CN116981669A - Pyrimidine or pyrido heterocyclic adenosine receptor inhibitor, preparation method and application thereof - Google Patents

Pyrimidine or pyrido heterocyclic adenosine receptor inhibitor, preparation method and application thereof Download PDF

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Publication number
CN116981669A
CN116981669A CN202280012721.7A CN202280012721A CN116981669A CN 116981669 A CN116981669 A CN 116981669A CN 202280012721 A CN202280012721 A CN 202280012721A CN 116981669 A CN116981669 A CN 116981669A
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mmol
pharmaceutically acceptable
solvate
methyl
pyridin
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潘建峰
孙大庆
闫琪
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Shanghai Qilu Pharmaceutical Research and Development Centre Ltd
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Shanghai Qilu Pharmaceutical Research and Development Centre 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Abstract

Disclosed are a novel pyrimidine/pyrido heterocyclic adenosine receptor inhibitor, a preparation method and application thereof, wherein the pyrimidine/pyrido heterocyclic adenosine receptor inhibitor is a compound shown in a formula II, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof. The pharmaceutical activity data show that the compounds have better inhibition effect on A2a or/and A2b, and partial compounds show better selectivity, thus being applicable to treating diseases related to A2a or/and A2b receptors.

Description

Pyrimidine or pyrido heterocyclic adenosine receptor inhibitor, preparation method and application thereof
The present application claims priority of chinese patent application 202110162277.4 with application date 2021/2/5, chinese patent application 202110175181.1 with application date 2021/2/9, chinese patent application 202110675861.X with application date 2021/6/18, chinese patent application 202110694192.0 with application date 2021/6/22, chinese patent application 202111292681.X with application date 2021/11/3, chinese patent application 202111293263.2 with application date 2021/11/3, chinese patent application 202210071111.6 with application date 2022/1/21. The present application incorporates the entirety of the above-mentioned chinese patent application.
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a novel pyrimidine/pyrido heterocyclic compound which can be used as an A2a or/and A2b adenosine receptor inhibitor and used for treating diseases related to an A2a or/and A2b receptor.
Background
Adenosine (adonosine, ADO) acts as a neurotransmitter and modulates various important physiological functions and is widely distributed in tissues such as nervous system, cardiovascular system, kidney, gastrointestinal tract and the like. ADO is involved in the pathophysiological processes of a variety of diseases by binding to its specific receptors A1R, A aR, A2bR and A3R. Of the four receptors for ADO, A1R and A2aR are significantly more distributed and number in the brain than the other two receptors, and also have a stronger affinity for ADO.
Adenosine receptors are present on the surface of most tissue cells of the body, and A1 receptors are mainly present in brain tissue, spinal cord and heart. A1 receptors in the heart are distributed on the surfaces of atrial, ventricular, sinus and atrioventricular node cells. Adenosine and its analogs inhibit Adenylate Cyclase (AC), G protein and catecholamines by exciting the A1 receptor, promoting outward potassium ion flow to produce negative timing, variability and negative transduction; through a post-receptor signal transduction mechanism, namely activating G protein and then phospholipase C (PLC), the PLC activates a phosphatidylinositol system to generate inositol triphosphate (IP 3) and Diglyceride (DG), and the DG activates corresponding Protein Kinase C (PKC) and then activates ATP sensitive potassium channel (KATP) ion flow, so that the myocardial ischemia type Pretreatment (PC) effect is generated; activates the nitric oxide synthase of sinus node and atrioventricular node, increases the synthesis of nitric oxide, inhibits the inward calcium ion flow of slow-response automatic cells to generate negative time-varying and negative conduction, and acts on the vascular dilation. The A2a receptor is mainly distributed in the dopamine-rich region of brain tissue, followed by renal nipple, endothelial cells of blood vessels (aorta and coronary arteries, etc.), platelets and polymorphonuclear leukocyte membranes. The A2b receptor is mainly distributed in the digestive system. After binding of adenosine and its analogs to the A2 receptor, AC is activated, which increases cyclic adenosine monophosphate (cAMP) formation, thereby dilating vascular smooth muscle and inhibiting the toxic effects of neutrophils. Adenosine A3 receptors are widely distributed on the surfaces of organs such as spleen, heart, kidney, etc. of rats, rabbits, dogs, sheep and humans, and on different areas of the brain and inflammatory cells. The A3 receptor has the effects of inhibiting AC from increasing cAMP and producing PC after being combined with the radioactive ligand; meanwhile, the PLC is activated through the G protein sensitive to pertussis toxin to generate IP3 and DG, so that PKC is activated, and PC effect is also generated; adenosine stimulates A3 receptors and promotes degranulation of mast cells, increasing the release of mast cell allergic mediators.
According to the published literature, A2a antagonists have been suggested for the management and treatment of e.g. parkinson's disease and cancer; modulation of A2b has been suggested for management and treatment of chronic lung diseases, including asthma, for example; modulation of A3 is suggested for management and treatment of, for example, asthma and chronic obstructive pulmonary disease, glaucoma, cancer, and stroke.
Currently, adenosine receptor inhibitors are increasingly receiving attention. Some potential A2a or/and A2b inhibitors were discovered sequentially. But the A2a and/or A2b inhibitor with stronger inhibition and better selectivity, in particular to the A2a/A2b double inhibitor, has important significance and development value.
Disclosure of Invention
In a first aspect, the present invention provides a compound as shown in formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, and a solvate of a pharmaceutically acceptable salt thereof:
wherein R is 2 H, CN, halogen atom, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, N (Re) (Rf) or Ar; preferably, R 2 Is NH 2 Or Ar;
re and Rf are independently H, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 alkyl-CO-, C 1-4 haloalkyl-CO-, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; or Re and Rf together with the attached N atom form a 4-6 membered ring, said 4-6 membered ring optionally being substituted with one or more groups selected from CN, OH, C 1-4 Alkyl, C 1-4 Haloalkyl and substituents of halogen atoms; preferably, the 4-6 membered ring is a 4-6 membered heterocycloalkyl; preferably, N (Re) (Rf) is NH 2 A tetrahydropyrrolyl, piperidinyl, piperazinyl or morpholinyl group;
ar is aryl or heteroaryl; the aryl group is preferably phenyl or naphthyl, more preferably phenyl; the heteroaryl group is preferably a 5-6 membered heteroaryl ring, more preferably pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazole, thiazolyl, more preferably pyridinyl, furanyl, pyrazolyl, thienyl, more preferably pyridinyl; the aryl and the heteroaryl are optionally independently substituted with one or more Rc; preferably, ar is substituted with 1, 2, 3 or 4 Rc; rc is independently H, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, CN or a halogen atom; preferably Rc is independently H, CN, F, cl, methyl, ethyl, methoxy, difluoromethyl or trifluoromethyl; more preferably, rc is independently H, CN, F, cl, methyl, ethyl or methoxy;
specifically, ar may be selected from any one of the following structures:
more specifically, ar is
In some embodiments of formula II of the present invention, R 2 Is NH 2 The method comprises the steps of carrying out a first treatment on the surface of the In other embodiments, R 2 Ar is preferably
X 1 Is N or C-Ra; preferably X 1 Is N or CH; more preferably X 1 CH;
X 2 、X 3 、X 4 is independently O, S, N, N-Ra, CH 2 C-Ra or c=o; preferably X 2 、X 3 、X 4 And X is as follows 2 、X 4 The directly linked atoms together form a five membered heteroaryl ring substituted with 1, 2 or 3 Ra, preferably pyrrolyl, furanyl, thienyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl, thiazolyl;
Z 1 is N or CH;
when Z is 1 When N is N, Z 1 The single and double construction among the vertex atoms of the 6-membered heterocyclic ring can be redetermined according to the valence of each vertex atom and the connected group;
Y 1 、Y 2 、Y 3 independently N and C-Rb; preferably Y 1 Is C-Rb, Y 2 Is N, Y 3 Is N; more preferably, Y 1 Is CH, Y 2 Is N, Y 3 Is N;
ra is independently H, CN, NH 2 CO-, halogen atom, C 1-4 Alkyl, C 1-4 Haloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, aryl or 5-6 membered heteroaryl; preferably, ra is independently H, CN, halogen, methyl, ethylIsopropyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclohexyl, azetidine, phenyl, pyrazolyl, furyl or imidazolyl; ra is optionally substituted with one or more groups selected from halogen atoms, CN, C 1-4 Alkyl and C 1-4 A substituent of a haloalkyl group; more preferably, ra is independently H, br, cl, F, CN, CHF 2 、CF 3 、NH 2 CO-, methyl, pyrazolyl, phenyl, cyclopropyl or 5-methyl-furan-2-yl;
rb is independently H, CN, C 1-4 Alkyl, C1-4 haloalkyl or halogen atom; preferably Rb is independently H, cl, F, CN, methyl, ethyl, isopropyl or trifluoromethyl; more preferably Rb is independently H, cl, methyl or trifluoromethyl;
l is- (CH) 2 )n-、-(CD 2 )n-、-NH-(CH 2 )n-、-O-(CH 2 ) n-or-S- (CH) 2 ) n-; preferably L is CH 2 Or CD (compact disc) 2 The method comprises the steps of carrying out a first treatment on the surface of the More preferably, L is CH 2 The method comprises the steps of carrying out a first treatment on the surface of the The D refers to deuterium;
is aryl or 5-6 membered heteroaryl, preferably phenyl, pyridyl, pyrimidinyl, pyrazolyl, furyl, thienyl,More preferably phenyl, pyridinyl;
R 1 is independently H, CN, halogen atom, NH 2 aminocarbonyl-C 1-4 Alkyl, C 1-4 Alkylsulfonyl, C 1-4 Alkylsulfonylamino, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 alkyl-O-C 1-4 Alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, 5-13 membered spirocyclic group, 5-13 membered heterospirocyclic group, 6-12 membered bridged cyclic group, 6-12 membered heterobridged cyclic group, phenyl, 5-6 membered heteroaryl, and di-C 1-4 Alkyl P (O) -, 3-7 membered cycloalkyl-O-C 1-4 Alkyl, 3-7 membered heterocycloalkyl-O-C 1-4 Alkyl and phenoxy-C 1-4 An alkyl group; preferably, R 1 Independently F, CN, C 1-4 Alkoxy, C 1-4 Haloalkoxy, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 7-9 membered heterospirocyclic, phenyl or 5-6 membered heteroaryl; preferably, R 1 Independently C 1-4 Alkoxy, C 1-4 Haloalkoxy, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 7-9 membered nitrogen containing heterospirocyclic, phenyl or 5-6 membered heteroaryl; r is R 1 Optionally substituted by one or more substituents selected from methyl, methoxy, ethyl, isopropyl, OH, CN, halogen atoms, COOH and 2-hydroxy-prop-2-yl;
specifically, R 1 Is F, -OCH 3 、 CN orPreferably, R 1 Is that
In some embodiments of formula II of the present invention, the building blockIs that
Alternatively, two adjacent R 1 Can be cyclized together with the atoms connecting them to form a saturated 5-6 membered ring or an unsaturated 5-6 membered ring, said saturated 5-6 membered ring and unsaturated 5-6 membered ring optionally being substituted with one or more substituents selected from C 1-4 Alkyl, C 1-4 Substituents for alkoxy groups and halogen atoms; preferably, the saturated 5-6 membered ring and unsaturated 5-6 membered ring are pyrazole ring, oxazole ring, thiazole ring, isothiazole ring, isoxazole ring, pyridine ring, pyrrole ring, thiophene ring, furan ring, imidazole ring, benzene ring, pyrimidine ring, pyrazine ring, pyridazine ring or 1, 3-dioxolane ring; more preferably, two R 1 And (3) withThe co-cyclisation is to the following group:
m is 0, 1, 2 or 3; preferably 1 or 2; more preferably 1;
n is 0, 1, 2 or 3, preferably 1 or 2; more preferably 1;
represents a single bond or a double bond.
In some embodiments of formula II of the present invention, ar is phenyl and the other variables are as defined in any one of the schemes of the present invention.
In some embodiments of formula II of the present invention, ar is pyridinyl and the other variables are as defined in any of the schemes of the present invention.
In some embodiments of formula II of the present invention, Z 1 For C, the other variables are as defined in any of the schemes of the invention.
In some embodiments of formula II of the present invention, X 2 For S, the other variables are as defined in any of the schemes of the invention.
In some embodiments of formula II of the present invention, X 2 Is S, X 3 And X 4 Independently N or C-Ra, the other variables being as defined in any one of the schemes of the invention.
In some embodiments of formula II of the present invention, X 2 Is S, X 3 Is CH, X 4 For C-Ra, the other variables are as defined in any of the schemes of the present invention.
In some embodiments of formula II of the present invention, X 2 Is S, X 3 Is CH, X 4 For C-Br, the other variables are as defined in any of the schemes of the invention.
In some embodiments of formula II of the present invention, X 2 Is S, X 3 Is N, X 4 For C-Ra, the other variables are as defined in any of the schemes of the present invention.
In some embodiments of formula II of the present invention, X 4 For S, the other variables are as defined in any of the schemes of the invention.
In some embodiments of formula II of the present invention, X 4 Is S, X 2 And X 3 Independently N or C-Ra, the other variables being as defined in any one of the schemes of the invention.
In some embodiments of formula II of the present invention, X 4 Is S, X 2 Is C-Ra, X 3 For N, the other variables are as defined in any of the schemes of the invention.
In some embodiments of formula II of the present invention, X 2 Is O, X 3 And X 4 Independently N or C-Ra, the other variables being as defined in any one of the schemes of the invention.
In some embodiments of formula II of the present invention, X 2 Is N-Ra, X 3 And X 4 Independently N or C-Ra, the other variables being as defined in any one of the schemes of the invention.
In some embodiments of formula II of the present invention, X 2 、X 3 And X 4 Independently C-Ra, N or N-Ra, with the other variables being as defined in any of the schemes herein.
In some embodiments of formula II of the present invention, X 2 For N, the other variables are as defined in any of the schemes of the invention.
In some embodiments of formula II of the present invention, X 2 Is N, X 3 For CH, the other variables are as defined in any of the schemes of the invention.
In some embodiments of formula II of the present invention, X 2 And X is 3 With double bonds, and other variables are as defined in any of the schemes of the invention.
In some embodiments of formula II of the present invention, X 2 And X is 3 Connected by double bonds, X 2 And X 3 Independently N or C-Ra, the other variables being as defined in any one of the schemes of the invention.
In some embodiments of formula II of the present invention, X 2 And X is 3 With single bonds, and other variables as defined in any of the schemes of the invention.
In some embodiments of formula II of the present invention, X 2 And X is 3 Connected by single bond, X 2 And X 3 Independently selected from NH, CH 2 And c=o; preferably X 2 And X 3 Independently selected from CH 2 And c=o, and the other variables are as defined in any of the schemes of the invention.
In some embodiments of formula II of the present invention, the building blockSelected from any one of the following structures: preferably is More preferably
In some embodiments of formula II of the present invention, the building blockSelected from any one of the following structures: preferably is
In some embodiments of formula II of the present invention, the building blockIs that
In some embodiments of formula II of the present invention, Y 1 、Y 2 、Y 3 All of which are N, and the other variables are as defined in any of the schemes of the present invention.
In some embodiments of formula II of the present invention, Y 1 Is CH, Y 2 Is CH, Y 3 For N, the other variables are as defined in any of the schemes of the invention.
In some embodiments of formula II of the present invention, Y 1 Is CH, Y 2 For N, the other variables are as defined in any of the schemes of the invention.
In some embodiments of formula II of the present invention, Y 3 For N, the other variables are as defined in any of the schemes of the invention.
In some embodiments of formula II of the present invention, L is CH 2 The other variables are as defined in any of the schemes of the present invention.
In some embodiments of formula II of the present invention, L is CD 2 The other variables are as defined in any of the schemes of the present invention.
In some embodiments of formula II of the present invention, R 2 Is NH 2 The other variables are as defined in any of the schemes of the present invention.
In some embodiments of formula II of the present invention,is pyridinyl, and the other variables are as defined in any aspect of the invention.
In some embodiments of formula II of the present invention, R 1 Is thatThe other variables are as defined in any of the schemes of the present invention.
In some embodiments of formula II of the present invention,selected from the group consisting ofThe other variables are as defined in any of the schemes of the present invention.
In some embodiments of formula II of the present invention, Selected from the group consisting ofThe other variables are as defined in any of the schemes of the present invention.
In some embodiments of formula II of the present invention,selected from the group consisting of
In some embodiments of formula II of the present invention, R 2 Ar is provided; x is X 3 And X is 4 Is connected with each other by a single bond or a double bond; when X is 2 And X is 3 X when connected by single bond 2 And X 3 Independently NH, CH 2 Or c=o; preferably X 2 And X 3 Independently CH 2 Or c=o; when X is 2 And X is 3 X when connected by double bonds 2 And X 3 Independently N and C-Ra.
In some embodiments of the invention, the compound of formula II has the structure of formula II-a:
wherein X is 2 、X 3 、X 4 、Y 1 、Y 2 、L、R 1 、m、 As defined in any of the aspects of the invention;
X 5 n, CH or c=o, preferably N or CH.
In some embodiments of the invention, in formula II-a, Y 1 Is CH, Y 2 For N, the other variables are as defined in any of the schemes of the invention.
In some embodiments of the invention, in formula II-a, X 5 For CH, the other variables are as defined in any of the schemes of the invention.
In some embodiments of the invention, in formula II-a, X 5 N, other variables such as the inventionIs defined in any one of the schemes.
In some embodiments of the invention, in formula II-a, L is CH 2 The other variables are as defined in any of the schemes of the present invention.
In some embodiments of the invention, in formula II-a, L is CD 2 The other variables are as defined in any of the schemes of the present invention.
In some embodiments of the invention, in formula II-a, R 1 Is thatThe other variables are as defined in any of the schemes of the present invention.
In some embodiments of the invention, in formula II-a, X 2 For S, the other variables are as defined in any of the schemes of the invention.
In some embodiments of the invention, in formula II-a, X 2 Is S, X 3 And X 4 Independently N or C-Ra, the other variables being as defined in any one of the schemes of the invention.
In some embodiments of the invention, in formula II-a, X 2 Is S, X 3 Is CH, X 4 For C-Ra, the other variables are as defined in any of the schemes of the present invention.
In some embodiments of the invention, in formula II-a, X 2 Is S, X 3 Is CH, X 4 For C-Br, the other variables are as defined in any of the schemes of the invention.
In some embodiments of the invention, in formula II-a, X 2 Is S, X 3 Is N, X 4 For C-Ra, the other variables are as defined in any of the schemes of the present invention.
In some embodiments of the invention, in formula II-a, X 4 For S, the other variables are as defined in any of the schemes of the invention.
In some of the invention In embodiments, in formula II-a, X 4 Is S, X 2 And X 3 Independently N or C-Ra, the other variables being as defined in any one of the schemes of the invention.
In some embodiments of the invention, in formula II-a, X 4 Is S, X 2 Is C-Ra, X 3 For N, the other variables are as defined in any of the schemes of the invention.
In some embodiments of the invention, in formula II-a, X 2 Is O, X 3 And X 4 Independently N or C-Ra, the other variables being as defined in any one of the schemes of the invention.
In some embodiments of the invention, in formula II-a, X 2 Is N-Ra, X 3 And X 4 Independently N or C-Ra, the other variables being as defined in any one of the schemes of the invention.
In some embodiments of the invention, in formula II-a, X 2 、X 3 And X 4 Independently C-Ra, N or N-Ra, with the other variables being as defined in any of the schemes herein.
In some embodiments of the invention, the compound of formula II has the structure of formula II-b:
wherein X is 2 、X 3 、X 4 、Y 1 、Y 2 、L、R 1 、m、 As defined in any of the aspects of the invention;
X 6 and X 7 Selected from N, O, S, NH, CH and CH 2 。
In some embodiments of the invention, in formula II-b, X 6 Is NH, X 7 Is N.
In some embodiments of the invention, in formula II-b, the structural unitIs thatFor example
In some embodiments of the invention, the compound of formula II has the structure of formula II-c:
wherein Ra, R 1 As defined in any of the schemes of the present invention.
In some embodiments of the invention, in formula II-c, R 1 Is that
In some embodiments of the invention, in formula II-c, ra is selected from methyl, br, cl, CN, CHF 2 、CF 3 And cyclopropyl.
In some embodiments of the invention, the compound of formula II has a structure of formula I',
wherein each group is as defined in any one of the schemes of the present invention.
In some embodiments of the invention, the compound of formula II has a structure of formula I' -a,
X 4-1 and X 5-1 Independently N or CH;
p is 0, 1, 2, 3 or 4;
X 1 、X 2 、X 3 、Y 1 、Y 2 、R 1 、Rc、 as defined in any of the schemes of the present invention.
In some embodiments of the invention, in formula I' -a, X 1 For CH, the other variables are as defined in any of the schemes of the invention.
In some embodiments of the invention, in formula I' -a, X 2 And X 3 With double bonds, and other variables are as defined in any of the schemes of the invention.
In some embodiments of the invention, in formula I' -a, X 2 And X 3 With single bonds, and other variables as defined in any of the schemes of the invention.
In some embodiments of the invention, in formula I' -a, X 3 For CH, the other variables are as defined in any of the schemes of the invention.
In some embodiments of the invention, in formula I' -a, X 4-1 For N, the other variables are as defined in any of the schemes of the invention.
In some embodiments of the invention, in formula I' -a, X 5-1 For CH, the other variables are as defined in any of the schemes of the invention.
In some embodiments of the invention, in formula I' -a, Y 1 Is CH, Y 2 For N, the other variables are as defined in any of the schemes of the invention.
In some embodiments of the invention, the compound of formula II has a structure of formula I' -b,
wherein R is 3 、R 4 And R is 5 Rc independently;
R 6 is Rb;
R 1 、Rb、Rc、X 1 、X 2 、X 3 、 as defined in any of the schemes of the present invention.
In some embodiments of the invention, in formula I' -b, X 2 And X 3 With double bonds, and other variables are as defined in any of the schemes of the invention.
In some embodiments of the invention, in formula I' -b, X 2 And X 3 With single bonds, and other variables as defined in any of the schemes of the invention.
In some embodiments of the invention, in formula I' -b, R 3 Is H, CH 3 、CH 3 O or Cl, other variables being as in any of the aspects of the invention Defined as follows.
In some embodiments of the invention, in formula I' -b, R 4 H, CH of a shape of H, CH 3 、Cl、CH 3 O, F or CN, and the other variables are as defined in any of the schemes of the invention.
In some embodiments of the invention, in formula I' -b, R 5 Is H or a halogen atom; preferably H or F, and the other variables are as defined in any of the schemes of the invention.
In some embodiments of the invention, in formula I' -b, R 6 H, C of a shape of H, C 1-4 Alkyl or C 1-4 A haloalkyl group; preferably H or CH 3 The other variables are as defined in any of the schemes of the present invention.
In some embodiments of the invention, in formula I' -b, R 3 Is CH 3 ，R 4 Is CN, R 5 Is H, R 6 For H, the other variables are as defined in any of the schemes of the invention.
In some embodiments of the invention, in formula I' -b, X 1 For CH, the other variables are as defined in any of the schemes of the invention.
In some embodiments of the invention, in formula I' -b, X 1 For N, the other variables are as defined in any of the schemes of the invention.
In some embodiments of the invention, in formula I' -b, X 2 For N, the other variables are as defined in any one of the aspects of the invention.
In some embodiments of the invention, in formula I' -b, X 3 For CH, the other variables are as defined in any of the schemes of the invention.
In some embodiments of the invention, in formula I' -b, R 1 Is thatThe other variables are as defined in any of the schemes of the present invention.
In some embodiments of formula I of the present invention, the compounds of formula II have the structures of formula I-c, formula I-d, or formula I-e,
wherein X is 1 、X 2 、X 3 、R 1 、R 3 、R 5 、R 6 As defined in any of the schemes of the present invention.
In another aspect, the invention provides a compound of formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, and a solvate of a pharmaceutically acceptable salt thereof:
wherein R is 2 H, CN, halogen atom, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, N (Re) (Rf) or Ar; preferably, R 2 Is NH 2 Or Ar;
re and Rf are independently H, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 alkyl-CO-, C 1-4 haloalkyl-CO-, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; or Re and Rf together with the attached N atom form a 4-6 membered ring, said 4-6 membered ring optionally being substituted with one or more groups selected from CN, OH, C 1-4 Alkyl, C 1-4 Haloalkyl and substituents of halogen atoms; preferably, the 4-6 membered ring is a 4-6 membered heterocycloalkyl; preferably, N (Re) (Rf) is NH 2 A tetrahydropyrrolyl, piperidinyl, piperazinyl or morpholinyl group;
Ar is aryl or heteroaryl; the aryl group is preferably benzeneA group or naphthyl group, more preferably a phenyl group; the heteroaryl group is preferably a 5-6 membered heteroaryl ring, more preferably pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazole, thiazolyl, more preferably pyridinyl, furanyl, pyrazolyl, thienyl, more preferably pyridinyl; the aryl and the heteroaryl are optionally independently substituted with one or more Rc; preferably, ar is substituted with 1, 2, 3 or 4 Rc; rc is independently H, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, CN or a halogen atom; preferably Rc is independently H, CN, F, cl, methyl, ethyl, methoxy, difluoromethyl or trifluoromethyl; more preferably, rc is independently H, CN, F, cl, methyl, ethyl or methoxy;
specifically, ar may be selected from any one of the following structures:
more specifically, ar is
Ra is independently H, CN, NH 2 CO-, halogen atom, C 1-4 Alkyl, C 1-4 Haloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, aryl or 5-6 membered heteroaryl; preferably, ra is independently H, CN, halogen, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclohexyl, azetidine, phenyl, pyrazolyl, furanyl or imidazolyl; ra is optionally substituted with one or more groups selected from halogen atoms, CN, C 1-4 Alkyl and C 1-4 A substituent of a haloalkyl group; more preferablyRa is independently H, br, cl, F, CN, CHF 2 、CF 3 、NH 2 CO-, methyl, pyrazolyl, phenyl, cyclopropyl or 5-methyl-furan-2-yl;
in some embodiments of the invention, R 2 Is NH 2 The method comprises the steps of carrying out a first treatment on the surface of the In other embodiments, R 2 Ar is preferably
X 1 Is N or C-Ra; preferably X 1 Is N or CH; more preferably X 1 CH;
X 2 、X 3 、X 4 is independently O, S, N, N-Ra, CH 2 C-Ra or c=o; preferably X 2 、X 3 、X 4 And X is as follows 2 、X 4 The directly linked atoms together form a five membered heteroaromatic ring substituted with 1 to 3 Ra, preferably pyrrolyl, furanyl, thienyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl, thiazolyl;
Z 1 is N or CH;
when Z is 1 When N is N, Z 1 The single and double construction among the vertex atoms of the 6-membered heterocyclic ring can be redetermined according to the valence of each vertex atom and the connected group;
Y 1 、Y 2 、Y 3 independently N or C-Rb; preferably Y 1 Is C-Rb, Y 2 Is N, Y 3 Is N; more preferably, Y 1 Is CH, Y 2 Is N, Y 3 Is N;
rb is independently H, CN, C 1-4 Alkyl, C 1-4 Haloalkyl or halogen atom; preferably Rb is independently H, cl, F, CN, methyl, ethyl, isopropyl or trifluoromethyl; better Alternatively, rb is independently H, cl, methyl or trifluoromethyl;
l is- (CH) 2 )n-、-(CD 2 )n-、-NH-(CH 2 )n-、-O-(CH 2 ) n-or-S- (CH) 2 ) n-; preferably L is CH 2 Or CD (compact disc) 2 The method comprises the steps of carrying out a first treatment on the surface of the More preferably, L is CH 2 The method comprises the steps of carrying out a first treatment on the surface of the The D refers to deuterium;
is aryl or 5-6 membered heteroaryl; preferably phenyl, pyridyl, pyrimidinyl, pyrazolyl, furyl, thienyl,More preferably phenyl, pyridinyl;
R 1 independently H, halogen atom, NH 2 aminocarbonyl-C 1-4 Alkyl, C 1-4 Alkylsulfonyl, C 1-4 Alkylsulfonylamino, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 alkyl-O-C 1-4 Alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, 5-13 membered spirocyclic group, 5-13 membered heterospirocyclic group, 6-12 membered bridged cyclic group, 6-12 membered heterobridged cyclic group, phenyl, 5-6 membered heteroaryl, and di-C 1-4 Alkyl P (O) -, 3-7 membered cycloalkyl-O-C 1-4 Alkyl, 3-7 membered heterocycloalkyl-O-C 1-4 Alkyl or phenoxy-C 1-4 An alkyl group; preferably, R 1 Independently C 1-4 Alkoxy, C 1-4 Haloalkoxy, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 7-9 membered heterospirocyclic, phenyl or 5-6 membered heteroaryl; preferably, R 1 Independently C 1-4 Alkoxy, C 1-4 Haloalkoxy, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 7-9 membered nitrogen containing heterospiro ringA group, phenyl or 5-6 membered heteroaryl; r is R 1 Optionally substituted by one or more substituents selected from methyl, methoxy, ethyl, isopropyl, OH, CN, halogen atoms, COOH and 2-hydroxy-prop-2-yl;
specifically, R 1 Is F, -OCH 3 、 Preferably, R 1 Is that
In some embodiments of formula II of the present invention, the building blockIs that
In some embodiments of formula II of the present invention, m=2, two adjacent R 1 Can be cyclized to form a saturated 5-6 membered ring or an unsaturated 5-6 membered ring, and these rings can optionally be substituted with one or more substituents selected from C 1-4 Alkyl, C 1-4 Substituents for alkoxy groups and halogen atoms; preferably, two adjacent R 1 Can be cyclized to form a pyrazole ring, an oxazole ring, a thiazole ring, an isothiazole ring, an isoxazole ring, a pyridine ring, a pyrrole ring, a thiophene ring, a furan ring, an imidazole ring, a benzene ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a 1, 3-dioxolane ring; preferably, two R 1 And (3) withThe co-cyclisation is to the following group:
m is 0, 1, 2 or 3; preferably 1 or 2; more preferably 1;
n is 0, 1, 2 or 3; preferably 1 or 2; more preferably 1.
In some embodiments of formula II of the present invention, R 1 H, NH independently 2 aminocarbonyl-C 1-4 Alkyl, C 1-4 Alkylsulfonyl, C 1-4 Alkylsulfonylamino, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 alkyl-O-C 1-4 Alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, 5-13 membered spirocyclic group, 5-13 membered heterospirocyclic group, 6-12 membered bridged cyclic group, 6-12 membered heterobridged cyclic group, phenyl, 5-6 membered heteroaryl, and di-C 1-4 Alkyl P (O) -, 3-7 membered cycloalkyl-O-C 1-4 Alkyl, 3-7 membered heterocycloalkyl-O-C 1-4 Alkyl or phenoxy-C 1-4 An alkyl group; preferably, R 1 Independently C 1-4 Alkoxy, C 1-4 Haloalkoxy, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 7-9 membered heterospirocyclic, phenyl or 5-6 membered heteroaryl; preferably, R 1 Independently C 1-4 Alkoxy, C 1-4 Haloalkoxy, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 7-9 membered nitrogen containing heterospirocyclic group,Phenyl or 5-6 membered heteroaryl; r is R 1 Optionally substituted by one or more substituents selected from methyl, methoxy, ethyl, isopropyl, OH, CN, halogen atoms, COOH and 2-hydroxy-prop-2-yl;
specifically, R 1 Is that
In some embodiments of formula II of the present invention, the building blockIs that
In some embodiments of formula II of the present invention, the building blockSelected from any one of the following structures: preferably is More preferably
In some embodiments of formula II of the present invention, R 1 H, NH independently 2 aminocarbonyl-C 1-4 Alkyl, C 1-4 Alkylsulfonyl, C 1-4 Alkylsulfonylamino, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 alkyl-O-C 1-4 Alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, 5-13 membered spirocyclic group, 5-13 membered heterospirocyclic group, 6-12 membered bridged cyclic group, 6-12 membered heterobridged cyclic group, phenyl, 5-6 membered heteroaryl, and di-C 1-4 Alkyl P (O) -, 3-7 membered cycloalkyl-O-C 1-4 Alkyl, 3-7 membered heterocycloalkyl-O-C 1-4 Alkyl or phenoxy-C 1-4 An alkyl group; preferably, R 1 Independently C 1-4 Alkoxy, C 1-4 Haloalkoxy, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 7-9 membered heterospirocyclic, phenyl or 5-6 membered heteroaryl; preferably, R 1 Independently selected from C 1-4 Alkoxy, C 1-4 Haloalkoxy, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 7-9 membered nitrogen containing heterospirocyclic, phenyl or 5-6 membered heteroaryl; and R is 1 Optionally substituted with one or more of the following groups: methyl, methoxy, ethyl, isopropyl, OH, CN, halogen, COOH;
specifically, R 1 Is that
In another aspect, the invention provides a compound of formula I:
wherein X is 1 Is N or C-Ra; ra is independently H, CN, C 1-4 Alkyl, C 1-4 Haloalkyl or halogen atom; preferably, ra is independently H, cl, F, CN, methyl, ethyl, isopropyl or trifluoromethyl; more preferably, ra is independently H, cl, methyl or trifluoromethyl; preferably X 1 CH;
X 2 and X is 3 Can be connected by single bond or double bond; when X is 2 And X is 3 X when connected by single bond 2 、X 3 Independently NH, CH 2 Or c=o, preferably X 2 、X 3 Independently selected from CH 2 Or c=o; when X is 2 And X is 3 X when connected by double bonds 2 、X 3 Independently N or C-Ra;
Y 1 、Y 2 、Y 3 independently N and C-Rb; rb is independently H, CN, C 1-4 Alkyl, C 1-4 Haloalkyl or halogen atom; preferably Rb is independently H, cl, F, CN, methyl, ethyl, isopropyl or trifluoromethyl; more preferably Rb is independently H, cl, methyl or trifluoromethyl;
l is- (CH) 2 )n-、-(CD 2 )n-、-NH-(CH 2 )n-、-O-(CH 2 ) n-or-S- (CH) 2 ) n-; preferably L is CH 2 Or CD (compact disc) 2 The method comprises the steps of carrying out a first treatment on the surface of the More preferably, L is CH 2 The method comprises the steps of carrying out a first treatment on the surface of the The D refers to deuterium;
ar is aryl or heteroaryl; the aryl group is preferably phenyl and naphthyl, more preferably phenyl; the heteroaryl group is preferably a 5-6 membered heteroaryl ring, more preferably pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazole, thiazolyl, more preferably pyridinyl, furanyl, pyrazolyl, thienyl, more preferably pyridinyl; the aryl and the heteroaryl are optionally independently substituted with one or more Rc; rc is independently H, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, CN and halogen atoms; preferably Rc is independently H, CN, F, cl, methyl, ethyl, methoxy, difluoromethyl or trifluoromethyl; more preferably, rc is independently H, CN, F, cl, methyl, ethyl or methoxy;
Specifically, ar may be selected from any one of the following structures:
more specifically, ar is
Is aryl or 5-6 membered heteroaryl, preferably phenyl, pyridyl, pyrimidinyl, pyrazolyl, furyl, thienyl,More preferably phenyl, pyridinyl;
R 1 is independently H, CN, halogen atom, NH 2 aminocarbonyl-C 1-4 Alkyl, C 1-4 Alkylsulfonyl, C 1-4 Alkylsulfonylamino, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 alkyl-O-C 1-4 Alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, 5-13 membered spirocyclic group, 5-13 membered heterospirocyclic group, 6-12 membered bridged cyclic group, 6-12 membered heterobridged cyclic group, phenyl, 5-6 membered heteroaryl, and di-C 1-4 Alkyl P (O) -, 3-7 membered cycloalkyl-O-C 1-4 Alkyl, 3-7 membered heterocycloalkyl-O-C 1-4 Alkyl or phenoxy-C 1-4 An alkyl group; preferably, R 1 Independently F, CN, C 1-4 Alkoxy, C 1-4 Haloalkoxy, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 7-9 membered heterospirocyclic, phenyl or 5-6 membered heteroaryl; preferably, R 1 Independently C 1-4 Alkoxy, C 1-4 Haloalkoxy, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 7-9 membered nitrogen containing heterospirocyclic, phenyl or 5-6 membered heteroaryl; and R is 1 Optionally substituted with one or more of the following groups: methyl, methoxy, ethyl, isopropyl, OH, CN, halogen, COOH;
Specifically, R 1 Independently F, CN, Preferably, R 1 Independently is
In some embodiments of the present invention,is that
In some embodiments of formula I of the present invention, two adjacent R' s 1 Can be cyclized to form a saturated 5-6 membered ring or an unsaturated 5-6 membered ring, and these rings can optionally be substituted with one or more substituents selected from C 1-4 Alkyl, C 1-4 Substituents for alkoxy groups and halogen atoms; preferably, two adjacent R 1 Can be cyclized to form a pyrazole ring, an oxazole ring, a thiazole ring, an isothiazole ring, an isoxazole ring, a pyridine ring, a pyrrole ring, a thiophene ring, a furan ring, an imidazole ring, a benzene ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a 1, 3-dioxolane ring; preferably, two adjacent R 1 And (3) withThe co-cyclisation is to the following group:
m is 0, 1, 2 or 3; preferably 1 or 2; more preferably 1;
n is 0, 1, 2 or 3; preferably 1 or 2; more preferably 1.
In some embodiments of formula I of the present invention, the building blockSelected from any one of the following structures:
in some embodiments of formula I of the present invention, the building blockIs that
In some embodiments of formula I of the present invention, the compounds are represented by formula I-a,
wherein X is 1 、X 2 、X 3 、Y 1 、Y 2 、R 1 Rc is as defined in any of the schemes of the invention；
X 4 And X 5 Independently N or CH;
p is 0, 1, 2, 3 or 4.
In some embodiments of the invention, in formula I-a, X 1 For CH, the other variables are as defined in any of the schemes of the invention.
In some embodiments of the invention, in formula I-a, X 2 And X 3 With double bonds, and other variables are as defined in any of the schemes of the invention.
In some embodiments of the invention, in formula I-a, X 2 And X 3 With single bonds, and other variables as defined in any of the schemes of the invention.
In some embodiments of the invention, in formula I-a, X 3 For CH, the other variables are as defined in any of the schemes of the invention.
In some embodiments of the invention, in formula I-a, X 4 For N, the other variables are as defined in any of the schemes of the invention.
