl } pyrimidine-2, 4-diamine (compound 21), having the formula:
Figure BDA0003269343280000201
similar to the process described in example 2, except that 4-methyl-3, 3,5,5-d 4-piperazine was used in place of N-methylpiperazine, the objective compound was obtained.
Example 5
Preparation of 5-chloro-N4- [2- (dimethylphosphoryl) phenyl group]-N2- { 2-methoxy-4- [4- (4-methyl-2, 2,3,3,5,5,6,6-d 8-piperazin-1-yl) piperidin-1-yl group]Phenyl } pyrimidine-2, 4-diamine (compound 22), having the formula:
Figure BDA0003269343280000202
similar to the procedure described in example 2, except that 4-methyl-2, 2,3,3,5,5,6,6-d 8-piperazine was used in place of N-methylpiperazine, the objective compound was obtained.
LC-MS(APCI):m/z＝592.4(M+1)+；1H NMR(400MHz,CD3OD)(δ/ppm) 8.35(dd,J＝8.4Hz,4.4Hz,1H),8.04(s,1H),7.69(d,J＝8.8Hz,1H),7.65-7.59(m, 1H),7.53(t,J＝8Hz,1H),7.29-7.25(m,1H),6.67(d,J＝2.4Hz,1H),6.46(dd,J＝ 8.8Hz,2.4Hz,1H),3.86(s,3H),3.71(d,J＝12.8Hz,2H),2.76-2.70(m,2H), 2.61-2.56(m,4H),2.04(d,J＝12.8Hz,2H),1.87(s,3H),1.83(s,3H),1.76-1.65(m, 2H)。
Example 6
Preparation of 5-chloro-N according to the following synthetic route4- [2- (dimethylphosphoryl) phenyl group]-N2- {2-d 3-methoxy-4- [4- (4-d 3-methylpiperazin-1-yl) piperidin-1-yl]Phenyl } pyrimidine-2, 4-diamine (compound 25 in the following synthetic route):
Figure BDA0003269343280000211
(1) preparation of compound 23:
in a 25mL single-neck flask, 5mL of acetonitrile is added, 4- (1- (3-methoxy-4-nitrophenyl) piperidin-4-yl) piperazine (0.32g, 1mmol) and triethylamine (0.12g, 1.2mmol) are sequentially added with stirring, the mixture is cooled in an ice water bath, deuterated iodomethane (0.16g, 1.1mmol) is slowly added dropwise, the mixture is stirred and reacted for 30min in an ice water bath, the mixture is concentrated to dryness under reduced pressure, and the residue is passed through a silica gel column to obtain 0.15g of yellow solid with the yield of 44.5%.
LC-MS(APCI):m/z＝340.2(M+1)+。
(2) Compound 24 was prepared in accordance with the preparation of compound 5, except that 1- [1- (3-d 3-methoxy-4-nitrophenyl) piperidin-4-yl ] -4-d 3-methylpiperazine was used in place of 1- [1- (3-d 3-methoxy-4-nitrophenyl) piperidin-4-yl ] -4-methylpiperazine.
(3) Compound 25 was prepared in accordance with the procedure for compound 9, except that 1- [1- (3-d 3-methoxy-4-aminophenyl) piperidin-4-yl ] -4-d 3-methylpiperazine was used in place of 1- [1- (3-d 3-methoxy-4-aminophenyl) piperidin-4-yl ] -4-methylpiperazine.
LC-MS(APCI):m/z＝587.2(M+1)+；1H NMR(300MHz,DMSO-d6) (δ/ppm)11.18(s,1H),8.51-8.47(m,1H),0.08-8.07(m,2H),7.57-7.50(m,1H), 7.40-7.32(m,2H),7.12-7.07(m,1H),6.62(d,J＝2.4Hz,1H),6.47(dd,J＝9.0 Hz,2.4Hz,1H),3.76-3.71(m,6H),2.82-2.61(m,11H),2.48-2.34(m,3H), 1.91-1.85(m,2H),1.79(s,3H),1.74(s,3H),1.59-1.52(m,2H)。
Example 7
Preparation of 5-chloro-N according to the following synthetic route4- [2- (dimethylphosphoryl) phenyl group]-N2- { 2-methoxy-4- [4- (4-d 3-methyl-2, 2,3,3,5,5,6,6-d 8-piperazin-1-yl) piperidin-1-yl group]Phenyl } pyrimidine-2, 4-diamine (compound 29 in the following synthetic route):
Figure BDA0003269343280000221
(1) preparation of compound 27:
compound 26(214mg, 652. mu. mol), deuterated Formaldehyde in heavy water (313mg,1.95 mmol, 20%/D)2O), and CH3COOD (1 drop) was stirred at room temperature for 10 minutes, sodium deuterocyanoborohydride (129mg,1.95mmol) was added, stirring was continued for 30 minutes, triethylamine was added to neutralize, and after concentration, separation and purification by column chromatography gave 175mg of a yellow solid with a yield of 77.8%.
LC-MS(APCI):m/z＝346.4(M+1)+。
