CN117222636A - Deuterated compounds as CDK4/6 inhibitors - Google Patents

Deuterated compounds as CDK4/6 inhibitors Download PDF

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Publication number
CN117222636A
CN117222636A CN202280027775.0A CN202280027775A CN117222636A CN 117222636 A CN117222636 A CN 117222636A CN 202280027775 A CN202280027775 A CN 202280027775A CN 117222636 A CN117222636 A CN 117222636A
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compound
acid
formula
pharmaceutically acceptable
acceptable salt
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尹磊
姚郑林
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Gan and Lee Pharmaceuticals Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

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Abstract

The invention relates to a deuterated compound serving as a CDK4/6 inhibitor, a preparation method thereof, a pharmaceutical composition containing the deuterated compound and application thereof, and compared with a non-deuterated control compound, the deuterated compound has better metabolic stability and better pharmacokinetic property, and is expected to reduce clinical application dose.

Description

Deuterated compounds as CDK4/6 inhibitors Technical Field
The invention belongs to the field of pharmaceutical chemistry, and in particular relates to a deuterated compound serving as a CDK4/6 inhibitor, a preparation method thereof, a pharmaceutical composition containing the deuterated compound and application thereof.
Background
Cyclin-dependent protein kinases (Cyclin Dependent Kinase, CDKs) are a class of serine/threonine kinases that act as important signal transduction molecules within cells, and Cyclin (Cyclin) forms CDK-Cyclin complexes that are involved in cell growth, proliferation, dormancy, or entry into apoptosis.
Currently 13 members of the CDK family, CDK1-CDK13 respectively, have been found, with CDK1, CDK2, CDK3, CDK4 and CDK6 being involved in regulating cell proliferation. The Cyclin is divided into A-L, and different CDKs are respectively connected with the Cyclin of different subtypes. Wherein the Cyclin D family (Cyclin D1, D2, D3) begins to express in the G1 phase, binds to and activates CDK4 and CDK6, forming CDK4/6-Cyclin D complexes, phosphorylating a range of substrates including retinoblastoma proteins. CDK 4/6-specific activation is closely related to proliferation of some tumors, and therefore development of CDK4/6 inhibitors is an effective means of targeted treatment of tumors.
5-fluoro-4- (7 '-fluoro-2' -methyl-spiro [ cyclopentane-1, 3 '-indol ] -5' -yl) -nitrogen- (5- (1-methylpiperidin-4-yl) pyridin-2-yl) pyrimidin-2-amine (hereinafter referred to as "control compound 1") is a highly selective CDK4/6 inhibitor. The structural formula of the medicine is as follows:
the synthesis method is described in WO2017/092635A 1.
Many drugs have limited their use in certain diseases due to poor absorption, distribution, metabolism and excretion (ADME) properties, and are responsible for many drug candidates failing clinical trials. Although special formulation techniques or prodrug technology may improve the ADME properties of some drugs in some cases, the ADME problem presented by most drug candidates is not solved effectively, especially for rapid metabolism of the drug, resulting in difficulty in preparing many drugs that would otherwise be effective in treating the disease due to too rapid metabolism away from the body.
Thus, there remains a need for compounds having CDK4/6 inhibitory activity, and which have better metabolic stability, longer half-life, and better pharmacokinetic properties.
Disclosure of Invention
The invention aims to provide a compound with CDK4/6 inhibitory activity, good pharmacokinetic property and reduced toxic and side effects.
The first aspect of the present invention provides a compound of formula (I):
wherein R is 1 -R 29 H or D, respectively, and R 1 -R 29 At least one of which is D; and
the compound of formula (I) excludes the following compounds:
in one embodiment, wherein R 1 -R 15 And R 17 -R 29 At least one of which is D; preferably, R 1 -R 15 、R 17 And R 19 -R 29 At least one of which is D; preferably, R 1 -R 12 、R 17 、R 19 -R 29 At least one of which is D; preferably, R 1 -R 3 、R 8 -R 9 、R 17 、R 21 、R 23 、R 27 -R 29 At least one of which is D.
In one embodiment, wherein R 1 -R 3 Is D; and/or R 8 And R is 9 Is D; and/or R 13 -R 15 Is D; and/or R 16 Is D; and/or R 17 Is D; and/or R 18 Is D; and/or R 21 And R is 23 Is D; and/or R 27 -R 29 Is D.
In one embodiment, wherein R 1 -R 3 Is D; and/or R 8 And R is 9 Is D; and/or R 13 -R 15 Is D; and/or R 17 Is D; and/or R 21 And R is 23 Is D; and/or R 27 -R 29 Is D.
In one embodiment, wherein R 1 -R 3 Is D; and/or R 8 -R 9 Is D; and/or R 17 Is D; and/or R 21 And R is 23 Is D; and/or R 27 -R 29 Is D.
In one embodiment, wherein R 16 Is H, or R 13 -R 15 Is H, or R 18 Is H.
In one embodiment, wherein, when R 16 When D is R 1 -R 3 Is D, and R 13 -R 15 Is D; and/or R 1 -R 3 Is D, R 8 -R 9 Is D, and R 13 -R 15 Is D; and/or R 21 And R is 23 Is D; and/or R 27 -R 29 Is D; and/or R 17 Is D and R 27 -R 29 Is D; and/or R 21 Is D, R 23 Is D, and R 27 -R 29 Is D; and/or R 1 -R 3 Is D, R 21 Is D, R 23 Is D, and R 27 -R 29 Is D.
In one embodiment, the compound has a structure of formula (II):
wherein R is 1 、R 2 、R 3 At least one of them is D, R 13 -R 15 H or D, respectively; preferably, R 1 、R 2 And R 3 Is D, R 13 -R 15 H or D, respectively; more preferably, R 1 、R 2 And R 3 Is D, R 13 -R 15 At least one is D.
In one embodiment, the compound has a structure represented by formula (III):
wherein R is 1 -R 3 、R 8 -R 9 、R 13 -R 15 H or D, respectively; preferably, R 1 -R 3 Is D, and/or R 8 -R 9 Is D, and/or R 13 -R 15 Is D; preferably, R 1 -R 3 Is D, and R 13 -R 15 Is D; preferably, R 1 -R 3 Is D, R 8 -R 9 Is D, and R 13 -R 15 Is D.
In one embodiment, the compound has a structure of formula (IV):
wherein R is 1 -R 15 At least one of which is D; preferably, R 1 -R 3 Is D, and/or R 8 -R 9 Is D.
In one embodiment, the compound has a structure represented by formula (V):
wherein R is 1 -R 3 、R 13 -R 16 H or D, respectively; preferably, R 1 -R 3 Is D, and/or R 13 -R 15 Is D.
In one embodiment, the compound has the structure of formula (VI):
wherein R is 1 -R 3 、R 8 、R 9 、R 13 -R 16 H or D, respectively; preferably, R 1 -R 3 Is D, and/or R 13 -R 15 Is D, and/or R 8 And R is 9 Is D; preferably, R 16 Is D.
In one embodiment, the compound has a structure of formula (VII):
Wherein R is 1 -R 3 、R 8 、R 9 、R 13 -R 26 H or D, respectively; preferably, R 1 -R 3 Is D; and/or R 8 And R is 9 Is D; and/or R 13 -R 15 Is D; and/or R 16 Is D; and/or R 17 Is D; and/or R 21 And R is 23 Is D.
In a preferred embodiment, the compound is selected from:
the term "compounds of the invention", unless otherwise specified, refers to compounds of formula (I) and salts thereof, including pharmaceutically acceptable salts of the compounds as well as all stereoisomers (including but not limited to diastereomers and enantiomers), tautomers, isotopic compounds, prodrugs, solvates, and hydrates thereof.
The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness of the free acids and bases of the particular compounds without biological adverse effects. Examples of pharmaceutically acceptable salts include, but are not limited to: (1) Acid addition salts, and salts formed with inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid, phosphoric acid, and the like; or with organic acids such as malic acid, fumaric acid, maleic acid, benzoic acid, phenylacetic acid, succinic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, glycolic acid, cinnamic acid, pyruvic acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, acrylic acid, mandelic acid, and the like; or (2) a salt of an alkali addition salt, and a salt of an alkali metal such as lithium, sodium, potassium, or the like; and alkaline earth metals such as calcium, magnesium, etc.; and organic bases such as ammonium, choline, diethanolamine, lysine, ethylenediamine, t-butylamine, t-octylamine, tris (hydroxymethyl) aminomethane, N-methylglucamine, triethanolamine, dehydroabietylamine, and the like. Other pharmaceutically acceptable salts are known to those skilled in the art.
The term "isotopic compound" means that the compound of formula (I) of the present invention contains one or more atomic isotopes of natural or unnatural abundance. Non-naturally abundant atomic isotopes include, but are not limited to, deuterium @, and 2 h or D) tritium 3 H or T) and iodine-125% 125 I) Phosphorus-32% 32 P), carbon-13% 13 C) Or C-14% 14 C) A. The invention relates to a method for producing a fibre-reinforced plastic composite Any atom of a compound synthesized in the present invention may represent any stable isotope of that atom unless specifically indicated. Unless otherwise specified, when a position in the structure is defined as H, i.e., hydrogen (H-1), that position contains only the naturally occurring isotope amount (0.015%).
"deuterium" or "D" refers to an isotope of hydrogen, the core of which contains one proton and one neutron. When a particular position is designated as containing deuterium, it is understood that the abundance of deuterium at that position is greater than the natural abundance of deuterium (typically 0.015%). Unless otherwise indicated, when a position is specifically designated as "D" or "deuterium," that position should be understood to contain deuterium that is more abundant than the natural abundance of deuterium.
The deuteration rate of a compound synthesized in the present invention refers to the ratio of the content of the synthesized isotope to the amount of the naturally occurring isotope. The deuteration of each designated deuterium atom of a compound synthesized in the present invention may be at least 3333.3 times (50%), at least 4000 times (60%), at least 4500 times (67.5%), at least 5000 times (75%), at least 5333.3 times (80%), at least 6000 times (90%), at least 6333.3 times (95%), at least 6466.7 times (97%), at least 6566.7 times (98.5%), at least 6600 times (99%), at least 6633.3 times (99.5%).
Synthesized in the inventionThe amount of hydrogen isotopologue at a position in the compound depends on a number of factors, including the deuterating agent (e.g., D 2 O、D 2 、NaBD 4 、LiAlD 4 Etc.) deuterium isotope purity and the effectiveness of the method of synthesizing the introduced deuterium isotopes. However, the total number of hydrogen isotopologues at such a position will be less than 49.9% as previously described. The total amount of hydrogen isotopologues at a position in the compound synthesized in the present invention will be less than 47.5%, 40%, 32.5%, 25%, 17.5%, 10%, 5%, 3%, 1% or 0.5%.
Any individual atom not designated as deuterium herein exists in its natural isotopic abundance.
The term "solvate" refers to a form of the compound of the present patent invention that forms a complex, either solid or liquid, by coordination with a solvent molecule. Examples of such forms are hydrates, alkoxides, and the like.
The term "prodrug" refers to any agent that is converted in vivo to the parent drug. Prodrugs are often useful because, in some cases, they are easier to administer than the parent drug. For example, by oral administration, they are bioavailable, whereas the parent drug is not. Prodrugs may also improve solubility in pharmaceutical compositions relative to the parent drug. Prodrugs can be converted to the parent drug via enzymatic methods as well as metabolic hydrolysis pathways.
In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.
The pharmaceutical compositions of the present invention may be administered by a variety of routes, depending upon whether local or systemic treatment and the area being treated is desired. Topical (e.g., transdermal, dermal, ocular, and mucosal including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal), oral, or parenteral administration. Parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration.
Some examples of acceptable carriers or excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose and the like. The pharmaceutical composition may further comprise: lubricants such as talc, magnesium stearate and mineral oil; a wetting agent; emulsifying and suspending agents; preservatives such as methyl benzoate and hydroxypropyl benzoate; sweeteners and flavoring agents. The pharmaceutical compositions of the present invention may be formulated so as to provide immediate, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
The compositions may be formulated in unit dosage form, with each dose containing from about 5 to 1000mg, more typically from about 100 to 500mg, of the active ingredient.
The compounds of the invention are CDK4/6 inhibitors and are therefore capable of treating diseases in which the underlying pathology is mediated, at least in part, by CDK 4/6. Such diseases include cancer and other diseases in which there is a disorder of cell proliferation, apoptosis or differentiation.
Examples of cancers that may be treated with the compounds of the present invention include, but are not limited to, cancers such as bladder cancer, breast cancer, colon cancer (e.g., colorectal cancer, such as colon adenocarcinoma and colon adenoma), kidney cancer, epidermis cancer, liver cancer, lung cancer (e.g., adenocarcinoma, small cell lung cancer and non-small cell lung cancer), esophagus cancer, gall bladder cancer, ovarian cancer, pancreatic cancer (e.g., exocrine pancreatic cancer), stomach cancer, cervical cancer, thyroid cancer, nasal cancer, head and neck cancer, prostate cancer, and skin cancer (e.g., squamous cell carcinoma). Other examples of cancers that may be treated with the compounds of the invention include hematopoietic tumors of lymphoid lineage (e.g., leukemia, acute lymphoblastic leukemia, mantle cell lymphoma, chronic lymphoblastic leukemia, B-cell lymphoma (e.g., diffuse large B-cell lymphoma), T-cell lymphoma, multiple myeloma, hodgkin's lymphoma, non-hodgkin's lymphoma, multicellular lymphoma, and burkitt's lymphoma); hematopoietic tumors of the myeloid lineage, such as acute and chronic myelogenous leukemia, myelodysplastic syndrome, and promyelocytic leukemia. Other cancers include thyroid follicular cancer; tumors of interstitial origin, such as fibrosarcoma or rhabdomyosarcoma (habdomyosacoma); tumors of the central or peripheral nervous system, such as astrocytomas, neuroblastomas, gliomas or schwannomas; melanoma; seminoma; teratocarcinoma; osteosarcoma; xeroderma pigmentosum; retinoblastoma; keratoacanthoma (keratoctanthoma); thyroid follicular carcinoma; and kaposi's sarcoma.
