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CN114805361B - Amino substituted aromatic heterocyclic pyrazole compound, preparation method and application - Google Patents

Amino substituted aromatic heterocyclic pyrazole compound, preparation method and application Download PDF

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CN114805361B
CN114805361B CN202210051634.4A CN202210051634A CN114805361B CN 114805361 B CN114805361 B CN 114805361B CN 202210051634 A CN202210051634 A CN 202210051634A CN 114805361 B CN114805361 B CN 114805361B
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CN114805361A (en
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万惠新
王亚周
马金贵
王亚辉
查传涛
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Shanghai Lingda Biomedical Co ltd
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Abstract

The invention discloses an amino-substituted aromatic heterocyclic pyrazole compound, a preparation method and application thereof, in particular to an amino-substituted aromatic heterocyclic pyrazole compound shown in a general formula I, or pharmaceutically acceptable salt thereof, or enantiomer, diastereoisomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, a preparation method and application thereof in pharmacy, wherein the definition of each group is as described in the specification.

Description

Amino substituted aromatic heterocyclic pyrazole compound, preparation method and application
Technical Field
The invention belongs to the field of medicinal chemistry, and discloses amino-substituted aromatic heterocyclic pyrazole compounds with CDK kinase inhibition activity, a pharmaceutical composition and application thereof, in particular to compounds shown in a general formula I. The compounds of the invention and pharmaceutical compositions comprising these compounds are useful in the prevention or treatment of related disorders, particularly those mediated by aberrant activity of CDK kinases, particularly CDK7 kinases.
Background
Cell cycle abnormalities are a hallmark feature of cancer, and cyclin-dependent kinases (CDKs) are a class of serine/threonine kinases that play a central role in the cell cycle, leading to initiation, progression, and termination of the cell cycle. The CDK family is an important intracellular signaling molecule that is involved in the growth, proliferation, dormancy and apoptosis of cells in the CDK-cyclin complex with cyclin (cyclin).
Over the last 20 years, drug development with CDK kinases as targets for tumor therapy has received extensive attention, such as Flavopiridol (Alvocidib), seliclib (CYC 202), dinaciclib (SCH 727965) and Milciclib (PHA-848125), among others, all entered different phases of clinical research. However, the early detection of CDK inhibitors has limited clinical utility due to their low inhibitory activity against each CDK family subtype, lack of selectivity, or poor in vivo absorption. In recent years, drug development in this area has become a hotspot again due to the discovery of selective inhibitors of CDK for each CDK family subtype, or of selective inhibitors that increase the inhibitory activity of CDK kinases, especially targeting CDK 4/6.
Recent studies have found that CDK7 kinases of the CDK family have dual functions of regulating both kinase and transcription: 1) In the cytoplasm, CDK7 exists in the form of a heterotrimeric complex and acts as an activated kinase (CAK) for CDK1/2, whereby phosphorylation of conserved residues in CDK1/2 by CDK7 is essential for complete catalytic CDK activity and cell cycle progression; 2) In the nucleus, CDK7 forms the kinase core of the RNA polymerase (RNAP) II universal transcription factor complex and is responsible for phosphorylating the C-terminal domain (CTD) of RNAPII, an essential step in the initiation of gene transcription. The two functions of CDK7, CAK and CTD phosphorylation, support key aspects of cell proliferation, cell circulation, and transcription. Studies show that CDK7 kinase plays a very important role in regulating triple negative breast cancer, and inhibiting CDK7 kinase plays a remarkable role in killing the growth of triple negative breast cancer cells.
In addition, CDK9 kinases of the CDK family play a major role in the regulation of transcriptional elongation without affecting cell cycle processes. CDK9 inhibitors can block the phosphorylation of RNA Poly-II C-terminal region by positive transcription elongation factor P-TEFb (positive transcription elongation factor b) by degrading and inhibiting CDK9, inhibit transcription, and rapidly reduce intracellular mRNA levels, thereby causing tumor cell apoptosis.
Despite the great progress in the development of CDK kinase inhibitors, there are also several unresolved problems, such as resistance to existing CDK kinase inhibitors, subtype selectivity towards CDK kinase family targets, etc., and therefore, there is an urgent need in the art to study and develop novel CDK kinase inhibitors, such as specific CDK7 kinase inhibitors, which are highly potent, low-toxic, resistant, and have clinical application value.
Disclosure of Invention
One of the technical problems to be solved by the invention is to provide a novel CDK7 inhibitor for preparing a tumor therapeutic drug.
The scheme for solving the technical problems is as follows:
an amino-substituted aromatic heterocyclic pyrazole compound shown in a general formula I, or pharmaceutically acceptable salt thereof, or enantiomer, diastereoisomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof,
Wherein:
w is selected from CR w Or N; rw is independently selected from H, halogen, cyano, C1-C6 alkyl or haloalkyl;
R 1 independently selected from the group consisting of C1-C10 alkyl or haloalkyl, 3-to 10-membered cycloalkyl or heterocycloalkyl, C1-C10 alkoxy or haloalkoxy, 3-to 10-membered cycloalkyl or heterocycloalkyl ether, C1-C10 alkyl or haloalkyl substituted amino, 3-to 10-membered cycloalkyl or heterocycloalkyl substituted amino; and the above alkyl, cycloalkyl, heterocycloalkyl groups may be substituted with one or several substituents selected from the group consisting of: halogen, deuterium, hydroxy, substituted or unsubstituted amino, C1-C6 alkyl, hydroxy substituted C1-C6 alkyl, amino substituted C1-C6 alkyl, C1-C6 alkoxy, 3-to 10-membered cycloalkyl or heterocycloalkyl substituted C1-C6 alkyl;
R 2 independently selected from C1-C10 alkyl or haloalkyl, 3-10 membered cycloalkyl or heterocycloalkyl;
ra is selected from hydrogen, deuterium, halogen, C1-C6 alkyl or haloalkyl, 3-10 membered cycloalkyl or heterocycloalkyl;
rb, rc, rd, re are each independently selected from hydrogen, deuterium, halogen, C1-C6 alkyl or haloalkyl, 3-to 10-membered cycloalkyl or heterocycloalkyl, or Rb and Rc, rd and Re form a c=o bond or a 3-to 6-membered carbocyclic or heterocyclic ring, respectively;
m, n are each independently selected from integers from 0 to 3;
cy is selected from 3-10 membered cycloalkyl or heterocycloalkyl, 5-12 membered monocyclic or bicyclic aryl or heteroaryl;
r3 is selected from hydrogen, deuterium, halogen, C1-C10 alkyl or haloalkyl, 3-10 membered cycloalkyl or heterocycloalkyl, 5-12 membered aryl or heteroaryl, substituted or unsubstituted amino, hydroxy, C1-C10 alkoxy or haloalkoxy, cyano, substituted or unsubstituted amido, substituted or unsubstituted sulfonamide, substituted or unsubstituted ureido, substituted or unsubstituted sulfonylureido, substituted or unsubstituted carbamoyl, substituted or unsubstituted phosphoryl, substituted or unsubstituted alkylphosphoxy, substituted or unsubstituted alkylsilyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acryloyl, substituted or unsubstituted propynyl, haloacetyl or haloethylsulfonyl;
y is selected from N or CRy, ry is independently selected from hydrogen, deuterium, halogen, hydroxy, amino, cyano, C1-C6 alkyl or haloalkyl, 3-10 membered cycloalkyl or heterocycloalkyl;
r4 is independently selected from hydrogen, deuterium, halogen, C1-C10 alkyl or haloalkyl, 3-C10 cycloalkyl or heterocycloalkyl, 5-C12 aryl or heteroaryl, substituted or unsubstituted amino, hydroxy, C1-C10 alkoxy or haloalkoxy, cyano, substituted or unsubstituted amido, substituted or unsubstituted sulfonamide, substituted or unsubstituted ureido, substituted or unsubstituted sulfonylureido, substituted or unsubstituted carbamoyl, substituted or unsubstituted phosphoryl, substituted or unsubstituted alkylphosphoxy, substituted or unsubstituted alkylsilyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acryloyl, substituted or unsubstituted propynyl, haloacetyl or haloethylsulfonyl
The above-mentioned substituted or unsubstituted substituents are each independently selected from the group consisting of: including but not limited to deuterium, halogen, hydroxy, monoalkylamino, dialkylamino, C1-C6 alkyl or haloalkyl, 3-to 10-membered cycloalkyl or heterocycloalkyl, cyano, C1-C6 alkoxy or haloalkoxy; wherein the heteroaryl group comprises 1 to 3 heteroatoms selected from the group consisting of: n, O, P or S, said heterocycloalkyl comprising 1 to 3 heteroatoms selected from the group consisting of: n, O, P or S, said ring system comprising a spiro, bridged, fused, or other saturated or partially unsaturated ring system.
In some of the preferred embodiments of the present invention,
R 1 independently selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, 5-8 membered heterocycloalkyl-O-, C1-C6 alkyl-substituted amino, C1-C6 haloalkyl-substituted amino, 3-8 membered cycloalkyl-substituted amino, 3-8 membered heterocycloalkyl-substituted amino; the R is 1 The 1 or more hydrogen atoms on may be optionally substituted with: halogen, hydroxy, amino, cyano, mono C1-C3 alkylamino, di C1-C3 alkylamino, C1-C3 alkyl, hydroxy-substituted C1-C3 alkyl, amino-substituted C1-C3 alkyl, C1-C3 alkoxy, 3-8 membered cycloalkyl C1-C3 alkyl-, 3-8 membered heterocycloalkyl-C1-C3 alkyl-, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl;
R 2 Independently selected from C1-C6 alkyl, C1-C6 haloalkyl, 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl;
cy is selected from 5-8 membered cycloalkyl, 5-8 heterocycloalkyl, 6-10 membered monocyclic or bicyclic aromatic group, 5-10 membered monocyclic or bicyclic heteroaromatic group;
R 3 selected from hydrogen, deuterium, halogen, hydroxy, cyano, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkyl, C1-C6 haloalkyl, 3-to 6-membered cycloalkyl or heterocycloalkyl, 6-to 10-membered aryl, 5-to 8-membered heteroaryl, substituted or unsubstituted amino, substituted or unsubstituted amido;
R 4 independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 haloalkyl, 3-6 cycloalkyl, 3-6 heterocycloalkyl, 6-10 aryl, 5-8 heteroaryl, C1-C6 alkoxy, C1-C6 haloalkoxy, 3-6 cycloalkyl-C (O) -, 3-6 heterocycloalkyl-C (O) -, 3-6 cycloalkyl-O-C (O) -, 3-6 heterocycloalkyl-O-C (O) -, 6-10 aryl-C (O) -, 5-8 heteroaryl-C (O) -; the R is 4 Optionally by R 41 Substitution, said R 41 Independently selected from: halogen, hydroxyA group, cyano, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, C1-C6 alkyl, C1-C6 haloalkyl, 3-6 cycloalkyl or heterocycloalkyl, C1-C6 alkoxy or haloalkoxy, C2-C6 alkenyl-C (O) -; the R is 41 May be further substituted with: halogen, hydroxy, cyano, mono C1-C6 alkylamino, di C1-C6 alkylamino.
In some preferred embodiments, R 1 Preferably is
Alternatively, R 2 Preferably methyl, isopropyl;
alternatively, R 3 H, F, cl, CN, CH of a shape of H, F, cl, CN, CH 3 、CH 3 O-、CF 3 、、
Alternatively, R 4 H, CH of a shape of H, CH 3 Isopropyl group,
In some preferred embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional, solvate, polymorph or prodrug thereof, is preferably a compound of formula (II), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional, solvate, polymorph or prodrug thereof:
all radicals, i.e. R 1 、R 2 、R 3 、R 4 、R a 、R b 、R c 、R d 、R e The scope of Cy, W, m, n is as defined above.
In some preferred embodiments, it is preferably a compound of formula (III), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof:
all radicals, i.e. R 1 、R 2 、R 3 、R 4 、R a 、R b 、R c 、R d 、R e The scope of Cy, W, m, n is as defined above.
In some preferred embodiments, it is preferably a compound of formula (IV), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof:
wherein Cy1 is selected from a 5-10 membered aryl or heteroaryl group and Cy2 is selected from a 3-12 membered saturated carbocyclic or heterocyclic group, the other groups being as defined above.