(2) Compound 28 was prepared in accordance with the preparation of compound 5 except that 1- [1- (3-d 3-methoxy-4-nitrophenyl) piperidin-4-yl ] -4-d 3-methyl-2, 2,3,3,5,5,6,6-d 8-piperazine was used in place of 1- [1- (3-d 3-methoxy-4-nitrophenyl) piperidin-4-yl ] -4-methylpiperazine.
(3) Compound 29 was prepared in accordance with the preparation of compound 9, except that 1- [1- (methoxy-4-aminophenyl) piperidin-4-yl ] -4-d 3-methyl-2, 2,3,3,5,5,6,6-d 8-piperazine was used in place of 1- [1- (3-d 3-methoxy-4-aminophenyl) piperidin-4-yl ] -4-methylpiperazine.
LC-MS(APCI):m/z＝595.4(M+1)+；1H NMR(300MHz,CDCl3)(δ/ppm) 10.80(s,1H),8.63(dd,J＝4.8Hz,2.4Hz,1H),8.09-8.07(m,2H),7.50(t,J＝4.5Hz, 1H),7.30-7.25(m,2H),7.14-7.10(m,1H),6.55(d,J＝1.5Hz,1H),6.49(dd,J＝ 5.4Hz,1.5Hz,1H),3.87(s,3H),3.66(d,J＝7.5Hz,2H),2.73-2.68(m,2H), 2.40-2.36(m,1H),1.95(d,J＝7.5Hz,2H),1.85(s,3H),1.82(s,3H),1.76-1.68(m, 2H)。
Example 8
Preparation of 5-chloro-N according to the following synthetic route4- [2- (dimethylphosphoryl) phenyl group]-N2- {2-d 3-methoxy-4- [4- (4-methyl-2, 2,3,3,5,5,6,6-d 8-piperazin-1-yl) piperidin-1-yl group]Phenyl } pyrimidine-2, 4-diamine (compound 32 in the following synthetic route):
Figure BDA0003269343280000231
(1) compound 30 was prepared in a manner consistent with that of compound 10, except that d 3-5-fluoro-2-nitrobenzylether was used in place of 5-fluoro-2-nitrobenzylether.
LC-MS(APCI):m/z＝254.5(M+1)+。
(2) Preparation of compound 31:
tetraisopropyl titanate (Ti (Oi-Pr)45mL) was added to a solution of compound 30(900mg,3.6mmol) and 2,2,3,3,5,5,6,6-d 8-piperazine (474mg,5.03mmol), stirred at room temperature overnight, 10mL of ethanol was added, sodium cyanoborohydride (678mg,10.79mmol) was added, and after the mixture was stirred at room temperature for 3 hours, water (10mL) in which 5g of celite was dissolved was poured, stirring was continued for 30 minutes, and after removal of the solvent, purification by column chromatography gave 300 mg of a yellow solid product with a yield of 25.4%.
LC-MS(APCI):m/z＝332.5(M+1)+。
(3) The preparation method of the compound 32 is the same as that of the compound 29, except that the compound 31 is used for replacing the compound 26, formaldehyde is used for replacing deuterated formaldehyde, and sodium cyanoborohydride is used for replacing deuterated sodium borohydride. The final target product was obtained as a white solid, amounting to 40mg, with a yield of 53.0%.
LC-MS(APCI):m/z＝595.5(M+1)+；1H NMR(300MHz,CDCl3)(δ/ppm) 10.80(s,1H),8.62(dd,J＝8.1Hz,4.5Hz,1H),8.11-8.08(m,2H),7.50(t,J＝7.8Hz, 1H),7.32-7.25(m,2H),7.16-7.11(m,1H),6.54(d,J＝1.6Hz,1H),6.48(dd,J＝ 8.4Hz,2.4Hz,1H),3.66(d,J＝12Hz,2H),2.74-2.67(m,2H),2.61-2.55(m,1H), 2.48(s,3H),2.02(d,J＝12.3Hz,2H),1.84(s,3H),1.81(s,3H),1.79-1.73(m,2H)。
Example 9
Preparation of 5-chloro-N4- [2- (dimethylphosphoryl) phenyl group]-N2- {2-d 3-methoxy-4- [4- (4-d 2-methyl-2, 2,3,3,5,5,6,6-d 8-piperazin-1-yl) piperidin-1-yl]Phenyl } pyrimidine-2, 4-diamine (compound 33), having the formula:
Figure BDA0003269343280000241
similar to the procedure described in example 7, except that compound 31 was used instead of compound 26 and sodium cyanoborohydride was used instead of sodium deuteroborohydride. The final product was obtained as a yellow solid, amounting to 70mg, with a yield of 27.2%.
LC-MS(APCI):m/z＝597.4(M+1)+；1H NMR(300MHz,CDCl3)(δ/ppm) 10.82(s,1H),8.62(dd,J＝8.4Hz,4.5Hz,1H),8.13-8.09(m,2H),7.50(t,J＝7.5Hz, 1H),7.33-7.26(m,2H),7.16-7.10(m,1H),6.54(d,J＝2.1Hz,1H),6.48(dd,J＝ 9.0Hz,2.4Hz,1H),3.66(d,J＝12.6Hz,2H),2.76-2.59(m,3H),2.56(s,1H), 2.08-2.00(m,2H),1.86(s,3H),1.81(s,3H),1.79-1.72(m,2H)。
Example 10
Preparation of 5-chloro-N4- [2- (dimethylphosphoryl) phenyl group]-N2- {2-d 3-methoxy-4- [4- (4-d 3-methyl-2, 2,3,3,5,5,6,6-d 8-piperazin-1-yl) piperidin-1-yl]Phenyl } pyrimidine-2, 4-diamine (compound 34), having the formula:
Figure BDA0003269343280000242