In a further aspect the present invention provides a method of treating a CDK4/6 mediated disorder or disease comprising administering to a patient suffering from said cell proliferative disorder an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, by oral or non-oral route.
In a further aspect the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of a CDK4/6 mediated disorder or disease.
In another aspect the invention provides a compound, or pharmaceutically acceptable salt thereof, for use in the treatment of a CDK4/6 mediated disorder or disease.
Preferably, the above-mentioned disorders or conditions caused by abnormal cell proliferation in mammals, including humans, refer to cancers of mammals or humans, more preferably to cancers of humans, including malignant solid tumors and malignant non-solid tumors, including in particular but not limited to breast cancer, lung cancer, prostate cancer, leukemia, brain cancer, glioma and gastric cancer; and/or the cell proliferation disorder disease is selected from one or more of aids, atherosclerosis, and restenosis after stent implantation.
In yet another aspect, the present invention provides a process for preparing a compound of formula (VII), comprising the steps of: reacting a compound of formula (VIII) with a deuterating agent in the presence of an acid to provide a compound of formula (VII)
Wherein R is 1 -R 3 、R 8 、R 9 、R 13 -R 26 H or D, respectively.
Preferably, the acid is selected from at least one of deuterated hydrochloric acid, ferric trichloride, aluminum trichloride, zinc chloride, acetic acid, acetic anhydride, trifluoroacetic acid, trifluoroacetic anhydride, trifluoromethanesulfonic acid, benzoic acid, p-methylbenzoic acid, p-nitrobenzoic acid, p-methoxybenzoic acid, 3, 5-dinitrobenzoic acid, diphenylphosphoric acid, phenylphosphinic acid, phosphoric acid, hypophosphorous acid, phenylacetic acid, phenylpropionic acid, trimethylacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, mandelic acid, and salicylic acid; and/or the deuterated reagent is selected from d 6 -DMSO、d 7 -DMF、d 6 Acetone, CD 3 OD、D 2 O、CD 3 CN, and C 6 D 6 At least one of (a) and (b); more preferably, the acid is deuterated hydrochloric acid and/or the deuterating agent is D 2 O。
Preferably, R in the above method 1 -R 3 Is D; and/or R 8 And R is 9 Is D; and/or R 13 -R 15 Is D; and/or R 16 Is D; and/or R 17 Is D; and/or R 21 And R is 23 Is D.
The preparation method realizes deuteration only on hydrogen on methyl on 3H-indole ring of the control compound 1, and has extremely strong selectivity.
In yet another aspect, the present invention provides a compound of formula (IX) or a pharmaceutically acceptable salt thereof,
wherein R is 18 -R 29 H or D, respectively; x is a leaving group or amino; preferably, X is halogen or amino, more preferably fluorine Bromine, chlorine or amino.
In yet another aspect, the present invention provides a process for preparing a compound of formula (I), comprising converting a compound of formula (IX) to a compound of formula (I):
wherein: r is R 17 Is D; and R is 1 -R 16 And R is 18 -R 29 H or D, respectively, preferably R 1 -R 3 Is D, and/or R 13 -R 15 Is D, and/or R 16 Is D.
In yet another aspect, the present invention provides a process for preparing a compound of formula (IX), comprising the steps of: reacting a compound of formula (X) or a salt thereof with a compound of formula (XI) in the presence of an acid to give a compound of formula (IX):
wherein R is 18 -R 29 H or D, respectively, preferably R 18 -R 29 Is hydrogen; x is a leaving group or amino; preferably, X is halogen or amino, more preferably fluoro, bromo, chloro or amino; and/or salts of the compounds of formula (X) are selected from the group consisting of hydrochloride, sulfate, mesylate and p-toluenesulfonate, preferably hydrochloride.
Preferably, the acid is an organic acid, an inorganic acid, or a lewis acid; preferably the acid is sulfuric acid, hydrochloric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, znCl 2 、FeCl 3 、AlCl 3 Or SnCl 4 The method comprises the steps of carrying out a first treatment on the surface of the Preferably, the acid is sulfuric acid.
Preferably, the above preparation method further comprises the steps of:
(1) Make the following stepsReaction with deuterated reagent to obtain
(2) Make the following stepsConversion to(X) or a salt thereof.
Preferably, the step (1) is carried out at Ir (OMe) (cod) 2 In the presence of; the deuterated reagent is selected from d 6 -DMSO、d 7 -DMF、d 6 Acetone, CD 3 OD、D 2 O、CD 3 CN, and C 6 D 6 At least one of (a) and (b); preferably, the deuterated reagent is D 2 O。
Hydrogen at certain positions on the drug molecule is also not easily deuterated due to steric hindrance and the like, and the compound of the formula (IX) is an important intermediate for synthesizing the compound of the formula (I), and R is synthesized by the inventor by a specific method 17 The compound of formula (IX) as D and the compound of formula (IX) is used as an intermediate to further synthesize an end product, thereby achieving the technical effect of deuterating hydrogen at a specific site of the control compound 1.
The invention has the beneficial effects that:
1) The compounds of the invention have comparable or superior inhibitory activity against human brain glioma U87MG cells compared to control compound 1.
2) The compounds of the present invention have better metabolic stability and superior pharmacokinetic properties in human liver microsomes than control compound 1, and are expected to reduce the clinically used dose, thereby reducing the cost of treatment to benefit more patients.
3) The invention also provides a method for realizing deuteration on hydrogen at a specific position of the control compound 1, which has extremely strong selectivity and specificity.
Abbreviations:
1atm: 1atm
ADME absorption, distribution, metabolism, excretion of drugs
C-D carbon deuterium bond
C-H hydrocarbon bond
CDK cyclin dependent kinase
CDCl 3 Deuterated chloroform
DAPI:4', 6-diamidino-2-phenylindole
DMSO-dimethyl sulfoxide
DMSO-d 6 Deuterated dimethyl sulfoxide
DMF N, N-dimethylformamide
DCM: dichloromethane
DCl deuterated hydrochloric acid
dtbpy 4,4 '-di-tert-butyl-2, 2' -bipyridine
EA ethyl acetate
FBS: fetal bovine serum
Grubbs Cat 1st Bis (tricyclohexylphosphine) benzylidene ruthenium dichloride
1 H-NMR hydrogen Spectroscopy
HPLC: high pressure liquid chromatography
Ir(OMe)(cod) 2 Methoxy (cyclooctadiene) iridium (I) dimer
LiAlD 4 Deuterated lithium aluminum tetrahydride
MeOH methanol
MEM minimum essential Medium
NaBD 4 Deuterated sodium borohydride
NEAA-nonessential amino acids
NBS N-bromosuccinimide
Pd/C palladium on carbon
PE Petroleum ether
PBS: phosphate buffer
Pd 2 (dba) 3 Tris [ dibenzylideneacetone ]]Dipalladium
Pd(pph 3 ) 4 Tetra (triphenylphosphine) palladium
Pd(dppf)Cl 2 1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride
SnCl 2 Tin dichloride
TLC thin layer chromatography
THF tetrahydrofuran
xant-phos 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene
Detailed Description
The experimental methods in the following examples are conventional methods unless otherwise specified. The chemical materials, reagents, etc. used in the examples described below were commercially available products unless otherwise specified.
Example 1 5-fluoro-4- (7 ' -fluoro-2 ' -methyl-spiro [ cyclopentane-1, 3' -indole)]-5' -yl) -nitrogen- (5- (1- (methyl- [ D) 3 ]) -piperidin-4-yl) pyridin-2-yl) pyrimidin-2-amine (compound 1)
Step 1) 6-nitro-3 ',6' -dihydro- [3,4' -bipyridine ] -1' (2 ' H) -carboxy tert-butyl ester
To a reaction flask was added 5-bromo-2-nitropyridine (20.0 g,99.05 mmol), 4- (4, 5-tetramethyl-1, 3, 2-dioxoboric acid-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxyl tert-butyl ester (33.44 g,108.16 mol), 1, 4-dioxane/water (200 mL/20 mL), potassium carbonate (40.2 g,291.3 mmol), pd (pph) 3 ) 2 Cl 2 (0.692 g,0.985 mmol). The mixture was heated to 80 ℃ under nitrogen for 12 hours, cooled to room temperature, concentrated, and separated by column chromatography (PE/ea=1:1-DCM/meoh=20:1) to give 19g of the title product as a yellow solid. MS (ESI): 306.1[ M+H ]] + 。
Step 2) 4- (6-aminopyridin-3-yl) piperidin-1-carboxytert-butyl ester
Into a reaction flask was charged 6-nitro-3 ',6' -dihydro- [3,4' -bipyridine]-1 '(2' h) -carboxyl tert-butyl ester (1.0 g,3.27 mmol), ethyl acetate/methanol (6 mL/6 mL), pd/C (0.2 g), hydrogen (1 atm) was introduced, heated to 50 ℃ for 6 hours, filtered, concentrated to give the title product 802mg as off-white solid. MS (ESI) 278.2[ M+H ]] + 。
Step 3) 5- (1- (methyl- [ D) 3 ]) Piperidin-4-yl) pyridin-2-amines
4- (6-Aminopyridin-3-yl) piperidine-1-carboxylic tert-butyl ester (700.0 mg,2.53 mmol) was dissolved in tetrahydrofuran (14 mL) and deuterated lithium aluminum hydride (253.4 mg,6.03 mmol) was slowly added at low temperature. Then heating to 70 ℃ for reaction for 3 hours. After completion of the reaction, the reaction was quenched by addition of ice, extracted, concentrated, and column chromatographed (DCM/meoh=20:1-10:1) to give 459mg of the title compound as an off-white solid. MS (ESI): 195.3[ M+H ]] + 。
Step 4) 5-fluoro-4- (7 ' -fluoro-2 ' -methyl-spiro [ cyclopentane-1, 3' -indole)]-5' -yl) -nitrogen- (5- (1- (methyl- [ D) 3 ]) -piperidin-4-yl) pyridin-2-yl) pyrimidin-2-amine
Sequentially adding 5'- (2-chloro-5-fluoropyrimidin-4-yl) -7' -fluoro-2 '-methyl spiro [ cyclopentane-1, 3' -indole into a reaction bottle](150.0 mg,0.449 mmol), 5- (1- (methyl- [ D) 3 ]) Piperidin-4-yl) pyridin-2-amine (78.4 mg,0.404 mmol), palladium acetate (10.05 mg,0.0448 mmol), xant-phos (25.95 mg,0.0448 mmol) and potassium carbonate (185.9 mg,1.347 mmol) were dissolved in toluene (10 mL) and water (2 mL) and then nitrogen was purged and heated to 100deg.C for 2 hours. After the reaction, the reaction mixture was concentrated, extracted, separated by celite, concentrated further, TLC separated and HPLC purified and lyophilized to give 90mg of the title compound as a white solid. MS (ESI): 492.3[ M+H ] ] + 。 1 H-NMR(400MHz,CDCl 3 )δ8.45(d,J＝3.6Hz,2H),8.35(d,J＝8.6Hz,1H),8.29-8.22(m,1H),7.97(s,1H),7.90(d,J＝11.0Hz,1H),7.62(d,J＝8.7Hz,1H),3.21-3.20(d,J＝11.4Hz,2H),2.65-2.53(m，1H),2.40(s,3H),2.37-2.26(m，2H),2.23-1.97(m，8H),1.96-1.87(m,4H)。
Example 2 5-fluoro-4- (7 '-fluoro-2' -methyl-spiro [ cyclopentane-1, 3 '-indol ] -5' -yl) -nitrogen- (5- (1- (methylpiperidin-4-yl) pyridin-2-yl) pyrimidin-6- [ D ] -2-amine (compound 5)
Step 1) 5-fluoropyrimidin-2, 4 (1H, 3H) -one-6- [ D ]
To a sealed iron can was added 5-fluorouracil (5.0 g,38.4 mmol) followed by heavy water (40 mL). Then heated to 190℃for 3 hours. After the reaction, it was cooled to room temperature and filtered to give 4g of the title compound as a yellow solid. MS (ESI): 130.2[ M-H ]] + 。
Step 2) 2, 4-dichloro-5-fluoropyrimidine-6- [ D ]