In some embodiments, it is preferably a compound of formula (V), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof:
r1 is preferably selected from C1-C6 alkyl groups, such as methyl; substituted or unsubstituted 5-6 membered saturated rings such as cyclohexenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, and the like; substituted or unsubstituted 5-6 membered saturated cyclic ethers such as cyclohexenyl ether, piperidinyl ether, tetrahydropyranyl ether; substituted or unsubstituted 5-6 membered saturated cyclic amine such as cyclohexane amino, piperidine amino, tetrahydropyran amino; substituted or unsubstituted 5-6 membered saturated cyclic alkylene ethers, such as piperidinyl methylene ether; substituted or unsubstituted 5-6 membered saturated cyclic alkylene amine groups, such as piperidinyl methylene amine; the substituent is preferably selected from deuterium, halogen, amino, hydroxyl, dimethylamino, methoxy, hydroxymethyl, aminomethyl and the like; the scope of the other groups is as defined above.
A method for preparing a compound of formula I is characterized in that a compound of formula (A) and an amino compound (B) undergo nucleophilic substitution reaction under the catalysis of alkali or acid to generate the compound of formula (I);
the definition of each group is as above;
preferably, the reaction is carried out in a solvent, and the solvent is selected from the group consisting of: water, methanol, ethanol, isopropanol, butanol, ethylene glycol methyl ether, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, toluene, methylene chloride, 1, 2-dichloroethane, acetonitrile, N-dimethylformamide, N-dimethylacetamide, dioxane, or a combination thereof.
Preferably, the inorganic base is selected from the group consisting of: sodium hydride, potassium hydroxide, sodium acetate, potassium t-butoxide, sodium t-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, or a combination thereof; the organic base is selected from the group consisting of: pyridine, triethylamine, N, N-diisopropylethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), lithium hexamethyldisilazide, sodium hexamethyldisilazide, lutidine, or combinations thereof.
Preferably, the acid is selected from the group consisting of: hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, formic acid, acetic acid, trifluoromethanesulfonic acid or combinations thereof.
The invention provides a class of preferred compounds of formula (I) including, but not limited to, the following structures:
example structural formula
It is another object of the present invention to provide a medicament for treating or preventing tumor or autoimmune disease and a composition thereof. The technical scheme for achieving the purpose is as follows:
in one aspect, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, and a pharmaceutically acceptable carrier. In certain embodiments of the pharmaceutical composition, the pharmaceutical composition is formulated for intravenous administration, intramuscular administration, oral administration, rectal administration, inhalation administration, nasal administration, topical administration, ocular administration, or otic administration. In other embodiments of the pharmaceutical composition, the pharmaceutical composition is a tablet, pill, capsule, liquid, inhalant, nasal spray solution, suppository, solution, emulsion, ointment, eye or ear drop. In other embodiments of the pharmaceutical composition, it further comprises one or more additional therapeutic agents.
In another aspect, the invention provides the use of a compound of formula I, a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, in the manufacture of a medicament for the prevention, treatment, or alleviation of a disorder or a disease of a CDK kinase, particularly a CDK7 kinase, mediated by abnormal activity.
In another aspect, the invention provides a method for preparing an amino-substituted aromatic heterocyclic pyrazole compound of formula (I), or a pharmaceutically acceptable salt, or enantiomer, diastereomer, tautomer, torsionally isomer, solvate, polymorph or prodrug thereof, for treating or preventing a proliferative disease (e.g., cancer (e.g., leukemia, melanoma, multiple myeloma), benign neoplasm, angiogenesis, inflammatory disease, auto-inflammatory disease, and autoimmune disease) in a subject, said tumor being independently selected from the group consisting of non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, stomach cancer, intestinal cancer, bile duct cancer, brain cancer, leukemia, lymphoma, fibroma, sarcoma, basal cell carcinoma, glioma, kidney cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal carcinoma, pancreatic cancer, and the like; the autoimmune disease is independently selected from rheumatoid arthritis, systemic lupus erythematosus, idiopathic thrombocytopenic purpura, hemolytic anemia, or psoriasis; the inflammatory diseases are independently selected from osteoarthritis, gouty arthritis, ulcerative colitis, inflammatory bowel disease and the like; the infectious disease is independently selected from sepsis, septic shock, endotoxic shock, gram negative sepsis and/or toxic shock syndrome.
The invention relates to a novel compound with the structural characteristics of a general formula (I), which selectively inhibits the enzyme activity of CDK7 and obviously inhibits the growth of various tumor cells, and is a therapeutic drug with a brand-new action mechanism.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. The limited space is not described in any more detail herein.
Detailed Description
The inventor has studied intensively for a long time to prepare an amino-substituted aromatic heterocyclic pyrazole compound with a novel structure shown in a formula I, and found that the compound has better activity of inhibiting cyclin dependent kinase 7 (CDK 7), has specific inhibition effect on cyclin dependent kinase 7 (CDK 7) at extremely low concentration (which can be as low as less than 10 nM), has quite excellent cell proliferation inhibition activity on CDK7, and can be used for treating diseases related to abnormal activity of cyclin dependent kinase 7 (CDK 7), such as tumors. Based on the above findings, the inventors have completed the present invention.
Terminology
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety unless otherwise indicated.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the inventive subject matter. In this application, the singular is used to include the plural unless specifically stated otherwise. It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the use of "or" means "and/or" unless stated otherwise. Furthermore, the terms "include," as well as other forms, such as "comprising," "including," and "containing," are not limiting.
The definition of standard chemical terms can be found in references (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY TH ED." vols. A (2000) and B (2001), plenum Press, new York). Conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV/VIS spectroscopy, and pharmacological methods are employed unless otherwise indicated. Unless specifically defined otherwise, the terms used herein in the description of analytical chemistry, organic synthetic chemistry, and pharmaceutical chemistry are known in the art. Standard techniques may be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using the manufacturer's instructions for the kit, or in a manner well known in the art or in accordance with the teachings of the present invention. The techniques and methods described above may generally be practiced according to conventional methods well known in the art, based on a number of general and more specific descriptions in the literature cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by one skilled in the art to provide stable moieties and compounds.
When substituents are described by conventional formulas written from left to right, the substituents also include chemically equivalent substituents obtained when writing formulas from right to left. For example, -CH 2O-is equivalent to-OCH 2-.
The section headings used herein are for purposes of organizing articles only and should not be construed as limiting the subject matter. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, operating manuals, and treatises, are hereby incorporated by reference in their entirety.
Certain chemical groups defined herein are preceded by a simplified symbol to indicate the total number of carbon atoms present in the group. For example, C1-6 alkyl refers to an alkyl group as defined below having a total of 1 to 6 carbon atoms. The total number of carbon atoms in the reduced notation does not include carbon that may be present in a substituent of the group.
In addition to the foregoing, when used in the specification and claims of this application, the following terms have the meanings indicated below, unless specifically indicated otherwise.
In the present application, the term "halogen" refers to fluorine, chlorine, bromine or iodine; "hydroxy" refers to an-OH group; "hydroxyalkyl" refers to an alkyl group as defined below substituted with a hydroxy (-OH); "carbonyl" refers to a-C (=o) -group; "nitro" means-NO 2 The method comprises the steps of carrying out a first treatment on the surface of the "cyano" refers to-CN; "amino" means-NH 2 The method comprises the steps of carrying out a first treatment on the surface of the "substituted amino" means an amino group which is substituted by one or two groups such asAlkyl, alkylcarbonyl, aralkyl, heteroaralkyl substituted amino groups as defined below, e.g., mono-alkylamino, di-alkylamino, alkylamido, aralkylamino, heteroaralkylamino; "carboxy" refers to-COOH.
In the present application, as part of a group or other group (e.g. as used in halogen substituted alkyl groups or the like), the term "alkyl" means a straight or branched hydrocarbon chain group consisting of only carbon atoms and hydrogen atoms, free of unsaturated bonds, having, for example, from 1 to 12 (preferably from 1 to 8, more preferably from 1 to 6) carbon atoms and being linked to the remainder of the molecule by a single bond. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl, decyl and the like.
In the present application, the term "alkenyl" as part of a group or other group means a straight or branched hydrocarbon chain group consisting of only carbon and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and being linked to the rest of the molecule by a single bond, such as, but not limited to, ethenyl, propenyl, allyl, but-1-enyl, but-2-enyl, pent-1, 4-dienyl, and the like.
In this application, the term "alkynyl" as part of a group or other group means a straight or branched hydrocarbon chain group consisting of only carbon and hydrogen atoms, containing at least one triple bond and optionally one or more double bonds, having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and being attached to the remainder of the molecule by a single bond, such as, but not limited to, ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-en-4-ynyl, and the like.
In this application, as part of a group or other group, the term "cycloalkyl" means a stable, non-aromatic, mono-or polycyclic hydrocarbon group consisting of only carbon and hydrogen atoms, which may include fused ring systems, bridged ring systems, or spiro ring systems, having from 3 to 15 carbon atoms, preferably from 3 to 10 carbon atoms, more preferably from 3 to 8 carbon atoms, and which is saturated or unsaturated and may be attached to the remainder of the molecule by a single bond via any suitable carbon atom. Unless otherwise specifically indicated in the specification, carbon atoms in cycloalkyl groups may optionally be oxidized. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexanyl, cyclooctyl, 1H-indenyl, 2, 3-indanyl, 1,2,3, 4-tetrahydro-naphthyl, 5,6,7, 8-tetrahydro-naphthyl, 8, 9-dihydro-7H-benzocyclohepten-6-yl, 6,7,8, 9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9, 10-hexahydro-benzocyclooctenyl, fluorenyl, bicyclo [2.2.1] heptyl, 7-dimethyl-bicyclo [2.2.1] heptyl, bicyclo [2.2.1] heptenyl, bicyclo [ 2.2.2.2 ] octyl, bicyclo [3.1.1] heptyl, bicyclo [3.2.1] octyl, bicyclo [2.2.2] octenyl, bicyclo [ 2.1.1 ] octadienyl, adamantylene, and the like.
In the present application, the term "heterocyclyl" as part of a group or other group means a stable 3-to 20-membered non-aromatic cyclic group consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur. Unless specifically indicated otherwise in the present specification, a heterocyclyl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, which may include fused, bridged or spiro ring systems; the nitrogen, carbon or sulfur atoms in the heterocyclyl may optionally be oxidized; the nitrogen atom may optionally be quaternized; and the heterocyclyl may be partially or fully saturated. The heterocyclic group may be attached to the remainder of the molecule via a carbon atom or a heteroatom and by a single bond. In heterocyclyl groups containing fused rings, one or more of the rings may be aryl or heteroaryl as defined below, provided that the point of attachment to the remainder of the molecule is a non-aromatic ring atom. For the purposes of the present invention, heterocyclyl groups are preferably stable 4-to 11-membered non-aromatic monocyclic, bicyclic, bridged or spiro groups comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably stable 4-to 8-membered non-aromatic monocyclic, bicyclic, bridged or spiro groups comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heterocyclyl groups include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2, 7-diaza-spiro [3.5] nonan-7-yl, 2-oxa-6-aza-spiro [3.3] heptan-6-yl, 2, 5-diaza-bicyclo [2.2.1] heptan-2-yl, azetidinyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxacyclopentyl, tetrahydroisoquinolyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, quinolizinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indolinyl, octahydroindolyl, octahydroisoindolyl, pyrrolidinyl, pyrazolidinyl, phthalimidyl, and the like.
In this application, the term "aryl" as part of a group or other group means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms, preferably having 6 to 10 carbon atoms. For the purposes of the present invention, aryl groups may be monocyclic, bicyclic, tricyclic or more ring systems, and may also be fused to cycloalkyl or heterocyclyl groups as defined above, provided that the aryl groups are linked to the remainder of the molecule by single bonds via atoms on the aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, fluorenyl, 2, 3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-benzoxazin-3 (4H) -one-7-yl, and the like.
In the present application, the term "arylalkyl" refers to an alkyl group as defined above substituted with an aryl group as defined above.
In this application, as part of a group or other group, the term "heteroaryl" means a 5-to 16-membered conjugated ring system group having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur within the ring. Unless otherwise specifically indicated in the present specification, heteroaryl groups may be monocyclic, bicyclic, tricyclic or more ring systems, and may also be fused to cycloalkyl or heterocyclyl groups as defined above, provided that heteroaryl groups are attached to the remainder of the molecule via an atom on an aromatic ring by a single bond. The nitrogen, carbon, or sulfur atoms in the heteroaryl group may optionally be oxidized; the nitrogen atom may optionally be quaternized. For the purposes of the present invention, heteroaryl groups are preferably stable 5-to 12-membered aromatic groups comprising 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably stable 5-to 10-membered aromatic groups comprising 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur or 5-to 6-membered aromatic groups comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolinyl, isoquinolinyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothienyl, oxatriazolyl, cinnolinyl, quinazolinyl, thiophenyl, indolizinyl, phenanthroline, isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6, 7-tetrahydrobenzo [ b ] thienyl, naphthyridinyl, [1,2,4] triazolo [4, 3-triazolo [1, 4] pyridazine, 3-1, 4-imidazo [1, 4] triazolo [1, 4, 3-triazolo [1, 4] pyridazine, 3-1, 4-imidazo [ 2,4] a ] 1, 4-imidazo [ 2, 4-a ] and the like.