a process similar to that described in example 7 except that compound 31 was used instead of compound 26. The final product was obtained as a white solid, amounting to 110mg, with a yield of 36.7%.
LC-MS(APCI):m/z＝598.4(M+1)+；1H NMR(300MHz,CDCl3)(δ/ppm) 8.35(dd,J＝8.4Hz,4.4Hz,1H),8.04(s,1H),7.68(d,J＝8.4Hz,1H),7.65-7.59(m, 1H),7.52(t,J＝8Hz,1H),7.29-7.25(m,1H),6.67(d,J＝6.8Hz,1H),6.46(dd,J＝ 8.8Hz,2.4Hz,1H),3.71(d,J＝12.4Hz,2H),2.76-2.70(m,2H),2.64-2.58(m,1H), 2.04(d,J＝12.4Hz,2H),1.87(s,3H),1.83(s,3H),1.76-1.66(m,2H)。
Example 11
Biological evaluation of Compounds
The compounds of the invention were evaluated in a number of assays to determine their biological activity. For example, compounds of the invention can be tested for their ability to inhibit a variety of protein kinases of interest. Some of the compounds tested showed potent inhibitory activity on ALK kinase.
(1) Evaluation of kinase inhibition
Compound preparation: test compounds were dissolved in DMSO to make 20mM stock. Compounds were diluted to 0.1mM (100-fold final dilution) in DMSO and diluted in 3-fold gradients, 11 concentrations, prior to use. When adding medicine, the medicine is diluted by buffer solution into 4 times of the dilution solution with final concentration.
And (3) kinase detection: after buffer preparation, the enzyme was mixed with the compounds of different concentrations prepared by dilution in advance, and left at room temperature for 30 minutes, each concentration being double-well. The corresponding substrate and ATP were added and the reaction was carried out at room temperature for 60 minutes (negative and positive controls were set). And (3) after the reaction is finished, adding an antibody for detection, incubating at room temperature for 60 minutes, then carrying out Evnvision detection, and collecting data. Data analysis and mapping were performed according to XLfit5 software. And crizotinib was used as a control.
IC50 ═ [ (ABS test-ABS onset)/(ABS control-ABS onset) ] x 100
The results of kinase inhibition in the examples are shown in table 1.
TABLE 1 comparison of kinase inhibition of examples 1-10 with control crizotinib
Example numbering ALK WT IC50(nM) ALK L1196M IC50(nM)
Example 1 <20 <20
Example 2 <20 <20
Example 3 <20 <20
Example 4 <20 <20
Example 5 <20 <20
Example 6 <20 <20
Example 7 <20 <20
Example 8 <20 <20
Example 9 <20 <20
Example 10 <20 <20
Control crizotinib <20 >75
As shown in Table 1, compared with the existing ALK inhibitor crizotinib, the compound of the invention shows excellent inhibitory activity (IC) on ALK L1196M mutant50Less than 20), indicating that the compound of the present invention has a strong inhibitory ability on Anaplastic Lymphoma Kinase (ALK).
(2) Cytotoxicity test
The inhibitory effect of the compounds of examples 1-10 on tumor cells was detected by a tetrazolium salt (MTS) method, and crizotinib was used as a control. The results of the experiment are shown in table 2.
TABLE 2 comparison of cytotoxicity tests of examples 1-10 and control crizotinib
Example numbering ALK WT IC50(nM) ALK L1196M IC50(nM)
Example 1 <20 <50
Example 2 <20 <50
Example 3 <20 <50
Example 4 <20 <50
Example 5 <20 <20
Example 6 <20 <20
Example 7 <20 <20
Example 8 <20 <20
Example 9 <20 <20
Example 10 <20 <20
Control crizotinib >70 >600
As shown in table 2, the compounds of the present invention all showed superior anticancer activity of inhibiting the growth of cancer cells expressing ALK mutant L1196M, compared to the existing ALK inhibitor crizotinib.
(3) Metabolic stability evaluation
Microsome experiment: human liver microsomes: 0.5mg/mL, Xenotech; rat liver microsomes: 0.5mg/mL, Xenotech; coenzyme (NADPH/NADH): 1mM, Sigma Life Science; magnesium chloride: 5mM, 100mM phosphate buffer (pH 7.4).