Sequentially adding 5-fluoropyrimidine-2, 4 (1H, 3H) -ketone-6- [ D into a reaction bottle](2.0 g,15 mmol), N, N-diisopropylethylamine (0.96 g,7.9 mmol) and phosphorus oxychloride (7 mL). Then heated to 110℃for 2 hours. After completion of the reaction, the solvent was dried by spinning, ice cubes were added to the reaction flask, followed by extraction, separation, drying over anhydrous sodium sulfate, filtration, concentration, and column chromatography to give the title compound 1.3g as a pale yellow oil. MS (ESI) 168.1[ M+H ]] + 。
Step 3) 5'- (2-chloro-5-fluoropyrimidin-4-yl-6- [ D ]) -7' -fluoro-2 '-methyl spiro [ cyclopentane-1, 3' -indole ]
Isopropanol (15 mL) and 5 '-bromo-7' -fluoro-2 '-methyl spiro [ cyclopentane-1, 3' -indole were added to the reaction flask under nitrogen protection](1.2 g,4.25 mmol), potassium acetate (0.5 g,5.1 mmol) and bis-pinacolato borate (1.2 g,4.67 mmol) were stirred and 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride (0.34 g,0.425 mmol) was added. Heating to 85+/-5 ℃ and preserving heat for reaction for 12 hours. The reaction solution was concentrated under reduced pressure, then purified water and ethyl acetate were added for extraction, the solution was separated, and the aqueous phase was discarded. The resulting organic phase was filtered and concentrated under reduced pressure to afford the intermediate. The intermediate and toluene (20 mL) were transferred to a reaction flask and stirred, then 2, 4-dichloro-5-fluoropyrimidine-6- [ D was added ](1.2 g,3.6 mmol) and potassium phosphate (1.94 g,7.2 mmol), and 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride (0.26 g,0.36 mmol) was added to the reaction flask, followed by addition of purified water (6 mL), heating to 85.+ -. 5 ℃ and incubating for 3 hours. After the reaction, concentration, extraction, separation, drying over anhydrous sodium sulfate, filtration, concentration and column chromatography gave the title compound as a pale yellow oil (1.0 g). MS (ESI) 335.3[ M+H ]] + 。
Step 4) 5-fluoro-4- (7 '-fluoro-2' -methyl-spiro [ cyclopentane-1, 3 '-indol ] -5' -yl) -nitrogen- (5- (1- (methylpiperidin-4-yl) pyridin-2-yl) pyrimidin-6- [ D ] -2-amine
Sequentially adding 5' - (2-chloro-5-fluoropyrimidin-4-yl-6- [ D) into a reaction flask]) -7' -fluoro-2 ' -methyl spiro [ cyclopentane-1, 3' -indole](112 mg, 0.336 mmol), 5- (1-methylpiperidin-4-yl) pyridin-2-amine (64.8 mg, 0.336 mmol), palladium acetate (7.5 mg,0.0334 mmol), xant-phos (19.32 mg,0.0334 mmol) and potassium carbonate (138 mg,1 mmol) were dissolved in toluene (10 mL) and water (2 mL) and then reacted by nitrogen and heating to 100℃for 2 hours. After the reaction, the reaction mixture was concentrated, extracted, separated by celite, concentrated further, TLC separated and HPLC purified and lyophilized to give the title compound 10mg as a white solid. MS (ESI) 490.3[ M+H ] ] + 。 1 H-NMR(400MHz,CDCl 3 )δ8.35(d,J＝8.4Hz,1H),8.23-8.20(m,2H),7.98(s,1H),7.91(d,J＝10.8Hz,1H),7.62(d,J＝7.6Hz,1H),3.15-3.13(m,2H),2.56-2.55(m,1H),2.45(s,3H),2.40(s,3H),2.03-2.24(m，8H),1.91-1.76(m，6H)。
Example 3 5-fluoro-4- (7 ' -fluoro-2 ' -methyl-spiro [ cyclopentane-1, 3' -indole)]-5' -yl) -nitrogen- (5- (1-methylpiperidin-4-yl-3, 4- [ D) 2 ]) Pyridin-2-yl) pyrimidin-2-amine (compound 13)
Step 1) 4- (6-aminopyridin-3-yl) piperidine-1-carboxytert-butyl-3, 4- [ D 2 ]
Adding 6-nitro-3 ',6' -dihydro- [3,4 ] into a reaction flask' -bipyridine]-1 '(2' h) -carboxyl tert-butyl ester (200.0 mg,0.66 mmol), deuterated methanol (5 mL), pd/C (20 mg), deuterium (1 atm) was introduced, heated to 50 ℃ for 12 hours, filtered and concentrated to give 162mg of the title product as a grey solid. MS (ESI) 280.3[ M+H ]] + 。
Step 2) 5- (1- (methylpiperidin-4-yl-3, 4- [ D) 2 ]) Pyridin-2-amines
4- (6-aminopyridin-3-yl) piperidine-1-carboxylic acid tert-butyl ester-3, 4- [ D 2 ](280 mg,1.00 mmol) was dissolved in tetrahydrofuran (10 mL) and lithium aluminum hydride (91.4 mg,2.4 mmol) was slowly added at low temperature. Then heating to 70 ℃ for reaction for 3 hours. After completion of the reaction, the reaction was quenched by addition of ice, extracted, concentrated, and column chromatographed (DCM/meoh=20:1-10:1) to give 123mg of the title compound as an off-white solid. MS (ESI) 194.3[ M+H ]] + 。
Step 3) 5-fluoro-4- (7 ' -fluoro-2 ' -methyl-spiro [ cyclopentane-1, 3' -indole)]-5' -yl) -nitrogen- (5- (1-methylpiperidin-4-yl-3, 4- [ D) 2 ]) Pyridin-2-yl) pyrimidin-2-amines
Sequentially adding 5'- (2-chloro-5-fluoropyrimidin-4-yl) -7' -fluoro-2 '-methyl spiro [ cyclopentane-1, 3' -indole into a reaction bottle ](100.0 mg,0.299 mmol), 5- (1- (methylpiperidin-4-yl-3, 4- [ D) 2 ]) Pyridine-2-amine (50.5 mg,0.26 mmol), palladium acetate (6.72 mg,0.0299 mmol), xant-phos (17.3 mg,0.0299 mmol) and potassium carbonate (129.8 mg,0.897 mmol) were dissolved in toluene (4 mL) and water (1 mL), followed by nitrogen and heating to 100deg.C for 2 hours. After completion of the reaction, the reaction mixture was concentrated, extracted, separated by celite, concentrated further, TLC separated and HPLC purified and lyophilized to give 75mg of the title compound as a white solid. MS (ESI): 491.3[ M+H ]] + 。 1 H-NMR(400MHz,CDCl 3 )δ8.64(brs,1H),8.46(d,J＝3.6Hz,1H),8.35(d,J＝8.8Hz,1H),8.27(d,J＝1.6Hz,1H),7.97(s,1H),7.90(d,J＝11.2Hz,1H),7.61(dd,J 1 ＝8.8Hz,J 2 ＝1.6Hz,1H),3.06-3.03(m,2H),2.40(s,3H),2.38(s,3H),2.23-2.09(m,8H),1.90-1.86(m,5H)。
Example 4 5-fluoro-4- (7 ' -fluoro-2 ' -methyl-spiro [ cyclopentane-1, 3' -indole)]-5' -yl) -nitrogen- (5- (1-methylpiperidin-4-yl) pyridin-2-yl-3, 4,6- [ D 3 ]) Pyrimidine-2-amine (Compound 20)
Step 1) pyridine- [ D 4 ]-2-amine
To a sealed iron pot was added 2-aminopyridine (3.0 g,31.9 mmol), pd/C (600 mg) and heavy water (100 mL) in sequence. Then, after bubbling with hydrogen for 5 minutes, the iron pot was heated to 210℃and reacted for 8 hours. After completion of the reaction, methylene chloride and methanol (50 mL) were added to the reaction mixture, palladium on carbon was removed by filtration, and the filtrate was concentrated to give 2.1g of the title compound as a gray solid. MS (ESI): 99.1[ M+H ]] + 。
Step 2) 5-bromopyridine-3, 4,6- [ D 3 ]-2-amine
Pyridine- [ D 4 ]2-amine (200 mg,2.02 mmol) was dissolved in DMF (5 mL) and NBS (399 mg,2.2 mmol) was added to the flask at about 10 ℃. After the addition, the reaction was stirred at room temperature for 2 hours. Adding water to quench reaction, extracting, separating liquid, drying with anhydrous sodium sulfate, filtering, concentrating The title compound 189mg are isolated as a grey solid by column chromatography. MS (ESI) 176.2[ M+H ]] + 。
Step 3) 6-amino-3 ',6' -dihydro- [3,4' -dihydropyridine]-1 '(2' H) -carboxylic acid tert-butyl ester-2, 4,5- [ D 3 ]
5-bromopyridine-3, 4,6- [ D was added in portions to the reaction flask 3 ]-2-amine (1.0 g,5.68 mmol), 4- (4, 5-tetramethyl-1, 3, 2-dioxoboronate-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxytert-butyl ester (2.15 g,6.95 mol), 1, 4-dioxane/water (6 mL/1 mL), potassium carbonate (2.175 g,17.2 mmol), pd (pph) 3 ) 4 (0.65 g,0.568 mmol). The reaction was carried out under nitrogen at 100℃for 1 hour, cooled to room temperature, extracted, concentrated and separated by column chromatography (PE/EA=1:1-DCM/MeOH=20:1) to give the title product as an off-white solid, 1.0 g. MS (ESI): 279.3[ M+H ]] + 。
Step 4) 5- (1- (methylpiperidin-4-yl) pyridin-3, 4,6- [ D 3 ]-2-amine
6-amino-3 ',6' -dihydro- [3,4' -dihydropyridine]-1 '(2' H) -carboxylic acid tert-butyl ester-2, 4,5- [ D 3 ](800 mg,2.85 mmol) was dissolved in tetrahydrofuran (30 mL) and a 2.5M solution of lithium aluminum hydride in tetrahydrofuran (2.86 mL,7.14 mmol) was slowly added at low temperature. Then heating to 70 ℃ for reaction for 4 hours. After completion of the reaction, the reaction was quenched by addition of ice, extracted, concentrated, and column chromatographed (DCM/meoh=20:1-10:1) to give 603mg of the title compound as a grey solid. MS (ESI): 195.3[ M+H ] ] + 。
Step 5) 5-fluoro-4- (7 ' -fluoro-2 ' -methyl-spiro [ cyclopentane-1, 3' -indole)]-5' -yl) -nitrogen- (5- (1-methylpiperidin-4-yl) pyridin-2-yl-3, 4,6- [ D 3 ]) Pyrimidine-2-amines
Sequentially adding 5'- (2-chloro-5-fluoropyrimidin-4-yl) -7' -fluoro-2 '-methyl spiro [ cyclopentane-1, 3' -indole into a reaction bottle](257 mg,0.769 mmol), 5- (1- (methylpiperidin-4-yl) pyridin-3, 4,6- [ D) 3 ]-2-amine (150 mg,0.769 mmol), pd 2 (dba) 3 (70 mg,0.077 mmol), xant-phos (88.9 mg,0.154 mmol) and cesium carbonate (750 mg,2.3 mmol) were dissolved in 1, 4-dioxane (8 mL) and then reacted for 1 hour by introducing nitrogen and microwave heating to 100 ℃. After completion of the reaction, the reaction mixture was concentrated, extracted, separated by celite, concentrated further, TLC separated and HPLC purified and lyophilized to afford 94mg of the title compound as a white solid. MS (ESI): 492.3[ M+H ]] + 。 1 H-NMR(400MHz,CDCl 3 )δ8.44(d,J＝3.6Hz,1H),8.00(s,1H),7.98(s,1H),7.61(dd,J 1 ＝9.2Hz,J 2 ＝3.6Hz,1H),3.45-3.44(m,2H),2.69(s,3H),2.65-2.64(m,3H),2.40(s,3H),2.39-2.34(m,2H),2.19-1.86(m,10H)。
Example 5 5-fluoro-4- (7 ' -fluoro-2 ' -methyl-spiro [ cyclopentane-1, 3' -indol ] -5' -yl-6 ' - [ D ])-N- (5- (1-methylpiperidin-4-yl) pyridin-2-yl) pyrimidin-2-amine (compound 21)
Step 1) 4-bromo-2-fluoro-3, 6-bis (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) amine
To the reaction flask were successively added 4-bromo-2-fluoroaniline (10 g,53 mmol), 4, 5-tetramethyl-1, 3, 2-dioxaborane (40 g, 1599 mmol),dtbpy(620mg,2.12mmol)、Ir(OMe)(cod) 2 (700 mg,1.06 mmol) and then tetrahydrofuran (100 mL) were added thereto, followed by nitrogen and then heating to 85℃for reaction for 12 hours. After the reaction, 3.1g of the title compound was obtained as a white solid by filtration, concentration, extraction, drying over anhydrous sodium sulfate, filtration, concentration and column chromatography. MS (ESI) 442.1[ M+H ] ] + 。
Step 2) 4-bromo-2-fluorobenzene-3, 6- [ D 2 ]-amines
To a sealed iron can was added in sequence 4-bromo-2-fluoro-3, 6-bis (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) amine (5.34 g,14.8 mmol), ir (OMe) (cod) 2 (0.39 g,0.6 mmol), heavy water (10 mL), and tetrahydrofuran (40 mL). The reaction solution was then heated to 145℃and reacted for 5 hours. After the reaction, it was cooled, extracted with ethyl acetate, concentrated and separated by column chromatography to give the title compound 2.85g as a pale yellow oil. MS (ESI) 192.1[ M+H ]] + 。 1 H-NMR(400MHz,DMSO-d 6 )δ7.30(s,1H),5.30(brs,2H)。
Step 3) (4-bromo-2-fluorobenzene-3, 6- [ D 2 ]) Hydrazine hydrochloride
4-bromo-2-fluorobenzene-3, 6- [ D 2 ]Amine (850 mg,4.45 mmol) was dissolved in 8mL of hydrochloric acid, nitrogen protected, then the reaction temperature was reduced to-5℃and sodium nitrite (370 mg,4.67 mmol) was slowly added dropwise to dissolve in 4mL of water. After the reaction is carried out for 30 minutes at the temperature of minus 5 ℃, snCl is slowly added into the reaction solution in a dropwise manner 2 (2.1 g,8.9 mmol) was dissolved in 1mL HCl. Then reacted at 0℃for 3 hours. After completion of the reaction, filtration, extraction and concentration gave 936mg of the title compound as a white solid. MS (ESI) 192.1[ M+H ]] + 。
Step 4) 5 '-bromo-7' -fluoro-2 '-methyl-spiro [ cyclopentane-1, 3' -indol ] -5 '-yl-6' - [ D ]