In some embodiments of the invention, in formula I-a, X 5 For CH, the other variables are as defined in any of the schemes of the invention.
In some embodiments of the invention, in formula I-a, Y 1 Is CH, Y 2 For N, the other variables are defined as described above.
In some embodiments of formula I of the present invention, the compounds are represented by formula I-b,
wherein R is 1 、X 1 、X 2 、X 3 As defined for formula I-a;
X 2 and X 3 Is connected by double bonds; or X 2 And X is 3 The two are connected by a single bond;
R 3 H, C of a shape of H, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, halogen atom or CN; preferably, R 3 Selected from H, CH 3 、CH 3 O or Cl;
R 4 h, C of a shape of H, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, halogen atom or CN; preferably, R 4 Selected from H, CH 3 、Cl、CH 3 O, F or CN;
R 5 is H or a halogen atom; preferably, R 5 Is H or F;
R 6 h, C of a shape of H, C 1-4 Alkyl or C 1-4 A haloalkyl group; preferably, R 6 Is H or R 6 Is CH 3 。
In some embodiments of the invention, in formula I-b, R 3 Is CH 3 ，R 4 Is CN, R 5 Is H, R 6 For H, the other variables are as defined in any of the schemes of the invention.
In some embodiments of the invention, in formula I-b, X 1 For CH, the other variables are as defined in any of the schemes of the invention.
In some embodiments of the invention, in formula I-b, X 1 For N, the other variables are as defined in any of the schemes of the invention.
In some embodiments of the invention, in formula I-b, X 2 For N, the other variables are as defined in any of the schemes of the invention.
In some embodiments of the invention, in formula I-b, X 3 For CH, the other variables are as defined in any of the schemes of the invention.
In one aspect of the inventionIn some embodiments, R in formula I-b 1 Is that The other variables are as defined in any of the schemes of the present invention.
In some embodiments of formula I of the present invention, the compounds are represented by formula I-c, formula I-d, or formula I-e,
wherein X is 1 、X 2 、X 3 、R 1 、R 3 、R 5 、R 6 As defined in any of the schemes of the present invention.
In some embodiments of formula I of the present invention, ar may be selected from any one of the following structures:
in some embodiments of formula I of the present invention, R 1 H, NH independently 2 aminocarbonyl-C 1-4 Alkyl, C 1-4 Alkylsulfonyl, C 1-4 Alkylsulfonylamino, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 alkyl-O-C 1-4 Alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, 5-13 membered spirocyclic group, 5-13 membered heterospirocyclic group, 6-12 membered bridged cyclic group, 6-12 membered heterobridged cyclic group, phenyl, 5-6 membered heteroaryl, and di-C 1-4 Alkyl P (O) -, 3-7 membered cycloalkyl-O-C 1-4 Alkyl, 3-7 membered heterocycloalkyl-O-C 1-4 Alkyl or phenoxy-C 1-4 An alkyl group; preferably, R 1 Independently C 1-4 Alkoxy, C 1-4 Haloalkoxy, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 7-9 membered heterospirocyclic, phenyl or 5-6 membered heteroaryl; preferably, R 1 Independently C 1-4 Alkoxy, C 1-4 Haloalkoxy, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 7-9 membered nitrogen containing heterospirocyclic, phenyl or 5-6 membered heteroaryl; and R is 1 Optionally substituted with one or more of the following groups: methyl, methoxy, ethyl, isopropyl, OH, CN, halogen and COOH;
specifically, R 1 Is that
In some embodiments of formula I of the present invention, R 1 Is that
In the present invention, substituents in different embodiments may be combined with each other, and the embodiments obtained by the combination thereof still belong to the embodiments described in the present invention.
In some embodiments of the invention, the compound is selected from:
in another aspect, the invention provides a pharmaceutical composition comprising an effective prophylactic or therapeutic amount of a compound as described above, a pharmaceutically acceptable salt thereof, a solvate thereof, and a solvate of a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable carriers or excipients.
In another aspect, the invention provides the use of a compound as described above, a pharmaceutically acceptable salt thereof, a solvate thereof, and a solvate of a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or/and prophylaxis of a disease or condition associated with the A2a and/or A2b receptor in a mammal, including a human.
In a further aspect, the present invention provides the use of a pharmaceutical composition as described above for the manufacture of a medicament for the treatment or/and prophylaxis of a disease or condition associated with the A2a and/or A2b receptor in a mammal, including a human.
In another aspect, the present invention provides a method for treating and/or preventing a disease or disorder associated with A2a and/or A2b receptors in a mammal (including a human being) in need thereof, which comprises administering to a mammal in need thereof (preferably a therapeutically effective amount) of a compound as described above, a pharmaceutically acceptable salt thereof, a solvate thereof, and a solvate of a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides a method for treating and/or preventing a disease or disorder associated with A2a and/or A2b receptors in a mammal (including a human) in need thereof, the method comprising administering to the mammal in need thereof (preferably a therapeutically effective amount) of a pharmaceutical composition as described above.
In some embodiments of the invention, the disease or disorder associated with A2a and/or A2b receptors is a cancer, which may be a solid or non-solid tumor.
Description and definition of the invention
In the present invention, the selected or optional substituent can be attached to the modified group at any attachable position of the substituent.
In the present invention, the sulfonyl group means-S (=o) 2 -; the two C 1-4 Alkyl phosphorus oxy means having two C 1-4 P (=o) wherein the alkyl group is directly attached to the phosphorus atom, such as dimethylphosphoxy;
In the present invention, in particular in the first aspect, the halogen atom refers to fluorine, chlorine, bromine, iodine; by "halo" is meant a group formed upon substitution of one or more hydrogen atoms in a substituent with a halogen atom.
The term "alkyl" refers to a straight or branched hydrocarbon group that is singly linked between carbon atoms, and between carbon atoms and hydrogen atoms. Alkyl is preferably C 1-4 Or C 1-6 Alkyl of (a); c (C) 1-4 Alkyl "means an alkyl group having 1 to 4 carbon atoms," C 1-6 Alkyl "means an alkyl group having 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl.
The term "cycloalkyl" refers to a saturated hydrocarbon group in which atoms are joined by single bonds to form a ring. C (C) 3-7 Cycloalkyl refers to cycloalkyl groups containing 3 to 7 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and the like.
The term "spiro" refers to a polycyclic hydrocarbon group having one carbon atom in common between monocyclic rings; spirocycloalkyl is preferably C 5-13 、C 6-12 Or C 7 - 11 A spirocycloalkyl group; examples of spirocycloalkyl groups include, but are not limited to, spiro [2.2]Pentane, spiro [2.3 ] ]Hexane, spiro [3.3 ]]Heptane, spiro [3.4 ]]Octane, spiro [4.4 ]]Nonane, spiro [4.5 ]]Decane, spiro [5.5 ]]Undecane, spiro [5.6 ]]Dodecane, spiro [6.6 ]]Tridecane, spiro [6.7 ]]Tetradecane.
The term "bridged ring" refers to a polycyclic hydrocarbon group having two or more carbon atoms in common. The bridged ring radical is preferably a 4-13 membered bridged ring, a 5-12 membered bridged ring, a 6-11 membered bridged ring, or a 7-11 membered bridged ring. Examples of bridged ring radicals include, but are not limited to, bicyclo [3.1.0] hexyl, bicyclo [3.2.0] heptyl, bicyclo [3.3.0] octyl, bicyclo [4.1.0] heptyl, bicyclo [4.2.0] octyl, bicyclo [4.3.0] nonyl, bicyclo [4.4.0] decyl, and bicyclo [3.2.1] octyl. The term "alkoxy" refers to an alkyl group attached through an oxygen bridge, i.e., a group resulting from substitution of an alkyl group for a hydrogen atom in a hydroxyl group. Alkoxy is preferably C1-4 or C1-6 alkoxy; examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, neopentoxy, n-hexyloxy.
The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced with halogen atoms. Haloalkyl is preferably C 1-6 Or C 1-4 A haloalkyl group. Examples of haloalkyl include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, tribromomethyl.
The term "haloalkoxy" refers to an alkoxy group in which one or more hydrogen atoms are replaced with halogen atoms. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, trichloromethoxy, 2-trifluoroethoxy, 2-trichloroethoxy.
The term "heterocycloalkyl" refers to a cycloalkyl group in which one or more carbon atoms in the ring backbone structure are replaced with heteroatoms; the heteroatom is typically selected from N, O, S. The heterocycloalkyl group is preferably a 3-6-membered, 3-7-membered, 4-6-membered, 4-7-membered, 5-6-membered, 5-7-membered heterocycloalkyl group. Examples of heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl.
The term "heterospirocyclic group" refers to a spirocyclic group in which one or more carbon atoms in the spirocyclic backbone structure are replaced with heteroatoms selected from N, O, S. Preferably, the heterospirocyclic group is selected from the following spirocyclic groups in which the spirocyclic backbone carbon atom is substituted with 1 to 3 heteroatoms selected from N, O, S: spiro [2.2] pentyl, spiro [2.3] hexyl, spiro [2.4] heptyl, spiro [2.5] octyl, spiro [2.6] nonyl, spiro [3.3] heptyl, spiro [3.4] octyl, spiro [3.5] nonyl, spiro [3.6] decyl, spiro [4.4] nonyl, spiro [4.5] decyl, spiro [4.6] undecyl, spiro [5.5] undecyl, spiro [5.6] dodecyl, spiro [6.6] tridecyl, spiro [6.7] tetradecyl. Examples of heterospirocyclic groups also include 2-oxa-7-azaspiro [5.3] nonan-7-yl, 2-oxa-6-azaspiro [3.3] heptan-6-yl, 2, 6-diazaspiro [3.3] heptan-2-yl, 2, 7-diazaspiro [5.3] nonyl, 2, 7-dioxaspiro [5.3] nonyl, 3, 9-diazaspiro [5.5] undec-3-yl, 1-oxa-4, 9-diazaspiro [5.5] undec-9-yl, 1-oxa-4, 8-diazaspiro [5.4] decan-8-yl, 3-azaspiro [5.5] undec-3-yl, 7-azaspiro [3.5] decan-7-yl, 1-oxa-4, 9-diazaspiro [5.5] undec-4-yl, 6-oxa-9-diazaspiro [5.5] undec-yl, 1-oxa-4, 9-diazaspiro [5.5] undec-9-yl, 1-oxa-4, 8-yl, 3-diazaspiro [ 5.5.5 ] decan-yl.
The term "nitrogen-containing heterospirocyclic group" refers to a heterospirocyclic group containing at least one N atom, which may also contain other heteroatoms, such as N, O, S; preferably, the nitrogen-containing heterospiro group is a heterospiro ring containing 1N and 1O; more preferably, the nitrogen-containing heterospiro ring is attached to the substituted structure through its N atom.
The term "heterobridged ring radical" refers to a bridged ring radical in which one or more of the carbon atoms that make up the bridged ring skeleton are replaced with heteroatoms selected from N, O, S. Preferably, the heterobridged ring radical is selected from the following bridged ring radicals in which the bridged ring backbone carbon atoms are substituted with 1 to 3 heteroatoms selected from N, O, S: bicyclo [3.1.0] hexyl, bicyclo [3.2.0] heptyl, bicyclo [3.3.0] octyl, bicyclo [4.1.0] heptyl, bicyclo [4.2.0] octyl, bicyclo [4.3.0] nonyl, bicyclo [4.4.0] decyl, and bicyclo [3.2.1] octyl. Examples of heterobridged cyclic groups include, but are not limited to, 1, 4-diazabicyclo [4.4.0] decan-4-yl, 1, 4-diazabicyclo [4.3.0] nonan-4-yl, 8-oxa-1, 4-diazabicyclo [4.4.0] decan-4-yl, 4, 7-diazabicyclo [4.3.0] nonan-4-yl, 2-oxa-5-azabicyclo [2.2.1] heptan-5-yl, 3, 7-diazabicyclo [4.3.0] nonan-3-yl, 3, 7-diazabicyclo [3.3.0] octan-3-yl, 3, 7-diazabicyclo [4.4.0] decan-3-yl, 3, 6-diazabicyclo [ 4.0] nonan-3-yl, 3, 6-diazabicyclo [4.3.0] nonan-3-yl, 3, 6-diazabicyclo [ 4.0.3.1 ] decan-3-yl, 3, 6-diazabicyclo [ 4.0.0 ] decan-3-yl.
The term "aryl" refers to an unsaturated, typically aromatic, hydrocarbon group that may be a single ring or multiple rings fused together. Examples of aryl groups include, but are not limited to, phenyl, naphthyl.
The term "heteroaryl" refers to a stable monocyclic or polycyclic aromatic hydrocarbon containing at least 1 heteroatom ring member selected from N, O, S, and also includes nitrogen oxides thereof when the heteroaryl contains an N atom. Heteroaryl groups include 5-6 membered heteroaryl, 8-14 membered fused heteroaryl. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, pyrazinyl, pyridazinyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, isoxazolyl, pyrazinyl, pyrimidinyl, indazolyl, indolyl, isoquinolyl, quinoxalinyl, benzoxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzimidazolyl, quinolinyl, quinazolinyl.
The term "substituted" means that one or more hydrogen atoms on a particular group are replaced with substituents, and may include deuterium and variants of hydrogen, provided that the valence of the particular group is normal and the substituted compound is stable.
The term "composition" as used herein is intended to include products comprising the specified amounts of the respective specified ingredients, as well as any product that results, directly or indirectly, from combination of the specified amounts of the respective specified ingredients. One skilled in the art can vary the actual dosage level of each active ingredient in the pharmaceutical compositions of the present invention so that the resulting amount of active compound is effective to achieve the desired therapeutic response for a particular patient, composition and mode of administration. The dosage level will be selected based on the activity of the particular compound, the route of administration, the severity of the condition being treated, the condition of the patient being treated, and the past history. However, it is practiced in the art that the dosage of the compound is gradually increased from a level below that required to achieve the desired therapeutic effect until the desired effect is achieved. In the present invention, the pharmaceutical composition may be specifically formulated for oral administration, for parenteral injection or for rectal administration in solid or liquid form.
The term "solvate" refers to a variable stoichiometric complex formed from a solute and a solvent. Such solvents for the purposes of the present invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water.
The term "pharmaceutically acceptable carrier" refers to a medium commonly accepted in the art for delivery of biologically active agents to animals, particularly mammals, and includes, for example, adjuvants, excipients or vehicles, such as diluents, preservatives, fillers, flow modifiers, disintegrants, wetting agents, emulsifying agents, suspending agents, sweetening, flavoring, perfuming, antibacterial, antifungal, lubricating and dispersing agents, depending on the mode of administration and nature of the dosage form. Pharmaceutically acceptable carriers are formulated within the purview of one of ordinary skill in the art according to a number of factors. Including but not limited to: the type and nature of the active agent formulated, the subject to which the composition containing the agent is to be administered, the intended route of administration of the composition, and the therapeutic indication of interest. Pharmaceutically acceptable carriers include both aqueous and nonaqueous media and a variety of solid and semi-solid dosage forms. Such carriers include many different ingredients and additives in addition to the active agent, and such additional ingredients included in the formulation for a variety of reasons (e.g., stabilizing the active agent, adhesive, etc.) are well known to those of ordinary skill in the art.
The term "excipient" generally refers to the carrier, diluent, and/or medium required to make an effective pharmaceutical composition.
The term "prophylactically or therapeutically effective amount" means that the compound of the invention, or a pharmaceutically acceptable salt thereof, is a sufficient amount of the compound to treat a disorder at a reasonable effect/risk ratio applicable to any medical treatment and/or prophylaxis. It will be appreciated that the total daily amount of the compounds, or pharmaceutically acceptable salts thereof, compositions of the present invention will be determined by the physician within the scope of sound medical judgment. For any particular patient, the particular therapeutically effective dose level will depend on a variety of factors including the disorder being treated and the severity of the disorder; the activity of the particular compound employed; the specific composition employed; age, weight, general health, sex and diet of the patient; the time of administration, route of administration and rate of excretion of the particular compound employed; duration of treatment; a medicament for use in combination with or simultaneously with the particular compound employed; and similar factors well known in the medical arts. For example, it is common in the art to start doses of the compound at levels below that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
The compound of the present invention may be used in combination with other pharmaceutically active ingredients as long as it does not cause other adverse effects such as allergic reactions.
The compounds of the present invention may be used alone as anticancer agents or in combination with one or more other antineoplastic agents. Combination therapy is achieved by simultaneous, sequential or separate administration of the individual therapeutic components.
The term "pharmaceutically acceptable salt" refers to salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like commensurate with a reasonable effect/risk ratio. Pharmaceutically acceptable salts are well known in the art. The salts may be prepared by reacting the acidic functional groups of the compounds of the present invention with a suitable organic or inorganic base. Prepared in situ or separately during the final isolation and purification of the compounds of the invention. The base can be a pharmaceutically acceptable hydroxide of a metal cation, an organic primary amine, a secondary amine, a tertiary amine or the like.
The pharmaceutically acceptable salts used in the present invention are specifically exemplified by salts of the compounds of the present invention with acids, or salts with bases.
In the present invention, the substituents areRepresents the attachment position of the substituent to the parent structure or other fragment.
In the embodiment of the invention, the composition ratio of the eluent is the volume ratio, for example, the eluent: petroleum ether/ethyl acetate=10/1-2/1' means that the eluent consists of petroleum ether and ethyl acetate, and the volume ratio is petroleum ether/ethyl acetate=10/1-2/1. The ratio "10/1 to 2/1" can also be expressed as (10 to 2): 1.
the chemical abbreviations used in the present invention and their chemical names are as follows:
chemical abbreviations Chemical name
DPPA Diphenyl azide phosphate
DBU 1, 8-diazabicyclo undec-7-ene
TBAF Tetrabutylammonium fluoride
DHP Dihydropyran compounds
THF Tetrahydrofuran (THF)
TEA Triethylamine
m-CPBA M-chloroperoxybenzoic acid
Pd(OAc) 2 Palladium acetate
Pd(PPh 3 ) 2 Cl 2 Bis (triphenylphosphine) palladium chloride
Pd(dppf)Cl 2 [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride
DMF N, N-dimethylformamide
PMB P-methoxybenzyl group
TIPS Triisopropyl silicon base
Me Methyl group
TBSCl T-butyldimethylchlorosilane
-OTBS T-butyldimethylsilyloxy group
DAST Diethylaminosulfur trifluoride
Detailed Description
The invention will be further illustrated in detail by means of specific preparation examples and biological experiments, but should beIt is understood that these examples and biological experiments are for illustrative purposes only and should not be construed as limiting the invention in any way. It will be clear to a person skilled in the art that hereinafter, unless specifically indicated, the materials used are known in the art and may be obtained commercially or by a person skilled in the art according to published or conventional methods. All reactions of the present invention, unless otherwise indicated, were carried out under continuous magnetic stirring under a dry nitrogen or argon atmosphere, the solvent being a dry solvent, wherein: (i) The temperature is expressed in degrees celsius (°c), and the operation is performed at room temperature, which generally refers to 15-35 ℃, preferably 20-30 ℃, more preferably 20-25 ℃; (ii) Removing the solvent by adopting a rotary evaporator for reduced pressure evaporation, wherein the bath temperature is not higher than 60 ℃; (iii) the reaction process is followed by Thin Layer Chromatography (TLC); (iv) The final product has satisfactory hydrogen nuclear magnetic resonance spectrum 1 H-NMR) and/or Mass Spectrometry (MS) data.
Test instrument:
the structure of the compounds of the present invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). Determination of NMR with Bruker Neo400M or Bruker Assend 400 nuclear magnetic instruments, the determination solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ) Deuterated methanol (CD) 3 OD) and/or deuterated chloroform (CDCl) 3 ) The internal standard is Tetramethylsilane (TMS).
LC-MS was performed using an Agilent 1260-6125B single quadrupole mass spectrometer or a Waters H-Class SQD2 mass spectrometer (electrospray ionization as the ion source). HPLC determinations used Waters e2695-2998 or Waters ARC and Agilent 1260 or Agilent Poroshell HPH high performance liquid chromatography.
The HPLC was performed using Waters 2555-2489 (10 μm, ODS 250 cm. Times.5 cm) or GILSON Trilution LC, and the column was a Welch XB-C18 column (5 um, 21.2. Times.150 mm).
The thin layer chromatography silica gel plate uses a smoke table Jiang You silica gel development company GF254 silica gel plate or a new material company GF254 silica gel plate on the market of the nissan, the specification adopted by TLC is 0.15-0.20 mm, the preparation is 20x 20cm, and column chromatography is generally used for forming 200-300 mesh silica gel as a carrier.
Example a-1:
preparation of 2- (6- ((4- (2-aminothiophene [3,2-d ] pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl) methyl) pyridin-2-yl) propan-2-ol (compound a-1)
The reaction steps are as follows:
step 1: methyl 6- (hydroxymethyl) picolinate (4.5 g,26.9 mmol) was dissolved in tetrahydrofuran (70 mL), cooled to 0deg.C, and a solution of methylmagnesium bromide in tetrahydrofuran (3 mol/L,54mL,162.0 mmol) was added dropwise. The reaction system was naturally warmed to room temperature and stirred for 4 hours. TLC monitoring showed that the reaction was complete, and the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (50 mL). The mixture was extracted with ethyl acetate (40 mL. Times.3), and the organic phases were combined, washed with saturated brine (30 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=10/1 to 2/1) to give 2- (6- (hydroxymethyl) pyridin-2-yl) propan-2-ol (1.3 g, yield 29%). MS (ESI) M/Z168.6 [ M+H ]] + . 1 H NMR(400MHz,DMSO-d6):δ7.75(t,J＝8.0Hz,1H),7.49(d,J＝7.6Hz,1H),7.29(t,J＝7.6Hz,1H),5.36(t,J＝5.6Hz,1H),5.21(s,1H),4.54(d,J＝5.6Hz,2H),1.41(s,6H).
Step 2: 2- (6- (hydroxymethyl) pyridin-2-yl) propan-2-ol (1.0 g,6.0 mmol) was dissolved in toluene (30 mL), cooled to 0deg.C, and DPPA (2.0 g,7.2 mmol) and DBU (1.1 g,7.2 mmol) were added. The reaction was allowed to warm to room temperature and stirred overnight. To the reaction mixture was added water (20 mL) to quench the reaction. The mixture was extracted with ethyl acetate (20 mL. Times.2), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=20/1 to 5/1) to give 2- (6- (azidomethyl) ) Pyridin-2-yl) propan-2-ol (1.0 g, 87% yield). MS (ESI) M/Z193.2 [ M+H ]] + . 1 H NMR(400MHz,CDCl 3 ):δ7.75(t,J＝8.0Hz,1H),7.34(d,J＝8.0Hz,1H),7.25(t,J＝7.6Hz,1H),4.95(br s,1H),4.47(s,2H),1.55(s,6H).
Step 3: 2, 4-dichloro-thieno [3,2-d ]]Pyrimidine (500 mg,2.4 mmol) in a mixed solvent of tetrahydrofuran and triethylamine (V Tetrahydrofuran (THF) /V Triethylamine =1/1, 20 mL). Under the protection of nitrogen, cuI (232 mg,1.2 mmol) and Pd (PPh) are added in sequence 3 ) 4 (277 mg,0.24 mmol) and triisopropylsilylacetylene (1.3 g,7.2 mmol). The reaction system was warmed to 60℃and stirred for 6 hours. The reaction mixture was cooled to room temperature, and a 5% aqueous solution of citric acid (40 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (40 ml×3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=40/1) to give 2-chloro-4- ((triisopropylsilicon) acetylene) thieno [3,2-d]Pyrimidine (0.8 g, 93% yield). MS (ESI) M/Z351.1 [ M+H ] + ]. 1 H NMR(400MHz,CDCl 3 ):δ8.09(d,J＝5.6Hz,1H),7.51(d,J＝5.6Hz,1H),1.24-1.22(m,3H),1.21-1.14(m,18H).
Step 4: 2-chloro-4- ((triisopropylsilicon) acetylene) thieno [3,2-d]Pyrimidine (500 mg,1.4 mmol) was dissolved in tetrahydrofuran (5 mL), and (4-methoxyphenyl) methylamine (3 mL,23 mmol) was added at room temperature. The reaction was warmed to 80 ℃ and stirred overnight. The reaction solution was cooled to room temperature, and ethyl acetate (50 mL) was added thereto for dilution. Then washed with 5% aqueous citric acid (20 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=40/1) to give N- (4-methoxybenzyl) -4- ((triisopropylsilicon) acetylene) thieno [3,2-d ]Pyrimidin-2-amine (334 mg, yellow oil, 52% yield). MS (ESI) M/Z452.2 [ M+H ]] + . 1 H NMR(400MHz,CDCl 3 ):δ9.89(s,1H),7.85(dd,J 1 ＝6.8Hz,J 2 ＝2.0Hz,2H),7.31(d,J＝8.4Hz,1H),7.01(d,J＝8.8Hz,2H),6.86(d,J＝8.8Hz,1H),3.90(s,3H),3.81(s,2H),1.21-1.17(m,21H).
Step 5: n- (4-methoxybenzyl) -4- ((triisopropylsilicon) acetylene) thieno [3,2-d]Pyrimidine-2-amine (334 mg,0.74 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (15 mL) was added. The reaction was stirred at room temperature overnight, concentrated under reduced pressure, ethyl acetate (50 mL) was added, and the mixture was washed with saturated aqueous sodium bicarbonate (20 mL. Times.3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the residue was dissolved in tetrahydrofuran (20 mL), and TBAF.3H was added 2 O (399mg, 1.2 mmol) was stirred at room temperature overnight. To the reaction solution was added ethyl acetate (50 mL), followed by washing with saturated brine (20 ml×2 times), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=10/1) to give 4-ethynyl thieno [3,2-d ]]Pyrimidin-2-amine (65 mg, yield 50%). MS (ESI) M/Z176.0 [ M+H ]] + . 1 H NMR(400MHz,CDCl 3 ):δ7.90(d,J＝5.6Hz,1H),7.21(d,J＝5.6Hz,1H),5.14(br s,2H),3.57(s,1H).
Step 6: 4-Acetylylthiophene [3,2-d ]]Pyrimidine-2-amine (65 mg,0.37 mmol) in a mixed solvent of tertiary butanol and water (V/v=2/1, 9 ml). 2- (6- (azidomethyl) pyridin-2-yl) propan-2-ol (71 mg,0.37 mmol), copper sulfate pentahydrate (5 mg,0.02 mmol) and sodium ascorbate (15 mg,0.074 mmol) were added sequentially under nitrogen. The reaction was stirred at room temperature overnight, diluted with ethyl acetate (50 mL), washed with saturated aqueous sodium bicarbonate (20 ml×3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by means of silica gel preparative chromatography (eluent: dichloromethane/methanol=10/1) to give the end product 2- (6- ((4- (2-aminothiophene [3,2-d ]) ]Pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl-methyl) pyridin-2-yl-propan-2-ol (15.6 mg, 11% yield). MS (ESI) M/Z368.0 [ M+H ]] + . 1 H NMR(400MHz,CD 3 OD):δ8.99(s,1H),8.50(dd,J 1 ＝5.6Hz,J 2 ＝1.2Hz,1H),7.85(t,J＝8.0Hz,1H),7.64(d,J＝8.0Hz,1H),7.39-7.31(m,2H),5.90(s,2H),1.49(s,6H).
Example a-2:
preparation of 2- (6- ((4- (2-aminothiophene [3,2-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) methyl) pyridin-2-yl) propan-2-ol (compound a-2)
The reaction steps are as follows:
step 1: 1H-pyrazole-4-pinacol borate (500 mg,2.6 mmol) and methyl 6- (bromomethyl) picolinate (460 mg,2.0 mmol) were dissolved in acetonitrile (30 mL) and cesium carbonate (1.1 g,3.4 mmol) was added. The reaction was stirred at room temperature for 3 hours, diluted with ethyl acetate (100 mL), filtered, and the filtrate was washed with saturated brine (30 ml×2 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=4/1) to give methyl 6- ((4- (4, 5-tetramethyl-1, 3, 2-dioxoborane-2-yl) -1H-pyrazol-1-yl) methyl) picolinate (550 mg, yield 80%). MS (ESI) M/Z344.1 [ M+H ]] + . 1 H NMR(400MHz,DMSO-d6):δ8.12(s,1H),7.98-7.96(m,2H),7.67(s,1H),7.19(dd,J 1 ＝6.4Hz, J 2 ＝2.4Hz,1H),5.55(s,2H),3.89(s,3H),1.25(s,12H).
Step 2: methyl 6- ((4- (4, 5-tetramethyl-1, 3, 2-dioxoborane-2-yl) -1H-pyrazol-1-yl) methyl) picolinate (500 mg,1.5 mmol) and 2, 4-dichlorothieno [3,2-d]Pyrimidine (837 mg,4.1 mmol) in a mixed solvent of 1, 4-dioxane and water (V 1, 4-Dioxahexacyclic ring /V Water and its preparation method =4/1, 25 mL). Potassium carbonate (673 mg,4.9 mmol) and Pd (dppf) Cl were added sequentially under nitrogen 2 (89 mg,0.12 mmol). The reaction was warmed to 80 ℃ and stirred overnight. Cooled to room temperature, and the reaction mixture was quenched by adding a saturated aqueous ammonium chloride solution (40 mL). The mixture was extracted with ethyl acetate (50 mL. Times.3), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtainedPurification by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=5/1) gives 6- ((4- (2-chlorothiophene [3, 2-d))]Pyrimidin-4-yl) -1H-pyrazol-1-yl-methyl) picolinic acid methyl ester (370 mg, 66% yield). MS (ESI) M/Z386.2 [ M+H ]] + .
Step 3: a solution of methylmagnesium bromide in tetrahydrofuran (3M, 1.3mL,3.9 mmol) was cooled to-10deg.C and 6- ((4- (2-chlorothiophene [3, 2-d) was added dropwise under nitrogen protection]Methyl pyrimidin-4-yl) -1H-pyrazol-1-yl-methyl) picolinate (370 mg,0.96 mmol) in tetrahydrofuran (5 mL). The reaction system was naturally warmed to room temperature and stirred overnight, and a saturated aqueous ammonium chloride solution (40 mL) was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (50 mL. Times.3), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=2/1) to give 2- (6- ((4- (2-chlorothiophene [3, 2-d)) ]Pyrimidin-4-yl) -1H-pyrazol-1-yl-methyl) pyridin-2-yl-propan-2-ol (40 mg, pale yellow oil, 11% yield). MS (ESI) M/Z386.2 [ M+H ]] + .
Step 4: 2- (6- ((4- (2-chlorothiophene-o [3, 2-d))]Pyrimidin-4-yl) -1H-pyrazol-1-yl-methyl) pyridin-2-yl) propan-2-ol (40 mg,0.10 mmol) was dissolved in tetrahydrofuran (2 mL), and (4-methoxyphenyl) methylamine (0.5 mL,3.8 mmol) was added at room temperature. The reaction was warmed to 80 ℃ and stirred overnight. The reaction solution was cooled to room temperature, and ethyl acetate (50 mL) was added thereto for dilution. Then washed with 5% aqueous citric acid (20 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained 2- (6- ((4- (2- ((4-methoxybenzyl) amino) thieno [3, 2-d)]The crude pyrimidin-4-yl) -1H-pyrazol-1-yl-methyl) pyridin-2-yl-propan-2-ol was used directly in the next reaction (yellow oil). MS (ESI) M/Z487.2 [ M+H ]] + .
Step 5: 2- (6- ((4- (2- ((4-methoxybenzyl) amino) thieno [3, 2-d)]Pyrimidin-4-yl) -1H-pyrazol-1-yl-methyl) pyridin-2-yl) propan-2-ol (crude) was dissolved in dichloromethane (0.5 mL) and trifluoroacetic acid (1.0 mL) was added. The reaction was stirred at room temperature overnight, concentrated under reduced pressure, and ethyl acetate (50 mL) was added, followed by The mixture was washed with saturated aqueous sodium hydrogencarbonate (20 mL. Times.3) and saturated brine (20 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by means of silica gel preparative chromatography (eluent: dichloromethane/methanol=10/1) to give the end product 2- (6- ((4- (2-aminothiophene [3,2-d ])]Pyrimidin-4-yl) -1H-pyrazol-1-yl-methyl) pyridin-2-yl-propan-2-ol (25 mg, 66% yield in two steps). MS (ESI) M/Z367.2 [ M+H ]] + . 1 H NMR(400MHz,CD 3 OD):δ8.62(s,1H),8.29(s,1H),8.07(d,J＝5.2Hz,1H),7.76(t,J＝8.0Hz,1H),7.57(d,J＝8.0Hz,1H),7.19(d,J＝5.2Hz,1H),7.08(d,J＝7.6Hz,1H),5.57(s,2H),1.51(s,6H).
Examples a-3:
preparation of 2- (6- ((4- (2-aminothiophene [2,3-d ] pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl) methyl) pyridin-2-yl) propan-2-ol (compound a-3)
The reaction steps are as follows:
step 1: 2, 4-dichloro-thieno [2,3-d ]]Pyrimidine (500 mg,2.4 mmol) in a mixed solvent of tetrahydrofuran and triethylamine (V Tetrahydrofuran (THF) /V Triethylamine =1/1, 20 mL). Under the protection of nitrogen, cuI (232 mg,1.2 mmol) and Pd (PPh) are added in sequence 3 ) 4 (277 mg,0.24 mmol) and triisopropylsilylacetylene (0.88 g,4.8 mmol). The reaction system was warmed to 60℃and stirred for 3 hours. The reaction mixture was cooled to room temperature, and a 5% aqueous solution of citric acid (40 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (40 ml×3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=50/1) to give 2-chloro-4- ((triisopropylsilicon) acetylene) thieno [2,3-d ]Pyrimidine (0.8 g, 93% yield). MS (ESI) M/Z351.1 [ M+H ]] + . 1 H NMR(400MHz,CDCl 3 ):δ7.61(d,J＝5.6Hz,1H),7.45(d,J＝5.6Hz,1H),1.26-1.15(m,21H).
Step 2: 2-chloro-4- ((triisopropylsilicon) acetylene) thieno [2,3-d]Pyrimidine (1.0 g,2.8 mmol) was dissolved in tetrahydrofuran (2 mL), and (4-methoxyphenyl) methylamine (5 mL,38 mmol) was added at room temperature. The reaction was warmed to 80 ℃ and stirred overnight. The reaction solution was cooled to room temperature, and ethyl acetate (50 mL) was added thereto for dilution. Then washed with 5% aqueous citric acid (20 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=40/1) to give N- (4-methoxybenzyl) -4- ((triisopropylsilicon) acetylene) thieno [2,3-d]Pyrimidin-2-amine (483 mg, yellow oil, yield 37%). MS (ESI) M/Z452.1 [ M+H ]] + .
Step 3: n- (4-methoxybenzyl) -4- ((triisopropylsilicon) acetylene) thieno [2,3-d]Pyrimidine-2-amine (480 mg,1.1 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (5 mL) was added. The reaction was stirred at room temperature overnight, concentrated under reduced pressure, ethyl acetate (50 mL) was added, and the mixture was washed with saturated aqueous sodium bicarbonate (20 mL. Times.3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (20 mL) and TBAF 3H was added 2 O (399mg, 1.2 mmol) was stirred at room temperature overnight. To the reaction solution was added ethyl acetate (50 mL), followed by washing with saturated brine (20 ml×2 times), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=5/1) to give 4-ethynyl thieno [2,3-d ]]Pyrimidin-2-amine (65 mg, yield 35%). MS (ESI) M/Z176.1 [ M+H ]] + .
Step 4: 4-Acetylylthiophene [2,3-d ]]Pyrimidine-2-amine (60 mg,0.34 mmol) in a mixed solvent of tert-butanol and water (V Tert-butanol /V Water and its preparation method =2/1, 3 ml). 2- (6- (azidomethyl) pyridin-2-yl) propan-2-ol (66 mg,0.34 mmol), copper sulfate pentahydrate (14 mg,0.06 mmol) and sodium ascorbate (15 mg,0.074 mmol) were added sequentially under nitrogen. The reaction was stirred at room temperature overnight, diluted with ethyl acetate (50 mL), washed with saturated aqueous sodium bicarbonate (20 mL. Times.3) and dried over anhydrous sodium sulfate,filtering, and concentrating under reduced pressure. The residue obtained is purified by means of silica gel preparative chromatography (eluent: dichloromethane/methanol=20/1) to give the end product 2- (6- ((4- (2-aminothiophene [2,3-d ])]Pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl-methyl) pyridin-2-yl-propan-2-ol (20 mg, 16% yield). MS (ESI) M/Z368.3 [ M+H ] ] + . 1 H NMR(400MHz,CDCl 3 ):δ8.46(s,1H),8.28(d,J＝6.0Hz,1H),7.73(t,J＝8.0Hz,1H),7.38(d,J＝8.0Hz,1H),7.16-7.13(m,2H),5.77(s,2H),5.08(br s,2H),4.72(br s,1H),1.55(s,6H).
Examples a-4:
preparation of 2- (6- ((4- (6-amino-1-methyl-1H-pyrazolo [3,4-d ] pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl) methyl) pyridin-2-yl) propan-2-ol (compound a-4)
The reaction steps are as follows:
step 1: 4, 6-dichloro-1-methyl-1H-pyrazolo [3,4-d]Pyrimidine (490 mg,2.4 mmol) in a mixed solvent of tetrahydrofuran and triethylamine (V) Tetrahydrofuran (THF) /V Triethylamine =1/1, 20 mL). Under the protection of nitrogen, cuI (228 mg,1.2 mmol) and Pd (dppf) Cl are added in sequence 2 (175 mg,0.24 mmol) and triisopropylsilylacetylene (0.66 g,3.6 mmol). The reaction was stirred at room temperature for 6 hours, and quenched by the addition of 5% aqueous citric acid (40 mL). The mixture was extracted with ethyl acetate (40 ml×3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=50/1) to give 6-chloro-1-methyl-4- ((triisopropylsilicon) acetylene) -1H-pyrazolo [3,4-d]Pyrimidine (200 mg, 24% yield). MS (ESI) M/Z349.2 [ M+H ]] + .