Preparing a stock solution: an amount of the compound of the example was weighed out precisely and dissolved in DMSO to 5mM each.
Preparation of phosphate buffer (100mM, pH 7.4): 150mL of 0.5M potassium dihydrogenphosphate and 700mL of a 0.5M dipotassium hydrogenphosphate solution prepared in advance were mixed, the pH of the mixture was adjusted to 7.4 with the 0.5M dipotassium hydrogenphosphate solution, the mixture was diluted 5-fold with ultrapure water before use, and magnesium chloride was added to obtain a phosphate buffer (100mM) containing 100mM potassium phosphate and 3.3mM magnesium chloride at a pH of 7.4.
NADPH regenerating system solution (containing 6.5mM NADP, 16.5mM G-6-P, 3U/mL G-6-P D, 3.3mM magnesium chloride) was prepared and placed on wet ice before use.
Preparing a stop solution: acetonitrile solution containing 50ng/mL propranolol hydrochloride and 200ng/mL tolbutamide (internal standard). 25057.5 mu L of phosphate buffer solution (pH7.4) is taken to a 50mL centrifuge tube, 812.5 mu L of human liver microsome is respectively added and mixed evenly, and liver microsome dilution liquid with the protein concentration of 0.625mg/mL is obtained. 25057.5 mu L of phosphate buffer (pH7.4) is taken to a 50mL centrifuge tube, 812.5 mu L of SD rat liver microsome is respectively added, and the mixture is mixed evenly to obtain liver microsome dilution with the protein concentration of 0.625 mg/mL.
Incubation of the samples: the stock solutions of the corresponding compounds were diluted to 0.25mM each with an aqueous solution containing 70% acetonitrile, and used as working solutions. 398. mu.L of human liver microsome or rat liver microsome dilutions were added to a 96-well plate (N2), 2. mu.L of 0.25mM working solution was added, and mixed well.
Determination of metabolic stability: 300. mu.L of pre-cooled stop solution was added to each well of a 96-well deep-well plate and placed on ice as a stop plate. The 96-well incubation plate and the NADPH regeneration system are placed in a 37 ℃ water bath box, shaken at 100 rpm and pre-incubated for 5 min. 80. mu.L of the incubation solution was taken out of each well of the incubation plate, added to the stop plate, mixed well, and supplemented with 20. mu.L of NADPH regenerating system solution as a 0min sample. Then 80. mu.L of NADPH regenerating system solution was added to each well of the incubation plate, the reaction was started, and the timer was started. The reaction concentration of the corresponding compound was 1. mu.M, and the protein concentration was 0.5 mg/mL. When the reaction was carried out for 10min, 30min and 90min, 100. mu.L of each reaction solution was added to the stop plate and vortexed for 3min to terminate the reaction. The stop plates were centrifuged at 5000 Xg for 10min at 4 ℃. And (3) taking 100 mu L of supernatant to a 96-well plate in which 100 mu L of distilled water is added in advance, mixing uniformly, and performing sample analysis by adopting LC-MS/MS.
And (3) data analysis: and detecting peak areas of the corresponding compound and the internal standard through an LC-MS/MS system, and calculating the peak area ratio of the compound to the internal standard. The slope is determined by plotting the natural logarithm of the percentage of compound remaining against time and calculating t according to the following formula1/2And CLintWhere V/M is equal to 1/protein concentration.
Figure BDA0003269343280000271