Sequentially adding (4-bromo-2-fluorobenzene-3, 6- [ D) into a reaction bottle 2 ]) Hydrazine hydrochloride (936 mg,3.89 mmol), cyclopentyl ethyl ketone (500 mg,4.27 mmol) and triethylamine (800 mg,7.7 mmol) and 15mL methanol. Then, after the reaction was carried out at 35℃for 3 hours, concentrated sulfuric acid (1.6 g,15.56 mmol) was slowly added dropwise thereto after the reaction mixture was cooled to-5 ℃. After the completion of the dropwise addition, the reaction was continued at 35℃for 12 hours. After the reaction, ph=8 was adjusted with aqueous ammonia, extracted, concentrated, and separated by column chromatography to give 439mg of the title compound as a yellow oil. MS (ESI): 283.1[ M+H ] ] + 。
Step 5) 5' - (2-chloro-5-fluoropyrimidin-4-yl) -7' -fluoro-2 ' -methyl spiro [ cyclopentane-1, 3' -indol ] -6' - [ D ]
Isopropanol (10 mL) and 5 '-bromo-7' -fluoro-2 '-methyl spiro [ cyclopentane-1, 3' -indole were added to the reaction flask under nitrogen protection]-5 '-yl-6' - [ D](239 mg,0.84 mmol), potassium acetate (99.6 mg,1 mmol) and bis-pinacolato borate (258 mg,1 mmol) were stirred and 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride (61.9 mg,0.084 mmol) was added. Heating to 85+/-5 ℃ and preserving heat for reaction for 12 hours. The reaction solution was concentrated under reduced pressure, then purified water and ethyl acetate were added for extraction, the solution was separated, and the aqueous phase was discarded. The resulting organic phase was filtered and concentrated under reduced pressure to afford the intermediate. The intermediate and 1, 4-dioxane (10 mL) were transferred into a reaction flask, stirred, then 2, 4-dichloro-5-fluoropyrimidine (141.5 mg,0.84 mmol) and potassium phosphate (449 mg,2.1 mmol) were added, stirred, tetrakis (triphenylphosphine) palladium (89.8 mg,0.07 mmol) was added to the flask, and then purified water (3.3 mL) was added, and the reaction was carried out at 100℃for 1 hour by microwaves. Concentrating, extracting, separating, and anhydrousDrying over sodium sulfate, filtering, concentrating, and column chromatography gave the title compound as 163mg as a yellow solid. MS (ESI): 335.1[ M+H ]] + 。
Step 6) 5-fluoro-4- (7 ' -fluoro-2 ' -methyl-spiro [ cyclopentane-1, 3' -indol ] -5' -yl-6 ' - [ D ])-nitrogen- (5- (1-methylpiperidin-4-yl) pyridin-2-yl) pyrimidin-2-amine
Sequentially adding 5'- (2-chloro-5-fluoropyrimidin-4-yl) -7' -fluoro-2 '-methyl spiro [ cyclopentane-1, 3' -indole into a reaction bottle]-6'-[D](163 mg,0.49 mmol), 5- (1- (methylpiperidin-4-yl) pyridin-2-amine (112 mg,0.58 mmol), pd 2 (dba) 3 (44.6 mg,0.05 mmol), xant-phos (56.4 mg,0.1 mmol) and cesium carbonate (470 mg,1.47 mmol) were dissolved in 1, 4-dioxane (10 mL), then nitrogen was introduced, and the mixture was heated to 100deg.C for microwave reaction for 1 hour. After the reaction, the reaction mixture was concentrated, extracted, separated by celite, concentrated further, TLC separated and HPLC purified and lyophilized to give 116mg of the title compound as a pale yellow solid. MS (ESI) 490.3[ M+H ]] + 。 1 H-NMR(400MHz,CDCl 3 )δ 8.45(d,J＝3.6Hz,1H),8.35(s,1H),8.33(s,1H),8.24(d,J＝2.4Hz,1H),7.98(s,1H),7.62(dd,J 1 ＝8.8Hz,J 2 ＝2.4Hz,1H),3.16-3.13(m,2H),2.59-2.53(m,1H),2.45(s,3H),2.40(s,3H),2.27-2.08(m,8H),1.96-1.87(m,6H)。
Example 6 5-fluoro-4- (7 ' -fluoro-2 ' -methyl-spiro [ cyclopentane-1, 3' -indol ] -5' -yl-4 ' - [ D ])-N- (5- (1- (methylpiperidin-4-yl) pyridin-2-yl) pyrimidin-2-amine (compound 25)
Step 1) (5-bromo-2-fluorophenyl) carbamic acid tert-butyl ester
To the reaction flask was added in sequence 5-bromo-2-fluoroaniline (1.89 g,10 mmol) and suspended in water (10 mL). Di-tert-butyl dicarbonate (2.16 g,12 mmol) was added, resulting in heating and effervescence. The reaction mixture was further diluted with water (50 mL) and then heated at 80 ℃ for 8 hours. Upon cooling to room temperature, water (100 mL) was added, and the precipitate was collected by filtration and washed thoroughly with water. The solid residue was extracted into dichloromethane (100 mL), dried over magnesium sulfate, filtered and concentrated to dryness to give the title compound 2.0g as a pale yellow solid. MS (ESI): 289.1[ M+H ] ] + 。
Step 2) (3-amino-4-fluorophenyl) boronic acid
To the reaction flask were successively added tert-butyl (5-bromo-2-fluorophenyl) carbamate (2 g,6.92 mmol), 1, 4-dioxane (10 mL), bis (pinacolato) diboron (2.74 g,10.38 mmol) and potassium acetate (1.36 g,13.84 mmol). Nitrogen was bubbled through the mixture for 5 minutes and [1,1' -bis (diphenylphosphino) ferrocene complexed with methylene chloride was added]Palladium (II) dichloride (0.56 g,0.069 mmol) and the reaction mixture was heated to 100℃for 12 hours. Upon cooling, the reaction mixture was partitioned between ethyl acetate (80 mL) and water (40 mL), the organic phase was washed with brine (20 mL), dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in 10mL of chloroform, and then 1mL of trifluoroacetic acid was added thereto for reaction at room temperature for 5 hours. And then concentrated to dryness. The crude residue was partitioned between chloroform (50 mL) and water (50 mL), the aqueous phase was washed with 10% methanol in chloroform (50 mL), the PH was adjusted to 7 by addition of sodium bicarbonate, and washed with dichloromethane. The aqueous phase was concentrated to dryness to give a solid residue which was washed with dichloromethane, dissolved in methanol, filtered and concentrated to give the title compound 1.18g as a white solid. MS (ESI): 156.3[M+H] + 。
Step 3) 2-fluorobenzene-5- [ D ] -amine
(3-amino-4-fluorophenyl) boric acid (1.18 g,7.54 mmol), ir (OMe) (cod) were added sequentially to a sealed iron pot 2 (131 mg,0.226 mmol), heavy water (5 mL), and tetrahydrofuran (20 mL). The reaction solution was then heated to 145℃and reacted for 5 hours. After the reaction, it was cooled, extracted with ethyl acetate, concentrated, and separated by column chromatography to give 900mg of the title compound as a pale yellow oil. MS (ESI) 113.3[ M+H ]] + 。
Step 4) 4-bromo-2-fluorobenzene-5- [ D ] -amine
2-fluorobenzene-5- [ D]Amine (400 mg,3.57 mmol) was dissolved in THF (5 mL) and NBS (690 mg,3.89 mmol) was added to the reaction flask at about 10deg.C. After the addition, the reaction was stirred at room temperature for 5 hours. The reaction was quenched with water, extracted, separated, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to give 438mg of the title compound as a white solid. MS (ESI): 191.3[ M+H ]] + 。 1 H-NMR(400MHz,CDCl 3 )δ7.17(d,J＝10.8Hz,1H),6.70(m,1H)，3.73(brs,2H)。
Step 5) (4-bromo-2-fluorophenyl-5- [ D ]) hydrazine hydrochloride
4-bromo-2-fluorobenzene-5- [ D]Amine (950 mg,5 mmol) was dissolved in 14mL of hydrochloric acid, nitrogen protected, then the reaction temperature was reduced to-5℃and sodium nitrite (2.26 g,10 mmol) was slowly added dropwise to dissolve in 7mL of water. Maintaining the temperature of minus 5 ℃ for reaction for 30 minutesThen, slowly dropwise adding SnCl into the reaction solution 2 .H 2 O (1.1 g,6 mmol) was dissolved in 3mL HCl. Then reacted at 0℃for 3 hours. After completion of the reaction, filtration, extraction and concentration gave 730mg of the title compound as a yellow solid. MS (ESI) 206.1[ M+H ] ] + 。
Step 6) 5 '-bromo-7' -fluoro-2 '-methyl-spiro [ cyclopentane-1, 3' -indol ] -5 '-yl-4' - [ D ]
Sequentially adding (4-bromo-2-fluorophenyl-5- [ D) into a reaction flask]) Hydrazine hydrochloride (730 mg,3.54 mmol), cyclopentyl ethyl ketone (383 mg,3.54 mmol) and triethylamine (716 mg,7.07 mmol) and 12mL methanol. Then, after the reaction was carried out at 35℃for 3 hours, concentrated sulfuric acid (1.42 g,14.5 mmol) was slowly added dropwise thereto after the reaction mixture was cooled to-5 ℃. After the completion of the dropwise addition, the reaction was continued at 40℃for 12 hours. After the reaction, ph=8 was adjusted with aqueous ammonia, extracted, concentrated, and separated by column chromatography to give 540mg of the title compound as a yellow oil. MS (ESI): 283.1[ M+H ]] + 。
Step 7) 5' - (2-chloro-5-fluoropyrimidin-4-yl) -7' -fluoro-2 ' -methyl spiro [ cyclopentane-1, 3' -indol ] -4' - [ D ]
Isopropanol (10 mL) and 5 '-bromo-7' -fluoro-2 '-methyl spiro [ cyclopentane-1, 3' -indole were added to the reaction flask under nitrogen protection]-5 '-yl-4' - [ D](540 mg,1.91 mmol), potassium acetate (225.2 mg,2.30 mmol) and bis-pinacolato borate (730 mg,2.87 mmol) were stirred and 1,1' -bis (diphenylphosphoryl) ferrocene palladium dichloride (134 mg,0.18 mmol) was added. Heating to 85+/-5 ℃ and preserving heat for reaction for 12 hours. The reaction solution was concentrated under reduced pressure, then purified water and ethyl acetate were added for extraction, the solution was separated, and the aqueous phase was discarded. The resulting organic phase was filtered and concentrated under reduced pressure to afford the intermediate. Transferring the intermediate and 1, 4-dioxane (8 mL) into a reaction bottle, stirring Then, 2, 4-dichloro-5-fluoropyrimidine (281mg, 1.67 mmol) and potassium phosphate (886.5 mg,4.18 mmol) were added, stirred, tetrakis (triphenylphosphine) palladium (161 mg,0.14 mmol) was added to the reaction flask, and then purified water (2 mL) was further added, followed by reaction at 100℃for 1 hour by microwaves. After the reaction, concentration, extraction, separation, drying over anhydrous sodium sulfate, filtration, concentration, and column chromatography separation gave the title compound as a yellow solid, 157 mg. MS (ESI): 335.1[ M+H ]] + 。 1 H-NMR(400MHz,CDCl 3 )δ8.55(d,J＝3.2Hz,1H),7.94(d,J＝10.4Hz,1H),2.44(s,3H),2.21-2.06(m,6H)，1.97-1.88(m,2H)。
Step 8) 5-fluoro-4- (7 ' -fluoro-2 ' -methyl-spiro [ cyclopentane-1, 3' -indol ] -5' -yl-4 ' - [ D ])-nitrogen- (5- (1- (methylpiperidin-4-yl) pyridin-2-yl) pyrimidin-2-amine
Sequentially adding 5'- (2-chloro-5-fluoropyrimidin-4-yl) -7' -fluoro-2 '-methyl spiro [ cyclopentane-1, 3' -indole into a reaction bottle]-4'-[D](112 mg,0.58 mmol), 5- (1- (methylpiperidin-4-yl) pyridin-2-amine (63 mg,0.19 mmol), pd 2 (dba) 3 (18 mg,0.02 mmol), xant-phos (22 mg,0.04 mmol) and cesium carbonate (184 mg,0.57 mmol) were dissolved in 1, 4-dioxane (5 mL), then nitrogen was introduced and reacted at 100℃for 1 hour with microwaves. After the reaction, the reaction mixture was concentrated, extracted, separated by celite, concentrated further, TLC separated and HPLC purified and lyophilized to give 89mg of the title compound as a pale yellow solid. MS (ESI) 490.3[ M+H ] ] + 。 1 H-NMR(400MHz,CDCl 3 )δ8.44(d,J＝3.6Hz,1H),8.35(d,J＝8.4Hz,1H),8.24(d,J＝2.0Hz,1H),8.16(s,1H),7.91(d,J＝11.2Hz,1H),7.63(dd,J 1 ＝8.8Hz,J 2 ＝2.4Hz,1H),3.13-3.10(m,2H),2.58-2.53(m,1H),2.44(s,3H),2.40(s,3H),2.26-2.08(m,8H),2.03-1.90(m,6H)。
Example 7 5-fluoro-4- (7 ' -fluoro-2 ' -methyl-spiro [ cyclopentane-1, 3' -indole)]-5' -yl-3, 4- [ D 2 ]) -nitrogen- (5- (1- (methylpiperidin-4-yl) pyridin-2-yl)) Pyrimidine-2-amines (Compound 27)
Step 1) 2-acetyl-2- (2-propen-1-yl) -4-pentenoic acid ethyl ester