Step 2: 6-chloro-1-methyl-4- ((triisopropylsilicon) acetylene) -1H-pyrazolo [3,4-d]Pyrimidine (200 mg,0.57 mmol) was dissolved in tetrahydrofuran (5 mL) and (4-methoxyphenyl) methylamine (3 mL,23 mmol) was added at room temperature. The reaction system is heated to 80 DEG C Stir overnight. The reaction solution was cooled to room temperature, and ethyl acetate (50 mL) was added thereto for dilution. Then washed with 5% aqueous citric acid (20 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=5/1) to give N- (4-methoxybenzyl) -1-methyl-4- ((triisopropylsilicon) acetylene) -1H-pyrazolo [3,4-d]Pyrimidin-6-amine (180 mg, yellow oil, yield 70%). MS (ESI) M/Z450.3 [ M+H ]] + .
Step 3: n- (4-methoxybenzyl) -1-methyl-4- ((triisopropylsilicon) acetylene) -1H-pyrazolo [3,4-d]Pyrimidine-6-amine (180 mg,0.4 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to 0deg.C, and TBAF. 3H was added 2 O (156 mg,0.5 mmol). The reaction was warmed to room temperature and stirred for 1 hour, and ethyl acetate (50 mL) was added to dilute. The mixture was washed with saturated brine (20 mL. Times.2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=2/1) to give 4-ethynyl-N- (4-methoxybenzyl) -1-methyl-1H-pyrazolo [3,4-d ]]Pyrimidin-6-amine (110 mg, 94% yield). MS (ESI) M/Z294.2 [ M+H ] ] + .
Step 4: 4-ethynyl-N- (4-methoxybenzyl) -1-methyl-1H-pyrazolo [3,4-d]Pyrimidine-6-amine (110 mg,0.38 mmol) in a mixed solvent of tert-butanol and water (V Tert-butanol /V Water and its preparation method =2/1, 6 ml). 2- (6- (azidomethyl) pyridin-2-yl) propan-2-ol (72 mg,0.38 mmol), copper sulfate pentahydrate (5 mg,0.02 mmol) and sodium ascorbate (15 mg,0.074 mmol) were added sequentially under nitrogen. The reaction was stirred at room temperature overnight, diluted with ethyl acetate (50 mL), washed with saturated aqueous sodium bicarbonate (20 ml×3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The residue obtained was purified by preparative chromatography on silica gel (eluent: dichloromethane/methanol=20/1) to give 2- (6- ((4- (6- ((4-methoxybenzyl) amino) -1-methyl-1H-pyrazolo [3, 4-d)]Pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl-methyl) pyridin-2-yl-propan-2-ol (130 mg, 71% yield). MS (ESI) M/Z486.4 [ M+H ]] + . 1 H NMR (400MHz,CDCl 3 ):δ8.71(br s,1H),7.74(t,J＝8.0Hz,1H),7.38(d,J＝8.0Hz,1H),7.35-7.26(m,4H),7.15(d,J＝7.6Hz,1H),6.88(dd,J 1 ＝6.8Hz,J 2 ＝2.0Hz,2H),5.80(s,2H),4.67(d,J＝6.0Hz,2H),3.97(s,3H),3.80(s,3H),1.55(s,6H).
Step 5: 2- (6- ((4- (6- ((4-methoxybenzyl) amino) -1-methyl-1H-pyrazolo [3, 4-d)]Pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl-methyl) pyridin-2-yl) propan-2-ol (100 mg,0.21 mmol) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (5 mL) was added. The reaction was stirred at room temperature overnight, diluted with ethyl acetate (50 mL), and washed successively with water (50 mL), saturated aqueous sodium bicarbonate (50 mL. Times.2) and saturated brine (20 mL. Times.2). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (20 mL) and TBAF 3H was added 2 O (399mg, 1.2 mmol) was stirred at room temperature overnight. To the reaction solution was added ethyl acetate (50 mL), followed by washing with saturated brine (20 ml×2 times), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by means of silica gel preparative chromatography (eluent: dichloromethane/methanol=40/1) to give the end product 2- (6- ((4- (6-amino-1-methyl-1H-pyrazolo [3, 4-d))]Pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl-methyl) pyridin-2-yl-propan-2-ol (31 mg, yield 41%). MS (ESI) M/Z366.3 [ M+H ]] + . 1 H NMR(400MHz,DMSO-d6):δ8.80(s,1H),8.33(s,1H),7.81(t,J＝7.6Hz,1H),7.61(d,J＝7.6Hz,1H),7.14(d,J＝7.6Hz,1H),6.91(br s,2H),5.85(s,2H),5.23(s,1H),3.83(s,3H),1.34(s,6H).
Examples a-5:
preparation of 2- (6- ((4- (6-amino-3-methylisothiazolo [5,4-d ] pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl) methyl) pyridin-2-yl) propan-2-ol (compound a-5)
The reaction steps are as follows:
with 4, 6-dichloro-3-methylisothiazolo [5,4- ]d]Pyrimidine as starting material was prepared in five steps by the procedure of reference example a-4 to give the final product 2- (6- ((4- (6-amino-3-methylisothiazolo) 5, 4-d)]Pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl-methyl) pyridin-2-yl-propan-2-ol (135 mg). MS (ESI) M/Z382.8 [ M+H ]] + . 1 H NMR(400MHz,DMSO-d6):δ8.73(s,1H),7.83(t,J＝7.6Hz,1H),7.63(d,J＝7.6Hz,1H),7.47(br s,2H),7.15(d,J＝7.6Hz,1H),5.87(s,2H),2.46(s,3H),1.38(s,6H).
Examples a-6:
preparation of 2- (6- ((4- (2-amino-6-methylthioeno [3,2-d ] pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl) methyl) pyridin-2-yl) propan-2-ol (compound a-6)
The reaction steps are as follows:
with 2, 4-dichloro-6-methylthiophene [3,2-d ]]Pyrimidine as a starting material was prepared in five steps by the procedure of reference example a-4 to give the final product 2- (6- ((4- (2-amino-6-methylthiophene [3,2-d ])]Pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl-methyl) pyridin-2-yl-propan-2-ol (56 mg). MS (ESI) M/Z382.3 [ M+H ]] + . 1 H NMR(400MHz,CDCl 3 ):δ8.46(s,1H),7.73(t,J＝8.0Hz,1H),7.38(d,J＝8.0Hz,1H),7.14(d,J＝7.6Hz,1H),6.94(s,1H),5.78(s,2H),5.22(br s,2H),3.77(br s,1H),2.66(s,3H),1.55(s,6H).
Examples a-7:
process for preparing 2- (6- ((4- (2-amino-6- (trifluoromethyl) thieno [3,2-d ] pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl) methyl) pyridin-2-yl) propan-2-ol (compound a-7)
The reaction steps are as follows:
with 2, 4-dichloro-6-trifluoromethylthiophene [3,2-d ]]Pyrimidine as a starting material, see example a-4Five steps of operation are carried out to obtain the final product 2- (6- ((4- (2-amino-6- (trifluoromethyl) thieno [3, 2-d))]Pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl-methyl) pyridin-2-yl-propan-2-ol (50 mg). MS (ESI) M/Z436.2 [ M+H ]] + . 1 H NMR(400MHz,DMSO-d6):δ8.91(s,1H),7.88(s,1H),7.82(t,J＝8.0Hz,1H),7.62(d,J＝8.0Hz,1H),7.18(d,J＝7.6Hz,1H),6.98(br s,2H),5.90(s,2H),1.37(s,6H).
Examples a-8:
preparation of 2- (6- ((4- (2-amino-7-methylthioeno [3,2-d ] pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl) methyl) pyridin-2-yl) propan-2-ol (compound a-8)
The reaction steps are as follows:
with 2, 4-dichloro-7-methylthiophene [3,2-d ]]Pyrimidine as a starting material was prepared in five steps by the procedure of reference example a-4 to give the final product 2- (6- ((4- (2-amino-7-methylthiophene [3,2-d ]) ]Pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl-methyl) pyridin-2-yl-propan-2-ol (32 mg). MS (ESI) M/Z382.2 [ M+H ]] + . 1 H NMR(400MHz,CDCl 3 ):δ8.48(s,1H),7.73(t,J＝7.6Hz,1H),7.63(s,1H),7.38(d,J＝7.6Hz,1H),7.15(d,J＝7.2Hz,1H),5.79(s,2H),5.23(br s,2H),4.70(br s,1H),2.42(s,3H),1.55(s,6H).
Examples a-9:
preparation of 2- (6- ((4- (2-amino-5-methylthioeno [2,3-d ] pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl) methyl) pyridin-2-yl) propan-2-ol (compound a-9)
The reaction steps are as follows:
with 2, 4-dichloro-5-methylthiophene [2,3-d ]]Pyrimidine as a starting material was prepared in five steps by the procedure of reference example a-4 to give the final product 2- (6- ((4- (2-amino-))5-methylthiophene [2,3-d ]]Pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl-methyl) pyridin-2-yl-propan-2-ol (63 mg). MS (ESI) M/Z382.1 [ M+H ]] + . 1 H NMR(400MHz,CD 3 OD):δ8.50(s,1H),7.84(t,J＝8.0Hz,1H),7.64(d,J＝8.0Hz,1H),7.27(d,J＝7.6Hz,1H),6.87(d,J＝1.2Hz,1H),5.86(s,2H),2.09(d,J＝1.2Hz,3H),1.52(s,6H).
Examples a-10:
preparation of 2- (6- ((4- (2-amino-7-bromothieno [3,2-d ] pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl) methyl) pyridin-2-yl) propan-2-ol (compound a-10)
The reaction steps are as follows:
step 1: thieno [3,2-d ]]Pyrimidine-2, 4 (1H, 3H) -dione (5.0 g,29.8 mmol) was dissolved in glacial acetic acid (200 mL) and liquid bromine (4.5 mL,82.9 mmol) was added. The reaction system was warmed to 120℃and stirred for 24 hours, cooled to room temperature, concentrated under reduced pressure to remove most of the solvent, ice water (600 mL) and ethyl acetate (600 mL) were added, stirred for 0.5 hour, filtered, and the filter cake was dried to give 7-bromothieno [3,2-d ]]Pyrimidine-2, 4 (1H, 3H) -dione (6.0 g, 82% yield) was used directly in the next reaction. MS (ESI) M/Z247.1 [ M+H ] ] + . 1 H NMR(400MHz,DMSO-d6):δ11.57(s,1H),11.45(s,1H),8.24(s,1H).
Step 2: 7-bromothieno [3,2-d ]]Pyrimidine-2, 4 (1H, 3H) -dione (12.0 g,48.8 mmol) was dissolved in phosphorus oxychloride (70 mL) and N, N-diisopropylethylamine (12.5 g,96.9 mmol) was added. The reaction system was warmed to 100℃and stirred for 16 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove most of phosphorus oxychloride, and a mixed solvent of ethyl acetate and tetrahydrofuran (V Acetic acid ethyl ester /V Tetrahydrofuran (THF) After dilution with =1/1, 200 mL), the mixture was poured into cold water (300 mL), stirred for 0.5 hours, separated, and the organic phase was washed with saturated aqueous sodium bicarbonate (100 ml×3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. For the residue obtainedPurification by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=200/1) gives 7-bromo-2, 4-dichlorothieno [3,2-d ]]Pyrimidine (7.6 g, 55% yield). MS (ESI) M/Z283.1 [ M+H ]] + . 1 H NMR(400MHz,DMSO-d6):δ8.87(s,1H).
Step 3: 7-bromo-2, 4-dichlorothieno [3,2-d ]]Pyrimidine (2.0 g,7.1 mmol) was dissolved in a mixed solvent of tetrahydrofuran and triethylamine (V Tetrahydrofuran (THF) /V Triethylamine =3/2, 15 mL). Under the protection of nitrogen, cuI (230 mg,1.2 mmol) and Pd (dppf) Cl are added in sequence 2 (307 mg,0.42 mmol) and triisopropylsilylacetylene (1.4 g,7.5 mmol). The reaction was stirred at room temperature overnight, TLC monitoring showed the reaction was complete, and 5% aqueous citric acid (40 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (40 ml×3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=200/1) to give 7-bromo-2-chloro-4- ((triisopropylsilyl) acetylene) thieno [3,2-d ]Pyrimidine (1.8 g, 59% yield). MS (ESI) M/Z429.2 [ M+H ]] + . 1 H NMR(400MHz,CDCl 3 ):δ8.06(s,1H),1.26-1.16(m,21H).
Step 4: 7-bromo-2-chloro-4- ((triisopropylsilyl) acetylene) thieno [3,2-d]Pyrimidine (900 mg,2.1 mmol) was dissolved in 1, 4-dioxane (10 mL), and (4-methoxyphenyl) methylamine (3.2 g,23.4 mmol) was added at room temperature. The reaction system was warmed to 80 ℃ and stirred for 4 hours. The reaction solution was cooled to room temperature, and ethyl acetate (50 mL) was added thereto for dilution. Then washed with 5% aqueous citric acid (20 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=40/1) to give 7-bromo-N- (4-methoxybenzyl) -4- ((triisopropylsilyl) acetylene) thieno [3,2-d]Pyrimidin-2-amine (1.1 g, 98% yield). MS (ESI) M/Z530.0 [ M+H ]] + . 1 H NMR(400MHz,CDCl 3 ):δ7.83(s,1H),7.36(d,J＝8.0Hz,2H),6.86(d,J＝8.0Hz,2H),4.67(d,J＝5.6Hz,2H),3.79(s,3H),1.26-1.17(m,21H).
Step 5: 7-bromo-N- (4-methyl)Oxybenzyl) -4- ((triisopropylsilicon) acetylene thieno [3,2-d]Pyrimidine-2-amine (370 mg,0.7 mmol) was dissolved in tetrahydrofuran (26 mL), cooled to-10deg.C, and TBAF. 3H was added 2 O (298 mg,0.95 mmol). The reaction system was stirred at-10℃for 1 hour, diluted with ethyl acetate (50 mL), washed with saturated brine (20 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 7-bromo-4-ethynyl-N- (4-methoxybenzyl) thieno [3,2-d ] ]Pyrimidine-2-amine (248 mg, 95% yield) was used directly in the next reaction. MS (ESI) M/Z374.0 [ M+H ]] + .
Step 6: 7-bromo-4-ethynyl-N- (4-methoxybenzyl) thieno [3,2-d]Pyrimidine-2-amine (70 mg,0.19 mmol) in a mixed solvent of tert-butanol and water (V Tert-butanol /V Water and its preparation method =2/1, 6 ml). 2- (6- (azidomethyl) pyridin-2-yl) propan-2-ol (36 mg,0.19 mmol), copper sulfate pentahydrate (12 mg,0.05 mmol) and sodium ascorbate (8 mg,0.04 mmol) were added sequentially under nitrogen. The reaction system was warmed to 50 ℃ and stirred for 2 hours. The reaction solution was cooled to room temperature, quenched with water (10 mL), the mixture was extracted with ethyl acetate (40 ml×3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=5/1 to 3/1) to give 2- (6- ((4- (7-bromo-2- ((4-methoxybenzyl) amino) thieno [3, 2-d)]Pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl-methyl) pyridin-2-yl-propan-2-ol (60 mg, yield 56%). MS (ESI) M/Z566.1 [ M+H ]] + .
Step 7: 2- (6- ((4- (7-bromo-2- ((4-methoxybenzyl) amino) thieno [3, 2-d)]Pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl-methyl) pyridin-2-yl) propan-2-ol (60 mg,0.11 mmol) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (5 mL) was added. The reaction was stirred at 40℃for 5 hours, concentrated under reduced pressure, diluted with dichloromethane (50 mL), then washed with saturated aqueous sodium bicarbonate (20 mL. Times.3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate/dichloromethane=10/1/1) to give the final product 2- (6- ((4- (2-amino-7-bromothieno [3, 2)) -d]Pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl-methyl) pyridin-2-yl-propan-2-ol (35 mg, yield 74%). MS (ESI) M/Z446.0 [ M+H ]] + . 1 H NMR(400MHz,DMSO-d6):δ8.85(s,1H),8.45(s,1H),7.79(t,J＝7.6Hz,1H),7.61(d,J＝7.6Hz,1H),7.16(d,J＝7.6Hz,1H),6.92(br s,2H),5.87(s,2H),5.22(s,1H),1.36(s,6H).
Examples a-11:
preparation of 2- (6- ((4- (2-amino-7-chlorothieno [3,2-d ] pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl) methyl) pyridin-2-yl) propan-2-ol (compound a-11)
The reaction steps are as follows:
step 1: thieno [3,2-d ]]Pyrimidine-2, 4 (1H, 3H) -dione (8.0 g,47.6 mmol) was dissolved in 6mol/L hydrochloric acid/glacial acetic acid mixed solvent (V Hydrochloric acid /V Glacial acetic acid =1/1, 480 mL), the temperature was raised to 100 ℃ under nitrogen, NCS (6.4 g,47.6 mmol) was added. The reaction system was stirred at 100℃for 3 hours, cooled to room temperature, ice water (2000 mL) and ethyl acetate (200 mL) were added to precipitate a solid, stirred for 0.5 hour, filtered, and the cake was dried to give 7-chlorothiophene [3,2-d ]]Pyrimidine-2, 4 (1H, 3H) -dione (4.3 g, 45% yield). MS (ESI) M/Z203.1 [ M+H ]] + . 1 H NMR(400MHz,CDCl 3 ):δ11.67(s,1H),11.38(s,1H),6.98(s,1H).
With 7-chlorothiophene [3,2-d ]]Pyrimidine-2, 4 (1H, 3H) -dione as starting material was prepared in six steps by the procedure of reference example a-10 to give the final product 2- (6- ((4- (2-amino-7-chlorothiophene [3,2-d ])]Pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl-methyl) pyridin-2-yl-propan-2-ol (90 mg). MS (ESI) M/Z402.1 [ M+H ]] + . 1 H NMR(400MHz,CDCl 3 ):δ8.83 (s,1H),7.81(t,J＝7.6Hz,1H),7.61(d,J＝8.0Hz,1H),7.34(s,1H),7.15(d,J＝7.6Hz,1H),6.75(br s,2H),5.87(s,2H),5.23(br s,1H),1.37(s,6H).
Examples a-12:
preparation of 2-amino-4- (1- ((6- (2-hydroxy-prop-2-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) thieno [3,2-d ] pyrimidine-7-carbonitrile (Compound a-12)
The reaction steps are as follows:
step 1: 2- (6- ((4- (7-bromo-2- ((4-methoxybenzyl) amino) thieno [3, 2-d)]Pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl-methyl) pyridin-2-yl) propan-2-ol (200 mg,0.35 mmol) was dissolved in NMP (18 mL) and CuCN (127 mg,1.4 mmol) was added. The reaction was warmed to 180 ℃ and stirred for 4 hours, cooled to room temperature, diluted with ethyl acetate (100 mL), filtered, the filtrate was washed with water (200 ml×3 times), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by column chromatography on silica gel (eluent: petroleum ether/dichloromethane/ethyl acetate=15/15/1 to 5/5/1) to give 4- (1- ((6- (2-hydroxypropan-2-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -2- ((4-methoxybenzyl) amino) thieno [3,2-d]Pyrimidine-7-carbonitrile (65 mg, 36% yield). MS (ESI) M/Z513.2 [ M+H ]] + .
Step 2: 4- (1- ((6- (2-hydroxy-prop-2-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -2- ((4-methoxybenzyl) amino) thieno [3,2-d]Pyrimidine-7-carbonitrile (60 mg,0.12 mmol) was dissolved in trifluoroacetic acid (5 mL). The reaction was stirred at 40℃for 5 hours, concentrated under reduced pressure, diluted with dichloromethane (50 mL), then washed with saturated aqueous sodium bicarbonate (20 mL. Times.3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate/dichloromethane=10/1/1) to give the final product 2-amino-4- (1- ((6- (2-hydroxypropan-2-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) thieno [3,2-d ]Pyrimidine-7-carbonitrile (16 mg, yield 35%). MS (ESI) M/Z392.9 [ M+H ]] + . 1 H NMR(400MHz,DMSO-d6):δ9.23(s,1H),8.88(s,1H),7.81(t,J＝7.6Hz,1H),7.61(d,J＝8.0Hz,1H),7.16(d,J＝7.6Hz, 1H),7.11(br s,2H),5.88(s,2H),5.22(s,1H),1.36(s,6H).
Examples a-13:
preparation of 4- (1- ((6- (2-oxo-6-azaspiro [3.3] heptan-6-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -7-methylthioeno [3,2-d ] pyrimidin-2-amine (compound a-13)
The reaction steps are as follows:
step 1: 6-bromo-2-pyridinecarboxylic acid ethyl ester (0.5 g,2.2 mmol) and 2-oxo-6-azaspiro [3.3]]Heptane (0.22 g,2.2 mmol) was dissolved in DMF (20 mL) and potassium carbonate (1.5 g,10.9 mmol) was added. The reaction was warmed to 90 ℃ and stirred overnight. TLC monitoring showed the reaction was complete, the reaction cooled to room temperature and diluted with water (60 mL). The mixture was extracted with ethyl acetate (50 mL. Times.3), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=10/1 to 5/1) to give 6- (2-oxo-6-azaspiro [ 3.3)]Heptane-6-yl) -2-pyridinecarboxylic acid ethyl ester (0.42 g, yield 78%). MS (ESI) M/Z249.1 [ M+H ]] + . 1 H NMR(400MHz,CDCl 3 ):δ7.58-7.54(m,1H),7.44(dd,J 1 ＝7.2Hz,J 2 ＝0.8Hz,1H),6.46(dd,J 1 ＝8.4Hz,J 2 ＝0.8Hz,1H),4.85(s,4H),4.40(q,J＝7.2Hz,2H),4.25(s,4H),1.42(t,J＝7.2Hz,3H).
Step 2: 6- (2-oxo-6-azaspiro [3.3]]Ethyl heptan-6-yl) -2-pyridinecarboxylate (750 mg,3.0 mmol) was dissolved in tetrahydrofuran (35 mL), cooled to 0℃and a red aluminum toluene solution (3.6M, 1.0mL,3.6 mmol) was added dropwise under nitrogen protection. The reaction was stirred at 0deg.C for 2 hours, and quenched by the addition of 10% aqueous sodium carbonate (70 mL). The mixture was filtered through celite to remove aluminum salts, the solution was separated, the aqueous phase was extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, the organic phase was washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and the most Concentrating under reduced pressure to obtain (6- (2-oxo-6-azaspiro [ 3.3)]Heptane-6-yl) pyridin-2-yl) methanol (560 mg, 90% yield). MS (ESI) M/Z207.1 [ M+H ]] + .
Step 3: (6- (2-oxo-6-azaspiro [ 3.3)]Heptan-6-yl) pyridin-2-yl) methanol (540 mg,2.6 mmol) was dissolved in toluene (15 mL), cooled to 0deg.C, and DPPA (860 mg,3.1 mmol) and DBU (480 mg,3.1 mmol) were added. The reaction was allowed to warm to room temperature and stirred overnight. To the reaction mixture was added water (20 mL) to quench the reaction. The mixture was extracted with ethyl acetate (20 mL. Times.2), and the organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=20/1 to 5/1) to give 6- (6- (azidomethyl) pyridin-2-yl) -2-oxo-6-azaspiro [ 3.3)]Heptane (450 mg, yield 74%). MS (ESI) M/Z232.1 [ M+H ]] + .
With 2, 4-dichloro-7-methylthiophene [3,2-d ]]Pyrimidine as a starting material was prepared in four steps by the procedure of reference example a-1 to give the final product 4- (1- ((6- (2-oxo-6-azaspiro [3.3 ])]Heptane-6-yl) pyridin-2-yl methyl) -1H-1,2, 3-triazol-4-yl) -7-methylthioeno [3,2-d]Pyrimidin-2-amine (67 mg). MS (ESI) M/Z421.2 [ M+H ] ] + . 1 H NMR(400MHz,DMSO-d6):δ8.72(s,1H),7.89(s,1H),7.52(t,J＝8.0Hz,1H),6.63(br s,2H),6.54(d,J＝7.2Hz,1H),6.34(d,J＝8.0Hz,1H),5.66(s,2H),4.69(br s,4H),4.04(br s,4H),2.30(s,3H).
Examples a-14:
preparation of 2- (6- ((4- (2-amino-7- (trifluoromethyl) thieno [3,2-d ] pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl) methyl) pyridin-2-yl) propan-2-ol (compound a-14)
The reaction steps are as follows:
step 1: 2, 4-dimethoxy-7- (trifluoromethyl) thieno [3,2-d]Pyrimidine (2.0 g,7.6 mmol) was dissolved in glacial acetic acid (10 mL) and sodium iodide (5) was added in portions.6g,37.3 mmol). The reaction system was warmed to 100deg.C and stirred for 2 hours, cooled to room temperature, concentrated under reduced pressure to remove most of the solvent, diluted with ethyl acetate (20 mL), washed with saturated sodium thiosulfate (15 mL), the organic layer was separated, the aqueous phase was extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, the organic phase was washed with saturated brine (50 mL. Times.3 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=20/1) to give 7-trifluoromethylthiopheno [3,2-d ]]Pyrimidine-2, 4 (1H, 3H) -dione (1.0 g, 56% yield). MS (ESI) M/Z237.0 [ M+H ]] + . 1 H NMR(400MHz,DMSO-d6):δ11.73(s,1H),11.55(s,1H),8.72(s,1H).
Step 2: 7-trifluoromethyl-thieno [3,2-d ]]Pyrimidine-2, 4 (1H, 3H) -dione (294 mg,1.2 mmol) was dissolved in redistilled phosphorus oxychloride (5 mL) and N, N-diisopropylethylamine (0.11 mL,0.9 mmol) was added at room temperature. The reaction system was warmed to 80 ℃ and stirred for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure to remove most of phosphorus oxychloride, diluted with ethyl acetate (20 mL), poured slowly into saturated aqueous sodium bicarbonate (30 mL), stirred until no bubbles were generated, the organic layer was separated, the aqueous phase was extracted with ethyl acetate (10 ml×3 times), the organic phases were combined, the organic phase was washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=10/1) to give 2, 4-dichloro-7- (trifluoromethyl) thieno [3, 2-d) ]Pyrimidine (195 mg, 58% yield). MS (ESI) M/Z273.0 [ M+H ]] + . 1 H NMR(400MHz,CDCl 3 ):δ8.53(s,1H).
2, 4-dichloro-7- (trifluoromethyl) thieno [3,2-d]Pyrimidine as a starting material was prepared in five steps by the procedure of reference example a-10 to give the final product 2- (6- ((4- (2-amino-7- (trifluoromethyl) thieno [3, 2-d))]Pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl-methyl) pyridin-2-yl-propan-2-ol (16 mg). MS (ESI) M/Z436.0 [ M+H ]] + . 1 H NMR(400MHz,CDCl 3 ):δ8.47(s,1H),8.35(d,J＝1.1Hz,1H),7.74(t,J＝8.0Hz,1H),7.39(dd,J 1 ＝8.0Hz,J 2 ＝0.8Hz,1H),7.17(dd,J 1 ＝7.6Hz,J 2 ＝0.8Hz,1H),5.78(s,2H),5.24(s,1H),1.55(s,6H).
Examples a-15:
preparation of 2- (6- ((4- (2-amino-7-cyclopropylthiophene [3,2-d ] pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl) methyl) pyridin-2-yl) propan-2-ol (compound a-15)
The reaction steps are as follows:
step 1: 7-iodo-2, 4-dimethoxy thieno [3,2-d]Pyrimidine (400 mg,1.2 mmol) and cyclopropylboronic acid (154 mg,1.8 mmol) in a mixed solvent of 1, 4-dioxane and water (V Dioxahexacyclic ring /V Water and its preparation method =10/1, 2.2 ml). Potassium phosphate (763 mg,3.6 mmol) and Pd (dppf) Cl were added under nitrogen 2 (175 mg,0.24 mmol). The reaction system was warmed to 120 ℃ and stirred for 4 hours. The reaction solution was cooled to room temperature, ethyl acetate (10 mL) was then added, the solution was separated, the aqueous phase was extracted with ethyl acetate (5 ml×3 times), the organic phases were combined, the organic phases were washed with saturated brine (20 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=20/1) to give 7-cyclopropyl-2, 4-dimethoxy thieno [3,2-d ] ]Pyrimidine (161 mg, 56% yield). MS (ESI) M/Z237.0 [ M+H ]] + . 1 H NMR(400MHz,CDCl 3 ):δ7.16(s,1H),4.13(s,3H),4.06(s,3H),2.32-2.25(m,1H),1.01-0.90(m,4H).
Step 2: 7-cyclopropyl-2, 4-dimethoxy thieno [3,2-d ]]Pyrimidine (161 mg,0.68 mmol) was dissolved in glacial acetic acid (5 mL) and sodium iodide (510 mg,3.4 mmol) was added in portions. The reaction system was warmed to 110℃and stirred for 2 hours, cooled to room temperature, concentrated under reduced pressure to remove most of the solvent, diluted with ethyl acetate (10 mL), washed with saturated sodium thiosulfate (10 mL), the organic phase was separated, washed with saturated saline (10 mL. Times.3 times), dried over anhydrous sodium sulfate, filtered, and finallyConcentrating under reduced pressure. The residue obtained was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=20/1) to give 7-cyclopropyl-thieno [3,2-d]Pyrimidine-2, 4 (1H, 3H) -dione (117 mg, 82% yield). MS (ESI) M/Z209.1 [ M+H ]] + . 1 H NMR(400MHz,DMSO-d6):δ11.53(s,1H),11.23(s,1H),7.51(s,1H),2.00-1.96(m,1H),0.94-0.85(m,2H),0.69-0.61(m,2H).
Step 3: 7-cyclopropyl thieno [3,2-d ]]Pyrimidine-2, 4 (1H, 3H) -dione (117 mg,0.56 mmol) was dissolved in redistilled phosphorus oxychloride (2 mL) and N, N-diisopropylethylamine (0.053 mL,0.42 mmol) was added at room temperature. The reaction was warmed to 80 ℃ and stirred overnight. The reaction solution was cooled to room temperature, concentrated under reduced pressure to remove most of phosphorus oxychloride, diluted with ethyl acetate (10 mL), poured slowly into saturated aqueous sodium bicarbonate (15 mL), stirred until no bubbles were generated, the organic layer was separated, the aqueous phase was extracted with ethyl acetate (10 ml×3 times), the organic phases were combined, the organic phase was washed with saturated brine (30 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=10/1) to give 2, 4-dichloro-7-cyclopropylthiophene [3,2-d ] ]Pyrimidine (106 mg, 77% yield). MS (ESI) M/Z245.2 [ M+H ]] + . 1 H NMR(400MHz,CDCl 3 ):δ7.45(d,J＝0.8Hz,1H),2.39-2.32(m,1H),1.16-1.02(m,2H),0.97-0.85(m,2H).
2, 4-dichloro-7-cyclopropylthiophene [3,2-d ]]Pyrimidine as a starting material was prepared in five steps by the procedure of reference example a-10 to give the final product 2- (6- ((4- (2-amino-7-cyclopropylthiophene [3,2-d ])]Pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl-methyl) pyridin-2-yl-propan-2-ol (18 mg). MS (ESI) M/Z408.2 [ M+H ]] + . 1 H NMR(400MHz,CDCl 3 ):δ8.43(s,1H),7.70(t,J＝8.0Hz,1H),7.36(dd,J 1 ＝8.0Hz,J 2 ＝0.8Hz,1H),7.32(d,J＝0.8Hz,1H),7.11(dd,J 1 ＝7.6Hz,J 2 ＝0.8Hz,1H),5.76(s,2H),2.28-2.21(m,1H),1.53(s,6H), 1.05-0.98(m,2H),0.84-0.78(m,2H).
Examples a-16:
preparation of 2- (6- ((4- (2-amino-7- (difluoromethyl) thieno [3,2-d ] pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl) methyl) pyridin-2-yl) propan-2-ol (compound a-16)
The reaction steps are as follows:
step 1: 7-bromo-2, 4-dimethoxy thieno [3,2-d]Pyrimidine (1.0 g,3.6 mmol) in a mixed solvent of 1, 4-dioxane and water (V Dioxahexacyclic ring /V Water and its preparation method =10/1, 22 mL). Under nitrogen, add vinyl boric acid pinacol ester (1.1 g,7.2 mmol), pdCl 2 (dppf) (531 mg,0.72 mmol) and potassium phosphate (2.3 g,10.8 mmol). The reaction was warmed to 120 ℃ and stirred for 2 hours, cooled to room temperature, ethyl acetate (10 mL) was added, the organic layer was separated, the aqueous layer was extracted with ethyl acetate (5 ml×3 times), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (eluent; petroleum ether/ethyl acetate=20/1) to give 2, 4-dimethoxy-7-vinylthieno [3,2-d ] ]Pyrimidine (300 mg, 38% yield). MS (ESI) M/Z223.0 [ M+H ]] + . 1 H NMR(400MHz,CDCl 3 ):δ7.68(s,1H),7.04-6.93(m,1H),6.41(dd,J＝17.6,1.6Hz,1H),5.44(dd,J＝11.2,1.6Hz,1H),4.15(s,3H),4.08(s,3H).
Step 2: n-methylmorpholine oxide (CAS number: 7529-22-8, 632mg,5.4 mmol) and potassium osmium dihydrate (50 mg,0.14 mmol) were dissolved in a mixed solvent of tetrahydrofuran and water (V Tetrahydrofuran (THF) /V Water and its preparation method =2/1, 6 ml), after stirring for 15 minutes, 2, 4-dimethoxy-7-vinylthieno [3,2-d ] was added]Pyrimidine (300 mg,1.4 mmol), room temperature reaction? Hours. Adding saturated Na 2 SO 3 The reaction was quenched with solution (10 mL), stirred for 30 min, ethyl acetate (10 mL) was added, the organic layer was separated, the aqueous layer was extracted with ethyl acetate (5 mL. Times.3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (4 mL). Sodium periodate (577 mg,2.7 mmol) was dissolved in water (2 mL)Dropwise adding the solution under ice bath condition, and reacting for 1 hour at room temperature. Ethyl acetate (10 mL) was added, the organic layer was separated, the aqueous layer was extracted with ethyl acetate (5 ml×3 times), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=5/1) to give 2, 4-dimethoxy thieno [3,2-d ]]Pyrimidine-7-carbaldehyde (99 mg, 33% yield). MS (ESI) M/Z225.0 [ M+H ] ] + . 1 H NMR(400MHz,CDCl 3 ):δ10.39(s,1H),8.62(s,1H),4.18(s,3H),4.11(s,3H).
Step 3: 2, 4-Dimethoxythieno [3,2-d ]]Pyrimidine-7-carbaldehyde (362 mg,1.6 mmol) was dissolved in dry dichloromethane (5 mL), cooled to-20deg.C, and DAST (719 mg,3.2 mmol) was added dropwise. The reaction system was warmed to room temperature naturally and stirred for 3 hours, after the reaction was completed, a saturated aqueous sodium bicarbonate solution was slowly added until no bubbles were generated, an organic layer was separated, the aqueous phase was extracted with methylene chloride (5 ml×3 times), the organic phases were combined, the organic phase was washed with saturated brine (20 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=5/1) to give 7- (difluoromethyl) -2, 4-dimethoxythieno [3, 2-d)]Pyrimidine (330 mg, 83% yield). MS (ESI) M/Z247.0 [ M+H ]] + . 1 H NMR(400MHz,CDCl 3 ):δ8.12(td,J＝2.0,1.2Hz,1H),7.02(td,J＝55.2,0.8Hz,1H),4.16(s,3H),4.07(s,3H). 19 F NMR(376MHz,CDCl 3 )δ-113.28.
Step 4: 7- (difluoromethyl) -2, 4-dimethoxy thieno [3,2-d]Pyrimidine (330 mg,1.3 mmol) was dissolved in glacial acetic acid (6 mL) and sodium iodide (602 mg,4.0 mmol) was added in portions. After the reaction system was warmed to 110℃and stirred for 2 hours, it was cooled to room temperature, concentrated under reduced pressure to remove most of the solvent, diluted with ethyl acetate (10 mL), washed with saturated sodium thiosulfate (20 mL), and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (5 mL. Times.3), the organic layers were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 7- (difluoromethyl) thieno [3, 2-d) ]Pyrimidine-2, 4 (1H, 3H) -dione (192 mg, crude product)) Directly used in the next reaction. MS (ESI) M/Z219.0 [ M+H ]] + .
Step 5: 7- (difluoromethyl) thieno [3,2-d]Pyrimidine-2, 4 (1H, 3H) -dione (100 mg, crude) was dissolved in redistilled phosphorus oxychloride (1 mL) and N, N-dimethylaniline (44 mg,0.36 mmol) was added at room temperature. The reaction was warmed to 80 ℃ and stirred overnight. The reaction solution was cooled to room temperature, concentrated under reduced pressure to remove most of phosphorus oxychloride, diluted with ethyl acetate (10 mL), slowly added dropwise with saturated sodium bicarbonate solution under ice until no bubbles were evolved, the organic layer was separated, the aqueous phase was extracted with ethyl acetate (5 ml×3 times), the organic phases were combined, the organic phase was washed with saturated brine (20 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=10/1) to give 2, 4-dichloro-7- (difluoromethyl) thieno [3, 2-d)]Pyrimidine (70 mg, 41% overall yield in two steps). MS (ESI) M/Z255.0 [ M+H ]] + . 1 H NMR(400MHz,CDCl 3 ):δ8.44(s,1H),7.08(td,J＝54.4,0.8Hz,1H). 19 F NMR(376MHz,CDCl 3 )δ-113.65.
2, 4-dichloro-7- (difluoromethyl) thieno [3,2-d]Pyrimidine as a starting material was prepared in five steps by the procedure of reference example a-10 to give the final product 2- (6- ((4- (2-amino-7- (difluoromethyl) thieno [3, 2-d)) ]Pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl-methyl) pyridin-2-yl-propan-2-ol (14 mg). MS (ESI) M/Z418.0 [ M+H ]] + . 1 H NMR(400MHz,CDCl 3 ): δ8.46(s,1H),8.26(t,J＝1.6Hz,1H),7.73(t,J＝7.6Hz,1H),7.38(dd,J＝8.0,0.8Hz,1H),7.16(dd,J＝7.6,0.8Hz,1H),7.00(t,J＝55.2Hz,1H),5.78(s,2H),5.15(s,2H),4.66(s,1H),1.54(s,6H). 19 F NMR(376MHz,CDCl 3 )δ-113.52.