The compounds of the invention and compounds without deuteration were tested simultaneously and compared to evaluate their metabolic stability in human and rat liver microsomes. The half-life and intrinsic hepatic clearance (Clint) as indicators of metabolic stability are shown in table 3. Compound AP26113 without deuteration was used as a control sample in table 3; the AP26113 is a third-generation ALK inhibitor in the prior art, is used for treating metastatic ALK positive non-small cell lung cancer resistant to crizotinib, and has continuous antitumor activity on ALK positive non-small cell lung cancer patients, including brain metastasis patients and AP26113 in phase I/II clinical tests.
As shown in table 3, by contrast with the non-deuterated compound AP26113, the compound of the present invention can significantly improve metabolic stability, and is further more suitable for preparing a drug for treating crizotinib-resistant metastatic ALK-positive non-small cell lung cancer.
TABLE 3 comparison of metabolic stability of examples 1-10 and AP26113 control
Figure BDA0003269343280000281
(4) Pharmacokinetic evaluation in rats
6 male Sprague-Dawley rats, 7-8 weeks old, weighing about 210g, were divided into 2 groups of 3 per group and compared for pharmacokinetic differences with a single intravenous or oral dose of compound (3 mg/kg intravenously, 10mg/kg orally).
Rats were fed with standard feed and given water. Fasting began 16 hours prior to the experiment. The drug was dissolved with PEG400 and dimethyl sulfoxide. Blood was collected from the orbit at 0.083 hr, 0.25 hr, 0.5 hr, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 12 hr and 24 hr post-dose.
The rats were briefly anesthetized after ether inhalation and 300 μ L of blood was collected from the orbit into a test tube. There was 30 μ L of 1% heparin salt solution in the tube. Before use, the tubes were dried overnight at 60 ℃. After completion of blood sample collection at a subsequent time point, rats were sacrificed after ether anesthesia.
Immediately after blood collection, the tubes were gently inverted at least 5 times to ensure mixing and then placed on ice. The blood samples were centrifuged at 5000rpm for 5 minutes at 4 ℃ to separate the plasma from the erythrocytes. Pipette out 100 μ L of plasma into a clean plastic centrifuge tube, indicating the name of the compound and the time point. Plasma was stored at-80 ℃ before analysis. The concentration of the compounds of the invention in plasma was determined by LC-MS/MS. Pharmacokinetic parameters were calculated based on the plasma concentration of each animal at different time points.
The experimental results are shown in table 4 below, and compared to the control compound AP26113, the oral availability (F) of the compound 15 of example 2 in the present invention is equivalent to the control compound AP26113, but the half-life is prolonged and the metabolic stability is significantly improved; the compound 9 of example 1 exhibited a dramatic increase (20%) in oral availability, indicating better pharmacokinetics in animals.
TABLE 4 rat pharmacokinetic experiments
Figure BDA0003269343280000291
It is to be understood that these examples are intended to illustrate the invention and are not intended to limit the scope of the invention, and that experimental procedures not specifically identified in the examples will generally be performed under conventional conditions, or under conditions recommended by the manufacturer. Parts and percentages are parts and percentages by weight unless otherwise indicated.
The foregoing is a more detailed description of the invention in connection with specific preferred embodiments and it is not intended that the invention be limited to these specific details. For those skilled in the art to which the invention pertains, several simple deductions or substitutions can be made without departing from the spirit of the invention, and all shall be considered as belonging to the protection scope of the invention.