To the reaction flask were added ethyl acetoacetate (13.2 g,100 mmol), potassium carbonate (42 g,304 mmol) and 60mL of DMF in this order. 3-bromopropene (30 g,248 mmol) was then slowly added dropwise to the reaction flask. And (3) introducing nitrogen to protect, and heating to 85 ℃ to react for 12 hours. The reaction was poured into ice water, extracted with ethyl acetate, separated, the organic phase was washed 3 times with brine (3 x 100 ml), concentrated and separated by column chromatography to give the title compound 7g as an anhydrous oil. MS (ESI): 211.3[ M+H ]] + 。
Step 2) 3- (2-propen-1-yl) -5-hexen-2-one
Ethyl 2-acetyl-2- (2-propen-1-yl) -4-pentenoate (7.0 g,35 mmol) was dissolved in 20mL of DMF and added to a reaction flask, liCl (2.8 g,60 mmol) was added, and after introducing nitrogen, the reaction mixture was warmed to 150℃and reacted for 20 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, ice water was added thereto, and then the mixture was extracted, separated, dried over anhydrous sodium sulfate, filtered, and concentrated, whereby 2.4g of the title compound was isolated as a colorless oil by column chromatography. MS (ESI): 139.3[ M+H ] ] + 。
Step 3) 1- (3-cyclopenten-1-yl) ethanone
To the reaction flask was added 3- (2-propen-1-yl) -5-hexen-2-one (2.4 g,17 mmol), grubbs cat in order 1st (720 mg,0.87 mmol) and 20mL of DCM were reacted at room temperature under nitrogen for 15 hours. After the reaction, the mixture was filtered and concentrated, and the title compound was isolated by column chromatography as a colorless oil at 450 mg. MS (ESI): 111.3[ M+H ]] + 。
Step 4) 1- (cyclopentyl-3, 4- [ D 2 ]) Ethyl ketone
To the reaction flask was added 1- (3-cyclopenten-1-yl) ethanone (450 mg,4.5 mmol), cesium carbonate (70 mg,0.21 mmol), palladium on carbon (20 mg) and 5mL deuterated methanol (CH) 3 OD) and then deuterium (1 atm) gas was introduced and heated to 40 ℃ for reaction for 12 hours. After the reaction, filtration and concentration gave 300mg of the title compound as a yellow oil. MS (ESI) 115.1[ M+H ]] + 。
Step 5) 5 '-bromo-7' -fluoro-2 '-methyl spiro [ cyclopentane-1, 3' -indole]-3,4-[D 2 ]
To the reaction flask were successively added 4-bromo-2-fluorophenylhydrazine hydrochloride (600 mg,2.91 mmol), 1- (cyclopentyl-3, 4- [ D) 2 ]) Ethanone (300 mg,2.71 mmol) and triethylamine (600 mg,5.9 mmol) and 12mL methanol. Then, after the reaction was carried out at 35℃for 3 hours, concentrated sulfuric acid (1.2 g,12.2 mmol) was slowly added dropwise thereto after the reaction mixture was cooled to-10 ℃. After the completion of the dropwise addition, the reaction was continued at 40℃for 12 hours. After the reaction, ph=8 was adjusted with aqueous ammonia, extracted, concentrated, and separated by column chromatography to give 130mg of the title compound as a yellow oil. MS (ESI): 284.3[ M+H ] ] + 。 1 H-NMR(400MHz,CDCl 3 )δ7.24(d,J＝3.6Hz,1H),7.27(d,J＝8.8Hz,1H),2.32(s,3H),2.06-2.01(m,4H)，1.83-1.80(m,2H)。
Step 6) 5'- (2-chloro-5-fluoropyrimidin-4-yl) -7' -fluoro-2 '-methyl spiro [ cyclopentane-1, 3' -indole]-3,4-[D 2 ]
Isopropanol (10 mL) and 5 '-bromo-7' -fluoro-2 '-methyl spiro [ cyclopentane-1, 3' -indole were added to the reaction flask under nitrogen protection]-5' -yl-3, 4- [ D 2 ](130 mg,0.46 mmol), potassium acetate (58 mg,0.59 mmol) and bis-pinacolato borate (152 mg,0.59 mmol) were stirred and 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride (134 mg,0.18 mmol) was added. Heating to 85+/-5 ℃ and preserving heat for reaction for 12 hours. The reaction solution was concentrated under reduced pressure, then purified water and ethyl acetate were added for extraction, the solution was separated, and the aqueous phase was discarded. The resulting organic phase was filtered and concentrated under reduced pressure to afford the intermediate. The intermediate and 1, 4-dioxane (8 mL) were transferred into a reaction flask, stirred, then 2, 4-dichloro-5-fluoropyrimidine (106 mg,0.63 mmol) and potassium phosphate (267 mg,1.26 mmol) were added, stirred, tetrakis (triphenylphosphine) palladium (48.5 mg,0.042 mmol) was added to the flask, and then purified water (2 mL) was added, and the reaction was carried out at 100℃for 1 hour by microwaves. After the reaction, concentration, extraction, separation, drying over anhydrous sodium sulfate, filtration, concentration, and column chromatography separation gave the title compound as a yellow solid, 87 mg. MS (ESI): 336.1[ M+H ]] + 。
Step 7) 5-fluoro-4- (7 ' -fluoro-2 ' -methyl-spiro [ cyclopentane-1, 3' -indole) ]-5' -yl-3, 4- [ D 2 ]) -nitrogen- (5- (1- (methylpiperidin-4-yl) pyridin-2-yl) pyrimidin-2-amine
Sequentially adding 5'- (2-chloro-5-fluoropyrimidin-4-yl) -7' -fluoro-2 '-methyl spiro [ cyclopentane-1, 3' -indole into a reaction bottle]-3,4-[D 2 ](70 mg,0.208 mmol), 5- (1- (methylpiperidin-4-yl) pyri-dine)Pyridin-2-amine (50 mg,0.25 mmol), pd 2 (dba) 3 (19.2 mg,0.021 mmol), xant-phos (24 mg,0.042 mmol) and cesium carbonate (202.8 mg,0.624 mmol) were dissolved in 1, 4-dioxane (8 mL) and then reacted for 1 hour at 100℃by introducing nitrogen gas and microwaves. After the reaction, the reaction mixture was concentrated, extracted, separated by celite, concentrated further, TLC separated and HPLC purified and lyophilized to afford the title compound 25mg as a pale yellow solid. MS (ESI): 491.3[ M+H ]] + 。 1 H-NMR(400MHz,CDCl 3 )δ8.45(d,J＝3.6Hz,1H),8.35(d,J＝8.4Hz,1H),8.29(s,1H),8.24(d,J＝2.0Hz,1H),7.91(d,J＝0.8Hz,1H),7.88(d,J＝0.8Hz,1H),7.62(dd,J 1 ＝8.8Hz,J 2 ＝2.4Hz,1H),3.12-3.09(m,2H),2.59-2.51(m,1H),2.42(s,3H),2.40(s,3H),2.23-2.07(m,7H),1.97-1.88(m,5H)。
Example 8 5-fluoro-4- (7 '-fluoro-2' - (methyl- [ D) 3 ]) Spiro [ cyclopentane-1, 3' -indoles]-5' -yl) -nitrogen- (5- (1- (methylpiperidin-4-yl) pyridin-2-yl) pyrimidin-2-amine (compound 32)
Step 1) 5-fluoro-4- (7 '-fluoro-2' - (methyl- [ D3 ]) spiro [ cyclopentane-1, 3 '-indol ] -5' -yl) -nitrogen- (5- (1- (methylpiperidin-4-yl) pyridin-2-yl) pyrimidin-2-amine
Sequentially adding 5-fluoro-4- (7 ' -fluoro-2 ' -methyl spiro [ cyclopentane-1, 3' -indole) into a reaction bottle]-5' -yl) -nitrogen- (5- (1-methylpiperidin-4-yl) pyridin-2-yl) pyrimidin-2-amino (230 mg,0.47 mmol), deuterated hydrochloric acid (87 mg,0.47 mmol) and 10mL heavy water. Then heated to 95℃for 3 hours. After the reaction, it was cooled to room temperature and adjusted to pH 8 with deuterated sodium hydroxide, extracted with DCM, concentrated, and recrystallized from DCM and deuterated methanol to give 163mg of the title compound as pale yellow A solid. MS (ESI): 492.3[ M+H ]] + 。 1 H-NMR(400MHz,CDCl 3 )δ8.44(d,J＝3.6Hz,1H),8.34(d,J＝8.8Hz,1H),8.23(d,J＝2.0Hz,1H),8.14(s,1H),7.98(s,1H),7.91(dd,J 1 ＝11.2Hz,J 2 ＝1.2Hz,1H),7.61(dd,J 1 ＝8.8Hz,J 2 ＝2.4Hz,1H),3.04-3.01(m,2H),2.53-2.49(m,1H),2.37(s,3H),2.22-2.07(m,8H),1.91-1.70(m,6H)。
Example 9 5-fluoro-4- (7 ' -fluoro-2 ' -methyl-spiro [ cyclopentane-1, 3' -indole)]-5' -yl) -nitrogen- (5- (1- (methyl- [ D) 3 ]) -piperidin-4-yl) pyridin-2-yl-3, 4,6- [ D 3 ]) Pyrimidine-2-amines (Compound 2)
The title compound was synthesized following a procedure similar to that of examples 1 and 4.
MS(ESI):495.3[M+H] + 。 1 H-NMR(400MHz,CDCl 3 )δ8.44(d,J＝3.6Hz,1H),8.05(s,1H),7.98(s,1H),7.91(d,J＝11.2Hz,1H),3.34-3.21(m,2H),2.65–2.60(m,1H),2.52–2.50(m,2H),2.40(s,3H),2.24–2.11(m,6H),2.09–1.88(m,6H)。
Example 10 5-fluoro-4- (7 '-fluoro-2' -methyl-spiro [ cyclopentane-1, 3 '-indol ] -5' -yl) -nitrogen- (5- (1- (methyl- [ D ]) piperidin-4-yl) pyridin-2-yl) pyrimidin-2-amine (compound 3)
The title compound was synthesized following a procedure similar to that of example 1. MS (ESI) 490.4[ M+H ]] + 。
Example 11 5-fluoro-4- (7 ' -fluoro-2 ' -methyl-spiro [ cyclopentane-1, 3' -indole)]-5' -yl) -nitrogen- (5- (1- (methyl- [ D) 2 ]) Piperidin-4-yl) pyridin-2-yl pyrimidin-2-amine (compound 4)
The title compound was synthesized following a procedure similar to that of example 1. MS (ESI): 491.4[ M+H ]] + 。
Example 12 5-fluoro-4- (7 ' -fluoro-2 ' -methyl-spiro [ cyclopentane-1, 3' -indole)]-5' -yl) -nitrogen- (5- (1-methylpiperidin-4-yl-3, 4- [ D) 2 ]) Pyridin-2-yl) pyrimidine-6- [ D]-2-amine (Compound 6)
The title compound was synthesized following a procedure similar to that described in examples 2 and 3.
MS(ESI):492.3[M+H] + 。 1 H-NMR(400MHz,DMSO-d 6 )δ9.99(s,1H),8.19(d,J＝2.4Hz,1H),8.12(d,J＝8.8Hz,1H)，8.01(s,1H),7.84(d,J＝11.6Hz,1H),7.66(dd,J 1 ＝8.4Hz,J 2 ＝2.4Hz,1H),2.88-2.85(m,2H),2.34(s,3H),2.20(s,3H),2.10-2.05(m,6H),2.08-1.96(m,2H),1.75-1.72(m,5H)。
Example 13 5-fluoro-4- (7 ' -fluoro-2 ' -methyl-spiro [ cyclopentane-1, 3' -indole)]-5' -yl) -nitrogen- (5- (1-methylpiperidin-4-yl) pyridin-2-yl-3, 4,6- [ D 3 ]) Pyrimidine-6- [ D]-2-amine (Compound 7)
The title compound was synthesized following a procedure similar to that of examples 2 and 4.
MS(ESI):493.3[M+H] + 。 1 H-NMR(400MHz,CDCl 3 )δ8.01-7.98(m,2H),7.91(d,J＝10.8Hz,1H),3.20-3.17(m,2H),2.62-2.55(m,1H),2.48(s,3H),2.41(s,3H),2.33-2.03(m，8H),2.08-1.86(m，6H)。
Example 14 5-fluoro-4- (7 ' -fluoro-2 ' -methyl-spiro [ cyclopentane-1, 3' -indole)]-5' -yl) -nitrogen- (5- (1-methyl- [ D) 3 ]) Piperidin-4-yl) pyridin-2-yl) pyrimidine-6- [ D]-2-amine (Compound 8)
The title compound was synthesized following a procedure similar to that of examples 1 and 2.
MS(ESI):493.2[M+H] + 。 1 H-NMR(400MHz,DMSO-d 6 )δ9.99(s,1H),8.20(d,J＝2.4Hz,1H),8.13(d,J＝8.8Hz,1H),8.01(s,1H),7.85(d,J＝12.0Hz,1H),7.66(dd,J 1 ＝8.4Hz,J 2 ＝2.0Hz,1H),2.89-2.85(m,2H),2.75-2.71(m,1H),2.34(s,3H),2.10-1.96(m,8H),1.76-1.65(m,6H)。
Example 15 5-fluoro-4- (7 ' -fluoro-2 ' -methyl-spiro [ cyclopentane-1, 3' -indole)]-5' -yl) -nitrogen- (5- (1-methyl- [ D) 3 ]) Piperidin-4-yl-3, 4- [ D 2 ]) Pyridin-2-yl-3, 4,6- [ D 3 ]) Pyrimidine-6- [ D]-2-amine (Compound 9)
The title compound was synthesized according to the procedure similar to examples 1-4.
MS(ESI):498.3[M+H] + 。 1 H-NMR(400MHz,CDCl 3 )δ8.02(s,1H),7.98(s,1H),7.91(dd,J 1 ＝10.8Hz,J 2 ＝0.8Hz,1H),3.17-3.14(m,2H),2.41(s,3H),2.26-2.08(m,8H),1.97-1.88(m,7H)。
Example 16 5-fluoro-4- (7 ' -fluoro-2 ' -methyl-spiro [ cyclopentane-1, 3' -indole)]-5' -yl) -nitrogen- (5- (1-methyl- [ D) 3 ]) Piperidin-4-yl-3, 4- [ D 2 ]) Pyridin-2-yl) pyrimidine-6- [ D]-2-amine (Compound 10)
The title compound was synthesized according to the procedure similar to examples 1-3.
MS(ESI):495.3[M+H] + 。 1 H-NMR(400MHz,CDCl 3 )δ9.99(s,1H),8.19(d,J＝2.4Hz,1H),8.12(d,J＝8.8Hz,1H)，8.01(s,1H),7.84(d,J＝11.6Hz,1H),7.65(dd,J 1 ＝8.4Hz,J 2 ＝2.4Hz,1H),2.89-2.86(m,2H),2.34(s,3H),2.08-2.05(m,6H),2.01-1.96(m,2H),1.75-1.72(m,5H)。
Example 17 5-fluoro-4- (7 ' -fluoro-2 ' -methyl-spiro [ cyclopentane-1, 3' -indole)]-5' -yl) -nitrogen- (5- (1-methylpiperidin-4-yl-3, 4- [ D) 2 ]) Pyridin-2-yl-3, 4,6- [ D 3 ]) Pyrimidine-6- [ D]-2-amine (Compound 11)
The title compound was synthesized according to the procedure similar to examples 2-4.
MS(ESI):495.3[M+H] + 。 1 H-NMR(400MHz,CDCl 3 )δ7.98(s,1H),7.95(s,1H),7.91(d,J＝10.8Hz,1H),3.15-3.12(m,2H),2.45(s,3H),2.41(s,3H),2.23- 2.09(m,7H),1.91-1.88(m,6H)。
Example 18 5-fluoro-4- (7 ' -fluoro-2 ' -methyl-spiro [ cyclopentane-1, 3' -indole) ]-5' -yl) -nitrogen- (5- (1-methyl- [ D) 3 ]) Piperidin-4-yl) pyridin-2-yl-3, 4- [ D 2 ]-6-[D]) Pyrimidine-6- [ D]-2-amine (Compound 12)
The title compound was synthesized following a procedure similar to that of examples 1, 2 and 4.