Examples a to 17:
preparation of 1- (6- ((4- (2-amino-7-bromothieno [3,2-d ] pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl) methyl) pyridin-2-yl) cyclobutyl-1-ol (compound a-17)
The reaction steps are as follows:
step 1: (6-bromopyridin-2-yl) methanol (17.6 g,94.1 mmol) was dissolved in methylene chloride (200 mL). Under nitrogen, cool to 0deg.C and add imidazole (7.7 g,113 mmol) followed by TBSCl (15.7 g,113 mmol). The reaction was warmed to 25 ℃ and stirred for 2 hours, water (100 mL) was added, the solution was separated, the aqueous phase was extracted with dichloromethane (100 ml×3 times), the organic phases were combined, the organic phases were washed with saturated brine (200 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=19/1 to 9/1) to give 2-bromo-6- (((tert-butyldimethylsilyloxy) methyl) pyridine (25.0 g, yield 88%). MS (ESI) M/Z302.0 [ M+H ]] + .
Step 2: 2-bromo-6- (((tert-Butyldimethylsilyloxy) methyl) pyridine (6.0 g,19.9 mmol) was dissolved in dry tetrahydrofuran (60 mL), cooled to-78℃under nitrogen protection, n-butyllithium (8.1 mL,20.3 mmol) was added dropwise, and after stirring for 0.5 hours, cyclobutylketone (1.54 g,22.0 mmol) was added. Then the reaction system naturally heats up to room temperature, stirs for 2 hours, then cools down to 0 ℃, adds TBAF 3H 2 O (6.3 g,20.0 mmol), stirring was continued for 20 hours at room temperature. Saturated aqueous ammonium chloride (50 mL) was slowly added, the organic layer was separated, the aqueous phase extracted with ethyl acetate (100 mL x 2 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=10/1 to 2/1) to give 1- (6- (hydroxymethyl) pyridin-2-yl) cyclobutyl-1-ol (2.0 g, yield 56%). MS (ESI) M/Z180.1 [ M+H ]] + .
Step 3: 1- (6- (hydroxymethyl) pyridin-2-yl) cyclobutyl-1-ol (1.0 g,5.6 mmol) was dissolved in toluene (20 mL), cooled to 0deg.C, and DPPA (1.9 g,6.8 mmol) and DBU (1.0 g,6.8 mmol) were added. The reaction was allowed to warm to room temperature and stirred overnight. To the reaction mixture was added water (20 mL) to quench the reaction. The mixture was extracted with ethyl acetate (30 mL. Times.3), and the organic phases were combined, washed with saturated brine (30 mL), and then withDried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=20/1 to 10/1) to give 1- (6- (azidomethyl) pyridin-2-yl) cyclobutyl-1-ol (700 mg, yield 61%). MS (ESI) M/Z204.7 [ M+H ] ] + .
Step 4: 7-bromo-4-ethynyl-N- (4-methoxybenzyl) thieno [3,2-d]Pyrimidine-2-amine (150 mg,0.40 mmol) in a mixed solvent of t-butanol, water and tetrahydrofuran (V Tert-butanol /V Water and its preparation method /V Tetrahydrofuran (THF) =2/1, 4 ml). Under nitrogen, 1- (6- (azidomethyl) pyridin-2-yl) cyclobutyl-1-ol (87 mg,0.43 mmol), copper sulfate pentahydrate (26 mg,0.08 mmol) and sodium ascorbate (16 mg,0.07 mmol) were added sequentially. The reaction system was warmed to 50 ℃ and stirred for 2 hours. The reaction solution was cooled to room temperature, quenched with water (10 mL), the mixture was extracted with ethyl acetate (40 ml×3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=5/1 to 3/1) to give 1- (6- ((4- (7-bromo-2- ((4-methoxybenzyl) amino) thieno [3, 2-d)]Pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl-methyl) pyridin-2-yl-cyclobutyl-1-ol (80 mg, 19% yield). MS (ESI) M/Z578.2 [ M+H ]] + .
Step 5: 1- (6- ((4- (7-bromo-2- ((4-methoxybenzyl) amino) thieno [3, 2-d)]Pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl-methyl) pyridin-2-yl cyclobutyl-1-ol (80 mg,0.14 mmol) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (5 mL) was added. The reaction was stirred at 40℃for 5 hours, concentrated under reduced pressure, diluted with ethyl acetate (50 mL), then washed with saturated aqueous sodium carbonate (20 mL. Times.3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is slurried with tert-butyl methyl ether to give the final product 1- (6- ((4- (2-amino-7-bromothieno [3, 2-d)) ]Pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl-methyl) pyridin-2-yl-cyclobutyl-1-ol (20 mg, 30% yield). MS (ESI) M/Z457.9 [ M+H ]] + . 1 H NMR(400MHz,DMSO-d6):δ8.87(s,1H),8.45(s,1H),7.81(t,J＝8.0Hz,1H),7.52(d,J＝8.0Hz,1H),7.23(d,J＝7.6Hz,1H),6.92(br s,2H),5.93(s,2H),5.75(s,1H),2.43-2.37(m,2H),2.19-2.11(m,2H),1.79-1.64(m,2H).
Examples a-18:
preparation of 1- (6- ((4- (2-amino-7-bromothieno [3,2-d ] pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl) methyl) pyridin-2-yl) cyclopentyl-1-ol (compound a-18)
The reaction steps are as follows:
the five steps of preparation of the final product 1- (6- ((4- (2-amino-7-bromothieno [3, 2-d)) by substituting cyclopentanone for cyclobutanone were carried out by the procedure of reference example a-17]Pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl-methyl) pyridin-2-yl-cyclopentyl-1-ol (36 mg). MS (ESI) M/Z471.9 [ M+H ]] + . 1 H NMR(400MHz,DMSO-d6):δ8.84(s,1H),8.46(s,1H),7.80(t,J＝7.6Hz,1H),7.63(d,J＝7.6Hz,1H),7.16(d,J＝7.6Hz,1H),6.92(br s,2H),5.87(s,2H),5.08(s,1H),2.00-1.97(m,2H),1.80-1.66(m,6H).
Examples a to 19:
preparation of (S) -7-bromo-4- (1- ((6- (((tetrahydrofuran-3-yl) oxo) methyl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) thieno [3,2-d ] pyrimidin-2-amine (compound a-19)
The reaction steps are as follows:
the final product (S) -7-bromo-4- (1- ((6- (((tetrahydrofuran-3-yl) oxo) methyl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) thieno [3, 2-d) was prepared in two steps by the procedure of reference example a-17 starting from (S) -2- (((tetrahydrofuran-3-yl) oxo) methyl) pyridine]Pyrimidin-2-amine (45 mg). MS (ESI) M/Z488.3 [ M+H ]] + . 1 H NMR(400MHz,DMSO-d6):δ8.85(s,1H),8.46(s,1H),7.86(t,J＝7.6Hz,1H),7.40(d,J＝7.6Hz,1H),7.29(d,J＝7.6Hz,1H),6.92(brs,2H),5.88(s,2H),4.51(s,2H),4.24(brs,1H),3.76-3.60(m,4H),1.96-1.93(m,2H).
Examples a to 20:
preparation of (R) -7-bromo-4- (1- ((6- (((tetrahydrofuran-3-yl) oxo) methyl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) thieno [3,2-d ] pyrimidin-2-amine (compound a-20)
The reaction steps are as follows:
using (R) -2- (azidomethyl) -6- (((tetrahydrofuran-3-yl) oxo) methyl) pyridine as raw material, the final product (R) -7-bromo-4- (1- ((6- (((tetrahydrofuran-3-yl) oxo) methyl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) thieno [3, 2-d) was prepared in two steps by the procedure of reference example a-17]Pyrimidin-2-amine (55 mg). MS (ESI) M/Z488.0 [ M+H ]] + . 1 H NMR(400MHz,DMSO-d6):δ8.85(s,1H),8.46(s,1H),7.86(t,J＝7.6Hz,1H),7.40(d,J＝7.6Hz,1H),7.29(d,J＝7.6Hz,1H),6.93(brs,2H),5.88(s,2H),4.51(s,2H),4.24(brs,1H),3.76-3.59(m,4H),1.96-1.91(m,2H).
Examples a-21:
preparation of 7-bromo-4- (1- ((6- (methoxymethyl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) thieno [3,2-d ] pyrimidin-2-amine (compound a-21)
The reaction steps are as follows:
the final product 7-bromo-4- (1- ((6- (methoxymethyl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) thieno [3,2-d was prepared in two steps by the procedure of reference example a-17 starting from 2- (azidomethyl) -6- (methoxymethyl) pyridine]Pyrimidin-2-amine (40 mg). MS (ESI) M/Z432.0 [ M+H ]] + . 1 H NMR(400MHz,DMSO-d6):δ8.85(s,1H),8.46(s,1H),7.86(t,J＝7.6Hz,1H),7.39(d,J＝7.6Hz,1H),7.27(d,J＝7.6Hz,1H),6.93(brs,2H),5.88(s,2H),4.46(s,2H),3.35(s,3H).
Examples a-22:
preparation of 2- ((4- (2-amino-7-bromothieno [3,2-d ] pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl) methyl) -6- (2-hydroxypropan-2-yl) pyridin-1-oxide (compound a-22)
The reaction steps are as follows:
step 1: 7-bromo-4-ethynyl-N- (4-methoxybenzyl) thieno [3,2-d]Pyrimidine-2-amine (1.6 g,4.3 mmol) was dissolved in trifluoroacetic acid (20 mL). The reaction system was stirred at 50℃for 12 hours, concentrated under reduced pressure to remove most of the trifluoroacetic acid, and 30% aqueous sodium carbonate (30 mL) was added. The mixture was extracted with dichloromethane (30 mL. Times.3). The combined organic phases were washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 7-bromo-4-ethynylthieno [3,2-d ] ]Pyrimidin-2-amine (1.0 g, 92% yield). MS (ESI) M/Z254.6 [ M+H ]] + .
Step 2: 7-bromo-4-ethynyl thieno [3,2-d ]]Pyrimidine-2-amine (100 mg,0.40 mmol) in a mixed solvent of t-butanol, water and tetrahydrofuran (V Tert-butanol /V Water and its preparation method /V Tetrahydrofuran (THF) =2/1, 4 ml). 2- (azidomethyl) -6- (2-hydroxypropyl-2-yl) pyridine-1-oxide (92 mg,0.40 mmol), copper sulfate pentahydrate (20 mg,0.08 mmol) and sodium ascorbate (8 mg,0.04 mmol) were added sequentially under nitrogen. After the reaction system was warmed to 50℃and stirred for 2 hours, it was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (40 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained is purified by means of silica gel preparative chromatography (eluent: petroleum ether/ethyl acetate/dichloromethane=5/1/1 to 1/1/1) to give the final product 2- ((4- (2-amino-7-bromothieno [3, 2-d)]Pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl) methyl) -6- (2-hydroxypropan-2-ylPyridine-1-oxide (70 mg, yield 38%). MS (ESI) M/Z462.0 [ M+H ]] + . 1 H NMR(400MHz,DMSO-d6):δ8.94(s,1H),8.46(s,1H),7.73(d,J＝6.8Hz,1H),7.49(t,J＝7.6Hz,1H),7.16(d,J＝6.8Hz,1H),6.96(brs,2H),6.63(s,1H),5.98(s,2H),1.60(s,6H).
The following target products were prepared by the synthetic method of reference examples a-22:
examples a-28:
preparation of 2- (3- ((4- (2-amino-7-bromothieno [3,2-d ] pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl) methyl) phenyl) propan-2-ol (compound a-28)
The reaction steps are as follows:
step 1: 2- (3- (hydroxymethyl) phenyl) propan-2-ol (750 mg,4.5 mmol) was dissolved in toluene (30 mL), cooled to 0deg.C, and DPPA (1.2 g,4.3 mmol) and DBU (653 mg,4.3 mmol) were added. The reaction was allowed to warm to room temperature and stirred overnight. To the reaction mixture was added water (20 mL) to quench the reaction. The mixture was extracted with ethyl acetate (20 mL. Times.2), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by column chromatography on silica gel (eluent: petroleum ether-Ethyl acetate=20/1 to 5/1) to give 2- (3- (azidomethyl) phenyl) propan-2-ol (492 mg, yield 57%). MS (ESI) M/Z174.0 [ M-H ] 2 O+H + ]. 1 H NMR(400MHz,DMSO-d6):δ7.47-7.43(m,2H),7.33(t,J＝7.6Hz,1H),7.19(d,J＝7.6Hz,1H),5.07(s,1H),4.44(s,2H),1.44(s,6H).
Step 2: 7-bromo-4-ethynyl thieno [3,2-d ]]Pyrimidine-2-amine (40 mg,0.16 mmol) in a mixed solvent of t-butanol, water and tetrahydrofuran (V Tert-butanol /V Water and its preparation method /V Tetrahydrofuran (THF) =2/1, 4 ml). 2- (3- (azidomethyl) phenyl) propan-2-ol (38 mg,0.20 mmol), copper sulfate pentahydrate (13 mg,0.04 mmol) and sodium ascorbate (8 mg,0.04 mmol) were added sequentially under nitrogen. The reaction system was warmed to 50 ℃ and stirred for 2 hours. The reaction solution was cooled to room temperature, quenched with water (10 mL), the mixture was extracted with ethyl acetate (40 ml×3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=5/1 to 3/1) to give 2- (3- ((4- (2-amino-7-bromothieno [3, 2-d)) ]Pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl-methyl) phenyl) propan-2-ol (30 mg, 43% yield). MS (ESI) M/Z445.2 [ M+H ]] + . 1 H NMR(400MHz,DMSO-d6):δ8.81(s,1H),8.45(s,1H),7.59(s,1H),7.43(d,J＝7.6Hz,1H),7.33(t,J＝7.6Hz,1H),7.23(d,J＝7.6Hz,1H),6.91(s,2H),5.75(s,2H),5.07(s,1H),1.45(s,6H).
Examples a-29:
preparation of 3- (6- ((4- (2-amino-7-bromothieno [3,2-d ] pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl) methyl) pyridin-2-yl) oxetan-3-ol (compound a-29)
The reaction steps are as follows:
step 1: 3- (6- (hydroxymethyl) pyridin-2-yl) oxetan-3-ol (1.0 g,5.5 mmol) was dissolved in toluene (20 ml), cooled to 0deg.C and DPPA (1.9 g, 6) was added.8 mmol) and DBU (1.0 g,6.8 mmol). The reaction was allowed to warm to room temperature and stirred overnight. To the reaction mixture was added water (20 ml) to quench the reaction. The mixture was extracted with ethyl acetate (30 ml. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=20/1 to 10/1) to give 3- (6- (azidomethyl) pyridin-2-yl) oxetan-3-ol (200 mg, yield 18%). MS (ESI) M/Z207.1 [ M+H ] + ].
Step 2: 7-bromo-4-ethynyl thieno [3,2-d ]]Pyrimidine-2-amine (50 mg,0.20 mmol) in a mixed solvent of t-butanol, water and tetrahydrofuran (V Tert-butanol /V Water and its preparation method /V Tetrahydrofuran (THF) =2/1, 4 ml). 3- (6- (azidomethyl) pyridin-2-yl) oxetan-3-ol (46 mg,0.22 mmol), copper sulfate pentahydrate (20 mg,0.07 mmol) and sodium ascorbate (8 mg,0.04 mmol) were added sequentially under nitrogen. The reaction system was warmed to 50 ℃ and stirred for 2 hours. The reaction solution was cooled to room temperature, quenched with water (10 mL), the mixture was extracted with ethyl acetate (40 ml×3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate/dichloromethane=5/1/1 to 3/1/1) to give 3- (6- ((4- (2-amino-7-bromothieno [3, 2-d)) ]Pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl-methyl) pyridin-2-yl-oxetan-3-ol (50 mg, 43% yield). MS (ESI) M/Z459.9 [ M+H ]] + . 1 H NMR(400MHz,DMSO-d6):δ8.89(s,1H),8.46(s,1H),7.88(t,J＝ 7.6Hz,1H),7.57(d,J＝8.0Hz,1H),7.28(d,J＝7.6Hz,1H),6.92(s,2H),6.56(s,1H),5.95(s,2H),4.84(d,J＝6.0Hz,2H),4.60(d,J＝6.0Hz,2H).
Examples a-30:
preparation of 2- (6- ((4- (2-amino-7-bromothieno [3,2-d ] pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl) methyl) pyridin-2-yl) -2-methylpropanenitrile (compound a-30)
The reaction steps are as follows:
step 1: 2-methyl-2- (6-methylpyridin-2-yl) propionitrile (800 mg,5.0 mmol) was dissolved in carbon tetrachloride (6 mL), and N-bromosuccinimide (976 mg,5.5 mmol) and benzoyl peroxide (120 mg,0.5 mmol) were added sequentially at room temperature. The reaction system was warmed to 78 ℃ under nitrogen protection, stirred for 16 hours, cooled to room temperature, and quenched by slowly adding saturated aqueous sodium bicarbonate (20 mL) to the reaction solution. The mixture was extracted with dichloromethane (40 ml×2 times), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=49/1) to give 2- (6- (bromomethyl) pyridin-2-yl) -2-methylpropanenitrile (400 mg, yield 34%). MS (ESI) M/Z239.1 [ M+H ] + ].
Step 2: 2- (6- (bromomethyl) pyridin-2-yl) -2-methylpropanenitrile (200 mg,0.84 mmol) was dissolved in dimethyl sulfoxide (6 mL), and sodium azide (82 mg,1.3 mmol) was added at room temperature. The reaction system was warmed to 50 ℃ and stirred for 16 hours. To the reaction mixture was added water (20 mL) to quench the reaction. The mixture was extracted with ethyl acetate (100 mL. Times.2), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=9/1) to give 2- (6- (azidomethyl) pyridin-2-yl) -2-methylpropanenitrile (80 mg, yield 47%). MS (ESI) M/Z201.8 [ M+H ] + ].
Step 3: 7-bromo-4-ethynyl thieno [3,2-d ]]Pyrimidine-2-amine (56 mg,0.22 mmol) in a mixed solvent of t-butanol, water and tetrahydrofuran (V Tert-butanol /V Water and its preparation method /V Tetrahydrofuran (THF) =2/1, 6 ml). 2- (6- (azidomethyl) pyridin-2-yl) -2-methylpropanenitrile (44 mg,0.22 mmol), copper sulfate pentahydrate (17 mg,0.067 mmol) and sodium ascorbate (10 mg,0.05 mmol) were added sequentially under nitrogen. The reaction system was warmed to 50 ℃ and stirred for 3 hours. The reaction solution was cooled to room temperature, quenched with water (20 mL), extracted with ethyl acetate (100 mL. Times.2), and the organic phases combined, taken withoutDrying with sodium sulfate, filtering, and concentrating under reduced pressure. The residue was crystallized from dry ether to give 2- (6- ((4- (2-amino-7-bromothieno [3, 2-d))]Pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl-methyl) pyridin-2-yl) -2-methylpropanenitrile (20 mg, 43% yield). MS (ESI) M/Z455.6 [ M+H ]] + . 1 H NMR(400MHz,DMSO-d6):δ8.89(s,1H),8.46(s,1H),7.94(t,J＝7.6Hz,1H),7.59(d,J＝8.0Hz,1H),7.30(d,J＝7.6Hz,1H),6.93(s,2H),5.94(s,2H),1.64(s,6H).
Examples a-31:
preparation of 7-bromo-4- (1- ((6- (cis-2, 6-dimethylmorpholin) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) thieno [3,2-d ] pyrimidin-2-amine (compound a-31)
The reaction steps are as follows:
step 1: 2-bromo-6- (((tert-butyldimethylsilyl) oxy) methyl) pyridine (1.0 g,3.3 mmol) was dissolved in DMF (15 mL) and cis-2, 6-dimethyl morpholine (460 mg,4.0 mmol), cuprous iodide (63 mg,0.33 mmol) and potassium carbonate (2.3 g,16.7 mmol) were added sequentially at room temperature. The reaction system was warmed to 95℃under nitrogen protection and stirred for 16 hours, cooled to room temperature, and quenched by slowly adding water (30 mL) to the reaction mixture. The mixture was extracted with ethyl acetate (40 ml×3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate/dichloromethane=20/1/1 to 3/1/1) to give cis-4- (6- (((tert-butyldimethylsilyl) oxy) methyl) pyridin-2-yl) -2, 6-dimethylmorpholine (600 mg, yield 52%). MS (ESI) M/Z337.2 [ M+H ] + ]. 1 H NMR(400MHz,DMSO-d6):δ7.52-7.48(m,1H),6.84(d,J＝7.2Hz,1H),6.48(d,J＝8.4Hz,1H),4.68(s,2H),4.07-4.03(m,2H),3.75-3.71(m,2H),2.50-2.44(m,2H),1.27(d,J＝6.4Hz,6H),0.96(s,9H),0.11(s,6H).
Step 2: cis-4- (6- (((tert-butyldimethylsilyloxy) methyl) pyridin-2-yl) -2, 6-dimethylMorphine (600 mg,1.8 mmol) was dissolved in tetrahydrofuran (6 ml), and TBAF.3H was added thereto 2 O (560 mg,2.1 mmol). After the reaction system was stirred at room temperature for 16 hours, the reaction was quenched by the addition of water (3 mL). The mixture was extracted with ethyl acetate (40 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (6- (cis-2, 6-dimethylmorpholin) pyridin-2-yl) methanol (350 mg, yield 88%). MS (ESI) M/Z222.9 [ M+H ] + ].
Step 3: (6- (cis-2, 6-dimethylmorpholin) pyridin-2-yl) methanol (350 mg,1.6 mmol) was dissolved in toluene (10 mL), cooled to 0deg.C, and DPPA (492 mg,1.8 mmol) and DBU (273 mg,1.8 mmol) were added. The reaction system was naturally warmed to room temperature and stirred for 5 hours. To the reaction mixture was added water (10 mL) to quench the reaction. The mixture was extracted with ethyl acetate (40 ml×3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate/dichloromethane=5/1/1 to 3/1/1) to give cis-4- (6- (azidomethyl) pyridin-2-yl) -2, 6-dimethylmorpholine (150 mg, yield 38%). MS (ESI) M/Z248.1 [ M+H ] + ].
Step 4: 7-bromo-4-ethynyl thieno [3,2-d ]]Pyrimidine-2-amine (51 mg,0.20 mmol) in a mixed solvent of t-butanol, water and tetrahydrofuran (V Tert-butanol /V Water and its preparation method /V Tetrahydrofuran (THF) =2/1, 4 ml). Cis-4- (6- (azidomethyl) pyridin-2-yl) -2, 6-dimethylmorpholine (49 mg,0.20 mmol), copper sulfate pentahydrate (20 mg,0.07 mmol) and sodium ascorbate (8 mg,0.04 mmol) were added sequentially under nitrogen. The reaction system was warmed to 50 ℃ and stirred for 2 hours. The reaction solution was cooled to room temperature, quenched with water (10 mL), the mixture was extracted with ethyl acetate (40 ml×3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate/dichloromethane=5/1/1 to 3/1/1) to give 7-bromo-4- (1- ((6- (cis-2, 6-dimethylmorpholin) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) thieno [3, 2-d)]Pyrimidin-2-amine (30 mg, 43% yield). MS (ESI) M/Z500.9 [ M+H ]] + . 1 H NMR(400MHz,DMSO-d6):δ8.80(s,1H),8.45(s,1H),7.58-7.54(m,1H),6.90(brs,2H),6.78(d,J＝8.4Hz,1H),6.57(d,J＝7.2Hz,1H),5.72(s,2H),4.04(d,J＝11.2Hz,2H),3.51-3.47(m,2H),2.34-2.28(m,2H),1.05(d,J＝6.0Hz,6H).
Examples a-32:
preparation of 1- (6- ((4- (2-amino-7-bromothieno [3,2-d ] pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl) methyl) pyridin-2-yl) -4-methylpiperidin-4-ol (compound a-32)
The reaction steps are as follows:
step 1: 1- (6- (hydroxymethyl) pyridin-2-yl) -4-methylpiperidin-4-ol (397 mg,1.8 mmol) was dissolved in toluene (6 mL), cooled to 0deg.C, and DPPA (492 mg,1.8 mmol) and DBU (273 mg,1.8 mmol) were added. The reaction system was naturally warmed to room temperature and stirred for 5 hours. To the reaction mixture was added water (10 mL) to quench the reaction. The mixture was extracted with ethyl acetate (40 ml×3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate/dichloromethane=5/1/1 to 3/1/1) to give 1- (6- (azidomethyl) pyridin-2-yl) -4-methylpiperidin-4-ol (230 mg, yield 52%). MS (ESI) M/Z248.2 [ M+H ] + ].
Step 2: 7-bromo-4-ethynyl thieno [3,2-d ]]Pyrimidine-2-amine (51 mg,0.20 mmol) in a mixed solvent of t-butanol, water and tetrahydrofuran (V Tert-butanol /V Water and its preparation method /V Tetrahydrofuran (THF) =2/1, 4 ml). 1- (6- (azidomethyl) pyridin-2-yl) -4-methylpiperidin-4-ol (49 mg,0.20 mmol), copper sulfate pentahydrate (20 mg,0.07 mmol) and sodium ascorbate (8 mg,0.04 mmol) were added sequentially under nitrogen. The reaction system was warmed to 50 ℃ and stirred for 2 hours. The reaction solution was cooled to room temperature, quenched with water (10 mL), the mixture was extracted with ethyl acetate (40 ml×3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatographyPurification (eluent: petroleum ether/ethyl acetate/dichloromethane=5/1/1 to 3/1/1) afforded 1- (6- ((4- (2-amino-7-bromothieno [3, 2-d))]Pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl-methyl) pyridin-2-yl) -4-methylpiperidin-4-ol (32 mg, yield 32%). MS (ESI) M/Z500.9 [ M+H ]] + . 1 H NMR(400MHz,DMSO-d6):δ8.78(s,1H),8.45(s,1H),7.50(t,J＝8.0Hz,1H),6.91(brs,2H),6.77(d,J＝8.8Hz,1H),6.48(d,J＝7.2Hz,1H),5.67(s,2H),4.30(s,1H),3.76-3.73(m,2H),3.33-3.25(m,2H),1.40-1.35(m,4H),1.08(s,3H).
Examples a-33:
preparation of 2- (6- ((4- (2-amino-7-bromothieno [3,2-d ] pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl) methyl-d 2) pyridin-2-yl) propan-2-ol (compound a-33)
The reaction steps are as follows:
step 1: methyl 6- (2-hydroxypropyl-2-yl) picolinate (1.0 g,5.1 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), cooled to 0deg.C, and lithium deuterated aluminum hydride (430 mg,10.2 mmol) was added. The reaction system was naturally warmed to room temperature and stirred for 2 hours. The reaction was quenched by slowly adding water (20 mL). The mixture was extracted with ethyl acetate (40 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2- (6- (hydroxymethyl-d 2) pyridin-2-yl) propan-2-ol (650 mg, yield 75%). MS (ESI) M/Z169.9 [ M+H ] + ].
Step 2: 2- (6- (hydroxymethyl-d 2) pyridin-2-yl) propan-2-ol (650 mg,3.8 mmol) was dissolved in toluene (10 mL), cooled to 0deg.C, and DPPA (1.0 g,3.9 mmol) and DBU (591 mg,3.9 mmol) were added. The reaction system was naturally warmed to room temperature and stirred for 5 hours. To the reaction mixture was added water (10 mL) to quench the reaction. The mixture was extracted with ethyl acetate (40 ml×3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=20/1 to 3/1) to give 2- (6- (azidomethyl-d 2) pyridine-2-yl) propan-2-ol (350 mg, 47% yield). MS (ESI) M/Z195.1 [ M+H ] + ].
Step 3: 7-bromo-4-ethynyl thieno [3,2-d ]]Pyrimidine-2-amine (51 mg,0.20 mmol) in a mixed solvent of t-butanol, water and tetrahydrofuran (V Tert-butanol /V Water and its preparation method /V Tetrahydrofuran (THF) =2/1, 4 ml). 2- (6- (azidomethyl-d 2) pyridin-2-yl) propan-2-ol (39 mg,0.20 mmol), copper sulfate pentahydrate (20 mg,0.07 mmol) and sodium ascorbate (8 mg,0.04 mmol) were added sequentially under nitrogen. The reaction system was warmed to 50 ℃ and stirred for 2 hours. The reaction solution was cooled to room temperature, quenched with water (10 mL), the mixture was extracted with ethyl acetate (40 ml×3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate/dichloromethane=5/1/1 to 1/1/1) to give 2- (6- ((4- (2-amino-7-bromothieno [3, 2-d)) ]Pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl) methyl-d 2) pyridin-2-yl) propan-2-ol (22 mg, yield 32%). MS (ESI) M/Z448.0 [ M+H ]] + . 1 H NMR(400MHz,DMSO-d6):δ8.85(s,1H),8.45(s,1H),7.81(t,J＝8.0Hz,1H),7.61(d,J＝8.0Hz,1H),7.17(d,J＝7.6Hz,1H),6.92(s,2H),5.22(s,1H),1.36(s,6H).
Examples a-34:
preparation of 1- (6- ((4- (2-amino-7-bromothieno [3,2-d ] pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl) methyl) pyridin-2-yl) -3-methylazetidin-3-ol (compound a-34)
The reaction steps are as follows:
step 1: 1- (6- (hydroxymethyl) pyridin-2-yl) -3-methylazetidin-3-ol (350 mg,1.8 mmol) was dissolved in toluene (10 mL), cooled to 0deg.C, and DPPA (492 mg,1.8 mmol) and DBU (279 mg,1.8 mmol) were added. The reaction system was naturally warmed to room temperature and stirred for 5 hours. To the reaction mixture was added water (10 mL) to quench the reaction. The mixture was extracted with ethyl acetate (40 mL. Times.3),the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=20/1 to 1/1) to give 1- (6- (azidomethyl) pyridin-2-yl) -3-methylazetidin-3-ol (150 mg, yield 38%). MS (ESI) M/Z242.3 [ M+Na ] + ].
Step 2: 7-bromo-4-ethynyl thieno [3,2-d ]]Pyrimidine-2-amine (51 mg,0.20 mmol) in a mixed solvent of t-butanol, water and tetrahydrofuran (V Tert-butanol /V Water and its preparation method /V Tetrahydrofuran (THF) =2/1, 4 ml). Under nitrogen, 1- (6- (azidomethyl) pyridin-2-yl) -3-methylazetidin-3-ol (44 mg,0.20 mmol), copper sulfate pentahydrate (20 mg,0.07 mmol) and sodium ascorbate (8 mg,0.04 mmol) were added sequentially. The reaction system was warmed to 50 ℃ and stirred for 2 hours. The reaction solution was cooled to room temperature, quenched with water (10 mL), the mixture was extracted with ethyl acetate (40 ml×3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate/dichloromethane=5/1/1 to 2/1/1) to give 1- (6- ((4- (2-amino-7-bromothieno [3, 2-d))]Pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl-methyl) pyridin-2-yl) -3-methylazetidin-3-ol (60 mg, yield 64%). MS (ESI) M/Z472.8 [ M+H ]] + . 1 H NMR(400MHz,DMSO-d6):δ8.77(s,1H),8.45(s,1H),7.52(t,J＝8.0Hz,1H),6.93(s,2H),6.52(d,J＝7.2Hz,1H),6.35(d,J＝8.4Hz,1H),5.67(s,2H),5.53(s,1H),3.78-3.70(m,4H),1.41(s,3H).
Examples a-35:
preparation of 2- (1- (6- ((4- (2-amino-7-bromothieno [3,2-d ] pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl) methyl) pyridin-2-yl) azetidin-3-yl) propan-2-ol (compound a-35)
The reaction steps are as follows:
step 1: 2-bromo-6- ((tert-butyldimethyl)Alkylsiloxy) methyl pyridine (1.4 g,4.7 mmol), 2- (azetidin-3-yl) propan-2-ol hydrochloride (850 mg,5.6 mmol), cesium carbonate (3.0 g,9.3 mmol), palladium acetate (105 mg,0.47 mmol) and 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine (290 mg,0.47 mmol) were dissolved in toluene (30 mL), replaced with nitrogen three times, and heated to 120℃with reflux and stirred for 2 hours. LCMS monitoring indicated complete reaction of starting material, cooling the reaction to room temperature, and adding water (20 mL). The mixture was extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=1/5) to give 2- (1- (6- ((tert-butyldimethylsilyloxy) methyl) pyridin-2-yl) azetidin-3-yl) propan-2-ol (600 mg, yield 38%). MS (ESI) M/Z337.3 [ M+H ] + ].
Step 2: 2- (1- (6- ((tert-Butyldimethylsilyloxy) methyl) pyridin-2-yl) azetidin-3-yl) propan-2-ol (600 mg,1.8 mmol) was dissolved in tetrahydrofuran (5 mL), tetrabutylammonium fluoride (560 mg,2.1 mmol) was added with ice-cooling, and the mixture was stirred at room temperature for 2 hours. LCMS monitoring showed complete reaction of starting material, water (10 mL) was added and the mixture extracted with ethyl acetate (40 mL x 2 times). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2- (1- (6- (hydroxymethyl) pyridin-2-yl) azetidin-3-yl) propan-2-ol (350 mg, yield 88%). MS (ESI) M/Z222.8 [ M+H ] + ].
Step 3: 2- (1- (6- (hydroxymethyl) pyridin-2-yl) azetidin-3-yl) propan-2-ol (350 mg,1.6 mmol) was dissolved in a mixed solution of toluene and tetrahydrofuran (V) Toluene (toluene) /V Tetrahydrofuran (THF) =5/1, 6 ml), cooled to 0-5 ℃, DPPA (492 mg,1.8 mmol) and DBU (2793 mg,1.8 mmol) were added. The reaction system was naturally warmed to room temperature and stirred for 5 hours. To the reaction mixture was added water (10 mL) to quench the reaction. The mixture was extracted with ethyl acetate (40 ml×2 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=1/10) to give 2- (1- (6- (azidomethyl) pyridin-2-yl) azetidin-3-yl) propan-2-ol (120 mg, yield 31%). MS (ESI) M/Z248.1 [ M+H ] + ].
Step 4: 7-bromo-4-ethynyl thieno [3,2-d ]]Pyrimidine-2-amine (110 mg,0.43 mmol) in a mixed solvent of t-butanol, water and tetrahydrofuran (V Tert-butanol /V Water and its preparation method /V Tetrahydrofuran (THF) =2/1, 6 ml). 2- (1- (6- (azidomethyl) pyridin-2-yl) azetidin-3-yl) propan-2-ol (109 mg,0.44 mmol), copper sulfate pentahydrate (20 mg,0.07 mmol) and sodium ascorbate (18 mg,0.08 mmol) were added sequentially under nitrogen. The reaction system was warmed to 50 ℃ and stirred for 3 hours. The reaction solution was cooled to room temperature, quenched with water (10 mL), the mixture was extracted with ethyl acetate (50 ml×2 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by crystallization from diethyl ether to give 2- (1- (6- ((4- (2-amino-7-bromothieno) 3, 2-d)]Pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl-methyl) pyridin-2-yl-azetidin-3-yl) propan-2-ol (40 mg, yield 18%). MS (ESI) M/Z500.9 [ M+H ]] + . 1 H NMR(400MHz,DMSO-d6):δ8.77(s,1H),8.46(s,1H),7.49(t,J＝7.6Hz,1H),6.92(s,2H),6.45(d,J＝7.6Hz,1H),6.30(d,J＝8.4Hz,1H),5.65(s,2H),4.44(s,1H),3.81-3.75(m,4H),2.70-2.60(m,1H),1.03(s,6H).
Examples a-36:
preparation of 7-bromo-4- (1- ((6- ((2-fluorophenoxy) methyl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) thieno [3,2-d ] pyrimidin-2-amine (compound a-36)
The reaction steps are as follows:
step 1: 2- (bromomethyl) -6- (((tert-butyldimethylsilyloxy) methyl) pyridine (800 mg,2.5 mmol) and 2-fluorophenol (3411 mg,3.0 mmol) were dissolved in dry DMF (10 mL), potassium carbonate (525 mg,3.8 mmol) was added and the reaction was stirred at 25℃for 20 hours. LCMS monitoring shows the completion of the starting material reaction, adding water(20 mL), the mixture was extracted with ethyl acetate (20 mL. Times.3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=9/1) to give 2- (((tert-butyldimethylsilyloxy) methyl) -6- ((2-fluorophenoxy) methyl) pyridine (800 mg, yield 91%). MS (ESI) M/Z347.9 [ M+H ] + ].
Step 2: 2- (((tert-Butyldimethylsilyloxy) methyl) -6- ((2-fluorophenoxy) methyl) pyridine (800 mg,2.3 mmol) was dissolved in tetrahydrofuran (10 mL), tetrabutylammonium fluoride trihydrate (428 mg,2.3 mmol) was added with ice-bath cooling, and stirring was maintained at 0deg.C for 1 hour. LCMS monitoring showed complete reaction of starting material, water (10 mL) was added and the mixture extracted with ethyl acetate (40 mL x 2 times). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=10/1 to 2/1) to give (6- ((2-fluorophenoxy) methyl) pyridin-2-yl) methanol (500 mg, yield 93%). MS (ESI) M/Z234.7 [ M+H ] + ].
Step 3: (6- ((2-fluorophenoxy) methyl) pyridin-2-yl) methanol (300 mg,1.3 mmol) was dissolved in toluene (10 mL), cooled to 0-5℃and DPPA (425 mg,1.5 mmol) and DBU (235 mg,1.5 mmol) were added. The reaction was allowed to warm to room temperature and stirred overnight. To the reaction mixture was added water (20 mL) to quench the reaction. The mixture was extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=50/1 to 20/1) to give 2- (azidomethyl) -6- ((2-fluorophenoxy) methyl) pyridine (300 mg, yield 90%). MS (ESI) M/Z259.2 [ M+H ] + ].
Step 4: 7-bromo-4-ethynyl thieno [3,2-d ]]Pyrimidine-2-amine (30 mg,0.12 mmol) in a mixed solvent of t-butanol, water and tetrahydrofuran (V Tert-butanol /V Water and its preparation method /V Tetrahydrofuran (THF) =2/1, 6 ml). Under the protection of nitrogen, adding 2- (azidomethyl) -6- ((2-fluorophenoxy) in sequenceMethyl) pyridine (30 mg,0.12 mmol), copper sulfate pentahydrate (7 mg,0.03 mmol) and sodium ascorbate (5 mg,0.02 mmol). The reaction system was warmed to 50 ℃ and stirred for 3 hours. The reaction solution was cooled to room temperature, quenched with water (10 mL), the mixture was extracted with ethyl acetate (50 ml×2 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by beating with diethyl ether to give 7-bromo-4- (1- ((6- ((2-fluorophenoxy) methyl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) thieno [3,2-d ]Pyrimidin-2-amine (40 mg, 65% yield). MS (ESI) M/Z512.0 [ M+H ]] + . 1 H NMR(400MHz,DMSO-d6):δ8.86(s,1H),8.46(s,1H),7.92(t,J＝7.6Hz,1H),7.52(d,J＝7.6Hz,1H),7.35(d,J＝8.0Hz,1H),7.24-7.18(m,2H),7.07(t,J＝8.0Hz,1H),6.94-6.85(m,3H),5.92(s,2H),5.21(s,2H).