In the present application, the term "heteroarylalkyl" refers to an alkyl group as defined above substituted with a heteroaryl group as defined above.
In this application, "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted aryl groups and unsubstituted aryl groups.
The terms "moiety", "structural moiety", "chemical moiety", "group", "chemical group" as used herein refer to a particular fragment or functional group in a molecule. Chemical moieties are generally considered to be chemical entities that are embedded or attached to a molecule.
"stereoisomers" refer to compounds that consist of the same atoms, are bonded by the same bonds, but have different three-dimensional structures. The present invention is intended to cover various stereoisomers and mixtures thereof.
When an olefinic double bond is contained in the compounds of the present invention, the compounds of the present invention are intended to include both E-and Z-geometric isomers unless otherwise specified.
"tautomer" refers to an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the invention are also intended to be included within the scope of the invention.
The compounds of the invention or pharmaceutically acceptable salts thereof may contain one or more chiral carbon atoms and thus may be produced in enantiomers, diastereomers and other stereoisomeric forms. Each chiral carbon atom may be defined as (R) -or (S) -, based on stereochemistry. The present invention is intended to include all possible isomers, as well as racemates and optically pure forms thereof. The compounds of the invention may be prepared by selecting racemates, diastereomers or enantiomers as starting materials or intermediates. Optically active isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.
Conventional techniques for preparing/separating individual isomers include chiral synthesis from suitable optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high performance liquid chromatography, see, for example, gerald gabiz and Martin g.schmid (eds.), chiral Separations, methods and Protocols, methods in Molecular Biology, vol.243,2004; m.stalcup, chiral Separations, annu.rev.animal.chem.3:341-63, 2010; fumigs et al (EDs.), VOGEL' S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY.sup.TH ED, longman Scientific and Technical Ltd., essex,1991,809-816; heller, acc.chem.Res.1990,23,128.
In the present application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
By "pharmaceutically acceptable acid addition salt" is meant a salt with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, and the like; organic acid salts include, but are not limited to, formate, acetate, 2-dichloroacetate, trifluoroacetate, propionate, hexanoate, octanoate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, adipate, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, alginate, ascorbate, salicylate, 4-aminosalicylate, naphthalenedisulfonate, and the like. These salts can be prepared by methods known in the art.
By "pharmaceutically acceptable base addition salt" is meant a salt formed with an inorganic or organic base that is capable of maintaining the bioavailability of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, the following: primary, secondary and tertiary amines, substituted amines including natural substituted amines, cyclic amines and basic ion exchange resins such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be prepared by methods known in the art.
"polymorphs" refer to the different solid crystalline phases of certain compounds of the present invention in the solid state due to the presence of two or more different molecular arrangements. Certain compounds of the present invention may exist in more than one crystal form, and the present invention is intended to include various crystal forms and mixtures thereof.
In general, crystallization will produce solvates of the compounds of the present invention. The term "solvate" as used herein refers to an aggregate comprising one or more molecules of a compound of the invention and one or more solvent molecules. The solvent may be water, in which case the solvate is a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present invention may exist as hydrates, including monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate, and the like, as well as the corresponding solvated forms. The compounds of the invention may form true solvates, but in some cases may also retain only adventitious water or a mixture of water plus a portion of the adventitious solvent. The compounds of the invention may be reacted in a solvent or precipitated or crystallized from a solvent. Solvates of the compounds of the present invention are also included within the scope of the present invention.
The invention also includes prodrugs of the above compounds. In this application, the term "prodrug" means a compound that can be converted into a biologically active compound of the invention under physiological conditions or by solvolysis. Thus, the term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of a compound of the invention. Prodrugs may not be active when administered to an individual in need thereof, but are converted in vivo to the active compounds of the present invention. Prodrugs are typically rapidly converted in vivo to the parent compounds of the present invention, for example, by hydrolysis in blood. Prodrug compounds generally provide solubility, histocompatibility, or sustained release advantages in mammalian organisms. Prodrugs include known amino protecting groups and carboxyl protecting groups. Specific methods of prodrug preparation can be found in saunnier, m.g., et al, biorg. Med. Chem. Lett.1994,4,1985-1990; greenwald, r.b., et al, j.med.chem.2000,43,475.
In this application, "pharmaceutical composition" refers to a formulation of a compound of the invention with a medium commonly accepted in the art for delivery of biologically active compounds to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote the administration of organisms, facilitate the absorption of active ingredients and further exert biological activity.
The term "pharmaceutically acceptable" as used herein refers to a material (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention, and is relatively non-toxic, i.e., the material can be administered to an individual without causing an adverse biological reaction or interacting in an adverse manner with any of the components contained in the composition.
In this application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonizing agent, solvent, or emulsifying agent that is approved by the relevant government regulatory agency as acceptable for human or livestock use.
The "tumor", "cell proliferation abnormality related disease", and the like of the present invention include, but are not limited to, leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, pancreatic cancer, lung squamous carcinoma, lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, cervical cancer, ovarian cancer, intestinal cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, renal cancer, oral cancer, and the like.
The terms "prevent", "preventing" and "preventing" as used herein include reducing the likelihood of a patient from developing or worsening a disease or condition.
The term "treatment" and other similar synonyms as used herein include the following meanings:
(i) Preventing the occurrence of a disease or disorder in a mammal, particularly when such mammal is susceptible to the disease or disorder, but has not been diagnosed as having the disease or disorder;
(ii) Inhibiting the disease or disorder, i.e., inhibiting its progression;
(iii) Alleviating a disease or condition, i.e., causing the state of the disease or condition to subside; or alternatively
(iv) Alleviating symptoms caused by the disease or condition.
The term "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" as used herein refers to an amount of at least one agent or compound that is sufficient to alleviate one or more symptoms of the disease or disorder being treated to some extent after administration. The result may be a reduction and/or alleviation of signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is required to provide clinically significant relief from a disorder. Effective amounts suitable in any individual case can be determined using techniques such as a dose escalation test.
The terms "administering," "administering," and the like as used herein refer to a method capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. Application techniques useful in the compounds and methods described herein are well known to those skilled in the art, for example, at Goodman and Gilman, the Pharmacological Basis of Therapeutics, current ed.; pergamon; and Remington's, pharmaceutical Sciences (current edition), mack Publishing co., easton, pa. In preferred embodiments, the compounds and compositions discussed herein are administered orally.
The terms "pharmaceutical combination", "co-administration", "administration of other treatments", "administration of other therapeutic agents" and the like as used herein refer to a pharmaceutical treatment obtained by mixing or combining more than one active ingredient, which includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity or single dosage form. The term "ambulatory combination" refers to the simultaneous administration, co-administration, or sequential administration of at least one compound described herein and at least one synergistic formulation as separate entities to a patient at variable intervals. These also apply to cocktail therapies, for example, administration of three or more active ingredients.
It will also be appreciated by those skilled in the art that in the methods described below, the intermediate compound functional groups may need to be protected by appropriate protecting groups. Such functional groups include hydroxyl, amino, mercapto and carboxylic acid. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl groups (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino and guanidino groups include t-butoxycarbonyl, benzyloxycarbonyl and the like. Suitable mercapto-protecting groups include-C (O) -R "(wherein R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl, and the like. Suitable carboxyl protecting groups include alkyl, aryl or aralkyl esters.
Protecting groups may be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Greene, t.w. and p.g.m. wuts, protective Groups in Organic Synthesis, (1999), 4th Ed. The protecting group may also be a polymeric resin.
The invention will be further illustrated with reference to specific examples. It should be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples, in which specific conditions are not noted, are generally in accordance with conventional conditions, or in accordance with the conditions recommended by the manufacturer. Percentages and parts are weight percentages and parts unless otherwise indicated.
In various embodiments, the laboratory instrument instructions (e.g. 1 H NMR was recorded by Varian Mercury-300 or Varian Mercury-400 nuclear magnetic resonance, 13 c NMR is carried out by Varian Mercury-400 or Varian Mercury-500 or Varian Mercury-60Type 0 nmr recordings, chemical shifts expressed as δ (ppm); mass spectra were recorded by Finnigan/MAT-95 (EI) and Finnigan LCQ/DECA and Micromass Ultra Q-TOF (ESI) type mass spectrometers; silica gel for reversed phase preparative HPLC separation was 200-300 mesh).
Wherein, the Chinese names of the reagents represented by chemical formulas or English letter abbreviations are as follows:
iPrOH: isopropyl alcohol; etOH: ethanol; DCM: dichloromethane; TFA: trifluoroacetic acid; meOH: methanol; naOH: sodium hydroxide; HCl: hydrogen chloride; TEA: triethylamine; raney Ni: raney nickel; 1,4-dioxane:1, 4-dioxane; naH: sodium hydride; h 2 O: water; pd/C: palladium on carbon; h 2 : hydrogen gas; HATU:2- (7-oxo-benzotriazol) -N, N' -tetramethyl urea hexafluorophosphate; DMF: n, N-dimethylformamide; THF: tetrahydrofuran; boc 2 O: di-tert-butyl dicarbonate; NBS: n-bromosuccinimide; NCS: n-chlorosuccinimide; NIS: n-iodosuccinimide; meCN: acetonitrile; DIPEA/DIEA: n, N-diisopropylethylamine; naBH 4 : sodium borohydride; acOH: acetic acid; ethylacetate: ethyl acetate; naBH 3 CN: sodium cyanoborohydride; k (K) 2 CO 3 : potassium carbonate; cs (cells) 2 CO 3 : cesium carbonate; nBuLi: n-butyllithium; liAlH 4 : lithium aluminum hydride; pd (dppf) Cl 2 : [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride; KOAc: potassium acetate. Fumaronitrile: fumaric acid nitrile; p (nBu) 3 : tri-n-butylphosphine; LDA: lithium diisopropylamide; liOH: lithium hydroxide; meI: methyl iodide; etI: iodoethane; (CH) 2 O) n : paraformaldehyde; HCO (hydrogen chloride) 2 H: formic acid; CH (CH) 3 COCl: acetyl chloride; LCMS: liquid chromatography mass spectrometry is used; xantphos:4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene; TLC: thin layer chromatography; eq. Equivalent weight; DCE:1, 2-dichloroethane; HEPES: 4-hydroxyethyl piperazine ethane sulfonic acid; EGTA: ethylene glycol bis (2-aminoethylether) tetraacetic acid; DTT: dithiothreitol
Examples general preparation method
Pyrazolo heterocyclic chlorine intermediates (1 eq.) were dissolved in acetonitrile, DIPEA (1.6 eq.) and benzylamine intermediates (1.0 eq.) were added sequentially and heated to 70 degrees under nitrogen protection with stirring for 12 hours. TLC monitoring reaction is complete, cooling to room temperature, decompressing and concentrating, separating and purifying the residue by silica gel column chromatography to obtain a target product, and confirming a structure by nuclear magnetism and mass spectrum.
Or dissolving the product (1 eq.) in methanol, adding hydrochloric acid aqueous solution/hydrochloric acid alcoholic solution (20 eq.) or hydrobromic acid/acetic acid (10 eq.) and stirring at room temperature or under heating for 3-10 hours to remove Boc and/or Cbz protecting groups, performing column chromatography separation and purification after conventional treatment to obtain the target product, and adopting nuclear magnetism and mass spectrum to confirm the structure;
or the above product (1 eq.) is dissolved in methanol and the protecting group such as Cbz/benzyl is removed by palladium carbon catalysis under hydrogen atmosphere. TLC monitoring reaction is complete, decompression concentration is carried out, the remainder is separated and purified by silica gel column chromatography to obtain a target product, and nuclear magnetism and mass spectrum are adopted to confirm the structure;
or dissolving the product (1 eq.) in a proper solvent, performing proper conversion through reactions such as carbonyl reagent acylation, acid amine condensation, reductive amination, halogenated compound alkylation, metal reagent cross coupling and the like to obtain a target product, and confirming a structure by adopting nuclear magnetism and mass spectrum.
Preparation of key intermediates:
example preparation
Example 1: n- (2- (4-aminopiperidin-1-yl) -8-isopropylpyrazolo [1,5, -a ] [1,3,5] triazin-4-yl) -1,2,3, 4-tetrahydroisoquinolin-4-amine
The first step: the intermediate is protected under nitrogenA (30 mg,0.1 mmol), tert-butyl 4-amino-3, 4-dihydroisoquinoline-2 (1H) carbonate (49 mg,0.2 mmol), DIEA (78 mg,0.6 mmol) were dissolved in acetonitrile (5 mL) and reacted at 70℃for 4H. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE: ea=2:1) to give intermediate product B (70 mg) as a yellow oil. LC-MS [ M+H ] ] + :m/z 641.3。
And a second step of: the above intermediate product B (70 mg) was dissolved in 6NHCl aqueous solution (5 mL), heated to 70℃and stirred for 4 hours. The reaction solution was cooled to room temperature, neutralized to ph=8-9 by adding aqueous ammonia, and extracted three times with dichloromethane (50 mL). The separated organic phase was dried over MgSO 4 Drying, filtering and concentrating. The crude product was purified by HPLC to afford the desired product as a yellow solid (37 mg). LC-MS [ M+H ]] + :m/z 407.2。 1 H-NMR(400MHz,MeOD-d 4 ):δ7.73(s,1H),7.49-7.32(m,4H),5.83(t,J＝6.0Hz,1H),4.91-4.83(m,2H),4.53-4.43(m,2H),3.81-3.71(m,2H),3.41-3.37(m,1H),3.08-2.99(m,3H),2.07-2.04(m,2H),1.61-1.52(m,2H),1.29(d,J＝6.8Hz,6H)。
Chiral preparation and separation of the intermediate A1 are carried out to obtain intermediates A1-1 and A1-2 respectively, and examples 1-1 and 1-2 are obtained by removing the protecting group according to the operation of the second reaction. The preparation conditions are as follows: separation column (SunFire Prep C18 OBDTM,10um,19 x 250 mm); gradient (5% -95% acetonitrile/0.1% formic acid/water, 16min, flow 20 mL/min). Analysis conditions: analytical column (Waters SunFire C18,4.6×50mm,5 um); gradient (5% -95% acetonitrile/0.1% formic acid/water, 3.0min, flow rate 2.0mL/min,2.6 min); column temperature: 40 ℃; detection wavelength: 254nM.
Examples 1-1 and 1-2.
Synthesized by the method of example 1 using intermediate a, and a different aromatic and saturated ring substituted amine as starting materials, to give examples 2-36;
example 17:1- (8-isopropyl-4- ((-1, 2,3, 4-tetrahydroisoquinolin-4-yl) amine) pyrazolo [1,5, -a ] [1,3,5] triazin-2-yl) piperidin-4-ol
The first step: intermediate B (73 mg,0.3 mmol), tert-butyl 4-amino-3, 4-dihydroisoquinoline-2 (1H) carbonate (74 mg,0.32 mmol), DIEA (78 mg,0.6 mmol) was dissolved in acetonitrile (10 mL) under nitrogen and reacted at 70℃for 4H. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE: ea=2:1) to give an intermediate product (80 mg) as a yellow oil. LC-MS [ M+H ]] + :m/z 455.6。
And a second step of: to a solution of the above intermediate compound (80 mg,0.17 mmol) in dichloromethane (10 mL) was added m-chloroperoxybenzoic acid (75 mg,0.34mmol,80% purity) under ice-bath cooling. After the reaction temperature was slowly raised to room temperature, the reaction was stirred for 3 hours. After the LC-MS detection reaction is completed, adding saturated NaSO into the reaction solution 3 Aqueous (10 mL) and dichloromethane (20 mL), the organic phase was separated. The aqueous phase was washed twice with dichloromethane (20 mL). The organic phases were combined and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: ea=2:1) to give the product as a yellow solid (50 mg). LC-MS [ M+H ]] + :m/z 487.6。
And a third step of: the intermediate compound (50.0 mg,0.10 mmol) and tetrahydroxypiperidine (61 mg,0.6 mmol) were dissolved in NMP (1 mL), DIEA (68 mg,0.62 mmol) was added and the mixture was heated to 115℃overnight. TLC detection reverseAfter completion, water (40 mL) and ethyl acetate (40 mL) were added. The separated aqueous phase was extracted twice with ethyl acetate (40 mL). The combined organic phases were concentrated under reduced pressure and dried to give intermediate (30 mg) as a white solid. LC-MS [ M+H ] ] + :m/z 508.6.
Fourth step: in dichloromethane (10 mL) of the above intermediate compound (30 mg,0.06 mmol), trifluoroacetic acid (3 mL) was added and the reaction stirred at room temperature for 4 hours. Ammonia was added to neutralize to ph=8-9 and extracted three times with dichloromethane (30 mL). The combined organic phases were concentrated under reduced pressure. The crude product was purified by HPLC to afford the desired product as a white solid (21 mg). LC-MS [ M+H ]] + :m/z 408.1。 1 H NMR(400MHz,MeOD-d 4 ):δ7.75(s,1H),7.50-7.52(m,1H),7.40-7.42(m,2H),7.32-7.34(m,1H),5.81(m,1H),4.47-4.52(m,2H),4.37-4.39(m,2H),3.87-3.91(m,1H),3.75-3.79(m,2H),3.47-3.40(m,2H),3.05-3.09(m,1H),1.89-1.93(m,2H),1.51(m,2H),1.24-1.31(d,J＝7.2Hz,6H).
Examples 18 to 26 were synthesized by the method of example 17 starting from intermediate B and a different aromatic and saturated ring-substituted amine and a heterocycloalkyl alcohol or heterocycloalkyl amine;
example 27: n- (5- (4- (dimethylamino) piperidin-1-yl) -3-isopropylpyrazolo [1,5, -a ] pyridin-7-yl) -1,2,3, 4-tetrahydroisoquinolin-4-amine
The first step: intermediate C (60.0 mg, 0).26 mmol) was dissolved in ethanol (5 mL), DIEA (1 mL) and tert-butyl 4-amino-3, 4-dihydroisoquinoline-2 (1H) carbonate (74 mg,0.32 mmol) were added, and the mixture was heated under reflux for 8H. After completion of the reaction by LC-MS, water (50 mL) and ethyl acetate (50 mL) were added to the reaction mixture, which was extracted twice with ethyl acetate (50 mL), and the separated organic phase was concentrated under reduced pressure and dried to give a yellow solid intermediate product (92 mg). LC-MS [ M+H ]] + :m/z 443.1。
And a second step of: to a solution of the intermediate (92 mg,0.21 mmol) in toluene (10 mL) was added 4-N, N-dimethylaminopiperidine (54 mg,0.42 mmol), pd 2 (dba) 3 (3 mg, 0.003mmol), potassium t-butoxide (36 mg,0.32 mmol) and BINAP (2 mg, 0.003mmol), heated to 100℃and stirred overnight. After the LC-MS detection reaction was substantially complete, water (50 mL) and methylene chloride (50 mL) were added to the reaction solution. The organic phase was separated and the aqueous phase was extracted once more with dichloromethane (50 mL). The organic phases were combined and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE: ea=2:1) to give the compound (65 mg) as a yellow solid. MS m/z 664.8[ M+H ]] + 。
And a third step of: to dichloromethane (10 mL) of the above intermediate (65 mg,0.1 mmol) was added trifluoroacetic acid (3 mL), and the reaction was stirred at room temperature for 4 hours. Ammonia is added to neutralize to pH=8-9, and extracted three times with dichloromethane (30 mL). The combined organic phases were concentrated under reduced pressure. The crude product was purified by HPLC to afford the desired product as a white solid (18 mg). MS: m/z 434.6[ M+H ]] + . 1 H NMR(400MHz,CD 3 OD):δ7.36(s,1H),7.50-7.42(m,3H),7.36-7.34(m,1H),5.46(m,1H),4.61-4.50(m,2H),4.53-4.35(m,2H),3.97-3.78(m,2H),3.48-3.41(m,1H),3.16-3.07(m,3H),2.92(s,6H),2.12-2.07(m,2H),1.73-1.62(m,2H),1.32-1.28(d,J＝6.8Hz,6H).
Examples 28 to 39 were synthesized by the method of example 27 starting from intermediate C or E with different aromatic and saturated ring-substituted amines and heterocycloalkyl-substituted amines or alcohols;
example 40:2- (4-aminophenyl) -N- (2- (4-aminopiperidin-1-yl) -8-isopropylpyrazolo [1,5, -a ] [1,3,5] triazin-4-yl) -1,2,3, 4-tetrahydroisoquinolin-4-amine
The first step: intermediate A1 (60.0 mg,0.093 mmol) was dissolved in methanol (10 mL) and after addition of 4M HCl/MeOH (1 mL) was stirred at room temperature for 2 hours. After completion of the LC-MS detection reaction, water (40 mL) and ethyl acetate (40 mL) were added to the reaction mixture, which was extracted twice with ethyl acetate (40 mL), and the separated organic phase was concentrated under reduced pressure and dried to give a yellow solid intermediate product (40.0 mg). LC-MS [ M+H ] ] + :m/z 541.7。
And a second step of: to a solution of the above intermediate (40 mg,0.074 mmol) in DMF (5 mL) was added anhydrous K 2 CO 3 After (21 mg,0.15 mmol) and p-fluoronitrobenzene (13 mg,0.092 mmol), the reaction was heated to 130℃overnight. After the LC-MS detection reaction was substantially complete, water (30 mL) and ethyl acetate (30 mL) were added to the reaction solution. The organic phase was separated and the aqueous phase was extracted once more with ethyl acetate (30 mL). The organic phases were combined and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE: ea=2:1) to give the compound (24 mg) as a yellow oil. LC-MS [ M+H ]] + :m/z 662.8。
And a third step of: pd/C (10% wt,5 mg) was added to a methanol solution (10 mL) of the above intermediate (24 mg,0.037 mmol), and the reaction mixture was stirred at room temperature under a hydrogen atmosphere at 1 atm for 3 hours. LC-MS detection reaction was completed, and the reaction solution was filtered through celite and concentrated under reduced pressure. After drying, the product was obtained as a white solid (14 mg). LC-MS [ M+H ]] + :m/z 498.7。 1 H NMR(400MHz,MeOD-d 4 ):δ7.66(s,1H),7.46(d,J＝7.6Hz,2H),7.26-7.33(m,2H),7.02-6.88(m,3H),6.69(d,J＝7.6Hz,1H),5.61-5.63(m,1H),4.97-4.92(m,2H),4.62-4.45(m,2H),3.89-3.75(m,2H),3.48-3.38(m,1H),3.07-3.00(m,3H),2.08-2.04(m,2H),1.63-1.56(m,2H),1.28(d,J＝6.8Hz,6H)。
Synthesized according to the procedure of example 40, intermediate a was used to react with 2-chloro-4-trifluoromethylpyridine to afford example 41;m/z:552.3[M+H] + . 1 H NMR(400MHz,CD 3 OD):δ8.27(m,1H),7.75(s,1H),7.34(s,1H),7.50-7.34(m,5H),5.46(m,1H),4.61-4.53(m,2H),4.53-4.43(m,2H),3.97-3.78(m,2H),3.48-3.40(m,1H),3.16-3.06(m,3H),2.12-2.09(m,2H),1.73-1.63(m,2H),1.32-1.29(d,J＝7.2Hz,6H).
example 42:2- (3-aminophenyl) -N- (2- (4-aminopiperidin-1-yl) -8-isopropylpyrazolo [1,5, -a ] [1,3,5] triazin-4-yl) -1,2,3, 4-tetrahydroisoquinolin-4-amine
The first step: n- (1, 2,3, 4-tetrahydroisoquinolin-4-yl) formyl-tert-butyl ester (405 mg,1.63 mol), 3-nitrobromobenzene (300 mg,1.48 mol), pd2 (dba) 3 (67.8 mg,0.074 mmol), xantphos (70 mg,0.148 mmol) and cesium carbonate (1.4 g,4.44 mol) were dissolved in 1, 4-dioxane (10 mL) under nitrogen. The reaction was heated to 110℃overnight. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=20:1) to give intermediate compound (322 mg) as a yellow oil. LC-MS [ M+H ] +: M/z 370.1.
And a second step of: the intermediate compound (322 mg) was dissolved in methylene chloride (15 mL), and trifluoroacetic acid (8 mL) was added thereto, followed by stirring at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to give the crude intermediate compound (250 mg) as a gray-black oil. LC-MS [ M+H ]] + :m/z 270.1。
And a third step of: the above intermediate compound (65.5 mg,0.24 mmol) and intermediate A (80 mg,0.19 mmol) were dissolved in acetonitrile (5 mL) andn, N-diisopropylethylamine (72.4 mg,0.56 mmol) was added. The reaction was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5:1) to obtain a yellow solid intermediate compound (102 mg). LC-MS [ M+H ]] + :m/z 662.2。
Fourth step: the intermediate compound (92 mg,0.13 mmol) was dissolved in MeOH/THF/H 2 To a mixed solution of O (4 mL/4mL/4 mL), ammonium chloride (46 mg,0.08 mmol), zinc powder (28.5 mg,0.08 mmol) were then added in this order, and the mixture was stirred at room temperature for 16 hours. The LC-MS detection reaction was substantially complete, the reaction was poured into water (20 mL) and extracted twice with ethyl acetate (30 mL). The combined organic phases were dried and concentrated under reduced pressure, and the resulting crude product was purified by Prep-TLC (eluent: petroleum ether/ethyl acetate=2:1) to give intermediate compound (78 mg) as a yellow solid. LC-MS [ M+H ] ] + :m/z 632.3。
Fifth step: the above intermediate compound (10.3 mg,0.016 mmol) was dissolved in ethyl acetate (1 mL), pd/C (5 mg) was added thereto, the mixture was stirred overnight at room temperature for 3 days under hydrogen balloon displacement for 3 times. The filtrate was filtered through celite and washed with methanol, the filtrate was concentrated under reduced pressure, and the resulting crude product was isolated by HPLC to give the compound of example 42 (1.04 mg) as a gray solid, LC-MS [ M+H ]] + :m/z 498.3。 1 H NMR(400MHz,MeOD-d 4 ):δ7.66(s,1H),7.46(d,J＝7.6Hz,1H),7.26-7.33(m,4H),7.02(d,J＝9.6Hz,1H),6.88(s,1H),6.69(d,J＝7.6Hz,1H),5.61-5.63(m,1H),4.92-4.97(m,2H),4.62(m,1H),4.45(m,1H),3.94-3.79(m,2H),3.38-3.48(m,1H),3.00-3.07(m,3H),2.04-2.08(m,2H),1.56-1.62(m,2H),1.28(d,J＝6.8Hz,6H)。
Synthesized according to the procedure of example 40, intermediate a was used to react with 2-chloro-4-cyanopyrimidine to afford example 43;
m/z:510.3[M+H] + 。 1 H NMR(400MHz,CD 3 OD):δ8.15(s,2H),7.34(s,1H),7.50-7.40(m,3H),7.36-7.34(m,1H),5.46(m,1H),4.61-4.53(m,2H),4.53-4.43(m,2H),3.97-3.78(m,2H),3.48-3.40(m,1H),3.16-3.06(m,3H),2.12-2.09(m,2H),1.73-1.63(m,2H),1.32-1.29(d,J＝7.2Hz,6H).
synthesized according to the procedure of example 42, using tert-butyl-N- (1, 2,3, 4-tetrahydroquinolin-4-yl) formyl tert-butyl ester reacted with 3-nitrobenzophenone to form intermediate A and then reacting the intermediate with example 44;
m/z:498.3[M+H] + 。 1 H NMR(400MHz,MeOD-d 4 ):δ7.68(s,1H),7.46(m,1H),7.26-7.02(m,5H),6.88-6.69(m,2H),5.61-5.63(m,1H),4.92-4.97(m,2H),4.62(m,1H),4.45(m,1H),3.94-3.79(m,2H),3.38-3.48(m,1H),3.00-3.07(m,3H),2.04-2.08(m,2H),1.56-1.62(m,2H),1.30(d,J＝6.8Hz,6H)。
example 45: n- (2- (4-aminopiperidin-1-yl) -8-isopropylpyrazolo [1,5, -a ] [1,3,5] triazin-4-yl) -2- (piperidin-3-yl) -1,2,3, 4-tetrahydroisoquinolin-4-amine
The first step: to a solution of intermediate A2 (60 mg,0.11 mmol) in 1, 2-dichloroethane (10 mL) was added N-t-butoxycarbonyl-3-piperidone (22 mg,0.11 mmol) and acetic acid (0.5 mL). After the reaction mixture was stirred at room temperature for 30 minutes, sodium cyanoborohydride (15 mg,0.24 mmol) was added to the reaction. The reaction was stirred at room temperature overnight. After completion of the LC-MS detection reaction, water (30 mL) and methylene chloride (50 mL) were added to the reaction solution. After the separation of the organic phase, the organic phase is separated, the aqueous phase was extracted once more with dichloromethane (50 mL). The combined organic phases were concentrated under reduced pressure, and dried to give the intermediate compound (51 mg) as an oil.
And a third step of: the above compound (51 mg,0.07 mmol) was dissolved in HBr/AcOH (2 mL) and reacted overnight, and NaOH solution (10 mL) and methylene chloride (30 mL) were added. The organic phase was separated and the aqueous phase was extracted twice more with dichloromethane (30 mL). The combined organic phases were concentrated under reduced pressure and the crude product was isolated by HPLC to give a pale yellow solid (15 mg). LC-MS [ M+H ]] + :m/z 490.3。 1 H NMR(400MHz,MeOD-d 4 ):7.72(s,1H),7.49-7.44(m,1H),7.36-7.21(m,4H),5.69-5.67(m,1H),4.25-4.15(m,1H),4.06-3.95(m,1H),3.53-3.34(m,4H),3.26-3.02(m,7H),2.09-2.97(m,4H),1.96-1.92(m,1H),1.89-1.57(m,3H),1.28(d,J＝6.8Hz,6H)。
Synthesized by the method of example 45, intermediate A2 or an analog thereof is reacted with various commercially available aldehydes or ketones to afford examples 46-55;
example 56: (E) -N- (4- (4- ((2- (4-aminopiperidin-1-yl) -8-isopropylpyrazolo [1,5, -a ] [1,3,5] triazin-4-yl) amino) -3, 4-dihydroisoquinolin-2- (1H) -yl) phenyl) -4- (dimethylamino) but-2-enoyl
The first step: to a solution of intermediate A3 (60 mg,0.09 mmol) in ethanol (10 mL) and water (5 mL) was added iron powder (30 mg,0.54 mmol) and ammonium chloride (30 mg,0.56 mmol). The reaction solution was heated to 80℃and stirred for 5 hours. LC-MS detection reaction is complete, the reaction solution is filtered, and the filtrate is concentrated under reduced pressure. The crude product was dried to give an off-white solid (51.2 mg).
And a second step of: to a solution of the above intermediate (51 mg,0.08 mmol) in dichloromethane (10 mL) were added (E) -3-N, N-dimethylaminomethacryloyl chloride hydrochloride (17 mg,0.09 mmol) and DIEA (40 mg,0.31 mmol). After completion of the LC-MS detection reaction, water (30 mL) and ethyl diacetate (50 mL) were added to the reaction solution. After separation of the organic phase, the aqueous phase was extracted twice more with ethyl acetate (50 mL). The combined organic phases were concentrated under reduced pressure, and dried to give the intermediate compound (52 mg) as an oil.
And a third step of: the above compound (52 mg,0.07 mmol) was dissolved in HBr/AcOH (2 mL) and reacted overnight, and NaOH solution (10 mL) and methylene chloride (30 mL) were added. The organic phase is separated off and the mixture is taken up in the solvent, the aqueous phase was extracted twice more with dichloromethane (30 mL). The combined organic phases were concentrated under reduced pressure and the crude product was isolated by HPLC to give a pale yellow solid (15 mg). LC-MS [ M+H ]] + :m/z 690.8。1H NMR(400MHz,MeOD-d4):δ7.67(s,1H),7.48-7.43(m,2H),7.30-7.25(m,4H),7.10(m,1H),6.81-6.89(m,2H),6.53(m,1H),5.64(m,1H),4.90-4.95(m,2H),4.57(m,1H),4.43(m,1H),3.97-3.99(m,2H),3.72-3.85(m,2H),3.36-3.49(m,2H),3.01-3.06(m,3H),2.92(s,6H),2.06-2.09(m,2H),1.54-1.66(m,2H),1.29(d,J＝6.8Hz,3H).
Synthesized by the method of example 56, intermediate A2 or an analog thereof is reacted with various commercially available carboxylic acids or acid chlorides to afford examples 57-63;
synthesized by the method of examples 27 and 56, intermediate D is reacted with various commercially available carboxylic acids or acid chlorides to afford examples 64-66;
example 67: n- (2- (4-aminopiperidin-1-yl) -8-isopropylpyrazolo [1,5, -a ] [1,3,5] triazin-4-yl) -2- (4-aminopyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-4-amine
The first step: the compound N- (1, 2,3, 4-tetrahydroisoquinolin-4-yl) formyl tert-butyl ester (400 mg,1.6 mol), 2-chloropyrimidin-4-amine (418 mg,3.2 mol), N, N-diisopropylethylamine (619.2 mg,4.8 mmol) was dissolved in DMF (8 mL) under nitrogen and heated to 80℃for reaction overnight. After filtration through celite, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (eluent: petroleum ether/ethyl acetate=10:1) to give a gray solid (96 mg). LC-MS [ M+H ] +: M/z 342.1.
And a second step of: the intermediate compound (76 mg) was dissolved in methylene chloride (1.5 mL), and trifluoroacetic acid (0.8 mL) was added thereto and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to give the crude intermediate compound (65 mg) as a gray-black oil. LC-MS [ M+H ]] + :m/z 242.2。
And a third step of: the above intermediate compound (45 mg,0.18 mmol) and intermediate A (65 mg,0.27 mmol) were dissolved in acetonitrile (5 mL), and N, N-diisopropylethylamine (104 mg,0.81 mmol) was added thereto, and the reaction was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by column chromatography (eluent: petroleum ether/ethyl acetate=5:1) to give an intermediate compound (110 mg) as a gray solid. LC-MS [ M+H ]] + :m/z 663.2。
Fourth step: the intermediate compound (21 mg,0.03 mmol) was dissolved in acetonitrile (5 mL), and trimethyliodosilane (0.5 mL) was added thereto, and the mixture was stirred at room temperature overnight. After adding water (30 mL) to the reaction solution, extraction was performed twice with ethyl acetate (30 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the crude product was purified by HPLC to give an off-white solid, example 67 compound (5.74 mg), LC-MS [ M+H] + :m/z 499.3。1H NMR(400MHz,MeOD-d 4 ):δ7.67(s,1H),7.65(d,J＝7.2Hz,1H),7.45(d,J＝7.6Hz,1H),7.40-7.37(m,1H),7.33-7.29(m,2H),6.14(d,J＝7.2Hz,1H),5.69(m,1H),5.11(m,1H),4.95-4.94(m,1H),4.81(m,1H),4.57-4.54(m,1H),4.02(m,1H),3.45-3.39(m,1H),3.09-3.00(m,3H),2.11-2.05(m,2H),1.64-1.58(m,2H),1.28(d,J＝6.8Hz,6H)。
Example 68: n- (2- (4-aminopiperidin-1-yl) -8-isopropylpyrazolo [1,5, -a ] [1,3,5] triazin-4-yl) -2- (4-aminopyridin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-4-amine
The first step: the compound N- (1, 2,3, 4-tetrahydroisoquinolin-4-yl) formyl tert-butyl ester (400 mg,1.6 mol), 2-chloro-4-nitropyridine (201.4 mg,1.2 mol), pd2 (dba) 3 (55.4 mg,0.06 mmol), xantphos (57.6 mg,0.12 mmol), cesium carbonate (1.2 g,3.63 mol) was dissolved in 1, 4-dioxane (10 mL) under nitrogen. The reaction was heated to 110℃overnight. The reaction solution was filtered through celite, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=10:1) to give intermediate product (26.5 mg) as a yellow solid. LC-MS [ M+H ] +: M/z 371.1.
And a second step of: the above intermediate compound (26.5 mg) was dissolved in methylene chloride (2 mL), TFA (1 mL) was added thereto, and the mixture was stirred at room temperature for 3 hours, and concentrated under reduced pressure to give an intermediate product (21 mg) as an off-black oil. LC-MS [ M+H ]] + :m/z 271.1
And a third step of: the above intermediate compound (21 mg,0.08 mmol) and intermediate A (33.4 mg,0.08 mmol) were dissolved in acetonitrile (2 mL), and N, N-diisopropylethylamine (30.2 mg,0.23 mmol) was added thereto, and the reaction was stirred at room temperature for 16 hours. The reaction was concentrated under reduced pressure and the resulting crude product was purified by Prep-TLC (eluent: petroleum ether/ethyl acetate=4:1) to give intermediate product (29 mg) as a yellow solid. LC-MS [ M+H ] ] + :m/z 663.2。
Fourth step: the intermediate compound (29 mg,0.04 mmol) was dissolved in MeOH/THF/H 2 To O (2 mL/2mL/2 mL) was added ammonium chloride (46 mg,0.08 mmol) and zinc powder (28.5 mg,0.08 mmol) in this order, followed by stirring at room temperature for 16 hours. Water (8 mL) was added to the reaction solution, and extracted twice with ethyl acetate (20 mL). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by Prep-TLC (eluent: dichloromethane/methanol=50:1) to give intermediate product (20 mg) as a white solid. LC-MS [ M+H ]] + :m/z 633.3。
Fifth step: the intermediate is preparedThe compound (5 mg) was dissolved in acetonitrile (1 mL), and trimethyliodosilane (0.3 mL) was added thereto, followed by stirring at room temperature overnight. After adding water (20 mL) to the reaction solution, extraction was performed twice with ethyl acetate (20 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the crude product was purified by HPLC to give an off-white solid intermediate (2.02 mg) LC-MS [ M+H)]+:m/z 499.3。 1 H NMR(400MHz,MeOD-d 4 ):δ7.68(s,1H),7.52(d,J＝6.8Hz,1H),7.45(d,J＝7.6Hz,1H),7.40-7.30(m,3H),6.32(m,1H),6.16(m,1H),5.72-5.70(m,1H),4.82(s,1H),4.68(m,1H),4.09-4.04(m,1H),3.93-3.88(m,1H),3.43-3.37(m,1H),3.06-2.98(m,3H),2.09-2.06(m,2H),1.61-1.55(m,2H),1.33-1.27(m,8H)。
Example 69: (E) -N- (3- (4- ((2- (4-aminopiperidin-1-yl) -8-isopropylpyrazolo [1,5, -a ] [1,3,5] triazin-4-yl) amino) -3, 4-dihydroisoquinolin-2 (1H) -yl) phenyl) -4- (dimethylamino) but-2-enoyl
The first step: the compound (1- (4- ((2- (3-aminophenyl) -1,2,3, 4-tetrahydroisoquinolin-4-yl) amino) -8-isopropylpyrazolo [1,5, -a) ][1,3,5]Triazin-2-yl) piperidin-4-yl) formyl benzyl ester (64 mg,0.1 mmol) was dissolved in pyridine/dichloromethane (2 mL/1 mL) followed by the addition of (E) -4- (dimethylamino) but-2-enoic acid (20.2 mg,0.12 mmol), one drop of POCl 3 Stirring at room temperature for 1.5 hr, pouring saturated NaHCO 3 In a solution of water (20 mL), ethyl acetate (20 mL) was extracted three times. The combined organic phases were dried over anhydrous sodium sulfate and the filtrate was concentrated under reduced pressure. The crude product was slurried with methanol, the filter cake washed with methanol, and the combined filtrates were concentrated to give a crude intermediate product (34 mg) as a yellow solid. LC-MS [ M+H ]] + :m/z 743.7。
And a second step of: the intermediate compound (29 mg,0.04 mmol) was dissolved in acetonitrile (1 mL), and trimethyliodosilane (42.2 mg,0.19 mmol) was added and stirred overnight at room temperature. The reaction was quenched by the addition of methanol, the reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to give example 69 (5.1 mg) as a pale yellow solid. LC-MS [ M+H ] +: M/z 609.4.1H NMR (400 MHz, meOD-d 4): delta 7.67 (s, 1H), 7.45-7.48 (m, 2H), 7.30-7.32 (m, 2H), 7.21-7.27 (m, 2H), 7.10 (d, J=8.4 Hz, 1H), 6.81-6.89 (m, 2H), 6.53 (m, 1H), 5.61-5.64 (m, 1H), 4.90-4.95 (m, 2H), 4.57 (m, 1H), 4.43 (m, 1H), 3.97-3.99 (m, 2H), 3.72-3.85 (m, 2H), 3.36-3.49 (m, 2H), 3.01-3.06 (m, 3H), 2.92 (s, 6H), 2.06-2.09 (m, 2H), 1.54-1.66 (m, 1.57 (m, 1H), 4.43 (m, 1H), 3.36-3.49 (m, 2H).
Example 70: (E) -1- (3- (4- ((2- (4-aminopiperidin-1-yl) -8-isopropylpyrazolo [1,5, -a ] [1,3,5] triazin-4-yl) amino) -3, 4-dihydroisoquinolin-2 (1H) -yl) piperidin-1-yl) -4- (dimethylamino) but-2-enoyl
The first step: the intermediate compound 3- (4- ((2- (4- (((benzyloxy) carbonyl) amino) piperidin-1-yl) -8-isopropylpyrazolo [1,5, -a)][1,3,5]Triazin-4-yl) amino) -3, 4-dihydroisoquinolin-2 (1H) -yl) piperidine-1-carboxylic acid tert-butyl ester (30 mg,0.04 mmol) was dissolved in dichloromethane (2 mL), TFA (1 mL) was added, and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to give a crude intermediate compound (20 mg) as an gray-black oil. LC-MS [ M+H ]] + :m/z 624.3。
And a second step of: the intermediate compound (34 mg,0.055 mmol) was dissolved in DMF (2 mL), and (E) -4- (dimethylamino) but-2-enoic acid (9.94 mg,0.06 mmol), HATU (27 mg,0.07 mmol), DIEA (21 mg,0.16 mmol) was added sequentially and stirred at room temperature for 5 hours. Water (8 mL) was added to the reaction solution, and a solid was precipitated. The precipitated solid was dried to give a crude intermediate compound (39 mg) as a white solid. LC-MS [ M+H ]] + :m/z 735.5。
And a third step of: the intermediate compound (39 mg,0.05 mmol) was dissolved in acetonitrile (1 mL), and trimethyliodosilane (0.3 mL) was added thereto and stirred at room temperature for 5 hours. After adding water (20 mL) to the reaction solution, extraction was performed twice with ethyl acetate (20 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the crude product was purified by HPLC to give a gray solid, example 70 compound (12.9 mg), LC-MS [ M+H ] ] + :m/z 601.5。 1 H NMR(400MHz,MeOD-d 4 ):δ7.73(s,1H),7.46-7.34(m,4H),6.98-6.93(m,1H),6.72-6.66(m,1H),5.97-5.92(m,1H),4.90-4.91(m,1H),4.78-4.66(m,2H),4.61-4.54(m,3H),4.05-3.92(m,4H),3.76-3.63(m,1H),3.51-3.33(m,4H),3.13-2.98(m,3H),2.90(s,6H),2.35-2.31(m,1H),2.04-1.98(m,4H),1.67-1.54(m,3H),1.29(d,J＝6.8Hz,6H)。
Synthesized by the method of examples 69 and 70, using intermediate A3 or an analog thereof, to react with various commercially available carboxylic acids or acid chlorides to afford examples 71-73;
example 74: n- (2- (4- ((2- (4-aminopyridin-1-yl) -8-isopropylpyrazolo [1,5, -a ] [1,3,5] triazin-4-yl) amino) -3, 4-dihydroisoquinolin-2 (1H) -yl) piperidin-4-yl) acrylamide
The first step: the intermediate compound (1- (4- ((2- (4-aminopyridin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-4-yl) amino) -8-isopropylpyrazolo [1,5, -a)][1,3,5]Triazin-2-yl) piperidin-4-yl formylbenzyl ester (15 mg,0.02 mmol), potassium phosphate (20 mg,0.08 mmol) was dissolved in THF/H 2 To a mixed solution of O (6 mL/3 mL), 3-chloropropionyl chloride (4 mg,0.02 mmol) was added, and the mixture was reacted at room temperature for 2 hours. After dilution with water (30 mL), the mixture was extracted three times with methylene chloride (30 mL) and the combined organic phases were dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to give the crude intermediate product as a grey solid (18 mg).
LC-MS[M-H] - :m/z 721.4。
And a second step of: the intermediate compound (18 mg,0.02 mmol) was dissolved in trifluoroacetic acid (3 mL) and reacted at room temperature for 5 hours. After the reaction solution was diluted with 30mL of water, dichloromethane (30 mL) was extracted three times. The combined organic phases were dried over anhydrous sodium sulfate and the filtrate was concentrated under reduced pressure to give the crude intermediate. Dissolving the crude intermediate in THF/H 2 To a mixed solvent of O (6 mL/3 mL), naOH (2 mg,0.04 mmol) was added, and the reaction mixture was stirred at room temperature overnight. Adding into the reaction solutionWater (50 mL) was diluted, extracted three times with dichloromethane (50 mL), the combined organic phases were dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the resulting crude product was prepared by HPLC as a yellow solid as example 74 (4.35 mg). LC-MS [ M+H ]] + :m/z 553.3。 1 H NMR(400MHz,DMSO-d 6 ):δ8.67(s,1H),8.02(d,J＝6.0Hz,1H),7.86-7.82(m,2H),7.75(s,1H),7.36-7.30(m,3H),7.26-7.22(m,1H),6.98(d,J＝6.0Hz,1H),6.47-6.40(m,1H),6.33(dd,J＝17.0,2.0Hz,1H),5.87(d,J＝11.6Hz,1H),5.63-5.59(m,1H),4.84-4.56(m,5H),4.17-4.11(m,2H),4.03-3.92(m,2H),3.31-3.25(m,1H),3.01-2.84(m,3H),1.95-1.91(m,2H),1.55-1.35(m,2H),1.25(d,J＝6.8Hz,6H)。
Example 75: n- (2- (4- ((2- (4-aminopyrimidin-1-yl) -8-isopropylpyrazolo [1,5, -a ] [1,3,5] triazin-4-yl) amino) -3, 4-dihydroisoquinolin-2 (1H) -yl) piperidin-4-yl) acrylamide
The first step: the intermediate compound (1- (4- ((2- (4-aminopyrimidin-2-yl) -1,2,3, 4-tetrahydroisoquinolin-4-yl) amino) -8-isopropylpyrazolo [1,5, -a)][1,3,5]Triazin-2-yl) piperidin-4-yl) formylbenzyl ester (60 mg,0.09 mmol), triethylamine (67 mg,0.66 mmol) was dissolved in DCM (6 mL) and 3-chloropropionyl chloride (60 mg,0.47 mmol) was added under ice-cooling to react for 2 hours at room temperature. After dilution with water (20 mL), the mixture was extracted three times with dichloromethane (20 mL) and the combined organic phases were dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to give the crude intermediate product as a grey solid (68 mg). LC-MS [ M-H ]] - :m/z 722.5。
And a second step of: the intermediate compound (68 mg,0.09 mmol) was dissolved in acetonitrile (3 mL), and TMSI (3 drops) was added dropwise to the reaction solution, followed by reaction at room temperature for 1 hour. The reaction was quenched by the addition of methanol (3 mL). Concentrating under reduced pressure, dissolving the crude product in THF/H 2 To a mixed solution of O (6 mL/3 mL), naOH (38 mg,0.94 mmol) was added and the mixture was reacted at room temperature for 5 hours. Diluting with water (50 mL), extracting with dichloromethane (50 mL) three times, drying the combined organic phases over anhydrous sodium sulfate, concentrating the filtrate under reduced pressure, and preparing the crude product by HPLC to obtain ashThe compound of example 75 (1.6 mg) was coloured solid. LC-MS [ M+H ]] + :m/z 554.3。 1 H NMR(400MHz,CD 3 OD):δ8.19(d,J＝5.6Hz,1H),7.64(s,1H),7.48(d,J＝5.6Hz,1H),7.43(d,J＝7.6Hz,1H),7.34-7.25(m,3H),6.46-6.42(m,2H),5.82(dd,J＝9.2,2.8Hz,1H),5.57-5.55(m,1H),5.11(d,J＝17.2Hz,1H),4.97-4.86(m,3H),4.48-4.40(m,1H),4.28-4.24(m,1H),3.41-3.36(m,1H),3.06-3.00(m,3H),2.07-2.03(m,2H),1.62-1.58(m,2H),1.28(d,J＝6.8Hz,6H).