MS(ESI):496.0[M+H] + 。 1 H-NMR(400MHz,DMSO-d 6 )δ10.00(s,1H),8.18(s,1H),8.01(s,1H),7.84(d,J＝11.6Hz,1H),2.91-2.88(m,2H),2.34(s,3H),2.10-1.99(m,9H),1.77-1.65(m,6H)。
Example 19 5-fluoro-4- (7 ' -fluoro-2 ' -methyl-spiro [ cyclopentane-1, 3' -indole)]-5' -yl) -nitrogen- (5- (1-methyl- [ D) 3 ]) Piperidin-4-yl-3, 4- [ D 2 ]) Pyridin-2-yl) pyrimidin-2-amine (compound 14)
The title compound was synthesized following a procedure similar to that described in examples 1 and 3.
MS(ESI):494.3[M+H] + 。 1 H-NMR(400MHz,CDCl 3 )δ8.51(brs,1H),8.46(d,J＝3.6Hz,1H),8.35(d,J＝8.8Hz,1H),8.26(d,J＝2.0Hz,1H),7.97(s,1H),7.90(d,J＝11.2Hz,1H),7.61(dd,J 1 ＝8.4Hz,J 2 ＝2.0Hz,1H),3.09-3.07(m,2H),2.40(s,3H),2.18-2.08(m,8H),1.90-1.87(m,5H)。
Example 20 5-fluoro-4- (7 ' -fluoro-2 ' -methyl-spiro [ cyclopentane-1, 3' -indole)]-5' -yl) -nitrogen- (5- (1-methylpiperidin-4-yl-3, 4- [ D) 2 ]) Pyridin-2-yl-3, 4,6- [ D 3 ]) Pyrimidine-2-amines (Compound 15)
The title compound was synthesized following a procedure similar to that described in examples 3 and 4.
MS(ESI):494.3[M+H] + 。 1 H-NMR(400MHz,CDCl 3 )δ8.43(d,J＝3.6Hz,1H),7.98(s,1H),7.95(s,1H),7.91(d,J＝10.8Hz,1H),3.23-3.21(m,2H),2.51(s,3H),2.41(s,3H),2.33-2.20(m,2H),2.19-1.82(m,11H)。
Example 21 5-fluoro-4- (7 ' -fluoro-2 ' -methyl-spiro [ cyclopentane-1, 3' -indole)]-5' -yl) -nitrogen- (5- (1-methyl- [ D) 3 ]) Piperidin-4-yl-3, 4- [ D 2 ]) Pyridin-2-yl-3, 4,6- [ D 3 ]) Pyrimidine-2-amines (Compound 16)
The title compound was synthesized following a procedure similar to that of examples 1,3 and 4.
MS(ESI):497.3[M+H] + 。 1 H-NMR(400MHz,CDCl 3 )δ8.43(d,J＝3.6Hz,1H),7.98(s,1H),7.95(s,1H),7.91(dd,J 1 ＝10.8Hz,J 2 ＝1.2Hz,1H),3.17-3.15(m,2H),2.41(s,3H),2.27-2.19(m,2H),2.16-1.87(m,11H)。
Example 22 5-fluoro-4- (7 ' -fluoro-2 ' -methyl-spiro [ cyclopentane-1, 3' -indole)]-5' -yl) -nitrogen- (5- (1-methylpiperidin-4-yl-2, 6- [ D) 4 ]) Pyridin-2-yl) pyrimidin-2-amine (compound 17)
The title compound was synthesized following a procedure similar to that described in example 3. MS (ESI): 493.3[ M+H ] ] + 。
Example 23 5-fluoro-4- (7 '-fluoro-2' -methyl-spiro [ cyclopentane-1, 3 '-indol ] -5' -yl) -nitrogen- (5- (1-methylpiperidin-4-yl-4- [ D ]) pyridin-2-yl) pyrimidin-2-amine (compound 18)
The title compound was synthesized following a procedure similar to that described in example 3. MS (ESI) 490.3[ M+H ]] + 。
EXAMPLE 24 5-fluoro-4- (7 '-fluoro-2'-methyl spiro [ cyclopentane-1, 3' -indole]-5' -yl) -nitrogen- (5- (1-methylpiperidin-4-yl-2,2,3,3,4,5,5,6,6- [ D) 9 ]) Pyridin-2-yl) pyrimidin-2-amine (compound 19)
The title compound was synthesized following a procedure similar to that described in example 3. MS (ESI): 498.2[ M+H ]] + 。
Example 25 5-fluoro-4- (7 ' -fluoro-2 ' -methyl-spiro [ cyclopentane-1, 3' -indole)]-5 '-yl-6' - [ D]) -nitrogen- (5- (1- (methyl) D) 3 ]) Piperidin-4-yl) pyridin-2-yl pyrimidin-2-amine (compound 22)
The title compound was synthesized following a procedure similar to that of examples 1 and 5.
MS(ESI):493.3[M+H] + 。 1 H-NMR(400MHz,CDCl 3 )δ8.43(d,J＝3.6Hz,1H),8.36(d,J＝8.8Hz,1H),8.21(d,J＝2.4Hz,1H),8.02(s,1H),7.98(s,1H),7.65(d,J＝8.8Hz,1H),3.28-3.27(m,2H),2.62-2.53(m,3H),2.40(s,3H),2.26-1.90(m,8H),1.88-1.72(m,4H)。
EXAMPLE 26 5-fluoro-4- (7 ' -fluoro-2 ' -methyl-spiro [ cyclopentane-1, 3' -indol ] -5' -yl-6 ' - [ D ])-N- (5- (1- (methylpiperidin-4-yl) pyridin-2-yl) pyrimidin-6- [ D ] -2-amine (compound 23)
The title compound was synthesized following a procedure similar to that of examples 2 and 5.
MS(ESI):491.3[M+H] + 。 1 H-NMR(400MHz,CDCl 3 )δ8.34(d,J＝8.4Hz,1H),8.24(s,1H),8.23(d,J＝8.0Hz,1H),7.98(s,1H),7.61(dd,J 1 ＝8.4Hz,J 2 ＝2.4Hz,1H),3.08-3.05(m,2H),2.53-2.50(m,1H),2.40(s,3H),2.39(s,3H),2.22- 2.08(m,8H),1.91-1.84(m,6H)。
EXAMPLE 27 5-fluoro-4- (7 ' -fluoro-2 ' -methyl-spiro [ cyclopentane-1, 3' -indole]-5 '-yl-6' - [ D]) -nitrogen- (5- (1- (methylpiperidin-4-yl) pyridin-2-yl-3, 4,6- [ D) 3 ]) Pyrimidine-2-amines (Compound 24)
The title compound was synthesized according to the procedure similar to examples 4 and 5.
MS(ESI):493.3[M+H] + 。 1 H-NMR(400MHz,CDCl 3 )δ8.44(d,J＝3.6Hz,1H),8.01(s,1H),7.98(s,1H),3.14-3.11(m,2H),2.57-2.53(m,1H),2.44(s,3H),2.40(s,3H),2.24-2.07(m,8H),1.96-1.88(m,6H)。
EXAMPLE 28 5-fluoro-4- (7 ' -fluoro-2 ' -methyl-spiro [ cyclopentane-1, 3' -indole)]-5' -yl-4 ',6' - [ D 2 ]) -nitrogen- (5- (1- (methylpiperidin-4-yl) pyridin-2-yl) pyrimidin-2-amine (compound 26)
The title compound was synthesized following a procedure similar to that described in example 6.
MS(ESI):491.3[M+H] + 。 1 H-NMR(400MHz,CDCl 3 )δ8.43(d,J＝3.6Hz,1H),8.32(d,J＝8.4Hz,1H),8.24(d,J＝2.4Hz,1H),8.15(s,1H),7.60(dd,J 1 ＝8.8Hz,J 2 ＝2.4Hz,1H),3.21-3.17(m,2H),2.58-2.53(m,1H),2.48(s,3H),2.43(s,3H),2.29-2.01(m,8H),1.98-1.86(m,6H)。
Example 29 5-fluoro-4- (7 ' -fluoro-2 ' -methyl-spiro [ cyclopentane-1, 3' -indole)]-5' -yl-3, 4- [ D 2 ]) -nitrogen- (5- (1- (methyl))Piperidin-4-yl) pyridin-2-yl-3, 4,6- [ D 3 ]) Pyrimidine-2-amines (Compound 28)
The title compound was synthesized according to the procedure similar to examples 4 and 7.
MS(ESI):494.3[M+H] + 。 1 H-NMR(400MHz,CDCl 3 )δ8.40(d,J＝3.6Hz,1H),8.10(s,1H),7.98(s,1H),7.91(d,J＝10.8Hz,1H),3.17-3.14(m,2H),2.57-2.56(m,1H),2.46(s,3H),2.40(s,3H),2.29-2.00(m,7H),1.97-1.88(m,5H)。
Example 30 5-fluoro-4- (7 ' -fluoro-2 ' -methyl-spiro [ cyclopentane-1, 3' -indole)]-5' -yl-3, 4- [ D 2 ]) -nitrogen- (5- (1- (methyl) D) 3 ]) Piperidin-4-yl) pyridin-2-yl pyrimidin-2-amine (compound 29)
The title compound was synthesized following a procedure similar to that of examples 1 and 7.
MS(ESI):494.3[M+H] + 。 1 H-NMR(400MHz,CDCl 3 )δ8.44(d,J＝3.6Hz,1H),8.36(d,J＝8.8Hz,1H),8.22(d,J＝2.0Hz,1H),8.06(s,1H),7.98(s,1H),7.91(dd,J 1 ＝10.8Hz,J 2 ＝1.2Hz,1H),7.66(dd,J 1 ＝8.8Hz,J 2 ＝2.0Hz,1H),3.27-3.26(m,2H),2.63-2.60(m,1H),2.40(s,3H),2.19-2.07(m,7H),1.97-1.86(m,5H)。
Example 31 5-fluoro-4- (7 ' -fluoro-2 ' -methyl-spiro [ cyclopentane-1, 3' -indole)]-5' -yl-3, 4- [ D 2 ]) -nitrogen- (5- (1- (methylpiperidin-4-yl) pyridin-2-yl) pyrimidine-6- [ D]-2-amine (Compound 30)
The title compound was synthesized according to the procedure similar to examples 2 and 7.
MS(ESI):492.3[M+H] + 。 1 H-NMR(400MHz,CDCl 3 )δ8.34(d,J＝3.6Hz,1H),8.22(d,J＝2.0Hz,1H),8.14(s,1H),7.98(s,1H),7.91(d,J＝10.8Hz,1H),7.63(dd,J 1 ＝8.8Hz,J 2 ＝2.4Hz,1H),3.20-3.17(m,2H),2.62-2.54(m,1H),2.47(s,3H),2.40(s,3H),2.30-2.01(m,7H),1.98-1.86(m,5H)。
Example 32 5-fluoro-4- (7 ' -fluoro-2 ' -methyl-spiro [ cyclopentane-1, 3' -indole) ]-5' -yl-3, 4- [ D 2 ]) -nitrogen- (5- (1- (methylpiperidin-4-yl) -3,4- [ D) 2 ]) Pyridin-2-yl-3, 4,6- [ D 3 ]) Pyrimidine-2-amines (Compound 31)
The title compound was synthesized following a procedure similar to that of examples 1,3, 4 and 7.
MS(ESI):499.3[M+H] + 。 1 H-NMR(400MHz,CDCl 3 )δ8.44(d,J＝3.6Hz,1H),8.06(s,1H),7.98(s,1H),7.91(dd,J 1 ＝10.8Hz,J 2 ＝1.2Hz,1H),3.28-3.25(m,2H),2.40(s,3H),2.19-2.09(m,6H),1.96-1.86(m,5H)。
Example 33 5-fluoro-4- (7 '-fluoro-2' - (methyl-D) 3 ) Spiro [ cyclopentane-1, 3' -indoles]-5' -yl-2, 3,4, 5- [ D 8 ]) -nitrogen- (5- (1- (methylpiperidin-4-yl) -pyridin-2-yl) pyrimidin-2-amine (compound 33)
The title compound was synthesized according to the procedure similar to examples 7 and 8. MS (ESI) 500.3[ M+H ]] + 。
Example 34 5-fluoro-4- (7 '-fluoro-2' - (methyl- [ D) 3 ]) Spiro [ cyclopentane-1, 3' -indoles]-5' -yl) -nitrogen- (5- (1- (methylpiperidin-4-yl) pyridin-2-yl) pyrimidine-6- [ D]-2-amine (Compound 34)
The title compound was synthesized according to the procedure similar to examples 2 and 8.
MS(ESI):493.3[M+H] + 。 1 H-NMR(400MHz,CDCl 3 )δ8.34(d,J＝8.8Hz,1H),8.24(s,1H),8.23(s,1H),7.98(s,1H),7.91(dd,J 1 ＝10.8Hz,J 2 ＝0.8Hz,1H),7.61(dd,J 1 ＝8.8Hz,J 2 ＝2.4Hz,1H),3.05-3.02(m,2H),2.54-2.50(m,1H),2.38(s,3H),2.22-2.08(m,8H),1.91-1.83(m,6H)。
Example 35 5-fluoro-4- (7 '-fluoro-2' - (methyl- [ D) 3 ]) Spiro [ cyclopentane-1, 3' -indoles]-5' -yl) -nitrogen- (5- (1- (methyl- [ D) 3 ]) Piperidin-4-yl) pyridin-2-yl pyrimidin-2-amine (compound 35)
The title compound was synthesized following a procedure similar to that of examples 1 and 8.
MS(ESI):495.3[M+H] + 。 1 H-NMR(400MHz,CDCl 3 )δ8.44(d,J＝3.6Hz,1H),8.34(d,J＝8.4Hz,1H),8.23(d,J＝2.4Hz,1H),8.13(s,1H),7.98(s,1H),7.91(d,J＝11.2Hz,1H),7.62(dd,J 1 ＝8.4Hz,J 2 ＝2.0Hz,1H),3.07-3.04(m,2H),2.57-2.51(m,1H),2.20-2.08(m,8H),1.91-1.88(m,6H)。
Example 36 5-fluoro-4- (7 '-fluoro-2' - (methyl- [ D) 3 ]) Spiro [ cyclopentane-1, 3' -indoles]-5' -yl) -nitrogen- (5- (1- (methylpiperidine)Pyridin-4-yl) pyridin-2-yl-3, 4,6- [ D 3 ]) Pyrimidine-2-amines (Compound 36)
The title compound was synthesized according to the procedure similar to examples 4 and 8.
MS(ESI):495.1[M+H] + 。 1 H-NMR(400MHz,CDCl 3 )δ8.45(d,J＝3.6Hz,1H),8.43(s,1H),7.98(s,1H),7.91(dd,J 1 ＝11.2Hz,J 2 ＝1.2Hz,1H),3.04-3.01(m,2H),2.53-2.49(m,1H),2.37(s,1H),2.21-2.08(m,8H),1.91-1.82(m,6H)。
Example 37 5-fluoro-4- (7 '-fluoro-2' - (methyl- [ D) 3 ]) Spiro [ cyclopentane-1, 3' -indoles]-5 '-yl-6' - [ D]) -nitrogen- (5- (1- (methylpiperidin-4-yl) pyridin-2-yl) pyrimidin-2-amine (compound 37)
The title compound was synthesized according to the procedure similar to examples 5 and 8.
MS(ESI):493.3[M+H] + 。 1 H-NMR(400MHz,CDCl 3 )δ8.44(d,J＝4.0Hz,1H),8.34(d,J＝8.4Hz,1H),8.23(d,J＝2.0Hz,1H),8.13(s,1H),7.98(s,1H),7.62 (dd,J 1 ＝8.8Hz,J 2 ＝2.4Hz,1H),3.08-3.05(m,2H),2.55-2.49(m,1H),2.40(s,3H),2.20-2.07(m,8H),1.91-1.88(m,6H)。
EXAMPLE 38 5-fluoro-4- (7 '-fluoro-2' - (methyl- [ D) 3 ]) Spiro [ cyclopentane-1, 3' -indoles]-5 '-yl-6' - [ D]) -nitrogen- (5- (1- (methylpiperidin-4-yl) pyridin-2-yl) pyrimidine-6- [ D]2-amine (Compound 38)
The title compound was synthesized following a procedure similar to that of examples 4, 5 and 8.
MS(ESI):494.3[M+H] + 。 1 H-NMR(400MHz,CDCl 3 )δ12.87(brs,1H),8.65(d,J＝8.8Hz,1H),8.23(s,1H),8.02(s,1H),8.00(s,1H),3.68-3.65(m,2H),2.98-2.92(m,3H),2.87(s,3H),2.75-2.66(m,2H),2.40-1.89(m,10H)。
Example 39 5-fluoro-4- (7 '-fluoro-2' - (methyl- [ D) 3 ]) Spiro [ cyclopentane-1, 3' -indoles]-5' -yl) -nitrogen- (5- (1- (methyl- [ D) 3 ]) Piperidin-4-yl-3, 4- [ D 2 ]) Pyridin-2-yl-3, 4,6- [ D 3 ]) Pyrimidine-2-amine (Compound 39)
The title compound was synthesized following a procedure similar to that of examples 1,3, 4 and 8.
MS(ESI):500.3[M+H] + 。 1 H-NMR(400MHz,CDCl 3 )δ8.44(d,J＝3.6Hz,1H),8.06(s,1H),7.98(s,1H),7.91(dd,J 1 ＝10.8Hz,J 2 ＝1.2Hz,1H),3.17-3.15(m,2H),2.30-2.20(m,1H),2.19-2.03(m,8H),1.93-1.87(m,4H)。
Example 40 5-fluoro-4- (7 '-fluoro-2' - (methyl- [ D) 3 ]) Spiro [ cyclopentane-1, 3' -indoles]-5' -yl-3, 4- [ D 2 ]) -nitrogen- (5- (1- (methylpiperidin-4-yl) pyridin-2-yl) pyrimidin-2-amine (compound 40)
The title compound was synthesized according to the procedure similar to examples 7 and 8.
MS(ESI):494.3[M+H] + 。 1 H-NMR(400MHz,CDCl 3 )δ8.44(d,J＝3.6Hz,1H),8.34(d,J＝8.4Hz,1H),8.23(s,1H),8.21(s,1H),8.14(s,1H),7.98(s,1H),7.91(d,J＝11.2Hz,1H),7.62(dd,J 1 ＝8.4Hz,J 2 ＝2.0Hz,1H),3.08-3.05(m,2H),2.55-2.51(m,1H),2.40(s,3H),2.18-2.07(m,6H),1.91-1.89(m,6H)。
Example 41 5-fluoro-4- (7 '-fluoro-2' - (methyl- [ D) 3 ]) Spiro [ cyclopentane-1, 3' -indoles]-5' -yl-3, 4- [ D 2 ]) -nitrogen- (5- (1- (methyl) D) 3 ]) Piperidin-4-yl-3, 4- [ D 2 ]) Pyridin-2-yl-3, 4,6- [ D 3 ]) Pyrimidine-2-amine (Compound 41)
The title compound was synthesized following a procedure similar to that of examples 1,3, 4, 7 and 8.
MS(ESI):502.3[M+H] + 。 1 H-NMR(400MHz,CDCl 3 )δ8.43(d,J＝3.6Hz,1H),8.07(s,1H),7.98(s,1H),7.91(dd,J 1 ＝10.8Hz,J 2 ＝2.8Hz,1H),3.06-3.03(m,2H),2.20-2.07(m,6H),1.91-1.86(m,5H)。
Example 42 5-fluoro-4- (7 '-fluoro-2' - (methyl- [ D) 3 ]) Spiro [ cyclopentane-1, 3' -indoles]-5' -yl-3, 4- [ D 2 ]) -nitrogen- (5- (1- (methyl) D) 3 ]) Piperidin-4-yl) pyridin-2-yl pyrimidin-2-amine (compound 42)
The title compound was synthesized following a procedure similar to that of examples 1, 7 and 8.
MS(ESI):497.3[M+H] + 。 1 H-NMR(400MHz,CDCl 3 )δ8.43(d,J＝3.6Hz,1H),8.34(d,J＝7.6Hz,1H),8.21(d,J＝2.4Hz,1H),8.02(s,1H),7.98(s,1H),7.91(dd,J 1 ＝11.2Hz,J 2 ＝1.6Hz,1H),7.63(dd,J 1 ＝8.4Hz,J 2 ＝2.4Hz,1H),3.09-3.07(m,2H),2.54-2.51(m,1H),2.18-2.07(m,6H),1.89-1.88(m,6H)。
Example 43 5-fluoro-4- (7 '-fluoro-2' - (methyl- [ D) 3 ]) Spiro [ cyclopentane-1, 3' -indoles]-5' -yl-3, 4- [ D 2 ]) -nitrogen- (5- (1- (methylpiperidin-4-yl) pyridin-2-yl) pyrimidine-6- [ D]-2-amine (Compound 43)
The title compound was synthesized following a procedure similar to that of examples 2, 7 and 8.
MS(ESI):495.3[M+H] + 。 1 H-NMR(400MHz,CDCl 3 )δ8.37(d,J＝8.8Hz,1H),8.23(d,J＝2.0Hz,1H),8.07(s,1H),7.98(s,1H),7.91(d,J＝11.2Hz,1H),7.66(d,J＝8.4Hz,1H),3.33-3.31(m,2H),2.62(s,3H),2.52-2.49(m,2H),2.27-2.07(m,7H),1.99-1.87(m,4H)。
Example 44 5-fluoro-4- (7 '-fluoro-2' - (methyl- [ D) 3 ]) Spiro [ cyclopentane-1, 3' -indoles]-5' -yl-3, 4- [ D 2 ]) -nitrogen- (5- (1- (methyl) D) 3 ]) Piperidin-4-yl) pyridin-2-yl) pyrimidine-6- [ D]-2-amine (Compound 44)
The title compound was synthesized following a procedure similar to that of examples 1, 2, 7 and 8.
MS(ESI):498.3[M+H] + 。 1 H-NMR(400MHz,CDCl 3 )δ8.39(d,J＝8.8Hz,1H),8.22(d,J＝3.6Hz,1H),8.05(s,1H),7.98(s,1H),7.91(dd,J 1 ＝11.2Hz,J 2 ＝0.8Hz,1H),7.70(d,J＝8.4Hz,1H),3.59-3.54(m,2H),2.84-2.75(m,3H),2.55-2.40(m,2H),2.55-2.40(m,2H),2.22-1.87(m,5H)。
EXAMPLE 45 5-fluoro-4- (7 '-fluoro-2' - (methyl- [ D) 3 ]) Spiro [ cyclopentane-1, 3' -indoles]-5 '-yl-4' - [ D]) -nitrogen- (5- (1- (methyl) D) 3 ]) Piperidin-4-yl) pyridin-2-yl pyrimidin-2-amine (compound 45)
The title compound was synthesized following a procedure similar to that of examples 1, 6 and 8.
MS(ESI):496.3[M+H] + 。 1 H-NMR(400MHz,CDCl 3 )δ8.43(d,J＝3.6Hz,1H),8.34(d,J＝8.8Hz,1H),8.22(d,J＝2.4Hz,1H),8.10(s,1H),7.91(d,J＝11.2Hz,1H),7.62(dd,J 1 ＝8.8Hz,J 2 ＝2.4Hz,1H),3.05-3.02(m,2H),2.54-2.48(m,1H),2.20-2.09(m,8H),1.91-1.80(m,6H)。
Example 46 5-fluoro-4- (7 '-fluoro-2' - (methyl- [ D) 3 ]) Spiro [ cyclopentane-1, 3' -indoles]-5 '-yl-4' - [ D]) -nitrogen- (5- (1- (methyl) D) 3 ]) Piperidin-4-yl) pyridin-2-yl) pyrimidine-6- [ D]-2-amine (Compound 46)
The title compound was synthesized following a procedure similar to that of examples 1, 2, 6 and 8.
MS(ESI):497.3[M+H] + 。 1 H-NMR(400MHz,CDCl 3 )δ8.34(d,J＝8.8Hz,1H),8.22(d,J＝2.0Hz,1H),8.14(s,1H),7.91(d,J＝10.8Hz,1H),7.62(dd,J 1 ＝8.4Hz,J 2 ＝2.4Hz,1H),3.06-3.03(m,2H),2.53-2.43(m,1H),2.18-2.08(m,8H),1.90-1.87(m,6H)。
The advantageous effects of the present invention will be described below by way of test examples.
Test example 1 proliferation inhibition assay of human brain glioma U87MG cells by the Compounds of the invention
1.1 Experimental materials
Human brain glioma cells U87MG were purchased from the south tokyo, herborist biotechnology limited; control compound 1, prepared by the preparation method described in reference to patent WO2017/092635 A1; the Cell detection device was In Cell Analyzer 2200 (GE Healthcare); reagents or consumables used in the experiments are shown in the following table:
TABLE 1
Reagents or consumables Goods number Manufacturer' s
DMSO D2650 Sigma
PBS 20012-17 Gibco
DAPI D8417 Sigma
Formaldehyde 47608 Sigma
Triton TM X-100 T9284 Sigma
MEM 12561-056 Gibco
MEM NEAA 2079705 Gibco
Pyruvic acid sodium salt 11140-050 Gibco
FBS 10099141 Gibco
Penicillin/streptomycin 15140122 Thermo Fisher
96-well black transparent bottom cell plate 3603 Corning
1.2 preparation of experiments
1.2.1 Preparation of U87MG Medium MEM (Low sugar) +10% FBS+1% penicillin/streptomycin+1% sodium pyruvate+1% MEM NEAA
1.2.2 preparation of control compound 1 and test compound solutions:
(1) Preparation of control Compound 1 solution
a. Adding 15 mu L of 1.25mM control compound 1 solution into a B1 hole of a 96-well plate, adding 20 mu L of DMSO into each hole of B2-B11, adding 5 mu L of solution into a B2 hole from the B1 hole, uniformly mixing, and sequentially diluting to B11 to obtain a control compound 1 solution which is sequentially diluted by 3 times;
b. To 96-well plate C2-C11, 95.2. Mu.L of the medium was added, 4.8. Mu.L of the diluted B2-B11 solution was added to C2-C11 (well C1 concentration: 60. Mu.M), and the mixture was homogenized.
(2) Preparing test compound solution
a. Respectively taking 15 mu L of 1.25mM test compound solution, adding the solution into a D1 hole of a 96-well plate, adding 20 mu L of DMSO into each hole of D2-D11, taking 5 mu L of solution from the D1 hole, adding the solution into the D2 hole, uniformly mixing, and sequentially diluting to D11 to obtain test compound solution which is sequentially diluted by 3 times;
b. to 96-well plate E2-E11, 95.2. Mu.L of the medium was added, 4.8. Mu.L of the diluted D2-D11 solution was added to E2-E11 (well E1 concentration: 60. Mu.M), and the mixture was homogenized.
1.3 Experimental procedure
1.3.1 U87 MG cells were inoculated into 96-well black transparent bottom cell plates at 4000 cells/100. Mu.L/well, respectively, and cultured overnight at 37 ℃;
1.3.2 adding the diluted control compound 1 solution and the test compound solution to the cell-inoculated culture plate at a concentration of 20. Mu.L/well, respectively, and incubating at 37℃for 72 hours;
1.3.3 fixing: taking out the 96-well plate, removing the culture medium, adding 50 mu L of neutral formaldehyde fixing solution (formaldehyde: PBS=1:9) into each well at room temperature, and fixing for 10-30min at room temperature in a dark place;
1.3.4 1 XPBS (50. Mu.L/well) was washed 2 times;
1.3.5 permeabilization treatment: 0.2% Triton TM Permeabilizing X-100 (50. Mu.L/well) for 5-10min;
1.3.6 1 XPBS (50. Mu.L/well) was washed 2 times;
1.3.7 staining: DAPI (50 μl/well) staining (PBS: dapi=5000:1), incubation for 20min at room temperature in the dark;
1.3.8 1 XPBS (50. Mu.L/well) was washed 3 times, and PBS (100. Mu.L/well) was added;
1.3.9 In Cell Analyzer scan, analyzing Cell number per well;
1.3.10 data processing:
the inhibition rate of each compound at each concentration point was calculated according to the following formula, and curve fitting was performed by software Graphpad Prism 6.0 to obtain IC 50 Values.
1.4 experimental results
TABLE 2 test results of inhibitory Activity of test Compounds on U87MG cells
Numbering of compounds IC 50 value (nM)
Control Compound 1 9.35
1 11.36
2 1.61
5 3.80
6 6.23
7 15.24
8 5.74
9 5.74
10 9.45
11 6.16
12 2.41
13 4.94
14 2.37
15 11.62
16 5.75
20 1.61
21 3.25
22 5.74
23 0.65
24 2.99
25 1.47
27 7.51
28 6.31
29 5.26
30 3.13
31 3.11
32 5.21
34 3.81
35 5.41
36 10.24
37 6.85
38 4.22
39 3.94
40 1.33
41 3.39
42 2.58
43 2.77
44 1.29
45 2.79
46 2.08
As can be seen from the data in table 2, the inhibitory activity of the test compound after deuteration on U87MG cells was similar to that of the control compound without deuteration, and the above experimental results prove that: the compound of the present invention retains the cytological activity of the drug after deuterated modification relative to control compound 1.
Test example 2 stability of the Compounds of the invention in human liver microsomes
2.1 Experimental materials
Human liver microsomes were purchased from Corning and stored in a-80 ℃ refrigerator; reduced Nicotinamide Adenine Dinucleotide Phosphate (NADPH) is purchased from Chem-impex international; control compound 1, prepared by the preparation method described in reference to patent WO2017/092635 A1; the controls were testosterone, diclofenac, and propafenone.
2.2 experimental conditions
-test concentration: 1 μM (DMSO 0.01%);
buffer solution: 100mM phosphate buffer, pH7.4;
microsomal protein concentration: 0.5mg/ml;
-cofactor: NADPH and MgCl 2 ；
NADPH concentration: 1nM.
2.3 Experimental procedure
2.3.1 8 96 Kong Fuyo plates were prepared, named T0, T5, T10, T20, T30, T60, blank60 and NCF60, respectively. The corresponding reaction time points for the first 6 incubation plates were 0, 5, 10, 20, 30 and 60 minutes, respectively. No test, control compound 1 or control was added to the Blank60 plate and samples were taken after 60 minutes incubation. Incubation was performed in NCF60 plates with potassium phosphate buffer instead of NADPH working solution for 60 min.
2.3.2 adding 5. Mu.L of test, control Compound 1 or control working solution and 445. Mu.L of microsomal working solution to T0, T5, T10, T20, T30, T60 and NCF60 plates, respectively, adding only microsomal working solution to Blank60 plates, and then pre-incubating the above incubation plates in a 37℃water bath for about 10 minutes.
2.3.3 after the end of pre-incubation, 44. Mu.L of NADPH working solution was added to each well of the samples to start the reaction, except for NCF60 plate and T0 plate, and 50. Mu.L of potassium phosphate buffer was added to each well on NCF60 plate.
2.3.4 after incubation for the appropriate time (5, 10, 20, 30 and 60 minutes) 180. Mu.L of stop solution (acetonitrile solution containing 200ng/mL of tolbutamide and 200ng/mL of labetalol) was added to each sample well to terminate the reaction.
2.3.5 Preparation of T0 plates: 180. Mu.L of stop solution (acetonitrile solution containing 200ng/mL of tolbutamide and 200ng/mL of labetalol) was added to the T0 plate, followed by 6. Mu.L of NADPH working solution.
2.3.6 all sample plates were shaken and centrifuged at 4000rpm for 20 minutes, and then 80. Mu.L of supernatant per well was diluted into 240. Mu.L of pure water for LC-MS/MS analysis.
2.3.7 data analysis:
the concentrations of the test sample, the control compound 1 and the control sample in the sample are all determined by adopting a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The slope value (Ke) is determined by linear regression of the residual percentage of the sample versus the natural logarithm of the incubation time curve. Half-life in vitro (T in vitro) 1/2 ) Determined by the slope value:
2.4 results of experiments on the metabolic stability of the Compounds of the invention in human liver microsomes
Half-life of test control compound 1 (T 1/2 ) Is 23.9 minutes; in the same batch of test samples, the half-life of the test compound is defined as C, the half-life of the test compound is within plus or minus 1 minute from that of the control compound 1, the half-life of the test compound is defined as B, the half-life of the test compound is 1.4 to 10 minutes longer than that of the control compound 1, the half-life of the test compound is defined as A, and the half-life of the test compound is 15 to 30 minutes longer than that of the control compound 1, the half-life of the test compound is defined as A + 。
TABLE 3 results of test compounds for their metabolic stability in human liver microsomes
Numbering of compounds Half-life (T1/2)
Control Compound 1 23.9 minutes
1 A
2 A
7 C
9 A
10 C
12 A
13 A
14 A
15 A
20 B
21 A
22 A
24 A
25 A
27 A
28 A
29 A
30 A
31 A
32 A
34 B
35 A +
36 A
37 A
38 A
39 A
40 A
41 A
42 A
43 A
44 A
As can be seen from the data in table 3, the metabolic stability of each of the compounds 1, 2, 9, 12-15, 21, 22, 24, 25, 27-32, 35-44 in human liver microsomes is better than that of the control compound 1, especially the compound 35, which has a longer half-life period in human liver microsomes than that of the control compound 1 by 15-30 minutes, and the metabolic stability in human liver microsomes is significantly improved than that of the control compound 1, which indicates that part of the compounds in the invention have longer action time and may have better clinical application value.
While compounds 7, 10 had a lower half-life than control compound 1, indicating that deuteration has an unpredictable effect on the metabolic properties of the compound, deuteration at certain sites may not only extend the half-life, but may instead shorten the half-life, deteriorating its pharmacokinetic properties.
The present invention has been illustrated by the above-described embodiments, but it should be understood that the above-described embodiments are for purposes of illustration and description only and are not intended to limit the invention to the embodiments described. In addition, it will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, and that many variations and modifications are possible in light of the teachings of the invention, which variations and modifications are within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.

Claims (27)

  1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
    wherein R is 1 -R 29 H or D, respectively, and R 1 -R 29 At least one of which is D; and
    the compound of formula (I) excludes the following compounds:
  2. the compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 -R 15 And R 17 -R 29 At least one of which is D;
    preferably, R 1 -R 15 、R 17 And R 19 -R 29 At least one of which is D;
    preferably, R 1 -R 12 、R 17 、R 19 -R 29 At least one of which is D;
    preferably, R 1 -R 3 、R 8 -R 9 、R 17 、R 21 、R 23 、R 27 -R 29 At least one of which is D.
  3. A compound or pharmaceutically acceptable salt thereof according to claim 1 or 2,
    R 1 -R 3 is D; and/or
    R 8 And R is 9 Is D; and/or
    R 13 -R 15 Is D; and/or
    R 16 Is D; and/or
    R 17 Is D; and/or
    R 18 Is D; and/or
    R 21 And R is 23 Is D; and/or
    R 27 -R 29 Is D.
  4. A compound or pharmaceutically acceptable salt thereof according to claim 1 or 2,
    R 1 -R 3 is D; and/or
    R 8 And R is 9 Is D; and/or
    R 13 -R 15 Is D; and/or
    R 17 Is D; and/or
    R 21 And R is 23 Is D; and/or
    R 27 -R 29 Is D.
  5. A compound or pharmaceutically acceptable salt thereof according to claim 1 or 2,
    R 1 -R 3 is D; and/or
    R 8 -R 9 Is D; and/or
    R 17 Is D; and/or
    R 21 And R is 23 Is D; and/or
    R 27 -R 29 Is D.
  6. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 16 Is H, or R 13 -R 15 Is H, or R 18 Is H.
  7. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein when R 16 In the case of the D-form,
    R 1 -R 3 is D, and R 13 -R 15 Is D; and/or
    R 1 -R 3 Is D, R 8 -R 9 Is D, and R 13 -R 15 Is D; and/or
    R 21 And R is 23 Is D; and/or
    R 27 -R 29 Is D; and/or
    R 17 Is D and R 27 -R 29 Is D; and/or
    R 21 Is D, R 23 Is D, and R 27 -R 29 Is D; and/or
    R 1 -R 3 Is D, R 21 Is D, R 23 Is D, and R 27 -R 29 Is D.
  8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure of formula (II):
    wherein R is 1 、R 2 、R 3 At least one of them is D, R 13 -R 15 H or D, respectively;
    preferably, R 1 、R 2 And R 3 Is D, R 13 -R 15 H or D, respectively;
    more preferably, R 1 、R 2 And R 3 Is D, R 13 -R 15 At least one is D.
  9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure of formula (III):
    wherein R is 1 -R 3 、R 8 -R 9 、R 13 -R 15 H or D, respectively;
    preferably, R 1 -R 3 Is D, and/or R 8 -R 9 Is D, and/or R 13 -R 15 Is D;
    preferably, R 1 -R 3 Is D, and R 13 -R 15 Is D;
    preferably, R 1 -R 3 Is D, R 8 -R 9 Is D, and R 13 -R 15 Is D.
  10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure of formula (IV):
    Wherein R is 1 -R 15 At least one of which is D;
    preferably, R 1 -R 3 Is D, and/or R 8 -R 9 Is D.
  11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (V):
    wherein R is 1 -R 3 、R 13 -R 16 H or D, respectively;
    preferably, R 1 -R 3 Is D, and/or R 13 -R 15 Is D.
  12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (VI):
    wherein R is 1 -R 3 、R 8 、R 9 、R 13 -R 16 H or D, respectively;
    preferably, R 1 -R 3 Is D, and/or R 13 -R 15 Is D, and/or R 8 And R is 9 Is D;
    preferably, R 16 Is D.
  13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (VII):
    wherein R is 1 -R 3 、R 8 、R 9 And R 13 -R 26 H or D, respectively.
  14. A compound or pharmaceutically acceptable salt thereof according to claim 13,
    R 1 -R 3 is D; and/or
    R 8 And R is 9 Is D; and/or
    R 13 -R 15 Is D; and/or
    R 16 Is D; and/or
    R 17 Is D; and/or
    R 21 And R is 23 Is D.
  15. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
  16. a pharmaceutical composition comprising a compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.
  17. A method of treating a CDK4/6 mediated disorder or disease comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 16.
  18. Use of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16, in the manufacture of a medicament for the treatment of a CDK4/6 mediated disorder or disease.
  19. A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, for use in the treatment of a CDK4/6 mediated disorder or disease.
  20. A process for preparing a compound of formula (VII), comprising the steps of: reacting a compound of formula (VIII) with a deuterating agent in the presence of an acid to provide a compound of formula (VII)
    Wherein R is 1 -R 3 、R 8 、R 9 、R 13 -R 26 H or D, respectively;
    preferably, the acid is selected from at least one of deuterated hydrochloric acid, ferric trichloride, aluminum trichloride, zinc chloride, acetic acid, acetic anhydride, trifluoroacetic acid, trifluoroacetic anhydride, trifluoromethanesulfonic acid, benzoic acid, p-methylbenzoic acid, p-nitrobenzoic acid, p-methoxybenzoic acid, 3, 5-dinitrobenzoic acid, diphenylphosphoric acid, phenylphosphinic acid, phosphoric acid, hypophosphorous acid, phenylacetic acid, phenylpropionic acid, trimethylacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, mandelic acid, and salicylic acid; and/or the deuterated reagent is selected from d 6 -DMSO、d 7 -DMF、d 6 Acetone, CD 3 OD、D 2 O、CD 3 CN, and C 6 D 6 At least one of (a) and (b);
    more preferably, the acid is deuterated hydrochloric acid and/or the deuterating agent is D 2 O。
  21. The method according to claim 20, wherein:
    R 1 -R 3 is D; and/or
    R 8 And R is 9 Is D; and/or
    R 13 -R 15 Is D; and/or
    R 16 Is D; and/or
    R 17 Is D; and/or
    R 21 And R is 23 Is D.
  22. A compound represented by the formula (IX) or a pharmaceutically acceptable salt thereof,
    wherein R is 18 -R 29 H or D, respectively, preferably R 18 -R 29 As defined in any one of claims 3 to 7, and 13 to 14, respectively; x is a leaving group or amino;
    preferably, X is halogen or amino, more preferably fluorine, bromine, chlorine or amino.
  23. A process for preparing a compound of formula (I), comprising converting a compound of formula (IX) to a compound of formula (I):
    wherein:
    R 17 is D; and
    R 1 -R 16 and R is 18 -R 29 H or D, respectively, preferably R 1 -R 16 And R is 18 -R 29 As defined in any one of claims 3 to 5 and 7, respectively, preferably R 1 -R 3 Is D, and/or R 13 -R 15 Is D, and/or R 16 Is D, and/or R 18 -R 29 Is hydrogen.
  24. A process for preparing a compound of formula (IX), comprising the steps of: reacting a compound of formula (X) or a salt thereof with a compound of formula (XI) in the presence of an acid to give a compound of formula (IX):
    wherein R is 18 -R 29 H or D, respectively, preferably R 18 -R 29 Preferably R as defined in any one of claims 3 to 7, and 13 to 14, respectively 18 -R 29 Is hydrogen; x is a leaving group or amino; preferably, X is halogen or amino, more preferably fluoro, bromo, chloro or amino; and/or
    The salt of the compound of formula (X) is selected from the group consisting of hydrochloride, sulfate, mesylate and p-toluenesulfonate, preferably hydrochloride.
  25. The method of claim 24, wherein the acid is an organic acid, an inorganic acid, or a lewis acid; preferably the acid is sulfuric acid, hydrochloric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, znCl 2 、FeCl 3 、AlCl 3 Or SnCl 4 The method comprises the steps of carrying out a first treatment on the surface of the Preferably, the acid is sulfuric acid.
  26. The method of claim 25, further comprising the step of:
    (1) Make the following stepsReaction with deuterated reagent to obtain
    (2) Make the following stepsConversion toOr a salt thereof.
  27. The method of claim 26, wherein said step (1) is at Ir (OMe) (cod) 2 In the presence of; and the deuterated reagent is selected from d 6 -DMSO、d 7 -DMF、d 6 Acetone, CD 3 OD、D 2 O、CD 3 CN, and C 6 D 6 At least one of (a) and (b); preferably, the deuterated reagent is D 2 O。
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