Examples a-37:
preparation of (R) -1- (6- ((4- (2-amino-7-bromothieno [3,2-d ] pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl) methyl) pyridin-2-yl) pyrrolin-3-ol (compound a-37)
The reaction steps are as follows:
step 1: methyl 6-fluoropyridine carboxylate (1.0 g,6.5 mmol) and (R) -pyrrolin-3-ol (560 mg,6.5 mmol) were dissolved in dry DMF (100 mL), potassium carbonate (4.5 g,32.2 mmol) and cuprous iodide (124 mg,0.65 mmol) were added, nitrogen was displaced 3 times, and the reaction was warmed to 98℃and stirred overnight. TLC monitoring showed that the starting material had reacted, the reaction was cooled to room temperature, filtered, the filter cake was washed with ethyl acetate (20 mL x 2 times) and the mixture concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=1/1) to give methyl (R) -6- (3-hydroxypyrrolin-1-yl) picolinate (850 mg, yield 59%). MS (ESI) M/Z222.7 [ M+H ] + ].
Step 2: methyl (R) -6- (3-hydroxypyrrolin-1-yl) picolinate (850 mg,3.8 mmol) and imidazole (785 mg,11.5 mmol) were dissolved in dichloromethane (30 mL), ice-bathTBSCl (1160 mg,7.7 mmol) was added under cooling, and stirred overnight at room temperature. TLC monitoring showed that the reaction of the starting material was complete, water (50 mL) was added, the solution was separated, the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=5/1) to give methyl (R) -6- (3- (tert-butyldimethylsilyloxy) pyrrolin-1-yl) picolinate (1.0 g, yield 78%). MS (ESI) M/Z336.9 [ M+H ] + ].
Step 3: methyl (R) -6- (3- (tert-butyldimethylsilyloxy) pyrrolin-1-yl) picolinate (1.0 g,3.0 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL), cooled to 0deg.C, and lithium borohydride in tetrahydrofuran (1M, 6.6mL,6.6 mmol) was added dropwise. The reaction system was naturally warmed to room temperature and stirred for 2 hours. The reaction was quenched by slowly adding cold saturated ammonium chloride solution (50 mL). The mixture was extracted with ethyl acetate (50 ml×2 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=5/1) to give (R) - (6- (3- (tert-butyldimethylsilyloxy) pyrrolin-1-yl) pyridin-2-yl) methanol (400 mg, yield 43%). MS (ESI) M/Z309.3 [ M+H ] + ].
Step 4: (R) - (6- (3- (tert-Butyldimethylsilyloxy) pyrrolin-1-yl) pyridin-2-yl) methanol (400 mg,1.3 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), cooled to 0-5℃and DPPA (430 mg,1.6 mmol) and DBU (240 mg,1.6 mmol) were added. The reaction was allowed to warm to room temperature and stirred overnight. To the reaction mixture was added water (50 mL) to quench the reaction. The mixture was extracted with ethyl acetate (50 ml×2 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=5/1) to give (R) -2- (azidomethyl) -6- (3- (tert-butyldimethylsilyloxy) pyrrolin-1-yl) pyridine (60 mg, yield 14%). MS (ESI) M/Z334.3 [ M+H ] + ].
Step 5: 7-bromo-4-ethynyl thieno [3,2-d ]]Pyrimidine-2-amine (30 mg,0.12 mmol) in t-butanol, water and tetrahydrofuranAgent (V) Tert-butanol /V Water and its preparation method /V Tetrahydrofuran (THF) =2/1, 6 ml). (R) -2- (azidomethyl) -6- (3- (tert-butyldimethylsilyloxy) pyrrolin-1-yl) pyridine (40 mg,0.12 mmol), copper sulfate pentahydrate (5 mg,0.02 mmol) and sodium ascorbate (10 mg,0.03 mmol) were added sequentially under nitrogen. The reaction system was warmed to 50 ℃ and stirred for 3 hours. The reaction solution was cooled to room temperature, quenched with water (10 mL), the mixture was extracted with ethyl acetate (50 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (R) -7-bromo-4- (1- ((6- (3- (tert-butyldimethylsilyloxy) pyrrolin-1-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) thieno [3, 2-d)]Pyrimidin-2-amine (51 mg, 73% yield). MS (ESI) M/Z587.2 [ M+H ]] + .
Step 6: (R) -7-bromo-4- (1- ((6- (3- (tert-butyldimethylsilyloxy) pyrrolin-1-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) thieno [3,2-d]Pyrimidine-2-amine (50 mg,0.085 mmol) was dissolved in tetrahydrofuran (5 mL), tetrabutylammonium fluoride trihydrate (54 mg,0.17 mmol) was added under ice-bath cooling, and stirred at room temperature for 12 hours. TLC monitoring showed that the starting material had reacted, water (10 mL) was added and the mixture was extracted with ethyl acetate (20 mL. Times.3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by crystallization from diethyl ether to give (R) -1- (6- ((4- (2-amino-7-bromothieno [3, 2-d)) ]Pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl-methyl) pyridin-2-yl-pyrrolin-3-ol (30 mg, yield 74%). MS (ESI) M/Z473.1 [ M+H ] + ]. 1 H NMR(400MHz,DMSO-d6):δ8.77(s,1H),8.45(s,1H),7.49(t,J＝7.6Hz,1H),6.93(s,2H),6.47(d,J＝6.8Hz,1H),6.38(d,J＝8.4Hz,1H),5.66(s,2H),4.92(s,1H),4.34(brs,1H),3.43-3.24(m,4H),1.96-1.86(m,2H).
Examples a-38:
preparation of (S) -1- (6- ((4- (2-amino-7-bromothieno [3,2-d ] pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl) methyl) pyridin-2-yl) pyrrolin-3-ol (compound a-38)
The reaction steps are as follows:
using (S) -pyrrolin-3-ol as raw material, the final product (S) -1- (6- ((4- (2-amino-7-bromothieno [3, 2-d)) is obtained by six steps of operation of reference example a-37]Pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl-methyl) pyridin-2-yl-pyrrolin-3-ol (50 mg). MS (ESI) M/Z473.2 [ M+H ] + ]. 1 H NMR(400MHz,DMSO-d6):δ8.77(s,1H),8.45(s,1H),7.49(t,J＝7.6Hz,1H),6.93(s,2H),6.47(d,J＝7.2Hz,1H),6.38(d,J＝8.0Hz,1H),5.66(s,2H),4.92(s,1H),4.34(brs,1H),3.42-3.22(m,4H),1.98-1.86(m,2H).
Examples a-39:
preparation of 7-bromo-4- (1- ((6- (3, 3-difluoroazetidin-1-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) thieno [3,2-d ] pyrimidin-2-amine (compound a-39)
The reaction steps are as follows:
step 1: 2-bromo-6- ((tert-butyldimethylsilyloxy) methyl) pyridine (2.0 g,6.6 mmol), 3-difluoroazetidine hydrochloride (2.1 g,16.3 mmol), cesium carbonate (3.0 g,9.3 mmol), palladium acetate (149 mg,0.66 mmol) and 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine (414 mg,0.66 mmol) were dissolved in toluene (30 mL), nitrogen was replaced three times, and the mixture was heated to 120℃and stirred under reflux for 2 hours. LCMS monitoring indicated complete reaction of starting material, cooling the reaction to room temperature, and adding water (20 mL). The mixture was extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=50/1) to give 2- ((tert-butyldimethylsilyloxy) methyl) -6- (3, 3-difluoroazetidin-1-yl) pyridine (700 mg, yield 34%). MS (ESI) M/Z315.3 [ M+H ] + ].
Step 2: 2- ((tert-Butyldimethylsilyloxy) methyl) -6- (3, 3-difluoroazetidin-1-yl) pyridine (700 mg,2.2 mmol) was dissolved in tetrahydrofuran (5 mL), tetrabutylammonium fluoride trihydrate (696 mg,2.2 mmol) was added with ice-cooling, and stirred at room temperature for 2 hours. LCMS monitoring showed complete reaction of starting material, water (10 mL) was added and the mixture extracted with ethyl acetate (40 mL x 2 times). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (6- (3, 3-difluoroazetidin-1-yl) pyridin-2-yl) methanol (400 mg, yield 90%). MS (ESI) M/Z200.6 [ M+H ] + ].
Step 3: (6- (3, 3-Difluoroazetidin-1-yl) pyridin-2-yl) methanol (400 mg,2.0 mmol) was dissolved in dichloromethane (5 mL), cooled to 0-5℃and triethylamine (606 mg,6.0 mmol) and methanesulfonyl chloride (344 mg,3.0 mmol) were added sequentially. The reaction system was naturally warmed to room temperature and stirred for 2 hours. TLC monitoring showed complete reaction of the starting material, water (10 mL) was added and the mixture extracted with dichloromethane (40 mL x 2 times). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give methyl (6- (3, 3-difluoroazetidin-1-yl) pyridin-2-yl) methanesulfonate (500 mg, yield 90%). MS (ESI) M/Z278.8 [ M+H ] + ].
Step 4: 7-bromo-4-ethynyl-N- (4-methoxybenzyl) thieno [3,2-d]Pyrimidine-2-amine (3.0 g,8.0 mmol) in DMF and absolute ethanol (V) DMF /V Absolute ethyl alcohol =1/1, 60 mL), azido trimethylsilane (1.4 g,12.0 mmol) and cuprous iodide (7.6 mg,0.04 mmol) were added. The reaction system was warmed to 90 ℃ and stirred for 12 hours. The reaction mixture was cooled to room temperature, diluted with water (200 mL), the mixture was extracted with ethyl acetate (200 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 7-bromo-N- (4-methoxybenzyl) -4- (1H-1, 2, 3-triazol-4-yl) thieno [3,2-d ]]Pyrimidin-2-amine (2.5 g, 75% yield). MS (ESI) M/Z417.2 [ M+H ]] + .
Step 5: 7-bromo-N- (4-methoxybenzyl) -4- (1H-1, 2, 3-triazol-4-yl) Thieno [3,2-d]Pyrimidine-2-amine (800 mg,1.9 mmol) and methyl (6- (3, 3-difluoroazetidin-1-yl) pyridin-2-yl) methanesulfonate (500 mg,1.8 mmol) were dissolved in dry DMF (3 mL), potassium carbonate (730 mg,5.3 mmol) and sodium iodide (264 mg,1.8 mmol) were added and the reaction stirred at 30℃for 3 hours. TLC monitoring showed that the starting material had reacted, water (10 mL) was added and the mixture was extracted with ethyl acetate (40 mL. Times.2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by high performance liquid chromatography to obtain 7-bromo-4- (1- (((6- (3, 3-difluoroazetidin-1-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -N- (4-methoxybenzyl) thieno [3, 2-d) ]Pyrimidin-2-amine (100 mg, yield 10%). MS (ESI) M/Z599.1 [ M+H ] + ].
Step 6: 7-bromo-4- (1- (((6- (3, 3-difluoroazetidin-1-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -N- (4-methoxybenzyl) thieno [3,2-d]Pyrimidine-2-amine (100 mg,0.17 mmol) was dissolved in trifluoroacetic acid (5 mL) and the reaction was warmed to 50deg.C and stirred for 12 hours. TLC monitoring showed that the starting material had reacted, concentrating under reduced pressure to remove most of the trifluoroacetic acid, adding 30% aqueous sodium carbonate (10 mL), and extracting the mixture with dichloromethane (20 mL. Times.3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by crystallization from diethyl ether to give 7-bromo-4- (1- ((6- (3, 3-difluoroazetidin-1-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) thieno [3,2-d]Pyrimidin-2-amine (45 mg, 56% yield). MS (ESI) M/Z478.9 [ M+H ] + ]. 1 H NMR(400MHz,DMSO-d6):δ8.81(s,1H),8.46(s,1H),7.64(t,J＝7.6Hz,1H),6.93(s,2H),6.67(d,J＝7.2Hz,1H),6.55(d,J＝8.4Hz,1H),5.73(s,2H),4.35(t,J＝12.4Hz,4H).
Examples a-40:
preparation of 7-bromo-4- (1- ((6- (2-fluoroprop-2-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) thieno [3,2-d ] pyrimidin-2-amine (compound a-40)
The reaction steps are as follows:
2- (6- ((4- (2-amino-7-bromothieno [3, 2-d))]Pyrimidin-4-yl]-1H-1,2, 3-triazol-1-yl) methyl pyridin-2-yl) propan-2-ol (300 mg,0.67 mmol) was dissolved in dichloromethane (8 mL), cooled to 0-5℃and diethylaminosulfur trifluoride (161 mg,1.0 mmol) was added dropwise and stirred at room temperature for 12 hours. TLC monitoring showed that the reaction of the starting materials was complete, saturated ammonium chloride solution (10 mL) was added, the mixture was extracted with dichloromethane (50 mL. Times.2), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by beating with diethyl ether to give 7-bromo-4- (1- ((6- (2-fluoroprop-2-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) thieno [3,2-d ]Pyrimidin-2-amine (40 mg, 13% yield). MS (ESI) M/Z448.0 [ M+H ] + ]. 1 H NMR(400MHz,DMSO-d6):δ8.88(s,1H),8.46(s,1H),7.90(t,J＝7.6Hz,1H),7.51(d,J＝7.6Hz,1H),7.26 (d,J＝7.6Hz,1H),6.94(s,2H),5.91(s,2H),1.62(s,3H),1.56(s,3H).
Examples a to 41:
preparation of 4- (1- (benzofuran-6-ylmethyl) -1H-1,2, 3-triazol-4-yl) -7-bromothieno [3,2-d ] pyrimidin-2-amine (compound a-41)
The reaction steps are as follows:
the final product 4- (1- (benzofuran-6-ylmethyl) -1H-1,2, 3-triazol-4-yl) -7-bromothieno [3,2-d ] was prepared in two steps by the procedure of reference example a-37 starting from benzofuran-6-yl methanol]Pyrimidin-2-amine (34.4 mg). MS (ESI) M/Z426.9 [ M+H ] + ]. 1 H NMR(400MHz,DMSO-d6):δ8.81(s,1H),8.45(s,1H),8.03(d,J＝2.0Hz,1H),7.76(s,1H),7.64(d,J＝8.4Hz,1H),7.43(d,J＝8.4Hz,1H),7.00(s,1H),6.90(brs,2H),5.84(s,2H).
Examples a-42:
preparation of 2- (6- ((4- (2-amino-7-bromothieno [3,2-d ] pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl) methyl) pyridin-2-yl) -2-methylpropan-1-ol (compound a-42)
The reaction steps are as follows:
the final product 2- (6- ((4- (2-amino-7-bromothieno [3, 2-d)) was prepared in five steps by the procedure of reference examples a-37 starting from methyl 6- (1-hydroxy-2-methylpropan-2-yl) picolinate (preparation can be referred to in WO2020/264499A 1)]Pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl-methyl) pyridin-2-yl) -2-methylpropan-1-ol (29 mg). MS (ESI) M/Z460.2 [ M+H ] + ]. 1 H NMR(400MHz,DMSO-d6):δ8.85(s,1H),8.46(s,1H),7.75(t,J＝8.0Hz,1H),7.37(d,J＝8.0Hz,1H),7.13(d,J＝7.6Hz,1H),6.93(brs,2H),5.87(s,2H),4.59(t,J＝5.6Hz,1H),3.47(d,J＝5.6Hz,1H),1.18(s,6H).
Examples a-43:
preparation of 2- (3- ((4- (2-amino-7-bromothieno [3,2-d ] pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl) methyl) -2-fluorophenyl) propan-2-ol (compound a-43)
The reaction steps are as follows:
step 1: ((3-bromo-2-fluorobenzyl) oxy) (tert-butyl) dimethylsilane (1.2 g,3.8 mmol) was dissolved in a mixed solution of methanol and dimethyl sulfoxide (V Methanol /V Dimethyl sulfoxide Triethylamine (0.9 g,8.9 mmol), palladium acetate (80 mg,0.36 mmol) and 1.3-bis-diphenylphosphinopropane (160 mg,0.39 mmol) were added sequentially and stirred under reflux at 80 ℃ for 16 hours under a pressure atmosphere of 8 kg carbon monoxide. TLC monitoring showed the starting material disappeared, cooled to room temperature, the catalyst was removed by filtration and the filtrate concentrated under reduced pressure. The residue was dissolved in ethyl acetate (60 mL) and washed with water2-3 times, washed with saturated brine 1 time, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 3- (((tert-butyldimethylsilyl) oxy) methyl) -2-fluorobenzoate (800 mg, yield 34%). MS (ESI) M/Z299.1 [ M+H ] + ].
Step 2: to the flask was added methyl magnesium bromide (6.0 mL,18.2mmol,3M in 2-methyltetrahydrofuran) under nitrogen, cooled to 0deg.C, and a solution of methyl 3- (((tert-butyldimethylsilyl) oxy) methyl) -2-fluorobenzoate (800 mg,2.7 mmol) in dry tetrahydrofuran (5 mL) was added dropwise over about 20 minutes, and the mixture was stirred at room temperature for 3 hours after completion of the dropwise addition. TLC monitoring showed the disappearance of starting material and the reaction was quenched with saturated ammonium chloride solution (30 mL) in ice bath and extracted with ethyl acetate (50 mL x 2 times). The organic layers were combined, washed with saturated brine (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2- (3- (((tert-butyldimethylsilyl) oxy) methyl) -2-fluorophenyl) propan-2-ol (300 mg, yield 38%). MS (ESI) M/Z299.2 [ M+H ] ] + .
Step 3: 2- (3- (((tert-Butyldimethylsilyl) oxy) methyl) -2-fluorophenyl) propan-2-ol (300 mg,1.0 mmol) was dissolved in tetrahydrofuran (10 mL), tetrabutylammonium fluoride (316 mg,1.2 mmol) was added, and stirred at room temperature for 12 hours. TLC monitoring showed the disappearance of starting material, which was diluted with ethyl acetate (20 mL), washed with water (100 mL. Times.3) and then with saturated brine (30 mL. Times.2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2- (2-fluoro-3- (hydroxymethyl) phenyl) propan-2-ol (190 mg, crude). MS (ESI) M/Z185.1 [ M+H ]] + . 1 H NMR(400MHz,CDCl 3 ):δ7.49(d,J＝7.6Hz,1H),7.34(t,J＝6.8Hz,1H),7.13(t,J＝7.6Hz,1H),4.76(s,2H),1.64(s,6H).
Step 4: 2- (2-fluoro-3- (hydroxymethyl) phenyl) propan-2-ol (190 mg, ca. 1.0 mmol) was dissolved in dry toluene (7 mL), cooled to 0-5℃and diphenyl azide phosphate (282 mg,1.0 mmol) and 1, 8-diaza [5,4,0 ] were added sequentially]Undecene-7 (157 mg,1.0 mmol) was stirred at room temperature for 2 hours. TLC monitoring showed the starting material disappeared and concentrated under reduced pressure to give 2- (3- (azidomethyl) -2-fluorophenyl) propan-2-ol (200 mg, crude product)) Directly used in the next reaction. MS (ESI) M/Z210.1 [ M+H ]] + .
Step 5: 7-bromo-4-ethynyl thieno [3,2-d ]]Pyrimidine-2-amine (100 mg,0.40 mmol) in a mixed solvent of t-butanol, water and tetrahydrofuran (V Tert-butanol /V Water and its preparation method /V Tetrahydrofuran (THF) =2/1, 6 ml). 2- (3- (azidomethyl) -2-fluorophenyl) propan-2-ol (100 mg,0.44 mmol), copper sulfate pentahydrate (26 mg,0.05 mmol) and sodium ascorbate (18 mg,0.06 mmol) were added sequentially under nitrogen. The reaction system was warmed to 50 ℃ and stirred for 3 hours. The reaction solution was cooled to room temperature, quenched with water (10 mL), extracted with ethyl acetate (50 mL. Times.2), the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by crystallization from anhydrous diethyl ether to give the final product 2- (3- ((4- (2-amino-7-bromothieno [3, 2-d))]Pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl-methyl) -2-fluorophenyl) propan-2-ol (41.5 mg). MS (ESI) M/Z463.2 [ M+H ] + ]. 1 H NMR(400MHz,DMSO-d6):δ8.80(s,1H),8.45(s,1H),7.66-7.62(m,1H),7.27-7.25(m,1H),7.21-7.17(m,1H),6.93(brs,2H),5.81(s,2H),5.34(s,1H),1.48(s,6H).
Examples a-44:
preparation of 2- (3- ((4- (2-amino-7-bromothieno [3,2-d ] pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl) methyl) -5-methoxyphenyl) propan-2-ol (compound a-44)
The reaction steps are as follows:
using 3- (((tert-butyldimethylsilyloxy) methyl) -5-methoxybenzoic acid methyl ester as raw material, the final product 2- (3- ((4- (2-amino-7-bromothieno [3, 2-d)) was prepared by four steps according to the procedure of examples a-43]Pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl-methyl) -5-methoxyphenyl) propan-2-ol (4.8 mg). MS (ESI) M/Z475.2 [ M+H ] + ]. 1 H NMR(400MHz,DMSO-d6):δ8.80(s,1H),8.45(s,1H),7.13(s,1H),7.01-6.98(m,1H),6.91(brs,2H),6.86-6.84(m,1H),5.69(s,2H),5.07(s,1H),3.74(s,3H),1.39(s,6H).
Examples a to 45:
preparation of 2- (2- ((4- (2-amino-7-bromothieno [3,2-d ] pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl) methyl) pyridin-4-yl) propan-2-ol (compound a-45)
The reaction steps are as follows:
the final product 2- (2- ((4- (2-amino-7-bromothieno [3, 2-d)) was obtained in three steps by the procedure of reference example a-43 starting from methyl 2- (hydroxymethyl) isonicotinate]Pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl-methyl) pyridin-4-yl-propan-2-ol (50 mg). MS (ESI) M/Z445.9 [ M+H ] + ]. 1 H NMR(400MHz,DMSO-d6):δ8.84(s,1H),8.46(s,2H),7.58(s,1H),7.42-7.40(m,1H),6.94(brs,2H),5.88(s,2H),5.33(s,1H),1.41(s,6H).
Examples a-46:
preparation of 2- (6- ((4- (2-amino-7-bromothieno [3,2-d ] pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl) methyl) -5-fluoropyridin-2-yl) propan-2-ol (compound a-46)
The reaction steps are as follows:
step 1: 6-chloro-5-fluoropyridine carboxylic acid methyl ester (500 mg,2.6 mmol) was dissolved in dioxane/water (V Dioxahexacyclic ring /V Water and its preparation method =3:1, 24 mL), styrylboronic acid (781 mg,5.3 mmol) and cesium carbonate (2.5 g,7.9 mmol) were added. 3 times of nitrogen substitution, pd (dppf) Cl is added 2 (95 mg,0.13 mmol) was replaced with nitrogen 3 times and stirred at room temperature for 16 hours. TLC monitoring showed the starting material disappeared and the reaction was extracted with ethyl acetate (20 mL x 2 times). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is taken through Purification by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1) gave methyl 5-fluoro-6-styrylpyridinium carboxylate (600 mg, yield 88%). MS (ESI) M/Z258.1 [ M+H ] + ].
Step 2: methyl 5-fluoro-6-styrylpyridinium carboxylate (800 mg,3.1 mmol) was dissolved in tetrahydrofuran/water (18/9 mL), followed by addition of 2, 6-lutidine (640 mg,6.2 mmol), sodium periodate (4 g,18.6 mmol) and potassium osmium dihydrate (52 mg,0.16 mmol), and stirring at room temperature for 20 hours. TLC monitoring showed the disappearance of starting material, extraction of the reaction with ethyl acetate (30 ml×2 times), combining the organic layers, washing with saturated brine (30 ml×2 times), drying over anhydrous sodium sulfate, filtration and concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1) to give methyl 5-fluoro-6-formylmethylpyridine carboxylate (400 mg, yield 70%). MS (ESI) M/Z184.2 [ M+H ] + ].
Step 3: methyl 5-fluoro-6-formylmethylpyridine carboxylate (300 mg,1.6 mmol) was dissolved in methanol (10 mL), cooled to 0℃and sodium borohydride (100 mg,2.6 mmol) was added thereto, and the mixture was stirred at room temperature for 3 hours. TLC monitoring showed the starting material disappeared, the reaction was quenched with saturated ammonium chloride solution (20 mL) in ice bath and extracted with ethyl acetate (30 mL x 2 times). The organic layers were combined, washed with saturated brine (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1) to give methyl 5-fluoro-6- (hydroxymethyl) picolinate (100 mg, yield 33%). MS (ESI) M/Z185.8 [ M+H ] + ].
The final product 2- (6- ((4- (2-amino-7-bromothieno [3, 2-d)) was prepared in three steps by the procedure of reference example a-43 starting from methyl 5-fluoro-6- (hydroxymethyl) picolinate]Pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl-methyl) -5-fluoropyridin-2-yl-propan-2-ol (7 mg). MS (ESI) M/Z464.1 [ M+H ] + ]. 1 H NMR(400MHz,CD 3 OD):δ8.79(s,1H),8.20(s,1H),7.71-7.60(m,2H),5.93(d,J＝1.6Hz,2H),1.44(s,6H).
Example b-1:
preparation of 3- (4- (1- ((6- (2-hydroxypropyl-2-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) -2-methylbenzonitrile (Compound b-1)
The reaction steps are as follows:
step 1: methyl 6- (hydroxymethyl) picolinate (4.5 g,26.9 mmol) was dissolved in tetrahydrofuran (70 mL), cooled to 0deg.C, and a solution of methylmagnesium bromide in tetrahydrofuran (3 mol/L,54mL,162.0 mmol) was added dropwise. The reaction system was naturally warmed to room temperature and stirred for 4 hours. TLC monitoring showed that the reaction was complete, and the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (50 mL). Ethyl acetate (40 ml×3 times) extraction, combining organic phases, washing the organic phases with saturated brine (30 ml×3 times), then drying over anhydrous sodium sulfate, filtering, and finally concentrating under reduced pressure; the resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=10/1 to 2/1) to give 2- (6- (hydroxymethyl) pyridin-2-yl) propan-2-ol (1.3 g, yield 29%).
MS(ESI)M/Z:168.6[M+H] + . 1 H NMR(400MHz,DMSO-d6):δ7.75(t,J＝8.0Hz,1H),7.49(d,J＝7.6Hz,1H),7.29(t,J＝7.6Hz,1H),5.36(t,J＝5.6Hz,1H),5.21(s,1H),4.54(d,J＝5.6Hz,2H),1.41(s,6H).
Step 2: 2- (6- (hydroxymethyl) pyridin-2-yl) propan-2-ol (1.0 g,6.0 mmol) was dissolved in toluene (30 mL), cooled to 0deg.C, and DPPA (2.0 g,7.2 mmol) and DBU (1.1 g,7.2 mmol) were added. The reaction was allowed to warm to room temperature and stirred overnight. To the reaction mixture was added water (20 mL) to quench the reaction. The mixture was extracted with ethyl acetate (20 mL. Times.2), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=20/1 to 5/1) to give 2- (6- (azidomethyl) pyridin-2-yl) propan-2-ol (1.0 g, yield 87%). MS (ESI) M/Z193.2 [ M+H ]] + . 1 H NMR(400MHz,CDCl 3 ):δ7.75(t,J＝8.0Hz,1H),7.34(d,J＝8.0Hz,1H),7.25(t,J＝7.6Hz,1H),4.95(br s,1H),4.47(s,2H),1.55(s,6H).
Step 3: 4-bromo-6-chloro-1H-pyrrolo [2,3-b]Pyridine (554 mg,2.4 mmol) in a mixed solvent of tetrahydrofuran and triethylamine (V THF /V TEA =2/3, 20 mL). Under the protection of nitrogen, cuI (45 mg,0.24 mmol), triphenylphosphine (63 mg,0.24 mmol) and Pd (PPh) were added successively 3 ) 2 Cl 2 (84 mg,0.12 mmol) and trimethylsilylacetylene (282 mg,2.9 mmol). The reaction was warmed to 60 ℃ and stirred overnight. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue obtained is purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=20/1 to 5/1) to give 6-chloro-4- ((trimethylsilyl) acetylene) -1H-pyrrolo [2,3-b ] ]Pyridine (0.5 g, 84% yield). MS (ESI) M/Z249.1 [ M+H ]] + . 1 H NMR(400MHz,CDCl 3 ):δ7.68-7.64(m,2H),7.57-7.53(m,1H),7.49-7.45(m,2H)，0.00(s,9H).
Step 4: 6-chloro-4- ((trimethylsilyl) acetylene) -1H-pyrrolo [2,3-b]Pyridine (124 mg,0.5 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to 0deg.C, and TBAF.3H was added 2 O (189 mg,0.6 mmol). The reaction was allowed to warm to room temperature and stirred overnight. To the reaction mixture was added a saturated aqueous ammonium chloride solution (10 mL) to quench the reaction. The mixture was extracted with ethyl acetate (10 mL. Times.2), and the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained 6-chloro-4-ethynyl-1H-pyrrolo [2,3-b]Crude pyridine (88 mg) was used directly in the next reaction. MS (ESI) M/Z177.1 [ M+H ]] + .
Step 5: by reacting 6-chloro-4-ethynyl-1H-pyrrolo [2,3-b]Pyridine (88 mg, crude product) in a mixed solvent of tertiary butanol and water (V Tert-butanol /V Water and its preparation method =2/1, 9 ml). 2- (6- (azidomethyl) pyridin-2-yl) propan-2-ol (84 mg,0.44 mmol), copper sulfate pentahydrate (2.4 mg,0.01 mmol) and sodium ascorbate (5 mg,0.025 mmol) were added sequentially under nitrogen. The reaction was warmed to 60 ℃ and stirred overnight. The reaction mixture was cooled to room temperature, extracted with ethyl acetate (10 mL. Times.2), and combined The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=10/1 to 3/1) to give 2- (6- ((4- (6-chloro-1H-pyrrolo [2, 3-b))]Pyridin-4-yl) -1H-1,2, 3-triazol-1-yl-methyl) pyridin-2-yl-propan-2-ol (120 mg, yield 65%). MS (ESI) M/Z369.4 [ M+H ]] + . 1 H NMR(400MHz,CDCl 3 ):δ9.17(br s,1H),8.28(s,1H),7.81(t,J＝7.6Hz,1H),7.62(s,1H),7.44-7.38(m,2H),7.25-7.20(m,1H),7.02-7.00(m,1H),5.86(s,2H),1.58(s,6H).
Step 6: 2- (6- ((4- (6-chloro-1H-pyrrolo [2, 3-b))]Pyridin-4-yl) -1H-1,2, 3-triazol-1-yl-methyl) pyridin-2-yl propan-2-ol (90 mg,0.24 mmol) and 3-cyano-2-methylbenzoboric acid (78 mg,0.48 mmol) in a mixed solvent of 1, 4-dioxane and water (V Dioxahexacyclic ring /V Water and its preparation method =3/1, 24 mL). Sodium carbonate (76 mg,0.72 mmol) and Pd (dppf) Cl were added sequentially under nitrogen blanket 2 (17 mg,0.024 mmol). The reaction was warmed to 98 ℃ and stirred overnight. The reaction solution was cooled to room temperature, extracted with ethyl acetate (20 ml×2 times), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=10/1 to 1/1) to give the final product 3- (4- (1- ((6- (2-hydroxypropyl-2-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -1H-pyrrolo [2, 3-b) ]Pyridin-6-yl) -2-methylbenzonitrile (30 mg, yield 27%). MS (ESI) M/Z450.2 [ M+H ]] + . 1 H NMR(400MHz,DMSO-d6):δ11.94(s,1H),9.11(s,1H),7.87-7.75(m,4H),7.67-7.59(m,2H),7.54-7.50(m,1H),7.14(d,J＝7.6Hz,1H),7.07-7.06(m,1H),5.82(s,2H),5.24(s,1H),2.56(s,3H),1.38(s,6H).
Example b-2:
preparation of 3- (7- (1- ((6- (2-hydroxypropyl-2-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) -2-methylbenzonitrile (Compound b-2)
The reaction steps are as follows:
step 1: 5, 7-dichloro-3H-imidazo [4,5-b]Pyridine (600 mg,3.2 mmol) and 3-cyano-2-methylbenzoic acid (560 mg,3.5 mmol) in a mixed solvent of 1, 4-dioxane and water (V Dioxahexacyclic ring /V Water and its preparation method =3/1, 20 mL). Sodium carbonate (1.0 g,9.5 mmol) and Pd (dppf) Cl were added sequentially under nitrogen 2 (117 mg,0.16 mmol). The reaction was warmed to 95 ℃ and stirred overnight. The reaction solution was cooled to room temperature, extracted with ethyl acetate (20 ml×2 times), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=10/1 to 1/1) to give 3- (7-chloro-3H-imidazo [4, 5-b)]Pyridin-5-yl) -2-methylbenzonitrile (200 mg, 23% yield).
MS(ESI)M/Z:269.1[M+H] + .
Step 2: 3- (7-chloro-3H-imidazo [4,5-b ] pyridin-5-yl) -2-methylbenzonitrile (110 mg,0.41 mmol) is dissolved in acetonitrile (10 mL) and acetyl chloride (161 mg,2.1 mmol) and sodium iodide (369 mg,2.5 mmol) are added. The reaction system was warmed to 90 ℃ and stirred for 20 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, extracted with saturated aqueous sodium bicarbonate (10 mL) and ethyl acetate (20 mL. Times.2), and the organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=10/1 to 2/1) to give 3- (7-iodo-3H-imidazo [4,5-b ] pyridin-5-yl) -2-methylbenzonitrile (147 mg, yield 99%).
MS(ESI)M/Z:361.1[M+H] + .
Step 3: 3- (7-iodo-3H-imidazo [4,5-b ] pyridin-5-yl) -2-methylbenzonitrile (147 mg,0.41 mmol) is dissolved in dichloromethane (10 mL) and p-toluenesulfonic acid monohydrate (8 mg,0.04 mmol) and DHP (53 mg,0.63 mmol) are added. The reaction system was stirred at room temperature for 4 hours, washed with saturated aqueous sodium hydrogencarbonate (15 mL) and saturated brine (15 mL) in this order, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=20/1 to 10/1) to give 3- (7-iodo-3- (tetrahydro-2H-pyran-2-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) -2-methylbenzonitrile (110 mg, yield 60%).
MS(ESI)M/Z:445.1[M+H] + .
Step 4: 3- (7-iodo-3- (tetrahydro-2H-pyran-2-yl) -3H-imidazo [4,5-b]Pyridin-5-yl) -2-methylbenzonitrile (110 mg,0.25 mmol) in a mixed solvent of tetrahydrofuran and triethylamine (V THF /V TEA =2/3, 10 mL). Under the protection of nitrogen, cuI (5 mg,0.03 mmol) and Pd (PPh) are added in sequence 3 ) 2 Cl 2 (9 mg,0.01 mmol) and triisopropylsilylacetylene (2793 mg,1.5 mmol). The reaction was warmed to 60 ℃ and stirred overnight. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue obtained is purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=20/1 to 10/1) to give 2-methyl-3- (3- (tetrahydro-2H-pyran-2-yl) -7- ((triisopropylsilyl) acetylene) -3H-imidazo [4,5-b ]Pyridin-5-yl) benzonitrile (103 mg, 83% yield).
MS(ESI)M/Z:499.4[M+H] + .
Step 5: 2-methyl-3- (3- (tetrahydro-2H-pyran-2-yl) -7- ((triisopropylsilyl) acetylene) -3H-imidazo [4,5-b]Pyridin-5-yl) benzonitrile (103 mg,0.21 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to 0℃and added with TBAF. 3H 2 O (78 mg,0.25 mmol). The reaction system was stirred at 0℃for 20 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution (10 mL) to quench the reaction. The mixture was extracted with ethyl acetate (20 mL. Times.2), and the organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained 3- (7-ethynyl-3H-imidazo [4, 5-b)]The crude pyridin-5-yl) -2-methylbenzonitrile was used directly in the next reaction (100 mg).
MS(ESI)M/Z:259.0[M+H] + .
Step 6: 3- (7-ethynyl-3H-imidazo [4, 5-b)]Pyridin-5-yl) -2-methylbenzonitrile (100 mg, crude product) in a mixed solvent of tert-butanol and water (V Tert-butanol /V Water and its preparation method =1/1, 20 mL). 2- (6- (azidomethyl) pyridin-2-yl) propan-2-ol (75 mg,0.39 mmol), copper sulfate pentahydrate (1 mg, 0.04 mmol) and sodium ascorbate (4 mg,0.02 mmol) were added sequentially under nitrogen. The reaction was warmed to 60 ℃ and stirred overnight. The reaction solution was cooled to room temperature, extracted with ethyl acetate (20 ml×2 times), and the organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by preparative high performance liquid chromatography to obtain the final product 3- (7- (1- ((6- (2-hydroxypropyl-2-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazole-4-yl) -3H-imidazole [4,5-b ] ]Pyridin-5-yl) -2-methylbenzonitrile (40 mg, 42% yield).
MS(ESI)M/Z:451.3[M+H] + .
1 H NMR(400MHz,CD 3 OD):δ8.96(s,1H),8.44(s,1H),7.87(s,1H),7.73-7.67(m,3H),7.51(d,J＝8.0Hz,1H),7.40(t,J＝8.0Hz,1H),7.17(d,J＝7.6Hz,1H),5.77(s,2H),2.47(s,3H),1.39(s,6H).
Example b-3:
preparation of 3- (4- (1- ((6- (2-hydroxypropyl-2-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -7H-pyrrolo [2,3-d ] pyrimidin-2-yl) -2-methylbenzonitrile (compound b-3)
The reaction steps are as follows:
step 1: 2, 4-dichloro-7H-pyrrolo [2,3-d]Pyrimidine (500 mg,2.7 mmol) in a mixed solvent of tetrahydrofuran and triethylamine (V THF /V TEA =2/3, 100 mL). Under the protection of nitrogen, cuI (101 mg,0.53 mmol) and Pd (PPh) are added in sequence 3 ) 4 (307 mg,0.27 mmol) and triisopropylsilylacetylene (581 mg,3.2 mmol).The reaction was warmed to 60 ℃ and stirred overnight. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue obtained is purified by column chromatography on silica gel (eluent: V petroleum ether/V ethyl acetate=20/1-5/1) to give 2-chloro-4- ((triisopropylsilyl) acetylene) -7H-pyrrolo [2,3-d]Pyrimidine (650 mg, 71% yield).
MS(ESI)M/Z:334.1[M+H] + .
Step 2: 2-chloro-4- ((triisopropylsilyl) acetylene) -7H-pyrrolo [2,3-d]Pyrimidine (334 mg,1.0 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to 0deg.C, and TBAF.3H was added 2 O (379 mg,1.2 mmol). The reaction system was stirred at 0℃for 30 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution (10 mL) to quench the reaction. The mixture was extracted with ethyl acetate (10 mL. Times.2), and the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained 2-chloro-4-ethynyl-7H-pyrrolo [2,3-d ] ]The crude pyrimidine was used directly in the next reaction (177 mg).
MS(ESI)M/Z:178.0[M+H] + .
Step 3: 2-chloro-4-ethynyl-7H-pyrrolo [2,3-d]Pyrimidine (177 mg, crude) in a mixed solvent of tertiary butanol and water (V Tert-butanol /V Water and its preparation method =2/1, 9 ml). 2- (6- (azidomethyl) pyridin-2-yl) propan-2-ol (192 mg,1.0 mmol), copper sulfate pentahydrate (2.5 mg,0.01 mmol) and sodium ascorbate (10 mg,0.05 mmol) were added sequentially under nitrogen. The reaction was warmed to 60 ℃ and stirred overnight. The reaction solution was cooled to room temperature, extracted with ethyl acetate (10 ml×2 times), and the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=10/1 to 2/1) to give 2- (6- ((4- (2-chloro-7H-pyrrolo [2, 3-d))]Pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl-methyl) pyridin-2-yl-propan-2-ol (260 mg, yield 70%). MS (ESI) M/Z370.2 [ M+H ]] + . 1 H NMR(400MHz,CDCl 3 ):δ10.83(s,1H),8.56(s,1H),7.75(t,J＝7.6Hz,1H),7.46(s,2H),7.40(d,J＝7.6Hz,1H),7.14(d,J＝7.6Hz,1H),5.82(s,2H),1.56(s,6H).
Step 4: 2- (6- ((4- (2-chloro-7H-pyrrolo [2, 3-d))]Pyrimidin-4-yl) -1H-1,2, 3-triazol-1-yl-methyl) pyridin-2-yl-propan-2-ol (120 mg,0.33 mmol) and 3-cyano-2-methylbenzeneboronic acid (105 mg,0.66 mmol) in a mixed solvent of 1, 4-dioxane and water (V Dioxahexacyclic ring /V Water and its preparation method =3/1, 24 mL). Sodium carbonate (106 mg,1.0 mmol) and Pd (dppf) Cl were added sequentially under nitrogen blanket 2 (24 mg,0.033 mmol). The reaction was warmed to 98 ℃ and stirred overnight. The reaction solution was cooled to room temperature, extracted with ethyl acetate (20 ml×2 times), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=10/1 to 1/1) to give the final product 3- (4- (1- ((6- (2-hydroxypropyl-2-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -7H-pyrrolo [2, 3-d)]Pyrimidin-2-yl) -2-methylbenzonitrile (50 mg, 34% yield).
MS(ESI)M/Z:451.4[M+H] + . 1 H NMR(400MHz,DMSO-d6):δ12.35(s,1H),9.07(s,1H),8.16-8.14(m,1H),7.91-7.89(m,1H),7.82-7.78(m,1H),7.71(m,1H),7.60(d,J＝8.0Hz,1H),7.54(t,J＝8.0Hz,1H),7.22(d,J＝3.6Hz,1H),7.19-7.16(m,1H),5.84(s,2H),5.22(s,1H),2.77(s,3H),1.38(s,6H).
Examples b-4:
preparation of 3- (4- (1- ((6- (2-hydroxypropyl-2-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -2-methyl-1H-pyrrolo [2,3-b ] pyridin-6-yl) -2-methylbenzonitrile (Compound b-4)
The reaction steps are as follows:
step 1: 4-bromo-2-methyl-1H-pyrrolo [2,3-b ] pyridine (1.0 g,4.8 mmol) was dissolved in diethyl ether (20 mL). Under nitrogen, m-CPBA (1.2 g,7.0 mmol) was added. The reaction was stirred at room temperature overnight. TLC monitoring showed that the reaction was complete, the reaction solution was filtered, the filter cake was washed with diethyl ether (20 mL) and dried to give 4-bromo-2-methyl-1H-pyrrolo [2,3-b ] pyridine-7-oxide (870 mg, yield 81%).
MS(ESI)M/Z:226.7. 1 H NMR(400MHz,CDCl 3 ):δ13.33(br s,1H),7.95(d,J＝6.4Hz,1H),7.18(d,J＝6.4Hz,1H),6.27(s,1H),2.53(s,3H).
Step 2: 4-bromo-2-methyl-1H-pyrrolo [2,3-b ] pyridine-7-oxide (340 mg,1.5 mmol) was dissolved in phosphorus oxychloride (10 mL), warmed to 110℃and stirred for 24 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, cold water (20 mL) was added to the residue, extracted with ethyl acetate (20 mL. Times.2), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=20/1 to 5/1) to give 4-bromo-6-chloro-2-methyl-1H-pyrrolo [2,3-b ] pyridine (321 mg, yield 87%).
MS(ESI)M/Z:244.9. 1 H NMR(400MHz，CDCl 3 ):δ9.02(br s，1H)，7.30(s，1H)，6.24(s，1H)，2.50(s，3H).
Step 3: 4-bromo-6-chloro-2-methyl-1H-pyrrolo [2,3-b]Pyridine (260 mg,1.1 mmol) in a mixed solvent of tetrahydrofuran and triethylamine (V) THF /V TEA =2/3, 15 mL). Under the protection of nitrogen, cuI (40 mg,0.21 mmol), triphenylphosphine (28 mg,0.11 mmol) and Pd (PPh) were added successively 3 ) 2 Cl 2 (74 mg,0.11 mmol) and triisopropylsilylacetylene (212 mg,1.2 mmol). The reaction was warmed to 60 ℃ and stirred overnight. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue obtained is purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=20/1 to 10/1) to give 6-chloro-2-methyl-4- ((triisopropylsilyl) acetylene) -1H-pyrrolo [2,3-b ]Pyridine (290 mg, 79% yield).
MS(ESI)M/Z:347.2[M+H] + . 1 H NMR(400MHz,DMSO-d6):δ11.98(br s,1H),7.11 (s,1H),6.17(s,1H),2.41(s,3H),2.01-1.99(m,3H),1.13(s,18H).
Step 4: 6-chloro-2-methyl-4- ((triisopropylsilyl) acetylene) -1H-pyrrolo [2,3-b]Pyridine (290 mg,0.84 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to 0deg.C, and TBAF.3H was added 2 O (315 mg,1.0 mmol). The reaction system was naturally warmed to room temperature and stirred for 20 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution (10 mL) to quench the reaction. The mixture was extracted with ethyl acetate (15 mL. Times.2), the organic phases were combined, the organic phases were washed with saturated brine (15 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to give 6-chloro-4-ethynyl-2-methyl-1H-pyrrolo [2,3-b ]]Crude pyridine (133 mg) was used directly in the next reaction.
MS(ESI)M/Z:190.8[M+H] + .
Step 5: by reacting 6-chloro-4-ethynyl-2-methyl-1H-pyrrolo [2,3-b]Pyridine (133 mg, crude product) in a mixed solvent of tertiary butanol and water (V Tert-butanol /V Water and its preparation method =1/1, 24 mL). 2- (6- (azidomethyl) pyridin-2-yl) propan-2-ol (110 mg,0.57 mmol), copper sulfate pentahydrate (1.2 mg,0.005 mmol) and sodium ascorbate (6 mg,0.03 mmol) were added sequentially under nitrogen. The reaction was warmed to 60 ℃ and stirred overnight. The reaction solution was cooled to room temperature, extracted with ethyl acetate (20 ml×2 times), and the organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by column chromatography on silica gel (eluent: dichloromethane/methanol=100/1 to 50/1) to give 2- (6- ((4- (6-chloro-2-methyl-1H-pyrrolo [2, 3-b)) ]Pyridin-4-yl) -1H-1,2, 3-triazol-1-yl-methyl) pyridin-2-yl-propan-2-ol (79 mg, 36% yield).
MS(ESI)M/Z:383.0[M+H] + .
Step 6: 2- (6- ((4- (6-chloro-2-methyl-1H-pyrrolo [2, 3-b))]Pyridin-4-yl) -1H-1,2, 3-triazol-1-yl-methyl) pyridin-2-yl propan-2-ol (79 mg,0.21 mmol) and 3-cyano-2-methylbenzoboric acid (100 mg,0.62 mmol) in a mixed solvent of 1, 4-dioxane and water (V Dioxahexacyclic ring /V Water and its preparation method =3/1, 12 mL). Under the protection of nitrogen, sodium carbonate (66 mg,0.62 mmol) and Pd (dppf) Cl were added sequentially 2 (30mg，0.04 mmol). The reaction system was warmed to 98 ℃ and stirred for 48 hours. The reaction solution was cooled to room temperature, extracted with ethyl acetate (15 ml×2 times), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by preparative high performance liquid chromatography to obtain the final product 3- (4- (1- ((6- (2-hydroxypropyl-2-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazole-4-yl) -2-methyl-1H-pyrrolo [2, 3-b)]Pyridin-6-yl) -2-methylbenzonitrile (12.4 mg, yield 13%).
MS(ESI)M/Z:464.1[M+H] + . 1 H NMR(400MHz,CD 3 OD):δ8.85(s,1H),7.77-7.68(m,4H),7.53(d,J＝7.6Hz,1H),7.43(t,J＝7.6Hz,1H),7.18(d,J＝7.6Hz,1H),6.82(s,1H),5.78(s,2H),2.48(s,3H),2.45(s,3H),1.40(s,6H).
Examples b-5:
preparation of 3- (4- (1- ((6- (2-hydroxypropyl-2-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -1H-pyrazolo [3,4-b ] pyridin-6-yl) -2-methylbenzonitrile (Compound b-5)
The reaction steps are as follows:
step 1: 4, 6-dichloro-1H-pyrazolo [3,4-b]Pyridine (400 mg,2.1 mmol) and 3-cyano-2-methylbenzoic acid (410 mg,2.5 mmol) in a mixed solvent of 1, 4-dioxane and water (V Dioxahexacyclic ring /V Water and its preparation method =3/1, 20 mL). Cesium carbonate (1.7 g,5.3 mmol) and Pd (OAc) were added sequentially under nitrogen blanket 2 (47.6 mg,0.21 mmol). The reaction was warmed to 98 ℃ and stirred overnight. The reaction solution was cooled to room temperature, extracted with ethyl acetate (20 ml×2 times), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=10/1 to 1/1) to give 3- (4-chloro-1H-pyrazolo [3, 4-b)]Pyridin-6-yl) -2-methylbenzonitrile (183)mg, yield 32%).
MS(ESI)M/Z:269.1[M+H] + .
Step 2: 3- (4-chloro-1H-pyrazolo [3,4-b ] pyridin-6-yl) -2-methylbenzonitrile (183 mg,0.68 mmol) was dissolved in acetonitrile (10 mL), and acetyl chloride (267 mg,3.4 mmol) and sodium iodide (803 mg,4.1 mmol) were added. The reaction was warmed to 98 ℃ and stirred overnight. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1 to 2/1) to give 3- (4-iodo-1H-pyrazolo [3,4-b ] pyridin-6-yl) -2-methylbenzonitrile (195 mg, yield 79%).
MS(ESI)M/Z:360.9[M+H] + .
Step 3: 3- (4-iodo-1H-pyrazolo [3, 4-b)]Pyridin-6-yl) -2-methylbenzonitrile (180 mg,0.5 mmol) in a mixed solvent of tetrahydrofuran and triethylamine (V THF /V TEA =2/3, 10 mL). Under the protection of nitrogen, cuI (15 mg,0.08 mmol), triphenylphosphine (20 mg,0.08 mmol) and Pd (PPh) were added successively 3 ) 2 Cl 2 (27 mg,0.04 mmol) and trimethylsilylacetylene (76 mg,0.78 mmol). The reaction was warmed to 60 ℃ and stirred overnight. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=20/1 to 5/1) to give 2-methyl-3- (4- ((trimethylsilyl) ethynyl) -1H-pyrazolo [3, 4-b)]Pyridin-6-yl) benzonitrile (140 mg, 85% yield).
MS(ESI)M/Z:331.1[M+H] + .
Step 4: 2-methyl-3- (4- ((trimethylsilyl) ethynyl) -1H-pyrazolo [3,4-b]Pyridin-6-yl) benzonitrile (140 mg,0.42 mmol) in a mixed solvent of tetrahydrofuran and water (V THF /V TEA =1/1, 10 mL), sodium carbonate (135 mg,1.3 mmol) was added. The reaction system was stirred at room temperature for 2 hours. To the reaction mixture was added ethyl acetate (10 mL), the mixture was separated, and the organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purifying the residue by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=20/1-5/1) to obtain To 3- (4-ethynyl-1H-pyrazolo [3, 4-b)]Pyridin-6-yl) -2-methylbenzonitrile (70 mg, 64% yield).
MS(ESI)M/Z:259.0[M+H] + .
Step 5: 3- (4-ethynyl-1H-pyrazolo [3, 4-b)]Pyridin-6-yl) -2-methylbenzonitrile (70 mg,0.27 mmol) in a mixed solvent of tert-butanol and water (V Tert-butanol /V Water and its preparation method =2/1, 9 ml). 2- (6- (azidomethyl) pyridin-2-yl) propan-2-ol (104 mg,0.54 mmol), copper sulfate pentahydrate (1.4 mg,0.005 mmol) and sodium ascorbate (3 mg,0.014 mmol) were added sequentially under nitrogen. The reaction was warmed to 60 ℃ and stirred overnight. The reaction solution was cooled to room temperature, extracted with ethyl acetate (15 ml×2 times), and the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by preparative high performance liquid chromatography to obtain the final product 3- (4- (1- ((6- (2-hydroxypropyl-2-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazole-4-yl) -1H-pyrazolo [3,4-b ]]Pyridin-6-yl) -2-methylbenzonitrile (27 mg, 22% yield).
MS(ESI)M/Z:451.3[M+H] + . 1 H NMR(400MHz,DMSO-d6):δ13.90(br s,1H),9.26(s,1H),8.68(s,1H),7.92(d,J＝7.6Hz,1H),7.85-7.80(m,3H),7.62-7.54(m,2H),7.19(d,J＝7.6Hz,1H),5.84(s,2H),5.22(s,1H),2.55(t,3H),1.37(s,6H).
Examples b-6:
preparation of 3- (4- (1- ((6- (2-oxo-6-azaspiro [3.3] heptan-6-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) -2-methylbenzonitrile (Compound b-6)
The reaction steps are as follows:
step 1: ethyl 6-bromo-2-picolinate (0.5 g,2.2 mmol) and 2-oxo-6-azaspiro [3.3] heptane (0.22 g,2.2 mmol) were dissolved in DMF (20 mL) and potassium carbonate (1.5 g,10.9 mmol) was added. The reaction was warmed to 90 ℃ and stirred overnight. TLC monitoring showed the reaction was complete, the reaction cooled to room temperature and diluted with water (60 mL). The mixture was extracted with ethyl acetate (50 mL. Times.3), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=10/1 to 5/1) to give ethyl 6- (2-oxo-6-azaspiro [3.3] heptane-6-yl) -2-picolinate (0.42 g, yield 78%).
MS(ESI)M/Z:249.1[M+H] + . 1 H NMR(400MHz,CDCl 3 ):δ7.58-7.54(m,1H),7.44(dd,J 1 ＝7.2Hz,J 2 ＝0.8Hz,1H),6.46(dd,J 1 ＝8.4Hz,J 2 ＝0.8Hz,1H),4.85(s,4H),4.40(q,J＝7.2Hz,2H),4.25(s,4H),1.42(t,J＝7.2Hz,3H).
Step 2: ethyl 6- (2-oxo-6-azaspiro [3.3] heptan-6-yl) -2-picolinate (750 mg,3.0 mmol) was dissolved in tetrahydrofuran (35 mL), cooled to 0℃and red aluminum toluene solution (3.6M, 1.0mL,3.6 mmol) was added dropwise under nitrogen protection. The reaction was stirred at 0deg.C for 2 hours, and quenched by the addition of 10% aqueous sodium carbonate (70 mL). The mixture was filtered through celite to remove the aluminum salt, the aqueous phase was extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to give (6- (2-oxo-6-azaspiro [3.3] heptan-6-yl) pyridin-2-yl) methanol (560 mg, yield 90%).
MS(ESI)M/Z:207.1[M+H] + .
Step 3: (6- (2-oxo-6-azaspiro [3.3] heptan-6-yl) pyridin-2-yl) methanol (540 mg,2.6 mmol) was dissolved in toluene (15 mL), cooled to 0℃and DPPA (860 mg,3.1 mmol) and DBU (480 mg,3.1 mmol) were added. The reaction was allowed to warm to room temperature and stirred overnight. To the reaction mixture was added water (20 mL) to quench the reaction. The mixture was extracted with ethyl acetate (20 mL. Times.2), and the organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=20/1 to 5/1) to give 6- (6- (azidomethyl) pyridin-2-yl) -2-oxo-6-azaspiro [3.3] heptane (450 mg, yield 74%).
MS(ESI)M/Z:232.1[M+H] + .
Step 4: by reacting 6-chloro-4-ethynyl-1H-pyrrolo [2,3-b]Pyridine (88 mg,0.5 mmol) in a mixed solvent of tertiary butanol and water (V/v=2/1, 9 ml). Under the protection of nitrogen, 6- (6- (azidomethyl) pyridin-2-yl) -2-oxo-6-azaspiro [3.3] are added in sequence]Heptane (102 mg,0.44 mmol), copper sulfate pentahydrate (2.4 mg,0.01 mmol) and sodium ascorbate (5 mg,0.025 mmol). The reaction was warmed to 60 ℃ and stirred overnight. The reaction solution was cooled to room temperature, extracted with ethyl acetate (10 ml×2 times), and the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=10/1 to 3/1) to give 6- (6- ((4- (6-chloro-1H-pyrrolo [2, 3-b)) ]Pyridin-4-yl) -1H-1,2, 3-triazol-1-yl-methyl) pyridin-2-yl) -2-oxo-6-azaspiro [3.3]Heptane (80 mg, 65% yield). MS (ESI) M/Z408.2 [ M+H ]] + .
Step 5: 6- (6- ((4- (6-chloro-1H-pyrrolo [2, 3-b))]Pyridin-4-yl) -1H-1,2, 3-triazol-1-yl-methyl) pyridin-2-yl) -2-oxo-6-azaspiro [3.3]A mixed solvent of heptane (80 mg,0.2 mmol) and 3-cyano-2-methylbenzoic acid (65 mg,0.4 mmol) in 1, 4-dioxane and water (V Dioxahexacyclic ring /V Water and its preparation method =3/1, 20 mL). Sodium carbonate (32 mg,0.3 mmol) and Pd (dppf) Cl were added sequentially under nitrogen 2 (15 mg,0.02 mmol). The reaction was warmed to 98 ℃ and stirred overnight. The reaction solution was cooled to room temperature, extracted with ethyl acetate (20 ml×2 times), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purifying the residue by preparative high performance liquid chromatography to obtain final product 3- (4- (1- ((6- (2-oxo-6-azaspiro [3.3 ])]Heptane-6-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl-1H-pyrrolo [2,3-b]Pyridin-6-yl) -2-methylbenzonitrile (13.5 mg, 14% yield).
MS(ESI)M/Z:489.4[M+H] + . 1 H NMR(400MHz,CDCl 3 ):δ9.91(br s,1H),8.30(s,1H),7.75-7.70(m,3H),7.47-7.37(m,3H),7.01(s,1H),6.59(d,J＝7.2Hz,1H),6.26(d,J＝8.4Hz,1H),5.60(s,2H),4.83(s,4H),4.17(s,4H),2.60(s,3H).
Examples b-7:
preparation of 3- (4- (1- ((6- (7-oxo-2-azaspiro [3.5] nonan-2-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) -2-methylbenzonitrile (Compound b-7)
The reaction steps are as follows:
with reference to the procedure of example b-6, 7-oxo-2-azaspiro [3.5] nonane was used instead of 2-oxo-6-azaspiro [3.3] heptane to give the final product 3- (4- (1- ((6- (7-oxo-2-azaspiro [3.5] nonan-2-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -1H-pyrrolo [2,3-b ] pyridin-6-yl) -2-methylbenzonitrile (15 mg, 14% yield).
MS(ESI)M/Z:517.4[M+H] + . 1 H NMR(400MHz,CD 3 OD):δ8.53(s,1H),7.74-7.70(m,3H),7.52-7.45(m,3H),6.96(d,J＝3.2Hz,1H),6.59(d,J＝7.2Hz,1H),6.32(d,J＝8.4Hz,1H),5.62(s,2H),3.81(s,4H),3.68(t,J＝5.2Hz,4H),2.58(s,3H),1.85(t,J＝5.2Hz,4H).
Examples b-8:
preparation of 3- (6- (1- ((6- (2-hydroxypropyl-2-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -9H-purin-2-yl) -2-methylbenzonitrile (Compound b-8)
The reaction steps are as follows:
step 1: 2, 6-dichloro-9H-purine (500 mg,2.7 mmol) was dissolved in dichloromethane (50 mL) and p-toluenesulfonic acid monohydrate (50 mg,0.25 mmol) and DHP (400 mg,4.8 mmol) were added. The reaction was stirred overnight at room temperature, washed with saturated aqueous sodium bicarbonate (30 mL) and saturated brine (30 mL) in this order, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to give 2, 6-dichloro-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (500 mg, yield 69%) which was used directly in the next reaction.
MS(ESI)M/Z:273.1[M+H] + .
Step 2: 2, 6-dichloro-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (500 mg,1.8 mmol) was dissolved in a mixed solvent of tetrahydrofuran and triethylamine (V THF /V TEA =1/1, 20 mL). Under the protection of nitrogen, cuI (175 mg,0.9 mmol) and Pd (dppf) Cl are added in sequence 2 (131 mg,0.18 mmol) and triisopropylsilylacetylene (335 mg,1.8 mmol). The reaction was stirred at room temperature overnight, TLC monitoring showed the reaction was complete, and 5% aqueous citric acid (40 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (40 mL. Times.3), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=20/1 to 5/1) to give 2-chloro-9- (tetrahydro-2H-pyran-2-yl) -6- ((triisopropylsilyl) acetylene) -9H-purine (490 mg, yield 64%).
MS(ESI)M/Z:419.2[M+H] + .
Step 3: 2-chloro-9- (tetrahydro-2H-pyran-2-yl) -6- ((triisopropylsilyl) acetylene) -9H-purine (420 mg,1.0 mmol) and 3-cyano-2-methylbenzoboric acid (161 mg,1.0 mmol) were dissolved in a mixed solvent of 1, 4-dioxane and water (V Dioxahexacyclic ring /V Water and its preparation method =4/1, 25 mL). Under the protection of nitrogen, potassium carbonate (277 mg,2.0 mmol) and Pd (dppf) Cl were added sequentially 2 (73 mg,0.1 mmol). The reaction was warmed to 80 ℃ and stirred overnight. The reaction solution was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with saturated aqueous sodium bicarbonate (20 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2-methyl-3- (9- (tetrahydro-2H-pyran-2-yl) -6- ((triisopropyl) Silicon-based) acetylene) -9H-purin-2-yl-benzonitrile (560 mg, crude).
MS(ESI)M/Z:500.4[M+H] + .
Step 4: 2-methyl-3- (9- (tetrahydro-2H-pyran-2-yl) -6- ((triisopropylsilyl) acetylene) -9H-purin-2-yl) benzonitrile (200 mg, crude) was dissolved in tetrahydrofuran (10 mL), and TBAF. 3H was added 2 O (125 mg,0.4 mmol). The reaction was stirred at room temperature for 2 hours, ethyl acetate (50 mL) was added to dilute the mixture, which was washed with saturated brine (20 ml×2 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to give 3- (6-ethynyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-2-yl) -2-methylbenzonitrile (65 mg, yield 53%) which was directly used in the next reaction.
MS(ESI)M/Z:344.3[M+H] + .
Step 5: 3- (6-ethynyl-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-2-yl) -2-methylbenzonitrile (65 mg, 0.2 mmol) was dissolved in a mixed solvent of tert-butanol and water (V Tert-butanol /V Water and its preparation method =2/1, 15 mL). 2- (6- (azidomethyl) pyridin-2-yl) propan-2-ol (65 mg,0.34 mmol), copper sulfate pentahydrate (7 mg,0.03 mmol) and sodium ascorbate (22 mg,0.1 mmol) were added sequentially under nitrogen. The reaction was warmed to 60 ℃ and stirred overnight. The reaction solution was cooled to room temperature, diluted with ethyl acetate (50 mL), and the mixture was washed with saturated aqueous sodium hydrogencarbonate (20 ml×3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to give the final product 3- (6- (1- ((6- (2-hydroxypropyl-2-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -9H-purin-2-yl) -2-methylbenzonitrile (21 mg, yield 25%). MS (ESI) M/Z452.2 [ M+H ] ] + . 1 H NMR(400MHz，DMSO-d6):δ9.24(br s,1H),8.72(s,1H),8.15(d,J＝7.6Hz,1H),7.92(d,J＝6.8Hz,1H),7.81(t,J＝8.0Hz,1H),7.61(d,J＝7.6Hz,1H),7.56(t,J＝7.6Hz,1H),7.20(d,J＝7.2Hz,1H),5.90(s,2H),5.24(s,1H),2.73(s,3H),1.37(s,6H).
Examples b-9:
preparation of 3- (7- (1- ((6- (2-hydroxypropyl-2-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -2-methyl-3H-imidazo [4,5-b ] pyridin-5-yl) -2-methylbenzonitrile (Compound b-9)
The reaction steps are as follows:
referring to the procedure of example b-2, substituting 5, 7-dichloro-2-methyl-3H-imidazo [4,5-b ] pyridine for 5, 7-dichloro-3H-imidazo [4,5-b ] pyridine gives 70mg of the final product 3- (7- (1- ((6- (2-hydroxypropyl-2-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -2-methyl-3H-imidazo [4,5-b ] pyridin-5-yl) -2-methylbenzonitrile.
MS(ESI)M/Z:464.6[M+H + ]. 1 H NMR(400MHz,CD 3 OD):δ9.04(s,1H),7.83-7.74(m,4H),7.61(d,J＝7.6Hz,1H),7.48(t,J＝7.6Hz,1H),7.26(d,J＝7.6Hz,1H),5.85(s,2H),2.69(s,3H),2.55(s,3H),1.50(s,6H).
Examples b-10:
preparation of 2-fluoro-3- (7- (1- ((6- (2-hydroxypropyl-2-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) benzonitrile (Compound b-10)
The reaction steps are as follows:
step 1: 5, 7-dichloro-3- (tetrahydro-2H-pyran-2-yl) -3H-imidazo [4,5-b]A mixed solvent (V) of pyridine (1.15 g,4.2 mmol) and 3-cyano-2-fluorobenzeneboronic acid (700 mg,4.2 mmol) in 1, 4-dioxane and water Dioxahexacyclic ring /V Water and its preparation method =3/1, 90 mL). Sodium carbonate (1.4 g,13.0 mmol) and Pd (dppf) Cl were added sequentially under nitrogen blanket 2 (155 mg,0.21 mmol). The reaction was warmed to 60 ℃ and stirred overnight. The reaction mixture was cooled to room temperature, extracted with ethyl acetate (100 mL. Times.3), and the organic phases were combined, washed with saturated brine (100 mL), and then Dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (eluent: petroleum ether/dichloromethane/ethyl acetate=20/10/3 to 2/1/2) to give 3- (7-chloro-3- (tetrahydro-2H-pyran-2-yl) -3H-imidazo [4, 5-b)]Pyridin-5-yl) -2-fluorobenzonitrile (300 mg, 20% yield).
MS(ESI)M/Z:356.8[M+H + ].
Step 2: 3- (7-chloro-3- (tetrahydro-2H-pyran-2-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) -2-fluorobenzonitrile (300 mg,0.84 mmol) is dissolved in dichloromethane (5 mL) and a solution of hydrogen chloride in ethyl acetate (3.7M, 1mL,3.7 mmol) is added. The reaction was stirred at room temperature for 2 hours, saturated aqueous sodium hydrogencarbonate (20 mL) was added, and the mixture was extracted with ethyl acetate (50 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in acetonitrile (10 mL), and acetyl chloride (328 mg,4.2 mmol) and sodium iodide (756 mg,5.0 mmol) were added. The reaction system was warmed to 90 ℃ and stirred for 20 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, extracted with saturated aqueous sodium bicarbonate (20 mL) and ethyl acetate (50 mL. Times.3), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=20/1 to 1/4) to give 2-fluoro-3- (7-iodo-3H-imidazo [4,5-b ] pyridin-5-yl) benzonitrile (160 mg, yield 52%).
MS(ESI)M/Z:365.0[M+H + ].
Step 3: 2-fluoro-3- (7-iodo-3H-imidazo [4,5-b ] pyridin-5-yl) benzonitrile (160 mg,0.44 mmol) is dissolved in dichloromethane (15 mL) and para-toluenesulfonic acid monohydrate (8 mg,0.04 mmol) and DHP (370 mg,4.4 mmol) are added. The reaction system was stirred at 30℃for 4 hours, washed with saturated aqueous sodium hydrogencarbonate (20 mL) and saturated brine (20 mL) in this order, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=20/1 to 3/1) to give 2-fluoro-3- (7-iodo-3- (tetrahydro-2H-pyran-2-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) benzonitrile (196 mg, yield 99%).
MS(ESI)M/Z:449.1[M+H + ].
Step 4: 2-fluoro-3- (7-iodo-3- (tetrahydro-2H-pyran-2-yl) -3H-imidazo [4,5-b]Pyridin-5-yl) benzonitrile (196 mg,0.44 mmol) in a mixed solvent of tetrahydrofuran and triethylamine (V THF /V TEA =2/3, 20 mL). Under the protection of nitrogen, cuI (8 mg,0.04 mmol) and Pd (PPh) are added in sequence 3 ) 2 Cl 2 (16 mg,0.02 mmol) and triisopropylsilylacetylene (480 mg,2.6 mmol). The reaction was warmed to 60 ℃ and stirred overnight. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue obtained is purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=20/1 to 5/1) to give 2-fluoro-3- (3- (tetrahydro-2H-pyran-2-yl) -7- ((triisopropylsilyl) acetylene) -3H-imidazo [4,5-b ]Pyridin-5-yl) benzonitrile (90 mg, 41% yield).
MS(ESI)M/Z:503.3[M+H + ].
Step 5: 2-fluoro-3- (3- (tetrahydro-2H-pyran-2-yl) -7- ((triisopropylsilyl) acetylene) -3H-imidazo [4,5-b]Pyridin-5-yl) benzonitrile (90 mg,0.18 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to-10deg.C and added TBAF.3H 2 O (68 mg,0.22 mmol). The reaction system was stirred at 0℃for 20 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution (10 mL) to quench the reaction. The mixture was extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained 2-fluoro-3- (3- (tetrahydro-2H-pyran-2-yl) - (7-ethynyl-3H-imidazo [4, 5-b)]The crude pyridin-5-yl) benzonitrile was used directly in the next reaction (62 mg).
MS(ESI)M/Z:347.1[M+H + ].
Step 6: 2-fluoro-3- (3- (tetrahydro-2H-pyran-2-yl) - (7-ethynyl-3H-imidazo [4, 5-b)]Pyridin-5-yl) benzonitrile (62 mg, crude) in a mixed solvent of tert-butanol and water (V Tert-butanol /V Water and its preparation method =1/1, 24 mL). 2- (6- (azidomethyl) pyridin-2-yl) propan-2-ol (35 mg,0.18 mmol), copper sulfate pentahydrate (1 mg, 0.04 mmol) and sodium ascorbate were added sequentially under nitrogen protection(4 mg,0.02 mmol). The reaction was warmed to 60 ℃ and stirred overnight. The reaction solution was cooled to room temperature, extracted with ethyl acetate (50 ml×3 times), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=5/1 to 1/4) to give 2-fluoro-3- (7- (1- ((6- (2-hydroxypropyl-2-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -3- (tetrahydro-2H-pyran-2-yl) -3H-imidazole [4, 5-b) ]Pyridin-5-yl) benzonitrile (40 mg, 41% in two steps).
MS(ESI)M/Z:538.7[M+H + ].
Step 7: 2-fluoro-3- (7- (1- ((6- (2-hydroxypropyl-2-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -3- (tetrahydro-2H-pyran-2-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) benzonitrile (40 mg,0.074 mmol) is dissolved in dichloromethane (2 mL). Under nitrogen, a solution of hydrogen chloride in ethyl acetate (3.7M, 0.03mL,0.10 mmol) was added. The reaction was stirred at room temperature for 2 hours, the reaction solution was poured into saturated aqueous sodium hydrogencarbonate (20 mL), extracted with ethyl acetate (50 ml×3 times), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to give the final product 2-fluoro-3- (7- (1- ((6- (2-hydroxypropyl-2-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) benzonitrile (25 mg, yield 74%).
MS(ESI)M/Z:455.3[M+H + ].
1 H NMR(400MHz,CD 3 OD):δ9.05(s,1H),8.50(s,1H),8.30(t,J＝7.6Hz,1H),7.86-7.79(m,3H),7.60(d,J＝7.6Hz,1H),7.51(t,J＝7.6Hz,1H),7.27(d,J＝8.0Hz,1H),5.87(s,2H),1.50(s,6H).
Examples b-11:
preparation of 2- (6- ((4- (5- (3-fluoro-2-methylphenyl) -3H-imidazo [4,5-b ] pyridin-7-yl) -1H-1,2, 3-triazol-1-yl) methyl) pyridin-2-yl) propan-2-ol (Compound b-11)
The reaction steps are as follows:
with reference to the procedure of example b-10, 3-fluoro-2-methylphenylboronic acid was substituted for 3-cyano-2-fluorophenylboronic acid to give the final product 2- (6- ((4- (5- (3-fluoro-2-methylphenyl) -3H-imidazo [4,5-b ] pyridin-7-yl) -1H-1,2, 3-triazol-1-yl) methyl) pyridin-2-yl) propan-2-ol (20 mg).
MS(ESI)M/Z:444.2[M+H + ]. 1 H NMR(400MHz,DMSO-d6):δ13.38(s,1H),9.23(s,1H),8.57(s,1H),7.99(s,1H),7.86-7.79(m,1H),7.62(d,J＝7.6Hz,1H),7.36-7.26(m,3H),7.18(d,J＝7.6Hz,1H),5.89(s,2H),5.22(s,1H),2.28(s,3H),1.39(s,6H).
Examples b-12:
preparation of 3- (7- (1- ((6- (2-hydroxypropyl-2-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) benzonitrile (Compound b-12)
The reaction steps are as follows:
referring to the procedure of example b-10, 3-cyano-2-fluorobenzeneboronic acid was replaced with 3-cyanobenzeneboronic acid to give the final product 3- (7- (1- ((6- (2-hydroxypropyl-2-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) benzonitrile (10 mg, white solid).
MS(ESI)M/Z:437.1[M+H + ]. 1 H NMR(400MHz,DMSO-d6):δ13.43(s,1H),9.25(s,1H),8.65-8.45(m,4H),7.93-7.62(m,4H),7.18(d,J＝7.6Hz,1H),5.91(s,2H),5.22(s,1H),1.39(s,6H).
Examples b-13:
preparation of 2- (6- ((4- (5- (3, 5-difluorophenyl) -3H-imidazo [4,5-b ] pyridin-7-yl) -1H-1,2, 3-triazol-1-yl) methyl) pyridin-2-yl) propan-2-ol (compound b-13)
The reaction steps are as follows:
with reference to the procedure of example b-10, 3, 5-difluorophenylboronic acid was used in place of 3-cyano-2-fluorophenylboronic acid to give the final product 2- (6- ((4- (5- (3, 5-difluorophenyl) -3H-imidazo [4,5-b ] pyridin-7-yl) -1H-1,2, 3-triazol-1-yl) methyl) pyridin-2-yl) propan-2-ol (22 mg).
MS(ESI)M/Z:448.0[M+H + ]. 1 H NMR(400MHz,CD 3 OD):δ8.68(s,1H),8.43(s,1H), 8.22(s,1H),7.83-7.79(m,3H),7.61(d,J＝8.0Hz,1H),7.25(d,J＝7.6Hz,1H),7.12(s,1H),5.82(s,2H),1.50(s,6H).
Examples b-14:
preparation of (S) -2-methyl-3- (7- (1- ((6- (((tetrahydrofuran-3-yl) oxo) methyl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) benzonitrile (Compound b-14)
The reaction steps are as follows:
referring to the preparation procedure of example b-10, (S) -2- (azidomethyl) -6- (((tetrahydrofuran-3-yl) oxo) methyl) pyridine was substituted for 2- (6- (azidomethyl) pyridin-2-yl) propan-2-ol to give the final product, (S) -2-methyl-3- (7- (1- ((6- (((tetrahydrofuran-3-yl) oxo) methyl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) benzonitrile (80 mg).
MS(ESI)M/Z:493.1[M+H + ]. 1 H NMR(400MHz,DMSO-d6):δ13.42(s,1H),9.19(s,1H),8.60(s,1H),8.00(s,1H),7.90-7.80(m,3H),7.53(t,J＝7.6Hz,1H),7.40(d,J＝7.6Hz,1H),7.26(d,J＝7.6Hz,1H),5.91(s,2H),4.52(s,2H),4.24(br s,1H),3.74-3.61(m,4H),2.54(s,3H),1.94-1.93(m,2H).
Examples b-15:
preparation of (R) -2-methyl-3- (7- (1- ((6- (((tetrahydrofuran-3-yl) oxo) methyl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) benzonitrile (Compound b-15)
The reaction steps are as follows:
referring to the preparation procedure of example b-10, (R) -2- (azidomethyl) -6- (((tetrahydrofuran-3-yl) oxo) methyl) pyridine was used instead of 2- (6- (azidomethyl) pyridin-2-yl) propan-2-ol to give the final product, (R) -2-methyl-3- (7- (1- ((6- (((tetrahydrofuran-3-yl) oxo) methyl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) benzonitrile (30 mg).
MS(ESI)M/Z:493.1[M+H + ]. 1 H NMR(400MHz,DMSO-d6):δ13.42(s,1H),9.19(s,1H),8.60(s,1H),8.00(s,1H),7.90-7.81(m,3H),7.53(t,J＝7.6Hz,1H),7.40(d,J＝7.6Hz,1H),7.25(d,J＝7.6Hz,1H),5.91(s,2H),4.52(s,2H),4.25(br s,1H),3.72-3.64(m,4H),2.54(s,3H),1.95-1.92(m,2H).
Examples b-16:
preparation of 3- (7- (1- ((6- (1-hydroxycyclopentyl) pyridin-2-yl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) -2-methylbenzonitrile (Compound b-16)
The reaction steps are as follows:
with reference to the analogous procedure of example b-10, substituting 1- (6- (azidomethyl) pyridin-2-yl) cyclopent-1-ol for 2- (6- (azidomethyl) pyridin-2-yl) propan-2-ol gave the final product 3- (7- (1- ((6- (1-hydroxycyclopentyl) pyridin-2-yl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) -2-methylbenzonitrile (8 mg).
MS(ESI)M/Z:476.9[M+H + ]. 1 H NMR(400MHz,CD 3 OD):δ9.12(s,1H),8.49(s,1H),8.02(s,1H),7.85-7.74(m,3H),7.62(d,J＝8.0Hz,1H),7.49(t,J＝7.6Hz,1H),7.25(d,J＝7.2Hz,1H),5.86(s,2H),2.57(s,3H),2.20-2.10(m,2H),1.95-1.75(m,6H).
Examples b-17:
preparation of 3- (7- (1- ((6- (1-hydroxycyclobutyl) pyridin-2-yl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) -2-methylbenzonitrile (Compound b-17)
The reaction steps are as follows:
with reference to the analogous procedure of example b-10, substituting 1- (6- (azidomethyl) pyridin-2-yl) cyclobutan-1-ol for 2- (6- (azidomethyl) pyridin-2-yl) propan-2-ol gives the final product 3- (7- (1- ((6- (1-hydroxycyclobutyl) pyridin-2-yl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) -2-methylbenzonitrile (20 mg).
MS(ESI)M/Z:463.2[M+H + ]. 1 H NMR(400MHz,CD 3 OD):δ9.10(s,1H),8.48(s,1H),7.95(s,1H),7.80-7.74(m,3H),7.54(d,J＝8.0Hz,1H),7.47(t,J＝8.0Hz,1H),7.28(d,J＝7.6Hz,1H),5.88(s,2H),2.60-2.50(m,5H),2.27-2.19(m,2H),1.90-1.75(m,2H).
Examples b-18:
preparation of 3- (7- (1- ((6- (7-oxo-2-azaspiro [3.5] nonan-2-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) -2-methylbenzonitrile (Compound b-18)
The reaction steps are as follows:
by analogy with the procedure described in reference to example b-10, 2- (6- (azidomethyl) pyridin-2-yl) -7-oxo-2-azaspiro [3.5] nonane was substituted for 2- (6- (azidomethyl) pyridin-2-yl) propan-2-ol to give the final product 3- (7- (1- ((6- (7-oxo-2-azaspiro [3.5] nonan-2-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) -2-methylbenzonitrile (15 mg).
MS(ESI)M/Z:518.1[M+H + ]. 1 H NMR(400MHz,CD 3 OD):δ9.13(s,1H),8.48(s,1H),8.03(s,1H),7.77(d,J＝7.6Hz,2H),7.53-7.47(m,2H),6.60(d,J＝6.8Hz,1H),6.36(d,J＝8.4Hz,1H),5.65(s,2H),3.75(br s,4H),3.62(t,J＝5.2Hz,4H),2.57(s,3H),1.79(t,J＝5.2Hz,4H).
Examples b-19:
preparation of 3- (7- (1- ((6- (methoxymethyl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) -2-methylbenzonitrile (Compound b-19)
The reaction steps are as follows:
by reference to a similar procedure as in example b-10, substituting 2- (azidomethyl) -6- (methoxymethyl) pyridine for 2- (6- (azidomethyl) pyridin-2-yl) propan-2-ol, the final product 3- (7- (1- ((6- (methoxymethyl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) -2-methylbenzonitrile (100 mg) is obtained.
MS(ESI)M/Z:437.1[M+H + ]. 1 H NMR(400MHz,DMSO-d6):δ13.41(s,1H),9.19(s,1H),8.60(s,1H),7.99(s,1H),7.90-7.80(m,3H),7.54(t,J＝7.6Hz,1H),7.38(d,J＝8.0Hz,1H),7.23(d,J＝7.6Hz,1H),5.91(s,2H),4.47(s,2H),3.35(s,3H),2.54(s,3H).
Examples b-20:
preparation of 3- (7- (1- ((1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-3-yl) methyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) -2-methylbenzonitrile (Compound b-20)
The reaction steps are as follows:
by analogy with the procedure described in example b-10, substituting 2- (6- (azidomethyl) pyridin-2-yl) propan-2-ol with 1- (3- (azidomethyl) -1H-pyrazol-1-yl) -2-methylpropan-2-ol gave the final product 3- (7- (1- ((1- (2-hydroxy-2-methylpropyl) -1H-pyrazol-3-yl) methyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) -2-methylbenzonitrile (10 mg).
MS(ESI)M/Z:454.0[M+H + ]. 1 H NMR(400MHz,CD 3 OD):δ8.96(s,1H),8.76(s,1H),8.03(s,1H),7.7-7.75(m,2H),7.64(d,J＝2.0Hz,1H),7.48(t,J＝7.6Hz,1H),6.40(s,1H),5.73(s,2H),4.10(s,2H),2.55(s,3H),1.16(s,6H).
Examples b-21:
preparation of 3- (7- (1- ((6- (2-hydroxypropyl-2-yl) pyridin-2-yl) methyl-d 2) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) -2-methylbenzonitrile (Compound b-21)
The reaction steps are as follows:
step 1: methyl 6- (2-hydroxypropyl-2-yl) picolinate (1.0 g,5.1 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), cooled to 0deg.C, and lithium deuterated aluminum hydride (430 mg,10.2 mmol) was added. The reaction system was naturally warmed to room temperature and stirred for 2 hours. The reaction was quenched by slowly adding water (20 mL). The mixture was extracted with ethyl acetate (40 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2- (6- (hydroxymethyl-d 2) pyridin-2-yl) propan-2-ol (650 mg, yield 75%).
MS(ESI)M/Z:169.9[M+H + ].
Step 2: 2- (6- (hydroxymethyl-d 2) pyridin-2-yl) propan-2-ol (650 mg,3.8 mmol) was dissolved in toluene (10 mL), cooled to 0deg.C, and DPPA (1.0 g,3.9 mmol) and DBU (591 mg,3.9 mmol) were added. The reaction system was naturally warmed to room temperature and stirred for 5 hours. To the reaction mixture was added water (10 mL) to quench the reaction. The mixture was extracted with ethyl acetate (40 ml×3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=20/1 to 3/1) to give 2- (6- (azidomethyl-d 2) pyridin-2-yl) propan-2-ol (350 mg, yield 47%).
MS(ESI)M/Z:195.1[M+H + ].
Step 3: reference to the relevant preparation procedure of example b-10 starting from 2- (6- (azidomethyl-d 2) pyridin-2-yl) propan-2-ol the final product 3- (7- (1- ((6- (2-hydroxypropyl-2-yl) pyridin-2-yl) methyl-d 2) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) -2-methylbenzonitrile (40 mg) is obtained.
MS(ESI)M/Z:453.3[M+H + ]. 1 H NMR(400MHz,CD 3 OD):δ9.06(s,2H),8.06(s,1H),7.85-7.79(m,3H),7.62(d,J＝8.0Hz,1H),7.51(t,J＝7.6Hz,1H),7.29(d,J＝7.6Hz,1H),2.58(s,3H),1.48(s,6H).
Examples b-22:
preparation of 2- ((4- (5- (3-cyano-2-methylphenyl) -3H-imidazo [4,5-b ] pyridin-7-yl) -1H-1,2, 3-triazol-1-yl) methyl) -6- (2-hydroxypropyl-2-yl) pyridin-1-oxide (Compound b-22)
The reaction steps are as follows:
with reference to the analogous procedure of example b-10, substituting 2- (azidomethyl) -6- (2-hydroxypropyl-2-yl) pyridin-1-oxide for 2- (6- (azidomethyl) pyridin-2-yl) propan-2-ol gave the final product 2- ((4- (5- (3-cyano-2-methylphenyl) -3H-imidazo [4,5-b ] pyridin-7-yl) -1H-1,2, 3-triazol-1-yl) methyl) -6- (2-hydroxypropyl-2-yl) pyridin-1-oxide (40 mg).
MS(ESI)M/Z:467.2[M+H + ]. 1 H NMR(400MHz,CD 3 OD):δ9.16(s,1H),8.49(s,1H),8.04(s,1H),7.77(d,J＝7.6Hz,2H),7.69(d,J＝8.0Hz,1H),7.56-7.49(m,2H),7.31(d,J＝7.6Hz,1H),6.02(s,2H),2.57(s,3H),1.68(s,6H).
Examples b-23:
preparation of 3- (7- (1- ((6- (cis-2, 6-dimethylmorpholin) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) -2-methylbenzonitrile (Compound b-23)
The reaction steps are as follows:
step 1: 2-bromo-6- (((tert-butyldimethylsilyl) oxy) methyl) pyridine (1.0 g,3.3 mmol) was dissolved in DMF (15 mL) and cis-2, 6-dimethyl morpholine (460 mg,4.0 mmol), cuprous iodide (63 mg,0.33 mmol) and potassium carbonate (2.3 g,16.7 mmol) were added sequentially at room temperature. The reaction system was warmed to 95℃under nitrogen protection, stirred for 16 hours, cooled to room temperature, and quenched by slowly adding water (30 mL) to the reaction mixture. The mixture was extracted with ethyl acetate (40 ml×3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate/dichloromethane=20/1/1 to 3/1/1) to give cis-4- (6- (((tert-butyldimethylsilyl) oxy) methyl) pyridin-2-yl) -2, 6-dimethylmorpholine (600 mg, yield 52%).
MS(ESI)M/Z:337.2[M+H + ]. 1 H NMR(400MHz,DMSO-d6):δ7.52-7.48(m,1H),6.84(d,J＝7.2Hz,1H),6.48(d,J＝8.4Hz,1H),4.68(s,2H),4.07-4.03(m,2H),3.75-3.71(m,2H),2.50-2.44(m,2H),1.27(d,J＝6.4Hz,6H),0.96(s,9H),0.11(s,6H).
Step 2: cis-4- (6- (((tert-butyldimethylsilyloxy) methyl) pyridin-2-yl) -2, 6-dimethylmorpholine (600 mg,1.8 mmol) was dissolved in tetrahydrofuran (6 mL) and TBAF.3H was added 2 O (560 mg,2.1 mmol). After the reaction system was stirred at room temperature for 16 hours, the reaction was quenched by the addition of water (3 mL). The mixture was extracted with ethyl acetate (40 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (6- (cis-2, 6-dimethylmorpholin) pyridin-2-yl) methanol (350 mg, yield 88%).
MS(ESI)M/Z:222.9[M+H + ].
Step 3: (6- (cis-2, 6-dimethylmorpholin) pyridin-2-yl) methanol (350 mg,1.6 mmol) was dissolved in toluene (10 mL), cooled to 0deg.C, and DPPA (492 mg,1.8 mmol) and DBU (273 mg,1.8 mmol) were added. The reaction system was naturally warmed to room temperature and stirred for 5 hours. To the reaction mixture was added water (10 mL) to quench the reaction. The mixture was extracted with ethyl acetate (40 ml×3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate/dichloromethane=5/1/1 to 3/1/1) to give cis-4- (6- (azidomethyl) pyridin-2-yl) -2, 6-dimethylmorpholine (150 mg, yield 38%).
MS(ESI)M/Z:248.1[M+H + ].
Subsequent procedure reference the similar preparation procedure of example b-10, starting from cis-4- (6- (azidomethyl) pyridin-2-yl) -2, 6-dimethylmorpholin, gives the final product 3- (7- (1- ((6- (cis-2, 6-dimethylmorpholin) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) -2-methylbenzonitrile (24 mg).
MS(ESI)M/Z:506.2[M+H + ]. 1 H NMR(400MHz,CD 3 OD):δ9.03(s,1H),8.71(s,1H),8.00(s,1H),7.79-7.76(m,2H),7.57-7.48(m,2H),6.74-6.68(m,2H),5.69(s,2H),4.07(d,J＝11.6Hz,2H),3.60-3.56(m,2H),2.56(s,3H),2.40-2.34(m,2H),1.09(d,J＝6.4Hz,6H).
Examples b-24:
preparation of 3- (7- (1- ((6- (4-hydroxy-4-methylpiperidin-1-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) -2-methylbenzonitrile (Compound b-24)
The reaction steps are as follows:
step 1: 1- (6- (hydroxymethyl) pyridin-2-yl) -4-methylpiperidin-4-ol (397 mg,1.8 mmol) was dissolved in toluene (6 mL), cooled to 0deg.C, and DPPA (492 mg,1.8 mmol) and DBU (273 mg,1.8 mmol) were added. The reaction system was naturally warmed to room temperature and stirred for 5 hours. To the reaction mixture was added water (10 mL) to quench the reaction. The mixture was extracted with ethyl acetate (40 ml×3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate/dichloromethane=5/1/1 to 3/1/1) to give 1- (6- (azidomethyl) pyridin-2-yl) -4-methylpiperidin-4-ol (230 mg, yield 52%).
MS(ESI)M/Z:248.2[M+H + ].
Subsequent procedure analogous to the preparation of example b-10 starting from 1- (6- (azidomethyl) pyridin-2-yl) -4-methylpiperidin-4-ol, the final product 3- (7- (1- ((6- (4-hydroxy-4-methylpiperidin-1-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) -2-methylbenzonitrile (22 mg) is obtained.
MS(ESI)M/Z:506.3[M+H + ]. 1 H NMR(400MHz,DMSO-d6):δ13.29(s,1H),9.18(s,1H),8.54(s,1H),7.95(s,1H),7.88(d,J＝7.6Hz,1H),7.81(d,J＝7.2Hz,1H),7.55-7.48(m,2H),6.77(d,J＝8.8Hz,1H),6.51(d,J＝7.2Hz,1H),5.68(s,2H),4.29(s,1H),3.80-3.77(m,2H),3.33-3.27(m,2H),2.51(s,3H),1.48-1.30(m,4H),1.06(s,3H).
Examples b-25:
preparation of 3- (7- (1- ((6- (3-hydroxy-3-methylazetidin-1-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) -2-methylbenzonitrile (Compound b-25)
The reaction steps are as follows:
step 1: 1- (6- (hydroxymethyl) pyridin-2-yl) -3-methylazetidin-3-ol (350 mg,1.8 mmol) was dissolved in toluene (10 mL), cooled to 0deg.C, and DPPA (492 mg,1.8 mmol) and DBU (279 mg,1.8 mmol) were added. The reaction system was naturally warmed to room temperature and stirred for 5 hours. To the reaction mixture was added water (10 mL) to quench the reaction. The mixture was extracted with ethyl acetate (40 ml×3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=20/1 to 1/1) to give 1- (6- (azidomethyl) pyridin-2-yl) -3-methylazetidin-3-ol (150 mg, yield 38%).
MS(ESI)M/Z:242.3[M+Na + ].
Subsequent procedure analogous to the preparation of example b-10 starting from 1- (6- (azidomethyl) pyridin-2-yl) -3-methylazetidin-3-ol, the final product 3- (7- (1- ((6- (3-hydroxy-3-methylazetidin-1-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) -2-methylbenzonitrile (34 mg) is obtained.
MS(ESI)M/Z:478.2[M+H + ]. 1 H NMR(400MHz,CD 3 OD):δ8.99(s,1H),8.48(s,1H),7.95(s,1H),7.77(d,J＝8.0Hz,2H),7.54-7.47(m,2H),6.62(d,J＝7.2Hz,1H),6.37(d,J＝8.4Hz,1H),5.65(s,2H),3.91-3.82(m,4H),2.57(s,3H),1.50(s,3H).
Examples b-26:
preparation of 3- (7- (1- ((6- (3-hydroxyoxetan-3-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) -2-methylbenzonitrile (Compound b-26)
The reaction steps are as follows:
step 1: 3- (6- (hydroxymethyl) pyridin-2-yl) oxetan-3-ol (1.0 g,5.5 mmol) was dissolved in toluene (20 mL), cooled to 0deg.C and DPPA (1.9 g,6.8 mmol) and DBU (1.0 g,6.8 mmol) were added. The reaction was allowed to warm to room temperature and stirred overnight. To the reaction mixture was added water (20 mL) to quench the reaction. The mixture was extracted with ethyl acetate (30 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=20/1 to 10/1) to give 3- (6- (azidomethyl) pyridin-2-yl) oxetan-3-ol (200 mg, yield 18%).
MS(ESI)M/Z:206.9[M+H + ].
Subsequent procedure reference the similar preparation procedure of example b-10, starting from 3- (6- (azidomethyl) pyridin-2-yl) oxetan-3-ol, gives the final product 3- (7- (1- ((6- (3-hydroxyoxetan-3-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) -2-methylbenzonitrile (8 mg).
MS(ESI)M/Z:465.1[M+H + ]. 1 H NMR(400MHz,CD 3 OD):δ9.15(s,1H),8.48(s,1H),8.02(s,1H),7.86(t,J＝8.0Hz,1H),7.77(d,J＝7.6Hz,2H),7.66(d,J＝7.6Hz,1H),7.49(t,J＝8.0Hz,1H),7.38(d,J＝7.2Hz,1H),5.93(s,2H),5.01(br s,2H),4.77(d,J＝6.4Hz,2H),2.56(s,3H).
Examples b-27:
preparation of 3- (7- (1- ((6- (2-cyanoprop-2-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) -2-methylbenzonitrile (Compound b-27)
The reaction steps are as follows:
step 1: 2-methyl-2- (6-methylpyridin-2-yl) propionitrile (800 mg,5.0 mmol) was dissolved in carbon tetrachloride (6 mL), and N-bromosuccinimide (976 mg,5.5 mmol) and benzoyl peroxide (120 mg,0.5 mmol) were added sequentially at room temperature. The reaction system was warmed to 78 ℃ under nitrogen protection, stirred for 16 hours, cooled to room temperature, and quenched by slowly adding saturated aqueous sodium bicarbonate (20 mL) to the reaction solution. The mixture was extracted with dichloromethane (40 ml×2 times), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=49/1) to give 2- (6- (bromomethyl) pyridin-2-yl) -2-methylpropanenitrile (400 mg, yield 34%).
MS(ESI)M/Z:239.1[M+H + ].
Step 2: 2- (6- (bromomethyl) pyridin-2-yl) -2-methylpropanenitrile (200 mg,0.84 mmol) was dissolved in dimethyl sulfoxide (6 mL), and sodium azide (82 mg,1.3 mmol) was added at room temperature. The reaction system was warmed to 50 ℃ and stirred for 16 hours. To the reaction mixture was added water (20 mL) to quench the reaction. The mixture was extracted with ethyl acetate (100 mL. Times.2), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=9/1) to give 2- (6- (azidomethyl) pyridin-2-yl) -2-methylpropanenitrile (80 mg, yield 47%).
MS(ESI)M/Z:201.8[M+H + ].
Subsequent procedure reference the similar preparation procedure of example b-10, starting from 2- (6- (azidomethyl) pyridin-2-yl) -2-methylpropanenitrile, gives the final product 3- (7- (1- ((6- (2-cyanoprop-2-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) -2-methylbenzonitrile (12 mg).
MS(ESI)M/Z:460.0[M+H + ]. 1 H NMR(400MHz,CD 3 OD):δ9.07(s,1H),8.50(s,1H),7.96(s,1H),7.89(t,J＝7.6Hz,1H),7.77(d,J＝7.6Hz,2H),7.59(d,J＝8.0Hz,1H),7.49(t,J＝7.6Hz,1H),7.39(d,J＝8.0Hz,1H),5.91(s,2H),2.57(s,3H),1.70(s,6H).
Examples b-28:
preparation of 3- (7- (1- ((6- (3, 3-difluoroazetidin-1-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) -2-methylbenzonitrile (Compound b-28)
The reaction steps are as follows:
step 1: 2-bromo-6- ((tert-butyldimethylsilyloxy) methyl) pyridine (2.0 g,6.6 mmol), 3-difluoroazetidine hydrochloride (2.1 g,16.3 mmol), cesium carbonate (3.0 g,9.3 mmol), palladium acetate (149 mg,0.66 mmol) and 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine (414 mg,0.66 mmol) were dissolved in toluene (30 mL), replaced with nitrogen three times, and heated to 120℃under reflux and stirred for 2 hours. LCMS monitoring indicated complete reaction of starting material, cooling the reaction to room temperature, and adding water (20 mL). The mixture was extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=50/1) to give 2- ((tert-butyldimethylsilyloxy) methyl) -6- (3, 3-difluoroazetidin-1-yl) pyridine (700 mg, yield 34%).
MS(ESI)M/Z:315.3[M+H + ].
Step 2: 2- ((tert-Butyldimethylsilyloxy) methyl) -6- (3, 3-difluoroazetidin-1-yl) pyridine (700 mg,2.2 mmol) was dissolved in tetrahydrofuran (5 mL), tetrabutylammonium fluoride trihydrate (696 mg,2.2 mmol) was added with ice-cooling, and stirred at room temperature for 2 hours. LCMS monitoring showed complete reaction of starting material, water (10 mL) was added and the mixture extracted with ethyl acetate (40 mL x 2 times). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (6- (3, 3-difluoroazetidin-1-yl) pyridin-2-yl) methanol (400 mg, yield 90%).
MS(ESI)M/Z:200.6[M+H + ].
Step 3: (6- (3, 3-Difluoroazetidin-1-yl) pyridin-2-yl) methanol (100 mg,0.5 mmol) was dissolved in tetrahydrofuran (7 mL), cooled to 0deg.C, and DPPA (165 mg,0.6 mmol) and DBU (91 mg,0.6 mmol) were added. The reaction system was naturally warmed to room temperature and stirred for 20 hours. To the reaction mixture was added water (10 mL) to quench the reaction. The mixture was extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=40/1) to give 2- (azidomethyl) -6- (3, 3-difluoroazetidin-1-yl) pyridine (39 mg, yield 29%).
MS(ESI)M/Z:226.2[M+H + ].
Subsequent procedure analogous to the preparation of example b-10 starting from 2- (azidomethyl) -6- (3, 3-difluoroazetidin-1-yl) pyridine, the final product 3- (7- (1- ((6- (3, 3-difluoroazetidin-1-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) -2-methylbenzonitrile (23 mg) is obtained.
MS(ESI)M/Z:484.2[M+H + ]. 1 H NMR(400MHz,DMSO-d6):δ13.42(s,1H),9.22(s,1H),8.59(s,1H),7.99(s,1H),7.88(d,J＝7.6Hz,1H),7.82(d,J＝7.2Hz,1H),7.63(t,J＝7.6Hz,1H),7.54(t,J＝7.6Hz,1H),6.70-6.68(m,1H),6.55(d,J＝8.4Hz,1H),5.75(s,2H),4.41-4.34(m,4H),2.54(s,3H).
Examples b-29:
preparation of 3- (7- (1- (3- (2-hydroxypropyl-2-yl) benzyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) -2-methylbenzonitrile (Compound b-29)
The reaction steps are as follows:
step 1: 2- (3- (hydroxymethyl) phenyl) propan-2-ol (750 mg,4.5 mmol) was dissolved in toluene (30 mL), cooled to 0deg.C, and DPPA (1.2 g,4.3 mmol) and DBU (653 mg,4.3 mmol) were added. The reaction was allowed to warm to room temperature and stirred overnight. To the reaction mixture was added water (20 mL) to quench the reaction. The mixture was extracted with ethyl acetate (20 mL. Times.2), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=20/1 to 5/1) to give2- (3- (azidomethyl) phenyl) propan-2-ol (492 mg, yield 57%). MS (ESI) M/Z174.0 [ M-H ] 2 O+H + ]. 1 H NMR(400MHz,DMSO-d6):δ7.47-7.43(m,2H),7.33(t,J＝7.6Hz,1H),7.19(d,J＝7.6Hz,1H),5.07(s,1H),4.44(s,2H),1.44(s,6H).
Step 2: 3- (7-ethynyl-3H-imidazo [4, 5-b)]Pyridin-5-yl) -2-methylbenzonitrile (70 mg,0.27 mmol) in a mixed solvent of tert-butanol and water (V Tert-butanol /V Water and its preparation method =1/1, 10 mL). 2- (3- (azidomethyl) phenyl) propan-2-ol (62 mg,0.33 mmol), copper sulfate pentahydrate (1 mg, 0.04 mmol) and sodium ascorbate (4 mg,0.02 mmol) were added sequentially under nitrogen. The reaction was warmed to 60 ℃ and stirred overnight. The reaction solution was cooled to room temperature, extracted with ethyl acetate (30 ml×3 times), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by preparative high performance liquid chromatography to obtain the final product 3- (7- (1- (3- (2-hydroxypropyl-2-yl) benzyl) -1H-1,2, 3-triazole-4-yl) -3H-imidazole [4, 5-b)]Pyridin-5-yl) -2-methylbenzonitrile (81 mg, 66% yield).
MS(ESI)M/Z:450.2[M+H + ]. 1 H NMR(400MHz,DMSO-d6):δ13.41(s,1H),9.13(s,1H),8.58(s,1H),7.97(s,1H),7.88(d,J＝7.6Hz,1H),7.80(d,J＝7.6Hz,1H),7.58-7.51(m,2H),7.42(d,J＝7.6Hz,1H),7.32(t,J＝7.6Hz,1H),7.21(d,J＝7.2Hz,1H),5.78-5.76(m,2H),5.06(br s,1H),2.53(s,3H),1.41(s,6H).
Examples b-30:
preparation of 3- (7- (1- ((6- (2-oxo-6-azaspiro [3.3] heptan-6-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) -2-methylbenzonitrile (Compound b-30)
The reaction steps are as follows:
referring to the procedure of example b-29, (6- (2-oxo-6-azaspiro [3.3] heptan-6-yl) pyridin-2-yl) methanol was used instead of 2- (3- (hydroxymethyl) phenyl) propan-2-ol to give the final product 3- (7- (1- ((6- (2-oxo-6-azaspiro [3.3] heptan-6-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) -2-methylbenzonitrile (4 mg).
MS(ESI)M/Z:490.2[M+H + ]. 1 H NMR(400MHz,CD 3 OD):δ9.00(s,1H),8.65(s,1H),7.98(s,1H),7.79-7.76(m,2H),7.60-7.54(m,1H),7.50(t,J＝7.6Hz,1H),6.67-6.44(m,2H),5.70(s,2H),4.81(br s,4H),4.21(br s,4H),2.57(s,3H).
Examples b-31:
preparation of (R) -3- (7- (1- ((6- (3-hydroxypyrrolidin-1-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) -2-methylbenzonitrile (Compound b-31)
The reaction steps are as follows:
step 1: methyl 6-fluoropyridine carboxylate (1.0 g,6.5 mmol) and (R) -pyrrolin-3-ol (560 mg,6.5 mmol) were dissolved in dry DMF (100 mL), potassium carbonate (4.5 g,32.2 mmol) and cuprous iodide (124 mg,0.65 mmol) were added, nitrogen was displaced 3 times, and the reaction was warmed to 98℃and stirred overnight. TLC monitoring showed that the starting material had reacted, the reaction was cooled to room temperature, filtered, the filter cake was washed with ethyl acetate (20 mL x 2 times) and the mixture concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=1/1) to give methyl (R) -6- (3-hydroxypyrrolin-1-yl) picolinate (850 mg, yield 59%). MS (ESI) M/Z222.7 [ M+H ] + ].
Step 2: methyl (R) -6- (3-hydroxypyrrolin-1-yl) picolinate (850 mg,3.8 mmol) and imidazole (785 mg,11.5 mmol) were dissolved in dichloromethane (30 mL), TBSCl (1160 mg,7.7 mmol) was added under ice-cooling, and stirred overnight at room temperature. TLC monitoring showed that the reaction of the starting material was complete, water (50 mL) was added, the solution was separated, the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, Filtering, and concentrating under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=5/1) to give methyl (R) -6- (3- (tert-butyldimethylsilyloxy) pyrrolin-1-yl) picolinate (1.0 g, yield 78%). MS (ESI) M/Z336.9 [ M+H ] + ].
Step 3: methyl (R) -6- (3- (tert-butyldimethylsilyloxy) pyrrolin-1-yl) picolinate (1.0 g,3.0 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL), cooled to 0deg.C, and lithium borohydride in tetrahydrofuran (1M, 6.6mL,6.6 mmol) was added dropwise. The reaction system was naturally warmed to room temperature and stirred for 2 hours. The reaction was quenched by slowly adding cold saturated ammonium chloride solution (50 mL). The mixture was extracted with ethyl acetate (50 ml×2 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=5/1) to give (R) - (6- (3- (tert-butyldimethylsilyloxy) pyrrolin-1-yl) pyridin-2-yl) methanol (400 mg, yield 43%). MS (ESI) M/Z309.3 [ M+H ] + ].
Step 4: (R) - (6- (3- (tert-Butyldimethylsilyloxy) pyrrolin-1-yl) pyridin-2-yl) methanol (400 mg,1.3 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), cooled to 0-5℃and DPPA (430 mg,1.6 mmol) and DBU (240 mg,1.6 mmol) were added. The reaction was allowed to warm to room temperature and stirred overnight. To the reaction mixture was added water (50 mL) to quench the reaction. The mixture was extracted with ethyl acetate (50 ml×2 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=5/1) to give (R) -2- (azidomethyl) -6- (3- (tert-butyldimethylsilyloxy) pyrrolin-1-yl) pyridine (60 mg, yield 14%). MS (ESI) M/Z334.3 [ M+H ] + ].
Step 5: 3- (7-ethynyl-3- (tetrahydro-2H-pyran-2-yl) -3H-imidazo [4,5-b]Pyridin-5-yl) -2-methylbenzonitrile (61 mg,0.18 mmol) in a mixed solvent of t-butanol, water and tetrahydrofuran (V Tert-butanol /V Water and its preparation method /V Tetrahydrofuran (THF) =5/5/2, 12 mL). Under the protection of nitrogen, adding (R) -2- (stack in turnAzithromethyl) -6- (3- (tert-butyldimethylsilyloxy) pyrrolin-1-yl) pyridine (60 mg,0.18 mmol), copper sulphate pentahydrate (0.5 mg,0.002 mmol) and sodium ascorbate (2 mg,0.01 mmol). The reaction was warmed to 60 ℃ and stirred overnight. The reaction solution was cooled to room temperature, quenched with water (50 m 1), the mixture was extracted with ethyl acetate (50 ml×2 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=1/1) to give 3- (7- (1- ((6- ((R) -3- (tert-butyldimethylsilyloxy) pyrrolin-1-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -3- (tetrahydro-2H-pyran-2-yl) -3H-imidazo [4, 5-b)]Pyridin-5-yl) -2-methylbenzonitrile (40 mg, 33% yield). MS (ESI) M/Z676.8 [ M+H ]] + .
Step 6: 3- (7- (1- ((6- ((R) -3- (tert-butyldimethylsilyloxy) pyrrolin-1-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -3- (tetrahydro-2H-pyran-2-yl) -3H-imidazo [4,5-b ]Pyridin-5-yl) -2-methylbenzonitrile (40 mg,0.06 mmol) was dissolved in tetrahydrofuran (10 m 1), a tetrahydrofuran solution of tetrabutylammonium fluoride (1.0M, 0.06mL,0.06 mmol) was added under ice-bath cooling, and stirred overnight at room temperature. TLC monitoring showed that the starting material was complete, sodium bicarbonate was added in water (20 mL) and the mixture was extracted with ethyl acetate (30 mL. Times.2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by high performance liquid chromatography to give 3- (7- (1- ((6- ((R) -3-hydroxypyrrolidin-1-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -3- (tetrahydro-2H-pyran-2-yl) -3H-imidazo [4, 5-b)]Pyridin-5-yl) -2-methylbenzonitrile (20 mg, 59% yield). MS (ESI) M/Z584.3 [ M+Na + ].
Step 7: 3- (7- (1- ((6- ((R) -3-hydroxypyrrolidin-1-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -3- (tetrahydro-2H-pyran-2-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) -2-methylbenzonitrile (20 mg,0.035 mmol) was dissolved in dichloromethane (2 m 1) and a solution of hydrogen chloride in ethyl acetate (3.7M, 0.1mL,0.37 mmol) was added with ice cooling. The reaction was stirred at room temperature overnight, a solid was precipitated, filtered, the filter cake was added to a saturated aqueous sodium bicarbonate solution (20 mL), extracted with ethyl acetate (30 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to give (R) -3- (7- (1- ((6- (3-hydroxypyrrolidin-1-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) -2-methylbenzonitrile (20 mg, yield 59%).
MS(ESI)M/Z:478.4[M+H + ]. 1 H NMR(400MHz,DMSO-d6):δ13.41(s,1H),9.23(s,1H),8.59(s,1H),7.99(s,1H),7.90-7.81(m,2H),7.55-7.43(m,2H),6.48(d,J＝7.2Hz,1H), 6.38(d,J＝8.4Hz,1H),5.68(s,2H),4.92(s,1H),4.34(s,1H),3.45-3.25(m,4H),2.55(s,3H),1.99-1.86(m,2H).
Examples b-32:
preparation of (S) -3- (7- (1- ((6- (3-hydroxypyrrolidin-1-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) -2-methylbenzonitrile (Compound b-32)
The reaction steps are as follows:
referring to the procedure of preparation example b-31, (S) -pyrrolin-3-ol was used instead of (R) -pyrrolin-3-ol to give the final product, (S) -3- (7- (1- ((6- (3-hydroxypyrrolin-1-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) -2-methylbenzonitrile (25 mg).
MS(ESI)M/Z:478.2[M+H + ]. 1 H NMR(400MHz,DMSO-d6):δ13.41(s,1H),9.23(s,1H),8.59(s,1H),7.99(s,1H),7.90-7.81(m,2H),7.56-7.47(m,2H),6.49(d,J＝7.2Hz,1H),6.38(d,J＝8.4Hz,1H),5.68(s,2H),4.92(s,1H),4.34(s,1H),3.44-3.25(m,4H),2.55(s,3H),1.99-1.86(m,2H).
Examples b-33:
preparation of 3- (7- (1- ((6- (2-hydroxy-prop-2-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) -2-methoxybenzonitrile (Compound b-33)
The reaction steps are as follows:
step 1: 7-bromo-3H-imidazo [4,5-b ] pyridine (4.6 g,23.0 mmol) is dissolved in dichloromethane (50 mL), dihydropyran (19.5 g,230 mmol) and p-toluenesulfonic acid monohydrate (0.44 g,2.3 mmol) are added and stirred at 30℃for 20 hours. TLC monitoring showed that the starting material had reacted, saturated aqueous sodium bicarbonate (20 mL) was added, the solution was separated, and the aqueous phase was extracted with dichloromethane (40 mL. Times.3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=10/1) to give 7-bromo-3- (tetrahydro-2H-pyran-2-yl) -3H-imidazo [4,5-b ] pyridine (6.0 g, yield 92%).
MS(ESI)M/Z:282.1[M+H + ].
Step 2: 7-bromo-3- (tetrahydro-2H-pyran-2-yl) -3H-imidazo [4,5-b]Pyridine (6.0 g,21.3 mmol) in a mixed solvent of tetrahydrofuran and triethylamine (V) THF /V TEA =2/3, 175 mL). Under the protection of nitrogen, cuI (0.39 g,0.23 mmol) and Pd (dppf) Cl are added in sequence 2 (1.6 g,2.1 mmol) and triisopropylsilane acetylene (13.5 g,63.9 mmol). The reaction system was warmed to 60 ℃ and stirred for 20 hours. The reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=10/1) to give 3- (tetrahydro-2H-pyran-2-yl) -7- (triisopropylsilane) ethynyl) -3H-imidazo [4,5-b]Pyridine (6.8 g, 83% yield).
MS(ESI)M/Z:384.0[M+H + ].
Step 3: 3- (tetrahydro-2H-pyran-2-yl) -7- (triisopropylsilane) ethynyl) -3H-imidazo [4,5-b ] pyridine (6.8 g,17.8 mmol) is dissolved in dichloromethane (70 mL), cooled to 0℃and a solution of hydrogen chloride in ethyl acetate (4M, 14mL,56 mmol) is added and stirred at room temperature for 2 hours. TLC monitoring showed that the starting material was reacted, ph=8 to 9 was adjusted by slowly adding saturated aqueous sodium bicarbonate, the solution was separated, and the aqueous phase was extracted with ethyl acetate (40 ml×3 times). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=10/1) to give 7- ((triisopropylsilane) ethynyl) -3H-imidazo [4,5-b ] pyridine (4.0 g, yield 75%).
MS(ESI)M/Z:300.1[M+H + ].
Step 4: 7- ((triisopropylsilane) ethynyl) -3H-imidazo [4,5-b ] pyridine (1.0 g,3.3 mmol) is dissolved in dichloromethane (10 mL), m-CPBA (864 mg,5.0 mmol) is added with ice-bath cooling, and the reaction system is naturally warmed to 30deg.C and stirred for 20 hours. TLC monitoring showed that the starting material had reacted, saturated aqueous sodium bicarbonate (20 mL) was added, the solution was separated, and the aqueous phase was extracted with ethyl acetate (40 mL. Times.2). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=3/1) to give 7- ((triisopropylsilane) ethynyl) -3H-imidazo [4,5-b ] pyridine-4-oxide (700 mg, yield 67%).
MS(ESI)M/Z:316.3[M+H + ].
Step 5: 7- ((triisopropylsilane) ethynyl) -3H-imidazo [4,5-b ] pyridine-4-oxide (700 mg,2.2 mmol) was dissolved in DMF (20 mL), cooled to 0℃and methanesulfonyl chloride (380 mg,3.3 mmol) was added dropwise, and the reaction system was warmed to 80℃and stirred for 5 hours. TLC monitoring showed that the starting material was reacted, the reaction solution was cooled to room temperature, saturated aqueous sodium bicarbonate solution was added to adjust ph=8 to 9, and the mixture was extracted with ethyl acetate (40 ml×2 times). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1) to give 5-chloro-7- (triisopropylsilane) ethynyl) -3H-imidazo [4,5-b ] pyridine (400 mg, yield 54%).
MS(ESI)M/Z:333.9[M+H + ].
Step 6: 5-chloro-7- (triisopropylsilane) ethynyl) -3H-imidazo [4,5-b ] pyridine (400 mg,1.2 mmol) is dissolved in dichloromethane (10 mL), dihydropyran (1.0 g,12.0 mmol) and p-toluenesulfonic acid monohydrate (22 mg,0.12 mmol) are added and stirred at 30℃for 20 hours. TLC monitoring showed that the starting material had reacted, saturated aqueous sodium bicarbonate (20 mL) was added, the solution was separated, and the aqueous phase was extracted with dichloromethane (20 mL. Times.3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=20/1) to give 5-chloro-3- (tetrahydro-2H-pyran-2-yl) -7- (triisopropylsilane) ethynyl) -3H-imidazo [4,5-b ] pyridine (450 mg, yield 90%).
MS(ESI)M/Z:418.3[M+H + ].
Step 7: 5-chloro-3- (tetrahydro-2H-pyran-2-yl) -7- (triisopropylsilane) ethynyl) -3H-imidazo [4,5-b]Pyridine (126 mg,0.3 mmol) and 2-methoxy-3- (4, 5-tetramethyl-1, 3, 2-dioxolan-2-yl) benzonitrile (156 mg,0.6 mmol) in a mixed solvent of 1, 4-dioxane and water (V Dioxahexacyclic ring /V Water and its preparation method =3/1, 12 mL). Cesium carbonate (300 mg,0.9 mmol) and Pd (dppf) Cl were added sequentially under nitrogen blanket 2 (22 mg,0.03 mmol). The reaction system was warmed to 98℃and stirred for 20 hours. The reaction solution was cooled to room temperature, extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=5/1) to give 2-methoxy-3- (3- (tetrahydro-2H-pyran-2-yl) -7- (triisopropylsilane) ethynyl) -3H-imidazo [4,5-b]Pyridin-5-yl) benzonitrile (140 mg, 91% yield).
MS(ESI)M/Z:515.4[M+H + ].
Step 8: 2-methoxy-3- (3- (tetrahydro-2H-pyran-2-yl) -7- (triisopropylsilane) ethynyl) -3H-imidazo [4,5-b]Pyridine-5-yl) benzonitrile (140 mg,0.27 mmol) was dissolved in THF (10 mL), cooled to-10deg.C, and TBAF.3H was added 2 O (103 mg,0.32 mmol), and the reaction system was warmed to 0deg.C and stirred for 0.5 hrWhen (1). TLC monitoring showed that the starting material had reacted, to the reaction mixture was added saturated ammonium chloride solution (10 mL), and extracted with ethyl acetate (20 mL. Times.3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 3- (7-ethynyl-3- (tetrahydro-2H-pyran-2-yl) -3H-imidazo [4, 5-b) ]Pyridin-5-yl) -2-methoxybenzonitrile (80 mg, crude) was used directly in the next reaction.
MS(ESI)M/Z:359.1[M+H + ].
Step 9: 3- (7-ethynyl-3- (tetrahydro-2H-pyran-2-yl) -3H-imidazo [4,5-b]Pyridin-5-yl) -2-methoxybenzonitrile (80 mg, crude) in a mixed solvent of t-butanol, water and tetrahydrofuran (V Tert-butanol /V Water and its preparation method /V Tetrahydrofuran (THF) =5/5/2, 12 mL). 2- (6- (azidomethyl) pyridin-2-yl) propan-2-ol (52 mg,0.27 mmol), copper sulfate pentahydrate (1 mg, 0.04 mmol) and sodium ascorbate (4 mg,0.02 mmol) were added sequentially under nitrogen. The reaction was warmed to 60 ℃ and stirred overnight. The reaction solution was cooled to room temperature, water (30 m 1) was then added, the mixture was extracted with ethyl acetate (30 ml×3 times), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by high performance liquid chromatography to give 3- (7- (1- ((6- (2-hydroxy-prop-2-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -3- (tetrahydro-2H-pyran-2-yl) -3H-imidazo [4, 5-b)]Pyridin-5-yl) -2-methoxybenzonitrile (40 mg, 27% two-step yield).
MS(ESI)M/Z:551.4[M+H] + .
Step 10: 3- (7- (1- ((6- (2-hydroxy-prop-2-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -3- (tetrahydro-2H-pyran-2-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) -2-methoxybenzonitrile (40 mg,0.07 mmol) was dissolved in dichloromethane (5 m 1) and a solution of hydrogen chloride in ethyl acetate (3.7M, 0.1mL,0.37 mmol) was added with ice-cooling. The reaction was stirred at room temperature for 2 hours, isopropyl ether (5 m 1) was added, a solid was precipitated, filtration was performed, the cake was added to a saturated aqueous sodium hydrogencarbonate solution (10 mL), extracted with ethyl acetate (30 ml×3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to give 3- (7- (1- ((6- (2-hydroxy-prop-2-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) -2-methoxybenzonitrile (28 mg, yield 83%).
MS(ESI)M/Z:467.5[M+H + ]. 1 H NMR(400MHz,DMSO-d6):δ13.44(s,1H),9.23(s,1H),8.60(s,1H),8.39(s,1H),8.09(dd,J＝8.0,1.6Hz,1H),7.90(dd,J＝7.6,1.6Hz,1H),7.81(t,J＝7.6Hz,1H),7.61(d,J＝8.0Hz,1H),7.46(t,J＝7.6Hz,1H),7.19(t,J＝7.6Hz,1H),5.89(s,2H),5.23(s,1H)3.74(s,3H),1.39(s,6H).
The following target products were prepared by the synthetic method of reference examples b-33:
examples b-50:
preparation of 3- (7- (1- (benzo [ d ] [1,3] dioxin-4-ylmethyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) -2-methylbenzonitrile (Compound b-50)
The reaction steps are as follows:
referring to the procedure of example b-31, (R) - (6- (3- (tert-butyldimethylsilyloxy) pyrrolin-1-yl) pyridin-2-yl) methanol was replaced with benzo [ d ] [1,3] dioxin-4-yl) methanol to give the final product 3- (7- (1- (benzo [ d ] [1,3] dioxin-4-ylmethyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) -2-methylbenzonitrile (140 mg).
MS(ESI)M/Z:436.3[M+H + ]. 1 H NMR(400MHz,DMSO-d6):δ13.42(s,1H),9.09(s,1H),8.59(s,1H),7.98(s,1H),7.90-7.80(m,2H),7.53(t,J＝8.0Hz,1H),6.96-6.87(m,3H),6.07(s,2H),5.76(s,2H),2.51(s,3H).
Examples b-51:
preparation of 3- (7- (1- (2-fluoro-3- (2-hydroxypropyl-2-yl) benzyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) -2-methylbenzonitrile (Compound b-51)
The reaction steps are as follows:
step 1: ((3-bromo-2-fluorobenzyl) oxy) (tert-butyl) dimethylsilane (1.2 g,3.8 mmol) was dissolved in a mixed solution of methanol and dimethyl sulfoxide (V Methanol /V Dimethyl sulfoxide Triethylamine (0.9 g,8.9 mmol), palladium acetate (80 mg,0.36 mmol) and 1.3-bis-diphenylphosphinopropane (160 mg,0.39 mmol) were added sequentially and stirred under reflux at 80 ℃ for 16 hours under a pressure atmosphere of 8 kg carbon monoxide. TLC monitoring showed the starting material disappeared, cooled to room temperature, the catalyst was removed by filtration, and the filtrate was depressurized Concentrating. The residue was dissolved in ethyl acetate (60 mL), washed 2-3 times with water, 1 time with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 3- (((t-butyldimethylsilyl) oxy) methyl) -2-fluorobenzoate (800 mg, yield 34%). MS (ESI) M/Z299.1 [ M+H ] + ].
Step 2: to the flask was added methyl magnesium bromide (6.0 mL,18.2mmol,3M in 2-methyltetrahydrofuran) under nitrogen, cooled to 0deg.C, and a solution of methyl 3- (((tert-butyldimethylsilyl) oxy) methyl) -2-fluorobenzoate (800 mg,2.7 mmol) in dry tetrahydrofuran (5 mL) was added dropwise over a period of about 20 minutes, and the mixture was stirred at room temperature for 3 hours after completion of the dropwise addition. TLC monitoring showed the disappearance of starting material and the reaction was quenched with saturated ammonium chloride solution (30 mL) in ice bath and extracted with ethyl acetate (50 mL x 2 times). The organic layers were combined, washed with saturated brine (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2- (3- (((tert-butyldimethylsilyl) oxy) methyl) -2-fluorophenyl) propan-2-ol (300 mg, yield 38%). MS (ESI) M/Z299.2 [ M+H ]] + .
Step 3: 2- (3- (((tert-Butyldimethylsilyl) oxy) methyl) -2-fluorophenyl) propan-2-ol (300 mg,1.0 mmol) was dissolved in tetrahydrofuran (10 mL), tetrabutylammonium fluoride (316 mg,1.2 mmol) was added, and stirred at room temperature for 12 hours. TLC monitoring showed the disappearance of starting material, which was diluted with ethyl acetate (20 mL), washed with water (100 mL. Times.3) and then with saturated brine (30 mL. Times.2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2- (2-fluoro-3- (hydroxymethyl) phenyl) propan-2-ol (190 mg, crude). MS (ESI) M/Z185.1 [ M+H ] ] + . 1 H NMR(400MHz,CDCl 3 ):δ7.49(d,J＝7.6Hz,1H),7.34(t,J＝6.8Hz,1H),7.13(t,J＝7.6Hz,1H),4.76(s,2H),1.64(s,6H).
Subsequent procedure reference the preparation procedure of example b-29 substituting 2- (2-fluoro-3- (hydroxymethyl) phenyl) propan-2-ol for 2- (3- (hydroxymethyl) phenyl) propan-2-ol to give the final product 3- (7- (1- (2-fluoro-3- (2-hydroxypropyl-2-yl) benzyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) -2-methylbenzonitrile (160 mg).
MS(ESI)M/Z:468.1[M+H + ]. 1 H NMR(400MHz,DMSO-d6):δ13.45(s,1H),9.13(s,1H),8.58(s,1H),7.96(s,1H),7.87(d,J＝7.6Hz,1H),7.80(d,J＝7.6,Hz,1H),7.64(t,J＝8.0Hz,1H),7.53(t,J＝7.6Hz,1H),7.26(t,J＝7.6Hz,1H),7.19(t,J＝7.6Hz,1H),5.84(s,2H),5.34(s,2H),2.53(s,3H),1.48(s,6H).
Examples b-52:
preparation of 3- (7- (1- ((6- (3- (2-hydroxypropyl-2-yl) azetidin-1-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) benzonitrile (Compound b-52)
The reaction steps are as follows:
step 1: 2-bromo-6- ((tert-butyldimethylsilyloxy) methyl) pyridine (1.4 g,4.7 mmol), 2- (azetidin-3-yl) propan-2-ol hydrochloride (850 mg,5.6 mmol), cesium carbonate (3.0 g,9.3 mmol), palladium acetate (105 mg,0.47 mmol) and 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine (290 mg,0.47 mmol) were dissolved in toluene (30 mL), replaced with nitrogen three times, and heated to 120℃under reflux and stirred for 2 hours. LCMS monitoring indicated complete reaction of starting material, cooling the reaction to room temperature, and adding water (20 mL). The mixture was extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=1/5) to give 2- (1- (6- ((tert-butyldimethylsilyloxy) methyl) pyridin-2-yl) azetidin-3-yl) propan-2-ol (600 mg, yield 38%). MS (ESI) M/Z337.3 [ M+H ] + ].
Step 2: 2- (1- (6- ((tert-Butyldimethylsilyloxy) methyl) pyridin-2-yl) azetidin-3-yl) propan-2-ol (600 mg,1.8 mmol) was dissolved in tetrahydrofuran (5 mL), tetrabutylammonium fluoride (560 mg,2.1 mmol) was added with ice-cooling, and the mixture was stirred at room temperature for 2 hours. LCMS monitoring shows the completion of the reaction of the starting materials, adding water (10 mL), mixingThe solution was extracted with ethyl acetate (40 mL. Times.2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2- (1- (6- (hydroxymethyl) pyridin-2-yl) azetidin-3-yl) propan-2-ol (350 mg, yield 88%). MS (ESI) M/Z222.8 [ M+H ] + ].
Step 3: 2- (1- (6- (hydroxymethyl) pyridin-2-yl) azetidin-3-yl) propan-2-ol (350 mg,1.6 mmol) was dissolved in a mixed solution of toluene and tetrahydrofuran (V) Toluene (toluene) /V Tetrahydrofuran (THF) =5/1, 6 ml), cooled to 0-5 ℃, DPPA (492 mg,1.8 mmol) and DBU (2793 mg,1.8 mmol) were added. The reaction system was naturally warmed to room temperature and stirred for 5 hours. To the reaction mixture was added water (10 mL) to quench the reaction. The mixture was extracted with ethyl acetate (40 ml×2 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=1/10) to give 2- (1- (6- (azidomethyl) pyridin-2-yl) azetidin-3-yl) propan-2-ol (120 mg, yield 31%). MS (ESI) M/Z248.1 [ M+H ] + ].
Subsequent procedure reference was made to the preparation procedure of example b-33, starting from 2- (1- (6- (azidomethyl) pyridin-2-yl) azetidin-3-yl) propan-2-ol and 5-chloro-3- (tetrahydro-2H-pyran-2-yl) -7- ((triisopropylsilyl) ethynyl) -3H-imidazo [4,5-b ] pyridine, the final product 3- (7- (1- ((6- (3- (2-hydroxypropyl-2-yl) azetidin-1-yl) pyridin-2-yl) methyl) -1H-1,2, 3-triazol-4-yl) -3H-imidazo [4,5-b ] pyridin-5-yl) benzonitrile (14 mg) is obtained by a four-step reaction.
MS(ESI)M/Z:492.3[M+H + ]. 1 H NMR(400MHz,DMSO-d6):δ9.23(s,1H),8.65-8.43(m,4H),7.92(d,J＝8.0Hz,1H),7.75(t,J＝8.0Hz,1H),7.50(t,J＝8.0Hz,1H),6.48(d,J＝7.2Hz,1H),6.31(d,J＝8.0Hz,1H),5.69(s,2H),4.43(s,1H),3.84-3.82(m,4H),1.27-1.23(m,1H),1.01(s,6H).
Biological Activity assay
Test example 1: evaluation of antagonism of the Compounds of the invention on the human adenosine A2a/A2b receptor
The experiment uses fluorescence resonance energy transfer (TR-FRE)T) method for detecting cAMP levels test compounds antagonism of human adenosine A2a/A2b and results in half inhibitory concentration IC of compounds for reducing cAMP levels after antagonism of human adenosine A2a/A2b 50 。
1. Experimental materials
Culture medium, FBS,100 XPen/Strep was purchased from Gibico; cAMP kit is available from Perkin Elmer;
rolipram, forskolin, NECA available from Sigma; ZM241385 is purchased from MCE company.
2. Experimental method
1) cAMP buffer was prepared as follows
Reagent Vol
1x HBSS with Ca 2+ and Mg 2+ 14ml
1M HEPES 75μl
7.5％(w/v)BSA stabilizer(pH 7.4) 200μl
20mM Rolipram 7.5μl
2) The Eu-cAMP tracker working solution and Ulight-anti-cAMP working solution were prepared as follows
3) Digestion of HEK293 cells stably transfected with ADORA2A/ADORA2B receptor were counted by a cytometer (more than 85% of live cells were available for subsequent experiments) and diluted to 2X10 with cAMP buffer, respectively 4 Cell/ml, 5X10 4 Cells/ml.
4) Cells of different densities were plated per well in 384 well plates (200/well HEK293-ADORA2A, 500/well HEK293-ADORA 2B).
5) EC50 and EC90 concentrations of NECA were determined:
a) 1000 XNECA concentration gradient stock (12 gradient, initial concentration 0.1mmol/L,1:3 dilution) was prepared.
b) 1000 XZM 241385 concentration gradient stock (10 gradient, initial concentration 0.3mmol/L,1:3 dilution) was prepared.
c) A1000 Xdestination compound concentration gradient stock (10 gradient, initial concentration 1mmol/L or 10mmol/L,1:3 dilution) was prepared.
d) 10nl of NECA stock (1000X) was added to 384 well plates of spread cells and incubated at 25℃for 10 min
e) Eu-cAMP tracker working solution and Ulight-anti-cAMP working solution were centrifuged at 1000rpm for 1 minute and 600rpm for 2 minutes each at 5ul per well.
f) EnVision read plates (λex=320 nm, λem=315 nm and 665 nm), comparing ratios of 665nm/615nm and plotting X-axis for different compound concentrations, the EC50 and EC90 concentrations of NECA were calculated.
6) Based on the calculated concentration, NECA stock (100% v/v in DMSO) was prepared at 1000 XEC 90 concentration.
7) 10nl of ZM241385 gradient stock and test compound gradient stock prepared per well were transferred with Echo in 384 well plates with cells spread.
8) Centrifuge at 1000rpm for 1 min, shake at 600rpm for 2 min, incubate 384 well plates in 37 degree incubator.
9) 10nl 1000 XEC90 concentration NECA was added to each well, centrifuged at 1000rpm for 1 min, and the 384 well plates were incubated at 25℃with shaking at 600rpm for 2 min.
10 Eu-cAMP tracker working solution and Ulight-anti-cAMP working solution 5ul each per well were centrifuged at 1000rpm for 1 minute and shaken at 600rpm for 2 minutes.
11 EnVision plate (λex=320 nm, λem=315 nm and 665 nm), comparing the ratios of 665nm/615nm and plotting X-axis according to the different compound concentrations, the IC50 concentration of the test compound is calculated.
The compound has better inhibition effect on A2a and/or A2b receptor and IC thereof 50 Values generally below 1000nmol/L; IC for A2a and/or A2b receptors of a part of the Compounds of the invention 50 IC of the compound of the present invention having a value of less than 100 nmol/L, more excellent 50 The value is lower than 10nmol/L, even lower than 1nmol/L. The results of partial compounds of the invention on inhibition of the human adenosine A2a/A2b receptor are shown in tables 1a and 1b.
TABLE 1A inhibition of the cAMP signaling pathway for the human adenosine A2a/A2b receptor
Examples A2a IC 50 A2b IC 50
a-1 B C
a-2 C F
a-3 B C
a-4 B E
a-5 D F
a-6 B E
a-7 D F
a-8 A C
a-9 D F
a-10 A B
a-11 B B
a-12 B C
a-13 A B
a-14 A C
a-15 A C
a-16 A C
a-17 A B
a-18 A B
a-19 B C
a-20 B B
a-21 A B
a-22 A B
a-23 C E
a-24 B D
a-25 A B
a-26 B B
a-27 C E
a-28 A B
a-29 A B
a-30 B B
a-31 C E
a-32 A B
a-33 A B
a-34 A B
a-35 A B
a-36 B C
a-37 A B
a-38 A B
a-39 A B
a-40 A B
a-41 B D
a-42 A B
a-43 A B
a-44 B B
a-45 B B
a-46 A B
TABLE 1b inhibition of cAMP signaling pathway by partial example compounds of the invention
Examples A2a IC 50 (nM) A2b IC 50 (nM)
b-1 B B
b-2 B B
b-3 B B
b-4 B B
b-5 B B
b-6 B C
b-7 C D
b-8 B B
b-9 B B
b-10 A B
b-11 C B
b-12 A B
b-13 B C
b-14 C B
b-15 C B
b-16 C C
b-17 B B
b-18 C C
b-19 B B
b-20 C B
b-21 B B
b-22 C B
b-23 C C
b-24 C C
b-25 B B
b-26 B B
b-27 B B
b-28 C B
b-29 B B
b-30 C C
b-31 B B
b-32 B B
b-33 B B
b-34 A B
b-35 C C
b-36 A B
b-37 B B
b-38 B B
b-39 A B
b-40 A B
b-41 A B
b-42 B B
b-43 B B
b-44 A A
b-45 B B
b-46 B B
b-47 B B
b-48 B B
b-49 B B
b-50 C B
b-51 B B
b-52 B B
Note that: a represents IC 50 <1nmol/L; b represents IC 50 1-10nmol/L; c represents IC 50 10-50nmol/L; d represents 50-100nmol/L; e represents IC 50 100-500nmol/L; f represents IC 50 >500nmol/L；
As can be seen from tables 1a and 1b, the compounds of the present invention have a good inhibitory effect on both human adenosine A2a and A2b receptors.
Test example 2: evaluation of antagonism of the inventive Compounds on the human adenosine A1/A3 receptor
The test uses fluorescence resonance energy transfer (TR-FRET) to test the antagonism of the compound to human adenosine A1/A3, and obtains the half inhibition concentration IC of the compound to reduce the cAMP level after antagonizing human adenosine A1/A3 50 。
1. Experimental materials
Culture medium, FBS,100 XPen/Strep were purchased from Gibico, and cAMP kit was purchased from Perkin Elmer. Rolipram, forskolin, NECA, DPCPX was purchased from Sigma corporation. MRS 1220 is available from Tocres corporation.
2. Experimental method
1) cAMP buffer was prepared as follows
Reagent Vol
1x HBSS with Ca 2+ and Mg 2+ 14ml
1M HEPES 75μl
7.5％(w/v)BSA stabilizer(pH 7.4) 200μl
20mM Rolipram 7.6μl
2) Eu-cAMP tracker working solution and Ulight-anti-cAMP working solution were prepared as follows
3) Digestion of CHO cells stably transfected with ADORA1 receptor/CHO-K1 cells stably transfected with ADORA3 were counted by a cytometer (more than 85% of live cells were available for subsequent experiments) and diluted 2X10 with cAMP buffer, respectively 5 Cells/ml.
4) 2000 cells per well were plated in 384 well plates.
5) EC50 and EC90 concentrations of Forskolin were determined:
a) A1000 XForskolin/NECA concentration gradient stock (12 gradient, starting concentration 100mmol/L or 1mmol/L,1:3 dilution) was prepared.
b) 1000 XDPCPX/MRS 1220 concentration gradient stock solution (10 gradient, initial concentration 0.3mmol/L,1:3 dilution) was prepared.
c) A1000 Xdestination compound concentration gradient stock (10 gradient, initial concentration 10mmol/L,1:3 dilution) was prepared.
d) 10nl of a concentration gradient Forskolin stock (1000X) was added to 384 well plates of spread cells and incubated for 10 minutes at 25 ℃
e) Eu-cAMP tracker working solution and Ulight-anti-cAMP working solution were centrifuged at 1000rpm for 1 minute and 600rpm for 2 minutes each at 5ul per well.
f) EnVision read plates (λex=320 nm, λem=315 nm and 665 nm), comparing ratios of 665nm/615nm and plotting X-axis for different compound concentrations, the EC50 and EC90 concentrations of NECA were calculated.
6) Based on the calculated concentration, a 1000 XEC 90 concentration of Forskolin stock (100% v/v in DMSO) was prepared.
7) EC50 and EC90 concentrations of NECA were determined:
a) Forskolin stock (1000X) was added to 384 well plates of spread cells at 10nl concentration gradient NECA and EC90 concentration, followed by incubation at 25℃for 10 minutes
b) Eu-cAMP tracker working solution and Ulight-anti-cAMP working solution were centrifuged at 1000rpm for 1 minute and 600rpm for 2 minutes each at 5ul per well.
c) EnVision read plates (λex=320 nm, λem=315 nm and 665 nm), comparing ratios of 665nm/615nm and plotting X-axis for different compound concentrations, the EC50 and EC90 concentrations of NECA were calculated.
8) 10nl of DPCPX/MRS1220 with different concentration gradients was added to 384 well plates and incubated at 37 ℃. Centrifuge at 1000rpm for 1 minute and shake at 600rpm for 2 minutes.
9) The EC90 concentration stock of 10nl 1000X Forskolin and NECA was added to 384 well plates, centrifuged at 1000rpm for 1 minute and shaken at 600rpm for 2 minutes. Incubate at 25 degrees.
10 Eu-cAMP tracker working solution and Ulight-anti-cAMP working solution 5ul each per well were centrifuged at 1000rpm for 1 minute and shaken at 600rpm for 2 minutes.
11 EnVision plate (λex=320 nm, λem=315 nm and 665 nm), comparing the ratios of 665nm/615nm and plotting X-axis according to the different compound concentrations, the EC50 of the test compound is calculated.
By measuring the compounds of the present invention, the inhibition of A1/A3 adenosine receptors by some of the compounds of the present invention was relatively weak, and the inhibition results of human adenosine A1/A3 receptors by some of the compounds of the present invention are shown in tables 2a and 2b.
TABLE 2 inhibition of the cAMP signaling pathway for the human adenosine A1/A3 receptor
Examples A1IC 50 A3IC 50
a-1 D F
a-3 B E
a-8 C E
a-10 B D
a-11 B D
a-12 D E
a-13 B E
a-14 B E
a-15 B E
a-17 B D
a-18 B D
a-19 C F
a-20 B E
a-21 B E
a-22 C F
a-25 A D
a-26 B E
a-28 B E
a-29 B E
a-30 C E
a-32 B E
a-33 B D
a-34 B E
a-35 A E
a-37 A E
a-38 A E
a-39 B E
a-40 B E
a-42 B E
a-43 C F
TABLE 2b inhibition of the cAMP signaling pathway for the human adenosine A1/A3 receptor
Examples A1IC 50 A3IC 50
b-1 B B
b-2 D C
b-3 C B
b-4 C B
b-5 D B
b-6 C C
b-8 E C
b-9 C B
b-10 B B
b-12 B B
b-17 C C
b-19 C C
b-21 C C
b-25 B C
b-26 D C
b-29 B C
b-33 D C
b-34 A A
b-36 B A
b-38 C C
b-39 C B
b-40 B B
b-44 A B
b-45 C C
Note that: a represents IC 50 <1nmol/L; b represents IC 50 1-10nmol/L; c represents IC 50 10-50nmol/L; d represents 50-100nmol/L; e represents IC 50 100-500nmol/L; f represents IC 50 >500nmol/L；
As can be seen from tables 2a and 2b, some of the compounds of the present invention have relatively weak inhibitory effects on A1 or/and A3, and exhibit selectivity to A2a/A2 b.

Claims (22)

  1. A compound according to formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof:
    wherein R is 2 H, CN, halogen atom, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, N (Re) (Rf) or Ar;
    re and Rf are independently H, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 alkyl-CO-, C 1-4 haloalkyl-CO-, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; or Re and Rf together with the attached N atom form a 4-6 membered ring, said 4-6 membered ring optionally being substituted with one or more groups selected from CN, OH, C 1-4 Alkyl, C 1-4 Haloalkyl and substituents of halogen atoms;
    ar is aryl or heteroaryl; the aryl group is preferably phenyl or naphthyl; the heteroaryl group is preferably a 5-6 membered heteroaryl ring; the aryl or heteroaryl groups are optionally independently substituted with one or more Rc;
    ra is independently H, CN, NH 2 CO-, halogen atom, C 1-4 Alkyl, C 1-4 Haloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, aryl or 5-6 membered heteroaryl; ra is optionally substituted with one or more groups selected from halogen atoms, CN, C 1-4 Alkyl and C 1-4 A substituent of a haloalkyl group;
    rb is independently H, CN, C 1-4 Alkyl, C 1-4 Haloalkyl or halogen atom;
    rc is independently H, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, CN and halogen atoms;
    X 1 is N or C-Ra;
    X 2 、X 3 、X 4 is independently O, S, N, N-Ra, CH 2 C-Ra or c=o;
    Z 1 is selected from N or CH;
    Y 1 、Y 2 、Y 3 independently N and C-Rb;
    l is- (CH) 2 )n-、-(CD 2 )n-、-NH-(CH 2 )n-、-O-(CH 2 ) n-or-S- (CH) 2 )n-；
    Selected from aryl and 5-6 membered heteroaryl;
    R 1 is independently H, CN, halogen atom, NH 2 aminocarbonyl-C 1-4 Alkyl, C 1-4 Alkylsulfonyl, C 1-4 Alkylsulfonyl radicalsAmino, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 alkyl-O-C 1-4 Alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, 5-13 membered spirocyclic group, 5-13 membered heterospirocyclic group, 6-12 membered bridged cyclic group, 6-12 membered heterobridged cyclic group, phenyl, 5-6 membered heteroaryl, and di-C 1-4 Alkyl P (O) -, 3-7 membered cycloalkyl-O-C 1-4 Alkyl, 3-7 membered heterocycloalkyl-O-C 1-4 Alkyl and phenoxy-C 1-4 An alkyl group; r is R 1 Optionally substituted by one or more substituents selected from methyl, methoxy, ethyl, isopropyl, OH, CN, halogen atoms, COOH and 2-hydroxy-prop-2-yl;
    Alternatively, two adjacent R 1 Cyclized together with the atoms to which they are attached to form a saturated 5-6 membered ring or an unsaturated 5-6 membered ring, the saturated 5-6 membered ring and the unsaturated 5-6 membered ring optionally being substituted with one or more substituents selected from C 1-4 Alkyl, C 1-4 Substituents for alkoxy groups and halogen atoms;
    m is 0, 1, 2 or 3;
    n is 0, 1, 2 or 3;
    represents a single bond or a double bond.
  2. The compound, pharmaceutically acceptable salt thereof, solvate thereof, or solvate of a pharmaceutically acceptable salt thereof according to claim 1, wherein N (Re) (Rf) is selected from NH 2 Tetrahydropyrrolyl, piperidinyl, piperazinyl, and morpholinyl;
    and/or, in Ar, the heteroaryl is selected from the group consisting of: pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazole and thiazolyl, preferably pyridyl, furyl, pyrazolyl, thienyl;
    and/or, in Ar, the aryl and heteroaryl groups are optionally independently substituted with 1, 2, 3 or 4 Rc;
    and/or Rc is independently H, CN, F, cl, methyl, ethyl, methoxy, difluoromethyl and trifluoromethyl, preferably H, CN, F, cl, methyl, ethyl or methoxy.
  3. The compound, pharmaceutically acceptable salt thereof, solvate thereof, or solvate of a pharmaceutically acceptable salt thereof according to claim 1, wherein Ar is pyridinyl substituted with one or more Rc, or Ar is phenyl substituted with one or more Rc.
  4. The compound, pharmaceutically acceptable salt thereof, solvate thereof, or solvate of a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein Ar is selected from any one of the following structures:
  5. a compound according to any one of claims 1-3, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein Ra is independently H, CN, NH 2 CO-, halogen atom, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclohexyl, azetidine, phenyl, pyrazolyl, furyl or imidazolyl; ra is optionally substituted with one or more groups selected from halogen atoms, CN, C 1-4 Alkyl and C 1-4 A substituent of a haloalkyl group; more preferably, ra is selected from H, br, cl, F, CN, CHF 2 、CF 3 、NH 2 CO-, methyl-, pyrazolyl-, phenyl-, cyclopropyl-, and 5-methyl-furan-2-yl;
    And/or Rb is independently H, cl, F, CN, methyl, ethyl, isopropyl or trifluoromethyl, preferably H, cl, methyl or trifluoromethyl.
  6. A compound according to any one of claims 1-3, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein R 2 N (Re) (Rf); preferably, R 2 Is NH 2 。
  7. A compound according to any one of claims 1-3, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein R 2 Ar is preferably
  8. A compound according to any one of claims 1-3, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein L is CH 2 Or CD (compact disc) 2 Preferably CH 2 。
  9. A compound, pharmaceutically acceptable salt thereof, solvate thereof, or solvate of a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3,is phenyl, pyridyl, pyrimidinyl, pyrazolyl, furyl, thienyl,Pyridine is preferred.
  10. A compound according to any one of claims 1-3, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein R 1 Independently a halogen atom, C 1-4 Alkoxy, C 1-4 Haloalkoxy, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 7-9 membered nitrogen containing heterospirocyclic, phenyl or 5-6 membered heteroaryl;
    alternatively, two adjacent R 1 Cyclized together with the atoms connecting them to form a saturated 5-6 membered ring or an unsaturated 5-6 membered ring, the saturated 5-6 membered ring and the unsaturated 5-6 membered ring being a pyrazole ring, an oxazole ring, a thiazole ring, an isothiazole ring, an isoxazole ring, a pyridine ring, a pyrrole ring, a thiophene ring, a furan ring, an imidazole ring, a benzene ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring or a 1, 3-dioxolane ring.
  11. A compound according to any one of claims 1-3, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein R 1 Independently F, -OCH 3 、
    Alternatively, two adjacent R 1 And (3) withThe co-cyclisation is to the following group:
    preferably, R 1 Is that
  12. A compound according to any one of claims 1 to 3, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein the structural units areIs that Preferably isMore preferably
  13. A compound according to any one of claims 1-3, a pharmaceutically acceptable salt thereof, a solvate thereof, or a pharmaceutically acceptable linker thereof A solvate of the salt, characterized in that X 1 、X 2 、X 3 Or X 4 Any one of the following conditions is satisfied:
    (1)X 1 is N or CH; preferably X 1 CH;
    (2)X 2 、X 3 、X 4 independently C-Ra, N or N-Ra;
    (3)X 2 and X is 3 Connected by double bonds; preferably X 2 And X 3 Independently N and C-Ra;
    (4)X 2 and X is 3 Connected by single bond; preferably X 2 And X 3 Independently selected from NH, CH 2 And c=o;
    (5)X 2 s is the same as the original formula;
    (6)X 2 is S, X 3 And X 4 Independently N and C-Ra;
    (7)X 2 is S, X 3 Is CH, X 4 Is C-Ra;
    (8)X 2 is S, X 3 Is CH, X 4 Is C-Br;
    (9)X 2 is S, X 3 Is N, X 4 Is C-Ra;
    (10)X 4 s is the same as the original formula;
    (11)X 4 is S, X 2 And X 3 Independently N or C-Ra;
    (12)X 4 is S, X 2 Is C-Ra, X 3 Is N;
    (13)X 2 is O, X 3 And X 4 Independently N or C-Ra;
    (14)X 2 is N-Ra, X 3 And X 4 Independently N orC-Ra；
    (15)X 2 Is N;
    (16)X 2 is N, X 3 CH.
  14. A compound according to any one of claims 1 to 3, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein the structural unit in formula IISelected from the following structures: preferably More preferably
  15. According to claim1-3, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that Y 1 、Y 2 Or Y 3 Any one of the following conditions is satisfied:
    (1)Y 1 、Y 2 、Y 3 Are all N;
    (2)Y 1 is C-Rb, Y 2 Is N, Y 3 Is N;
    (3)Y 1 is CH, Y 2 Is N, Y 3 Is N;
    (4)Y 1 is CH, Y 2 Is CH, Y 3 Is N;
    (5)Y 1 is CH, Y 2 Is N;
    (6)Y 3 is N.
  16. A compound according to any one of claims 1-3, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein Z 1 Is C;
    and/or m is 1 or 2;
    and/or n is 1 or 2.
  17. A compound according to any one of claims 1-3, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula II-a, formula II-b, or formula II-c:
    wherein,
    X 5 n, CH or c=o; preferably X 5 Is N or CH;
    X 6 and X 7 N, O, S, NH, CH or CH independently 2 The method comprises the steps of carrying out a first treatment on the surface of the Preferably X 6 Is NH, X 7 Is N;
    represents a single bond or a double bond;
    ra is as defined in claim 1 or 5; preferably, ra is independently methyl, br, cl, CN, CHF 2 、CF 3 Or cyclopropyl;
    l is as defined in claim 1 or 8; r is R 1 As defined in any one of claims 1 and 10 to 11; m is as defined in claim 1 or 16; x is X 2 、X 3 、X 4 As defined in claim 1 or 13; y is Y 1 、Y 2 As defined in claim 1 or 15.
  18. A compound according to any one of claims 1-3, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula I ', formula I ' -a, formula I ' -b, formula I-c, formula I-d, or formula I-e:
    Wherein,
    X 4-1 and X 5-1 Independently N or CH;
    R 3 、R 4 and R is 5 Rc independently;
    R 6 is Rb;
    p is 0, 1, 2, 3 or 4;
    represents a single bond or a double bond;
    rb is as defined in claim 1 or 5; rc is as defined in claim 1 or 2; r is R 1 As defined in claim 1 or 11; m is as defined in claim 1 or 16; x is X 1 、X 2 、X 3 As defined in claim 1 or 13; y is Y 1 、Y 2 As defined in claim 1 or 15.
  19. The compound, pharmaceutically acceptable salt thereof, solvate thereof, or solvate of a pharmaceutically acceptable salt thereof according to claim 18, wherein X 4-1 Is N;
    and/or X 5-1 CH;
    and/or R 3 Is H, CH 3 、CH 3 O or Cl;
    and/or R 4 H, CH of a shape of H, CH 3 、Cl、CH 3 O, F or CN;
    and/or R 5 Is H or a halogen atom; preferably H or F;
    and/or R 6 H, C of a shape of H, C 1-4 Alkyl or C 1-4 A haloalkyl group; preferably H or CH 3 。
  20. The compound, pharmaceutically acceptable salt thereof, solvate thereof, or solvate of a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from the group consisting of:
  21. a pharmaceutical composition comprising an effective prophylactic or therapeutic amount of a compound of any one of claims 1-20, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable carriers or excipients.
  22. The use of a compound of any one of claims 1-20, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof for the manufacture of a medicament; the medicament is preferably a medicament for the treatment or/and prophylaxis of a disease or condition associated with A2a and/or A2b receptors in a mammal; the disease or disorder associated with A2a and/or A2b receptors is preferably a cancer, such as a solid or non-solid tumor.
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