Claims (10)

1. A diaminopyrimidine compound characterized by: a diaminopyrimidine compound represented by the formula (I), or a crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof,
Figure FDA0003269343270000011
wherein R is1a、R1b、R1c、R2a、R2b、R3a、R3b、R4a、R4b、R5a、R5b、R6、R7a、R7b、R8a、R8b、R9a、R9b、R10a、R10b、R11、R12、R13、R14a、R14b、R14c、R15、R16、R17a、R17b、R17c、R18a、R18b、R18c、R19、R20、R21And R22Each independently is hydrogen, deuterium, halogen or trifluoromethyl;
R16is hydrogen, deuterium, halogen, cyano, non-deuterated C1-C6Alkyl or C1-C6Alkoxy, mono-or multidutero or per-deuterated C1-C6Alkyl or C1-C6Alkoxy, or one or more halogen-substituted or perhalogen-substituted C1-C6Alkyl or C1-C6An alkoxy group;
with the proviso that R1a、R1b、R1c、R2a、R2b、R3a、R3b、R4a、R4b、R5a、R5b、R6、R7a、R7b、R8a、R8b、R9a、R9b、R10a、R10b、R11、R12、R13、R14a、R14b、R14c、R15、R16、R17a、R17b、R17c、R18a、R18b、R18c、R19、R20、R21And R22At least one of which is deuterated or deuterium.
2. A diaminopyrimidine compound as claimed in claim 1, characterized in that: r1a、R1bAnd R1cIs deuterium.
3. A diaminopyrimidine compound as claimed in claim 1, characterized in that: r7a、R7b、R8a、R8b、R9a、R9b、R10aAnd R10bEach independently is deuterium or hydrogen.
4. A diaminopyrimidine compound as claimed in claim 1, characterized in that: r14a、R14bAnd R14cIs deuterium.
5. A diaminopyrimidine compound as claimed in claim 1, characterized in that: the compound is selected from the following group of compounds or pharmaceutically acceptable salts thereof:
Figure FDA0003269343270000021
Figure FDA0003269343270000031
Figure FDA0003269343270000041
6. a process for the preparation of a pharmaceutical composition of a diaminopyrimidine compound as claimed in any one of claims 1 to 5, characterized in that: mixing a pharmaceutically acceptable carrier with a compound described in the first aspect of the invention, or a crystalline form, a pharmaceutically acceptable salt, a prodrug, a stereoisomer, an isotopic variant hydrate, or a solvate thereof, to form a pharmaceutical composition.
7. A pharmaceutical composition characterized by: a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a diaminopyrimidine compound according to any one of claims 1 to 5, or a crystalline form, a pharmaceutically acceptable salt, hydrate, or solvate, a stereoisomer, a prodrug, or an isotopic variant thereof.
8. The pharmaceutical composition of claim 7, wherein: it further comprises other therapeutic agents, which are agents for cancer, cardiovascular disease, inflammation, infection, immune disease, cell proliferative disease, viral disease, metabolic disease, or organ transplantation.
9. Use of a diaminopyrimidine compound according to any one of claims 1 to 5, or a crystalline form, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, wherein: used for preparing a pharmaceutical composition for inhibiting anaplastic lymphoma kinase.
10. An intermediate compound selected from:
Figure FDA0003269343270000051
CN202111097366.1A 2015-12-02 2016-07-22 Diaminopyrimidine compound and composition containing same Pending CN113912648A (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CN2015108755061 2015-12-02
CN201510875506 2015-12-02
CN201610587472.0A CN106188138B (en) 2015-12-02 2016-07-22 A kind of diaminopyrimidine compounds and the composition comprising the compound