Synthesized by the method of example 56, intermediate A2 or an analog thereof is reacted with various commercially available carboxylic acids or acid chlorides to afford examples 76-77;
example 78: r-1- ((E) -4- (dimethylamino) but-2-enyl) piperidin-3-yl-4- ((8-isopropyl-2- (((R) -piperidin-3-yl) -oxy) pyrazolo [1,5, -a ] [1,3,5] triazin-4-yl) amino) -3, 4-dihydroisoquinolin-2 (1H) -carbonyl
The first step: to a solution of 4-amino-3, 4-dihydroisoquinoline-2 (1H) -carboxylic acid benzyl ester (500 mg,1.77 mmol) and triethylamine (335 mg,3.3 mmol) in dichloromethane (10 mL) was added intermediate B (436 mg,1.8 mmol). The reaction mixture was reacted at 60℃for 2 hours. After dilution with water (20 mL), the mixture was extracted three times with dichloromethane (20 mL) and the combined organic phases were dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to give the crude intermediate product as a gray solid (630 mg). LC-MS [ M-H ]] - :m/z 489.2。
And a second step of: to a solution (10 mL) of the intermediate (630 mg,1.29 mmol) in methylene chloride was added m-chloroperoxybenzoic acid (225 mg,1.30 mmol). The reaction mixture was reacted at room temperature for 2 hours. After dilution with aqueous sodium thiosulfate (20 mL) was added, the mixture was extracted three times with methylene chloride (20 mL), and the combined organic phases were dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to give the crude intermediate product as a gray solid (330 mg) )。LC-MS[M-H] - :m/z 521.2。
And a third step of: to the above intermediate compound (101 mg,0.19 mmol) in N, N-dimethylformamide (1 mL) under nitrogen, naH (7 mg,0.28 mmol) was then added. The reaction mixture was stirred at room temperature for 30 minutes. (S) -3-hydroxypiperidine-1-carbonyl tert-butyl ester (200 mg,1.0 mmol) was then added and the reaction was heated to 80℃overnight. After the reaction was cooled to room temperature, water (10 mL) was added, and extraction was performed twice with ethyl acetate (30 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting crude product was separated by HPLC to give a white solid (12.4 mg). LC-MS [ M+H ]] + :m/z 642.2。
Fourth step: pd/C (10 mg) was added to a solution of the above intermediate compound (12.4 mg,0.02 mmol) in ethyl acetate (2 mL), and after 3 times of hydrogen balloon displacement, the mixture was stirred at room temperature overnight for 2 days. After filtration through celite, concentration under reduced pressure gave crude product as a pale yellow solid (13 mg). LC-MS [ M+H ]] + :m/z 508.3。
Fifth step: to a solution of (S) -3-hydroxypiperidine-1-formylbenzyl ester (100 mg,0.43 mmol) in tetrahydrofuran (5 mL) under nitrogen was added triphosgene (148 mg,0.50 mmol). The reaction mixture was stirred at room temperature for 30 minutes. Then, after the above intermediate compound (50 mg,0.1 mmol) was added, the reaction was carried out at room temperature overnight. After addition of water (30 mL), extraction was performed with ethyl acetate (50 mL). The separated organic phase was dried over anhydrous sodium sulfate, and the crude product obtained after concentration under reduced pressure was separated by HPLC to give a white solid (40 mg). LC-MS [ M+H ] ] + :m/z 769.4。
Sixth step: pd/C (10 mg) was added to the above intermediate compound (40 mg,0.05 mmol) in ethyl acetate solution (5 mL), and after 3 times of hydrogen balloon displacement, the mixture was stirred at room temperature overnight for 2 days. After filtration through celite, concentration under reduced pressure gave crude product as a pale yellow solid (20 mg). LC-MS [ M+H ]] + :m/z 635.4。
Seventh step: the intermediate compound (20 mg,0.03 mmol) was dissolved in DMF (2 mL), and (E) -4- (dimethylamino) but-2-enoic acid (6 mg,0.04 mmol), HATU (16 mg,0.04 mmol), DIEA (21 mg,0.16 mmol) was added sequentially and stirred at room temperature for 5 hours. Water (8 mL) was added to the reaction solution, and a solid was precipitated. Drying the precipitated solid to obtain whiteCrude intermediate compound (20 mg) was a coloured solid. LC-MS [ M+H ]] + :m/z 746.4。
Eighth step: the intermediate compound (20 mg,0.03 mmol) was dissolved in acetonitrile (1 mL), and trimethyliodosilane (0.3 mL) was added thereto, followed by stirring at room temperature for 5 hours. After adding water (20 mL) to the reaction solution, extraction was performed twice with ethyl acetate (20 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the crude product was purified by HPLC to give a gray solid, example 78 (5 mg), LC-MS [ M+H] + :m/z 646.2。 1 H NMR(400MHz,MeOD-d 4 ):δ7.81-7.85(m,1H),7.28-7.39(m,4H),6.59-6.79(m,2H),5.47-5.56(m,2H),3.43-3.87(m,12H),3.05-3.29(m,3H),2.83-2.87(m,6H),1.86-2.18(m,6H),1.30-1.31(m,2H),1.20-1.29(m,7H)。
Synthesized by the method of example 78, intermediate A2 or an analog thereof is reacted with various commercially available carboxylic acids or acid chlorides to afford example 79-63;
Examples 82 and 83: (R, E) -1- (4- ((2- (4-aminopiperidin-1-yl) -8-isopropylpyrazolo [1,5, -a ] [1,3,5] triazin-4-yl) amino) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (dimethylamino) but-2-enoyl and (S, E) -1- (4- ((2- (4-aminopiperidin-1-yl) -8-isopropylpyrazolo [1,5, -a ] [1,3,5] triazin-4-yl) amino) -3, 4-dihydroisoquinolin-2 (1H) -yl) -4- (dimethylamino) but-2-enoyl
The first step: intermediate A2 (130 mg) was isolated via SFC chiral preparation to afford intermediate P1 (61 mg) and P2 (52 mg).
The preparation conditions are as follows: separation columnOD,250 x 25mm10 μm); gradient (mobile phase: A: supercritical CO) 2 B: etOH (+0.1% 7.0mol/l AmmoniainmeOH), A: B=60:40, 5min, flow rate 100 g/min). The retention times (Rt) on the preparation column for P1 and P2 were (rt=7.553min, P1) and (rt=6.741min, P2), respectively.
Analysis conditions: analytical column @OD-H,250 x 4.6mm,5 μm); gradient (mobile phase: A: supercritical CO) 2 EtOH (0.1% dea), a: b=60:40, 10min, flow 3.0 mL/min; column temperature: 35 ℃; detection wavelength: 214nM.
In a second step, intermediate compound P1 (61.0 mg,0.11 mol) and (E) -4- (dimethylamino) but-2-enoic acid (20.0 mg,0.12 mol) were dissolved in anhydrous DMF (3.0 mL) and HATU (54.0 mg,0.14 mol) and DIPEA (43.0 mg,0.33 mol) were added. The reaction solution was stirred at room temperature for 4 hours under nitrogen protection. After completion of the reaction by LCMS, water (8 mL) and saturated aqueous sodium carbonate (2 mL) were added, a white solid precipitated, the solid was filtered off and washed with water, and the filter cake was dried to give the white intermediate product P1-1 (56 mg). LC-MS [ M+H ] ] + :m/z 652.4。
Referring to the above synthetic method for P1-1, a white solid intermediate P2-1 (50 mg) was obtained.
In the third step, compound P1-1 (56.0 mg,0.09 mmol) was dissolved in acetonitrile (3 mL), and trimethyliodosilane (0.3 mL) was added thereto, and the mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. After completion of the LCMS reaction, the reaction was concentrated, 10mL of methanol was added thereto for concentration, and the procedure was repeated three times. The concentrated crude product was purified by HPLC to afford example 82 as a white solid (17.8 mg). LC-MS [ M+H ]] + :m/z 518.3。 1 H NMR(400MHz,MeOD-d 4 ):7.66(d,J＝6.4Hz,1H),7.45-7.26(m,4H),7.07(d,J＝14.8Hz,0.5H),6.84(d,J＝15.2Hz,0.5H),6.70-6.57(m,1H),5.52-5.47(m,1H),5.33(d,J＝17.6Hz,0.5H),5.07(d,J＝16.4Hz,0.5H),4.95-4.88(m,2H),4.83-4.82(m,0.5H),4.63-4.53(m,1H),4.40(dd,J＝14.0Hz,4.0Hz,0.5H),3.97-3.90(m,1.5H),3.82-3.73(m,1H),3.55-3.39(m,0.5H),3.38-3.31(m,1H),3.08-3.00(m,3H),2.90(s,3H),2.72(s,3H),2.09-2.07(m,2H),1.66-1.54(m,2H),1.30-1.27(m,6H)。
Referring to the procedure for the synthesis of the compound of example 82, example 83 (15.6 mg) was obtained as a white solid. LC-MS [ M+H ]] + :m/z 518.3。 1 H NMR(400MHz,MeOD-d 4 ):7.66(d,J＝4.8Hz,1H),7.44-7.25(m,4H),7.08(d,J＝15.2Hz,0.5H),6.87(d,J＝15.2Hz,0.5H),6.71-6.57(m,1H),5.52-5.47(m,1H),5.33(d,J＝17.6Hz,0.5H),5.07(d,J＝17.8Hz,0.5H),4.94-4.80(m,2H),4.85-4.83(m,0.5H),4.60-4.53(m,1H),4.41(dd,J＝14.0Hz,3.6Hz,0.5H),3.97-3.94(m,1.5H),3.85-3.74(m,1H),3.56-3.39(m,0.5H),3.38-3.31(m,1H),3.09-2.91(m,3H),2.90(s,3H),2.72(s,3H),2.10-2.07(m,2H),1.68-1.56(m,2H),1.30-1.27(m,6H)。
Synthesized by the method of examples 74, 78, 82 and 83, using intermediate A2 or an analog thereof, the reaction with various commercially available carboxylic acids or acid chlorides gave examples 84-93;
example 94:1- ((2- (4-aminopiperidin-1-yl) -8-isopropylpyrazolo [1,5, -a ] [1,3,5] triazin-4-yl) amino) -2, 3-dihydro-1H-indene-5-carbonitrile
The first step: intermediate A (50 mg,0.11 mmol), 5-bromo-2, 3-dihydro-1H-inden-1-amine (42 mg,0.2 mmol), DIEA (78 mg,0.6 mmol) was dissolved in acetonitrile (5 mL) under nitrogen and reacted at 70℃for 4H. Concentrating the reaction solution under reduced pressure to obtain crude productThe product was purified by silica gel column chromatography (PE: ea=2:1) to give the intermediate product (84 mg) as a yellow solid. LC-MS [ M+H ] ] + :m/z 604.2。
And a second step of: to the above intermediate (84 mg,0.14 mmol) and zinc cyanide (25 mg,0.21 mmol) in N, N-dimethylformamide (10 mL) under nitrogen was added tetrakis triphenylphosphine palladium (24 mg,0.02 mmol). The reaction mixture was heated to 110 degrees and reacted for 10 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE: ea=2:1) to give an intermediate product (50 mg) as a white solid. LC-MS [ M+H ]] + :m/z 551.2。
And a third step of: to a solution of the intermediate compound (50 mg,0.09 mmol) in acetonitrile (3 mL) under nitrogen, was added trimethyliodosilane (0.5 mL). Stirred at room temperature for 2 hours. After completion of the LCMS reaction, the reaction was concentrated under reduced pressure, then 10mL of methanol was added and concentrated again, and this was repeated three times. The concentrated crude product was purified by HPLC to give example 94 as a white solid (24 mg). LC-MS [ M+H ]] + :m/z 417.6. 1 H NMR(400MHz,MeOD-d 4 ):8.54(s,1H),7.68(s,1H),7.65(s,1H),7.54(d,J＝7.6Hz，1H),7.45(d,J＝8.0Hz,1H),5.77(t,J＝8.4Hz,1H),4.78-4.72(m,2H),3.31-3.30(m,1H),3.24-3.19(m,1H),3.12-3.05(m,4H),2.90-2.65(m,1H),2.30-2.20(m,1H),1.98-1.94(m,2H),1.54-1.41(m,2H),1.29(d,J＝6.8Hz,6H).
Example 95: (3- ((2- (4-aminopiperidin-1-yl) -8-isopropylpyrazolo [1,5, -a ] [1,3,5] triazin-4-yl) amino) -2, 3-dihydro-1H-inden-4-yl) dimethylphosphoryl oxide
The first step: intermediate A (30 mg,0.10 mmol), 5-bromo-2, 3-dihydro-1H-inden-1-amine (42 mg,0.20 mmol), DIEA (78 mg,0.6 mmol) was dissolved in acetonitrile (5 mL) under nitrogen and reacted at 70℃for 4H. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE: ea=2:1) to give a yellow solid intermediate product (34 mg). LC-MS [ M+H ] ] + :m/z 602.2。
And a second step of: combining the above intermediates under nitrogen protectionTo a solution of the material (34 mg,0.06 mmol) in acetonitrile (3 mL) was added trimethyliodosilane (0.5 mL). Stirred at room temperature for 2 hours. After completion of LCMS detection, the reaction was concentrated under reduced pressure and the crude product obtained was purified by HPLC to give example 95 compound as a white solid (5 mg). LC-MS [ M+H ]] + :m/z 468.5. 1 H NMR(400MHz,CDCl 3 ):7.50(s,1H),7.41(m,1H),7.35-7.32(m,2H),6.38(m,1H),5.96(m,1H),4.81-4.72(m,2H),3.26-2.97(m,4H),2.84-2.75(m,4H),2.39(m,2H),2.30(m,2H),2.12(m,2H),1.76-1.68(m,6H),1.20(m,6H).
Synthesized by the method of example 94, 95, intermediate A2 or an analog thereof is reacted with various commercially available carboxylic acids or acid chlorides to afford examples 96-98;
test example 1 enzyme Activity test
The inhibition rates of the example compounds on CDK7/CycH/MAT1 (Cana) and CDK9/CycT1 (Cana) kinases were tested using PHA-793887 and Dinaciclib as positive control compounds. The activity test of the compounds of the examples was carried out on 2 kinases using the method of Mobility shift assay.
The specific operation flow is as follows: (1) preparing a 1 XKinase buffer; (2) preparation of compound concentration gradient: test compounds were tested at 10000nM starting and diluted in 384source plates to 100-fold final concentration of 100% DMSO solution, 3-fold diluted compound, 10 concentrations. 250nL of 100-fold final concentration of compound was transferred to the destination plate 384-well-plate using a dispenser Echo 550. A2.5-fold final concentration of Kinase solution was prepared using a 1 XKinase buffer. (3) Adding 10 mu L of kinase solution with 2.5 times of final concentration to each of the compound well and the positive control well; to the negative control wells, 10. Mu.L of 1 XKinase buffer was added. (4) Centrifugation at 1000rpm for 30 seconds, the reaction plate was shaken and mixed well and incubated at room temperature for 10 minutes. (5) A5/3-fold final concentration of a mixed solution of ATP and Kinase substrate was prepared using a 1 XKinase buffer. (6) The reaction was initiated by adding 15. Mu.l of a 5/3-fold final concentration of the mixed solution of ATP and substrate. (7) The 384-well plate was centrifuged at 1000rpm for 30 seconds, and after shaking and mixing, incubated at room temperature for a corresponding period of time. (8) The kinase reaction was stopped by adding 30. Mu.l of stop detection solution, centrifuging at 1000rpm for 30 seconds, and shaking and mixing. (9) conversion was read with Caliper EZ Reader. (10) Calculation formula% inhibition=conversion% _ max -Conversion％_ sample/ Conversion％_ max -Conversion％_ min X 100, wherein: convergence% - sample Is a conversion reading of the sample; convergence% - min Is a negative control Kong Junzhi, representing a conversion reading without enzyme wells; convergence% - max Is a positive control Kong Junzhi representing a conversion reading without compound inhibition wells. The fitted amount effect curve takes the log value of the concentration as the X axis, the percent inhibition rate as the Y axis, and log (inhibitor) vs. response-Variable slope fitted amount effect curve of analytical software GraphPad Prism 5 is adopted, so that the IC50 value of each compound on the enzyme activity is obtained. The calculation formula is Y=bottom+ (Top-Bottom)/(1+10 ((LogIC) 50 -X)*Hill Slope))。
Results: most of the compounds of the examples of the present invention have higher CDK7 kinase inhibitory activity, and still show higher inhibitory activity (greater than 60% inhibition) at concentrations as low as 100 nM; and most of the example compounds showed weak inhibitory activity against CDK9, still showed low inhibitory activity (inhibition less than 50%) at a concentration of 1000 nM. Most of the example compounds showed higher CDK7/CDK9 kinase selectivity. (wherein inhibition ratio representing++ + + of the + > 80%;80 percent of <+++≤60％；60％<++≤30％；+<30％；IC 50 Represents A.ltoreq.20 nM;20nM<B≤100nM；100nM<C≤1000nM；D>1000nM。)
All documents mentioned in this application are incorporated by reference as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the claims appended hereto.

Claims (13)

1. An amino-substituted aromatic heterocyclic pyrazole compound shown in a general formula I, or pharmaceutically acceptable salt thereof, or enantiomer, diastereoisomer, tautomer and torsional isomer thereof,
wherein:
w is selected from CR w Or N; r is R w Independently selected from H, halogen, cyano, C1-C6 alkyl;
R 1 independently selected from the group consisting of C1-C10 alkyl, 3-10 membered cycloalkyl or heterocycloalkyl, C1-C10 alkoxy, 3-10 membered cycloalkyl or heterocycloalkyl ether, C1-C10 alkylamino, 3-10 membered cycloalkyl or heterocycloalkyl substituted amino; and the above alkyl, cycloalkyl, heterocycloalkyl groups may be substituted with one or several substituents selected from the group consisting of: halogen, deuterium, hydroxy, substituted or unsubstituted amino, C1-C6 alkyl, hydroxy substituted C1-C6 alkyl, amino substituted C1-C6 alkyl, C1-C6 alkoxy, 3-to 10-membered cycloalkyl or heterocycloalkyl substituted C1-C6 alkyl;
R 2 Independently selected from C1-C10 alkyl or haloalkyl, 3-8 membered cycloalkyl or heterocycloalkyl;
R a selected from hydrogen;
R b 、R c 、R d 、R e each independently selected from hydrogen;
m, n are each independently selected from integers from 0 to 3;
cy is selected from 5-12 membered monocyclic aromatic or heteroaromatic groups;
R 3 selected from hydrogen, deuterium, halogen, C1-C10 alkyl or haloalkyl, 3-to 10-membered cycloalkyl or heterocycloalkyl, 5-to 12-membered aryl or heteroaryl, substituted or unsubstituted amino, hydroxy, C1-C10 alkoxy or haloalkoxy, cyano, substituted or unsubstituted phosphoryl;
y is selected from N or CRy, ry is independently selected from hydrogen;
R 4 independently selected from hydrogen, deuterium, halogen, C1-C10 alkyl or haloalkyl, 3-10 membered cycloalkyl or heterocycloalkyl, 5-12 membered aryl or heteroaryl, substituted or unsubstituted acryloyl;
the above-mentioned substituted or unsubstituted substituents are each independently selected from the group consisting of: deuterium, halogen, hydroxy, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, C1-C6 alkyl or haloalkyl, 3-to 10-membered cycloalkyl or heterocycloalkyl, cyano, C1-C6 alkoxy or haloalkoxy;
wherein the heteroaryl group comprises 1 to 3 heteroatoms selected from the group consisting of: n, O, P or S, said heterocycloalkyl comprising 1 to 3 heteroatoms selected from the group consisting of: n, O, P or S.
2. The compound of claim 1, which is a compound of formula (II), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, or torsional isomer thereof:
wherein R is 1 、R 2 、R 3 、R 4 、R a 、R b 、R c 、R d 、R e Cy, W, m, n are as defined in claim 1.
3. The compound of claim 1, which is a compound of formula (III), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, or torsional isomer thereof:
wherein R is 1 、R 2 、R 3 、R 4 、R a 、R b 、R c 、R d 、R e Cy, W, m, n are as defined in claim 1.
4. The compound of claim 1, which is a compound of formula (IV), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, or torsional isomer thereof:
wherein Cy1 is selected from the group consisting of 5-10 membered aryl or heteroaryl groups, the other groups being as defined in claim 1.
5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, or torsional isomer thereof, which is a compound represented by formula V:
wherein R is 1 Selected from the group consisting of C1-C6 alkyl, substituted or unsubstituted 5-6 membered saturated ring, substituted or unsubstituted 5-6 membered saturated cyclic ether, substituted or unsubstituted 5-6 membered saturated cyclic amine, substituted or unsubstituted 5-6 membered saturated cyclic C1-C6 alkylene ether, substituted or unsubstituted 5-6 membered saturated cyclic group A C1-C6 alkylene amine group; the substituent is selected from deuterium, halogen, amino, hydroxyl, dimethylamino, methoxy, hydroxymethyl and aminomethyl;
R 3 、R 4 the ranges of W, m and n are defined in claim 1.
6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, or torsional isomer thereof, wherein: r is R 1 Selected from the group consisting of methyl, substituted or unsubstituted cyclohexenyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted cyclohexenyl ether, substituted or unsubstituted piperidinyl ether, substituted or unsubstituted tetrahydropyranyl ether, substituted or unsubstituted cyclohexanylamino, substituted or unsubstituted piperidylamino, substituted or unsubstituted tetrahydropyranyl amino, substituted or unsubstituted piperidinyl methylene ether, substituted or unsubstituted piperidinyl methylene amine; the substituent is selected from deuterium, halogen, amino, hydroxyl, dimethylamino, methoxy, hydroxymethyl and aminomethyl.
7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, or torsional isomer thereof, wherein:
R 1 Independently selected from the group consisting of C1-C6 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C1-C6 alkoxy, 5-8 membered heterocycloalkyl-O-, C1-C6 alkyl-substituted amino, 3-8 membered cycloalkyl-substituted amino, 3-8 membered heterocycloalkyl-substituted amino; the R is 1 The 1 or more hydrogen atoms on may be optionally substituted with: halogen, hydroxy, amino, mono C1-C3 alkylamino, di C1-C3 alkylamino, C1-C3 alkyl, hydroxy-substituted C1-C3 alkyl, amino-substituted C1-C3 alkyl, 3-8 membered cycloalkyl C1-C3 alkyl-, 3-8 membered heterocycloalkyl-C1-C3 alkyl-, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl;
alternatively, R 2 Independently selectFrom C1-C6 alkyl, C1-C6 haloalkyl, 3-8 cycloalkyl or 3-8 heterocycloalkyl;
alternatively, cy is selected from 6-10 membered monocyclic aromatic groups, 5-10 membered monocyclic heteroaromatic groups;
alternatively, R 3 Selected from hydrogen, deuterium, halogen, hydroxy, cyano, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkyl, C1-C6 haloalkyl, 3-to 6-membered cycloalkyl or heterocycloalkyl, 6-to 10-membered aryl, 5-to 8-membered heteroaryl, substituted or unsubstituted amino, substituted or unsubstituted phosphoryl;
alternatively, R 4 Independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 haloalkyl, 3-6 cycloalkyl, 3-6 heterocycloalkyl, 6-10 aryl, 5-8 heteroaryl, 3-6 cycloalkyl-C (O) -, 3-6 heterocycloalkyl-C (O) -, 3-6 cycloalkyl-O-C (O) -, 3-6 heterocycloalkyl-O-C (O) -, 6-10 aryl-C (O) -, 5-8 heteroaryl-C (O) -; the R is 4 Optionally by R 41 Substitution, said R 41 Independently selected from: halogen, hydroxy, cyano, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, C1-C6 alkyl, C1-C6 haloalkyl, 3-6 membered cycloalkyl or heterocycloalkyl, C1-C6 alkoxy or haloalkoxy, C2-C6 alkenyl-C (O) -; the R is 41 May be further substituted with: halogen, hydroxy, cyano, mono C1-C6 alkylamino, di C1-C6 alkylamino.
8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, or torsional isomer thereof, wherein:
R 1 is that
Alternatively, R 2 Methyl, isopropyl;
alternatively, R 3 H, F, cl, CN, CH of a shape of H, F, cl, CN, CH 3 、CH 3 O-、CF 3 、
Alternatively, R 4 H, CH of a shape of H, CH 3 Isopropyl group,
9. An amino-substituted aromatic heterocyclic pyrazole compound, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, or torsional isomer thereof, characterized in that the compound has the following structure:
10. the use of a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, or stereoisomer thereof, for the manufacture of a medicament for the prevention, treatment, or alleviation of a disorder or a disease mediated by aberrant activity of CDK kinase, which disease is cancer, benign neoplasm, inflammatory disease, autoinflammatory disease, autoimmune disease, or infectious disease; the autoimmune disease is independently selected from rheumatoid arthritis, systemic lupus erythematosus, idiopathic thrombocytopenic purpura, hemolytic anemia, or psoriasis; the inflammatory disease is independently selected from osteoarthritis, gouty arthritis, ulcerative colitis and/or inflammatory bowel disease; the infectious disease is independently selected from sepsis, septic shock, endotoxic shock, gram negative sepsis and/or toxic shock syndrome.
11. The use according to claim 10, wherein the CDK kinase is a CDK7 kinase.
12. The use of claim 10, wherein the cancer is leukemia, melanoma, multiple myeloma.
13. A pharmaceutical composition, said pharmaceutical composition comprising:
(i) An effective amount of a compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, or torsional isomer thereof; and
(ii) A pharmaceutically acceptable carrier.
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