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
CN201610587472.0A Division CN106188138B (en) 2015-12-02 2016-07-22 A kind of diaminopyrimidine compounds and the composition comprising the compound

Publications (1)

Publication Number Publication Date
CN113912648A true CN113912648A (en) 2022-01-11

Family

ID=57491836

Family Applications (3)

Application Number Title Priority Date Filing Date
CN202111097366.1A Pending CN113912648A (en) 2015-12-02 2016-07-22 Diaminopyrimidine compound and composition containing same
CN201810922557.9A Pending CN108948082A (en) 2015-12-02 2016-07-22 A kind of diaminopyrimidine compounds and the composition comprising the compound
CN201610587472.0A Active CN106188138B (en) 2015-12-02 2016-07-22 A kind of diaminopyrimidine compounds and the composition comprising the compound

Family Applications After (2)

Application Number Title Priority Date Filing Date
CN201810922557.9A Pending CN108948082A (en) 2015-12-02 2016-07-22 A kind of diaminopyrimidine compounds and the composition comprising the compound
CN201610587472.0A Active CN106188138B (en) 2015-12-02 2016-07-22 A kind of diaminopyrimidine compounds and the composition comprising the compound

Country Status (2)

Country Link
CN (3) CN113912648A (en)
WO (1) WO2017092413A1 (en)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108350006B (en) * 2015-11-27 2020-01-03 正大天晴药业集团股份有限公司 Deuterium-modified Brigatinib derivative, pharmaceutical composition containing compound and application of deuterium-modified Brigatinib derivative
CN106220608B (en) 2016-07-25 2018-11-27 安润医药科技（苏州）有限公司 Diphenylamino pyrimidine and triaizine compounds, its Pharmaceutical composition and purposes
WO2019007293A1 (en) * 2017-07-01 2019-01-10 浙江同源康医药股份有限公司 Compound used as alk kinase inhibitor and use thereof
CN109593102B (en) * 2018-01-04 2022-02-08 深圳市塔吉瑞生物医药有限公司 Preparation method and crystal form of deuterated diphenylaminopyrimidine compound
WO2019154091A1 (en) * 2018-02-07 2019-08-15 深圳市塔吉瑞生物医药有限公司 Substituted diaminopyrimidine compound
AU2020385527B2 (en) * 2019-11-21 2023-04-13 Tyk Medicines, Inc. Compound used as EGFR kinase inhibitor and use thereof
WO2021150613A1 (en) 2020-01-20 2021-07-29 Incyte Corporation Spiro compounds as inhibitors of kras
US11739102B2 (en) 2020-05-13 2023-08-29 Incyte Corporation Fused pyrimidine compounds as KRAS inhibitors
WO2022072783A1 (en) 2020-10-02 2022-04-07 Incyte Corporation Bicyclic dione compounds as inhibitors of kras
WO2023064857A1 (en) 2021-10-14 2023-04-20 Incyte Corporation Quinoline compounds as inhibitors of kras

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2209774A1 (en) * 2007-10-02 2010-07-28 Concert Pharmaceuticals Inc. Pyrimidinedione derivatives
ES2645689T3 (en) * 2008-05-21 2017-12-07 Ariad Pharmaceuticals, Inc. Phosphorus derivatives as kinase inhibitors
MX2015008187A (en) * 2012-12-20 2016-02-05 Concert Pharmaceuticals Inc Deuterated alk inhibitors.
CN103965114B (en) * 2013-01-28 2016-01-06 苏州泽璟生物制药有限公司 Deuterated phenyl amino pyrimidine compounds and comprise the pharmaceutical composition of this compound
CN104109149B (en) * 2013-04-22 2018-09-28 苏州泽璟生物制药有限公司 Deuterated diaminopyrimidine compounds and the pharmaceutical composition comprising the compound
CN112110897B (en) * 2014-08-06 2021-05-11 北京凯悦宁医药科技有限公司 Preparation method of deuterated crizotinib and derivative thereof
CN111170998B (en) * 2014-11-05 2023-04-11 益方生物科技(上海)股份有限公司 Pyrimidine or pyridine compound, preparation method and medical application thereof
CN105061506B (en) * 2015-07-27 2017-08-29 苏州明锐医药科技有限公司 Antineoplastic AP26113 preparation method
CN108350006B (en) * 2015-11-27 2020-01-03 正大天晴药业集团股份有限公司 Deuterium-modified Brigatinib derivative, pharmaceutical composition containing compound and application of deuterium-modified Brigatinib derivative

Also Published As

Publication number Publication date
CN106188138B (en) 2018-07-24
CN106188138A (en) 2016-12-07
WO2017092413A1 (en) 2017-06-08
CN108948082A (en) 2018-12-07

Similar Documents

Publication Publication Date Title
CN113912648A (en) Diaminopyrimidine compound and composition containing same
EP3350180B1 (en) 8-[6-[3-(amino)propoxy]-3-pyridyl]-1-isopropyl-imidazo[4,5-c]quinolin-2-one derivatives as selective modulators of ataxia telangiectasia mutated (atm) kinase for the treatment of cancer
CN110407856B (en) Macrocyclic compound and composition containing same
EP3814341B1 (en) Erbb receptor inhibitors
CN109153687B (en) Tricyclic heteroaryl-containing compounds
BR112017027414B1 (en) HYDROXYESTER DERIVATIVES, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
BR112015002709B1 (en) COMPOUNDS, PHARMACEUTICAL COMPOSITION, USE THEREOF AND USE OF A COMPOUND COMBINATION OR PHARMACEUTICAL COMPOSITION AND A SECOND PROPHYLATIC OR THERAPEUTIC AGENT
JP2019521980A (en) Crystals of pyrrolopyrimidine compounds as JAK inhibitors
JP2019526605A (en) Crystal form and salt form of substituted 2-H-pyrazole derivative and method for producing the same
CN109593102B (en) Preparation method and crystal form of deuterated diphenylaminopyrimidine compound
CN106232602B (en) Deuterated quinazolinone compound and pharmaceutical composition containing same
CN113045569B (en) Compounds useful as RET kinase inhibitors and uses thereof
JP2021504332A (en) Pyrazolopyridinone compound
JPH09511527A (en) 2,7-Substituted octahydro-1H-pyrido [1,2-A] pyrazine derivative
CN108137614B (en) Fused pyrimidine compound, composition containing compound and application of compound
JP7369798B2 (en) CDK kinase inhibitor
CN114437077A (en) Compounds useful as kinase inhibitors and uses thereof
CN115746002B (en) Deuterated aza-indolyl amino-pyrazole carboxamide compound and application thereof
RU2806625C2 (en) Compounds based on pyrazolopyridinone
CN115380024B (en) Crystalline forms of diazaspiropyran compounds
CN117500813A (en) Arylphosphine compounds
WO2023110970A1 (en) Macrocyclic btk inhibitors
US20210276997A1 (en) Crystal of pyrido[3,4-d]pyrimidine derivative or solvate thereof
CN117412971A (en) Pyrrolopyrimidine derivatives containing pyrazine structures
JP2024050653A (en) ERBB receptor inhibitors

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination