CN115403584A - 2-thio-2, 3-dihydropyrimidine-4-one derivative, pharmaceutical composition, preparation method and application thereof - Google Patents

2-thio-2, 3-dihydropyrimidine-4-one derivative, pharmaceutical composition, preparation method and application thereof Download PDF

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CN115403584A
CN115403584A CN202210600006.7A CN202210600006A CN115403584A CN 115403584 A CN115403584 A CN 115403584A CN 202210600006 A CN202210600006 A CN 202210600006A CN 115403584 A CN115403584 A CN 115403584A
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宋云龙
俞立挺
李曼华
任琳
傅啸云
骆庆和
黄悦
王国成
金磊
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Abstract

The invention provides a 2-sulfo-2, 3-dihydropyrimidine-4-ketone derivative shown as a formula I, a pharmaceutical composition, a preparation method and application thereof. The compound has good MPO inhibition effect, and can be used for treating or preventing myeloperoxidase-related diseases and disorders, and preparing medicines for the diseases and disorders.

Description

2-thio-2, 3-dihydropyrimidine-4-one derivative, pharmaceutical composition, preparation method and application thereof
The present invention claims priority to prior applications entitled "2-thio-2, 3-dihydropyrimidine-4-one derivatives, pharmaceutical compositions, and methods of preparation and use thereof" filed on 26.5.2021 and the patent application number 202110580748.3 and entitled "2-thio-2, 3-dihydropyrimidine-4-one derivatives, pharmaceutical compositions, and methods of preparation and use thereof" filed on 9.10.2021 and the patent application number 202111179651.8 and entitled "2-thio-2, 3-dihydropyrimidine-4-one derivatives, pharmaceutical compositions, and methods of preparation and use thereof". The entire disclosures of both prior applications are incorporated herein by reference.
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a 2-thio-2, 3-dihydropyrimidine-4-ketone derivative, a pharmaceutical composition, and a preparation method and application thereof.
Background
Myeloperoxidase (MPO), also known as myeloperoxidase, is a heme protease of heme prosthetic groups and is one of the members of the heme peroxidase superfamily. MPO is present in the azurophil granules of cells of the myeloid lineage (mainly neutrophils and monocytes) and is a specific marker for myeloid cells. The main function of MPO is to utilize hydrogen peroxide and chlorine ions to generate hypochlorite to form MPO-H 2 O 2 The halogen system, killing microorganisms in phagocytic cells. In addition, MPO can be released to the outside of cells to destroy various target substances, such as tumor cells, platelets, NK cells, protozoa, toxins and the like, and has various effects on the body in generating and regulating inflammatory responses and the like. However, under certain conditions, MPO catalyzes the reaction to form excess oxidation productsChloric acid, 3-chlorotyrosine, nitrotyrosine, etc.), which, beyond the defense reaction of topical antioxidants, can lead to oxidative stress and oxidative tissue damage. It has been found that MPO over-activation is closely related to cardiovascular diseases, neurodegenerative diseases, tumors and inflammations.
MPO inhibitor can be combined with MPO enzyme in a reversible or irreversible mode to inhibit the activity of the MPO enzyme, so as to achieve the purpose of treating diseases. Currently no MPO inhibitors are on the market, and the MPO covalent inhibitors in clinical development are mainly BHV3241 from Bioheaven (purchased from astrazene, seq id no AZD 3241) and AZD4831 from astrazene. BHV3241 is in clinical stage three, and the indications are Multiple System Atrophy (MSA) and Amyotrophic Lateral Sclerosis (ALS). AZD4831 is in second stage of clinical application, and can be used for treating cardiovascular diseases such as heart failure. At present, no non-covalent inhibitor enters the clinic.
Although a great deal of significant research has been conducted in this field, there is a continuing need to develop more effective small molecule MPO inhibitors, and the present invention provides a novel structure of MPO inhibitors and finds that compounds having such a structure have good activity.
Disclosure of Invention
In order to improve the technical problems, the invention provides a compound shown as a formula I, a racemate, a stereoisomer, a tautomer, an isotopic marker, a solvate, a polymorph, a pharmaceutically acceptable salt or a prodrug compound thereof:
Figure BDA0003664464850000011
wherein:
a is present or absent;
when A is absent, the carbon-carbon double bond may be substituted by one or two R's selected from hydrogen, deuterium, halogen, hydroxy, mercapto, nitro, cyano, unsubstituted or optionally substituted by one, two or more R a Substituted of the following groups: amino group, C 1-40 Alkyl radical, C 1-40 Alkyloxy, C 1-40 Hydroxyalkyl, C 1-40 A halogenated alkyl group,C 1-40 Alkylamino radical, (C) 1-8 Alkyl radical) 2 Amino, amino-C 1-40 Alkyl radical, C 2-40 Alkenyl radical, C 2-40 Alkynyl, C 3-40 Cycloalkyl, 3-20 membered heterocyclyl, C 6-20 Aryl, 5-20 membered heteroaryl, C 3-40 Cycloalkylamino, 3-20 membered heterocyclylamino, C 6-20 Arylamino, 5-20 membered heteroarylamino, C 3-40 Cycloalkyloxy, 3-20 membered heterocyclyloxy, C 6-20 Aryloxy or 5-20 membered heteroaryloxy;
when A is present, A is selected from unsubstituted or optionally substituted by one, two or more R a Substituted C 3-40 Cycloalkyl radical, C 3-40 Cycloalkenyl radical, C 3-40 Cycloalkynyl, 3-to 20-membered heterocyclic group, C 6-20 Aryl or 5-20 membered heteroaryl;
each R a Identical or different, independently of one another, from hydrogen, halogen, OH, CN, NO 2 Oxo (= O), thio (= S), unsubstituted or optionally substituted by one, two or more R a1 Substituted of the following groups: c 1-40 Alkyl radical, C 1-40 Haloalkyl, C 2-40 Alkenyl radical, C 2-40 Alkynyl, C 3-40 Cycloalkyl, C 3-40 Cycloalkenyl radical, C 3-40 Cycloalkynyl group, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, C 1-40 Alkyloxy, C 2-40 Alkenyloxy radical, C 2-40 Alkynyloxy, C 3-40 Cycloalkyloxy radical, C 3-40 Cycloalkenyloxy, C 3-40 Cycloalkynyloxy, C 6-20 Aryloxy, 5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, NH 2 ；
Each R a1 Identical or different, independently of one another, from hydrogen, halogen, OH, NH 2 、CN、NO 2 Oxo (= O), C 1-40 Alkyl radical, C 1-40 Haloalkyl, C 2-40 Alkenyl radical, C 2-40 Alkynyl, C 3-40 Cycloalkyl radical, C 3-40 Cycloalkenyl radical, C 3-40 Cycloalkynyl group, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, C 1-40 Alkylamino radical, (C) 1-40 Alkyl radical) 2 An amino group;
R is selected from unsubstituted or optionally substituted by one, two or more R b Substituted of the following groups: c 1-40 Alkyl radical, C 1-40 Haloalkyl, C 2-40 Alkenyl radical, C 2-40 Alkynyl, C 3-40 Cycloalkyl, C 3-40 Cycloalkenyl radical, C 3-40 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, C 1-40 Alkyloxy, C 2-40 Alkenyloxy radical, C 2-40 Alkynyloxy, C 3-40 Cycloalkyl oxy, C 3-40 Cycloalkenyloxy, C 3-40 Cycloalkynyloxy, C 6-20 Aryloxy, 5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, NH 2 ；
Each R b Identical or different, independently of one another, from hydrogen, halogen, OH, CN, NO 2 Oxo (= O), thio (= S), unsubstituted or optionally substituted by one, two or more R b1 Substituted of the following groups: c 1-40 Alkyl radical, C 1-40 Haloalkyl, C 2-40 Alkenyl radical, C 2-40 Alkynyl, C 3-40 Cycloalkyl radical, C 3-40 Cycloalkenyl radical, C 3-40 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, C 1-40 Alkyloxy, C 2-40 Alkenyloxy radical, C 2-40 Alkynyloxy, C 3-40 Cycloalkyloxy radical, C 3-40 Cycloalkenyloxy, C 3-40 Cycloalkynyloxy, C 6-20 Aryloxy, 5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, NH 2 ；
Each R b1 Identical or different, independently of one another, from hydrogen, halogen, OH, CN, NO 2 Oxo (= O), thio (= S), unsubstituted or optionally substituted by one, two or more R b2 Substituted of the following groups: c 1-40 Alkyl radical, C 1-40 Haloalkyl, C 2-40 Alkenyl radical, C 2-40 Alkynyl, C 3-40 Cycloalkyl radical, C 3-40 Cycloalkenyl radical, C 3-40 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, C 1-40 Alkyloxy, C 2-40 Alkenyloxy radical, C 2-40 Alkynyloxy, C 3-40 Cycloalkyloxy radical, C 3-40 Cycloalkenyloxy, C 3-40 Cycloalkynyloxy, C 6-20 Aryloxy, 5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, NH 2 ；
Each R b2 Identical or different, independently of one another, from hydrogen, halogen, OH, CN, NO 2 Oxo (= O), thio (= S), unsubstituted or optionally substituted by one, two or more R b3 Substituted of the following groups: c 1-40 Alkyl radical, C 1-40 Haloalkyl, C 2-40 Alkenyl radical, C 2-40 Alkynyl, C 3-40 Cycloalkyl, C 3-40 Cycloalkenyl radical, C 3-40 Cycloalkynyl group, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, C 1-40 Alkyloxy, C 2-40 Alkenyloxy radical, C 2-40 Alkynyloxy, C 3-40 Cycloalkyloxy radical, C 3-40 Cycloalkenyloxy, C 3-40 Cycloalkynyloxy, C 6-20 Aryloxy, 5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, NH 2 ；
Each R b3 Identical or different, independently of one another, from hydrogen, halogen, OH, NH 2 、CN、NO 2 Oxo (= O), thio (= S), C 1-40 Alkyl radical, C 1-40 Haloalkyl, C 2-40 Alkenyl radical, C 2-40 Alkynyl, C 3-40 Cycloalkyl radical, C 3-40 Cycloalkenyl radical, C 3-40 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl.
According to an embodiment of the invention, when A is absent, formula I has the structure shown in formula I-1:
Figure BDA0003664464850000031
wherein R' is selected from 3-10 member heterocyclic radical, C 6-14 Aryl, 5-14 membered heteroaryl, 3-10 membered heterocyclylamino, C 6-14 Arylamino, 5-14 membered heteroarylamino, 3-10 membered heterocyclyloxy, C 6-14 Aryloxy or 5-14 membered heteroaryloxy；
When A is present, formula I has a structure represented by formula I-2, formula I-2', or formula I-3:
Figure BDA0003664464850000032
wherein:
Figure BDA0003664464850000033
represents a single bond or a double bond;
m is an integer from 0 to 4;
when formula I has a structure shown in formula I-2, D is selected from O, C (O), CH 2 Or NH; e is selected from C (O), CH or N;
when formula I has a structure as shown in formula I-2', D is selected from O, C (O), CH 2 Or NH;
Figure BDA0003664464850000034
is selected from C 3-8 Cycloalkyl radical, C 3-8 Cycloalkenyl, 3-8 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl;
each R a Identical or different, independently of one another, from hydrogen, halogen, OH, CN, NO 2 Oxo (= O), thio (= S), unsubstituted or optionally substituted by one, two or more R a1 Substituted of the following groups: c 1-8 Alkyl radical, C 1-8 Haloalkyl, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl radical, C 3-8 Cycloalkynyl, C 6-14 Aryl, 5-14 membered heteroaryl, 3-8 membered heterocyclyl, C 1-8 Alkyloxy, C 2-8 Alkenyloxy radical, C 2-8 Alkynyloxy, C 3-8 Cycloalkyl oxy, C 3-8 Cycloalkenyloxy, C 3-8 Cycloalkynyloxy, C 6-14 Aryloxy, 5-14 membered heteroaryloxy, 3-8 membered heterocyclyloxy, NH 2 ；
Each R a1 Identical or different, independently of one another, from hydrogen, halogen, OH, NH 2 、CN、NO 2 Oxo (= O), thio (= S), C 1-8 Alkyl radical, C 1-8 Hydroxyalkyl, C 1-8 Haloalkyl, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkenyl radical, C 3-8 Cycloalkynyl group, C 6-14 Aryl, 5-14 membered heteroaryl, 3-8 membered heterocyclyl, C 1-8 Alkylamino radical, (C) 1-8 Alkyl radical) 2 An amino group;
r is selected from unsubstituted or optionally substituted by one, two or more R b Substituted of the following groups: c 1-8 Alkyl radical, C 1-8 Haloalkyl, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkenyl radical, C 3-8 Cycloalkynyl group, C 6-14 Aryl, 5-14 membered heteroaryl, 3-8 membered heterocyclyl, C 1-8 Alkyloxy, C 2-8 Alkenyloxy radical, C 2-8 Alkynyloxy, C 3-8 Cycloalkyl oxy, C 3-8 Cycloalkenyloxy, C 3-8 Cycloalkynyloxy, C 6-14 Aryloxy, 5-14 membered heteroaryloxy, 3-8 membered heterocyclyloxy, NH 2 ；
Each R b Identical or different, independently of one another, from hydrogen, halogen, OH, CN, NO 2 Oxo (= O), thio (= S), unsubstituted or optionally substituted by one, two or more R b1 Substituted of the following groups: c 1-8 Alkyl radical, C 1-8 Haloalkyl, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkenyl radical, C 3-8 Cycloalkynyl group, C 6-14 Aryl, 5-14 membered heteroaryl, 3-8 membered heterocyclyl, C 1-8 Alkyloxy, C 2-8 Alkenyloxy radical, C 2-8 Alkynyloxy, C 3-8 Cycloalkyl oxy, C 3-8 Cycloalkenyloxy, C 3-8 Cycloalkynyloxy, C 6-14 Aryloxy, 5-14 membered heteroaryloxy, 3-8 membered heterocyclyloxy, NH 2 ；
Each R b1 Identical or different, independently of one another, from hydrogen, halogen, OH, CN, NO 2 Oxo (= O), thio (= S), unsubstituted or optionally substituted by one, two or more R b2 Substituted of the following groups: c 1-8 Alkyl radical, C 1-8 Haloalkyl, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkenyl radical, C 3-8 Cycloalkynyl group, C 6-14 Aryl, 5-14 membered heteroaryl, 3-8 membered heterocyclyl, C 1-8 Alkyloxy, C 2-8 Alkenyloxy radical, C 2-8 Alkynyloxy, C 3-8 Cycloalkyl oxy, C 3-8 Cycloalkenyloxy, C 3-8 Cycloalkynyloxy, C 6-14 Aryloxy, 5-14 membered heteroaryloxy, 3-8 membered heterocyclyloxy, NH 2 ；
Each R b2 Identical or different, independently of one another, from hydrogen, halogen, OH, CN, NO 2 Oxo (= O), thio (= S), unsubstituted or optionally substituted by one, two or more R b3 Substituted of the following groups: c 1-8 Alkyl radical, C 1-8 Haloalkyl, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl radical, C 3-8 Cycloalkynyl, C 6-14 Aryl, 5-14 membered heteroaryl, 3-8 membered heterocyclyl, C 1-8 Alkyloxy, C 2-8 Alkenyloxy radical, C 2-8 Alkynyloxy, C 3-8 Cycloalkyloxy radical, C 3-8 Cycloalkenyloxy, C 3-8 Cycloalkynyloxy, C 6-14 Aryloxy, 5-14 membered heteroaryloxy, 3-8 membered heterocyclyloxy, NH 2 ；
Each R b3 Identical or different, independently of one another, from hydrogen, halogen, OH, NH 2 、CN、NO 2 Oxo (= O), thio (= S), C 1-8 Alkyl radical, C 1-8 Hydroxyalkyl, C 1-8 Haloalkyl, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl radical, C 3-8 Cycloalkynyl group, C 6-14 Aryl, 5-14 membered heteroaryl, 3-8 membered heterocyclyl.
According to an embodiment of the invention, when a is absent, R' is selected from phenyl, pyridyl, imidazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, thiazolyl, pyrrolyl, pyrazolyl, phenylamino, pyridylamino, imidazolylamino, 1,2, 3-triazolylamino, 1,2, 4-triazolylamino, thiazolylamino, pyrazolyl-amino, phenyloxy, pyridyloxy, imidazolyloxy, 1,2, 3-triazolyloxy, 1,2, 4-triazolyloxy, thiazolyloxy or pyrazolyl-oxy;
When A is present, A is selected from optionally substituted by one, two or more R a Substituted by
Figure BDA0003664464850000041
Figure BDA0003664464850000042
Each R a Identical or different, independently of one another, from hydrogen, halogen, OH, unsubstituted or optionally substituted by one, two or more R a1 Substituted of the following groups: c 1-8 Alkyl radical, C 1-8 Hydroxyalkyl radical, C 1-8 Haloalkyl, C 1-8 Alkyloxy, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkenyl radical, C 3-8 Cycloalkynyl group, C 6-14 Aryl, 5-14 membered heteroaryl, 3-8 membered heterocyclyl, NH 2 ；
Each R a1 Identical or different, independently of one another, from halogen, OH, NH 2 、C 1-8 Alkyl radical, C 1-8 Hydroxyalkyl radical, C 1-8 Haloalkyl, C 3-8 Cycloalkyl radical, C 1-8 Alkylamino radical, (C) 1-8 Alkyl radical) 2 An amino group;
r is selected from unsubstituted or optionally substituted by one, two or more R b Substituted of the following groups: c 1-8 An alkyl group;
each R b Identical or different, independently of one another, from halogen, OH, unsubstituted or optionally substituted by one, two or more R b1 Substituted of the following groups: c 1-8 Alkyl radical, C 1-8 Haloalkyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, C 6-14 Aryl, 5-14 membered heteroaryl, 3-8 membered heterocyclyl, C 1-8 Alkyloxy, C 3-8 Cycloalkyloxy, 3-8 membered heterocyclyloxy,NH 2 ；
Each R b1 Identical or different, independently of one another, from halogen, OH, oxo (= O), unsubstituted or optionally substituted by one, two or more R b2 Substituted of the following groups: c 1-8 Alkyl radical, C 1-8 Haloalkyl, C 1-8 Alkyloxy, C 3-8 Cycloalkyl, 3-to 8-membered heterocyclyl, CN, NH 2 ；
Each R b2 Identical or different, independently of one another, from halogen, OH, unsubstituted or optionally substituted by one, two or more R b3 Substituted of the following groups: c 1-8 Alkyl radical, C 1-8 Haloalkyl, C 1-8 Alkyloxy, C 3-8 Cycloalkyl, CN, NH 2 ；
Each R b3 Identical or different, independently of one another, from the group consisting of halogen, OH, NH 2 、C 1-8 Alkyl radical, C 1-8 Haloalkyl, C 1-8 Alkyloxy, C 3-8 A cycloalkyl group.
According to an embodiment of the invention, the compound of formula I has the structure shown in formula I-4, formula I-5, formula I-6, formula I-7, formula I-8, formula I-9, or formula I-10:
Figure BDA0003664464850000051
wherein m, R a Having the definitions as described above.
According to an embodiment of the invention, the compound of formula I has the structure shown in formula II:
Figure BDA0003664464850000052
wherein:
Figure BDA0003664464850000053
represents a single bond or a double bond;
m is a bond, O, S, NR 5 C (O) or CR 5 R 6 ；
R 1 And R 2 Identical or different, independently of one another, from the group consisting of hydrogen, deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, C 1-8 Alkyl radical, C 1-8 Alkyloxy, C 1-8 Hydroxyalkyl radical, C 1-8 Haloalkyl, C 1-8 Alkylamino radical, (C) 1-8 Alkyl radical) 2 Amino, amino-C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said amino, C 1-8 Alkyl radical, C 1-8 Alkyloxy, C 1-8 Hydroxyalkyl, C 1-8 Haloalkyl, C 1-8 Alkylamino radical, (C) 1-8 Alkyl radical) 2 Amino, amino-C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted by deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, C 1-8 Alkyl radical, C 1-8 Alkyloxy, C 1-8 Hydroxyalkyl, C 1-8 Haloalkyl, C 1-8 Alkylamino radical, (C) 1-8 Alkyl radical) 2 Amino, amino-C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl;
R 3 and R 4 Identical or different, independently of one another, from the group consisting of hydrogen, deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, C 1-8 Alkyl radical, C 1-8 Alkyloxy, C 1-8 Hydroxyalkyl radical, C 1-8 Haloalkyl, C 1-8 Alkylamino radical, (C) 1-8 Alkyl radical) 2 Amino, amino-C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 Aryl or 5-to 14-membered heteroaryl, said amino, C 1-8 Alkyl radical, C 1-8 Alkyloxy, C 1-8 Hydroxyalkyl, C 1-8 Haloalkyl, C 1-8 Alkyl radicalAmino group, (C) 1-8 Alkyl radical) 2 Amino, amino-C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted by deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, C 1-8 Alkyl radical, C 1-8 Alkyloxy, C 1-8 Hydroxyalkyl, C 1-8 Haloalkyl, C 1-8 Alkylamino, amino-C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl;
or, R 3 And R 4 Connection formation C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, said C 3-8 Cycloalkyl and 3-8 membered heterocyclyl, optionally further substituted with deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, C 1-8 Alkyl radical, C 1-8 Alkyloxy, C 1-8 Hydroxyalkyl radical, C 1-8 Haloalkyl, C 1-8 Alkylamino radical, (C) 1-8 Alkyl radical) 2 Amino, amino-C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl;
R 5 and R 6 Identical or different, independently of one another, from the group consisting of hydrogen, deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, C 1-8 Alkyl radical, C 1-8 Alkyloxy, C 1-8 Hydroxyalkyl radical, C 1-8 Haloalkyl, C 1-8 Alkylamino radical, (C) 1-8 Alkyl radical) 2 Amino, amino-C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said amino, C 1-8 Alkyl radical, C 1-8 Alkyloxy, C 1-8 Hydroxyalkyl radical, C 1-8 Haloalkyl, C 1-8 Alkylamino radical, (C) 1-8 Alkyl radical) 2 Amino, amino-C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted by deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, C 1-8 Alkyl radical, C 1-8 Alkyloxy, C 1-8 Hydroxyalkyl, C 1-8 Haloalkyl, C 1-8 Alkylamino, amino-C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl;
or, R 5 And R 6 Connection formation C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, said C 3-8 Cycloalkyl and 3-8 membered heterocyclyl, optionally further substituted with deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, C 1-8 Alkyl radical, C 1-8 Alkyloxy, C 1-8 Hydroxyalkyl, C 1-8 Haloalkyl, C 1-8 Alkylamino radical, (C) 1-8 Alkyl radical) 2 Amino, amino-C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl;
E. m and R a Having the definitions as described above.
According to an embodiment of the invention, the compound of formula I has the structure of formula III:
Figure BDA0003664464850000061
wherein: m is N or CH;
n is 0, 1, 2, 3, 4 or 5;
m、R a and R b1 Having the definitions described above.
According to an embodiment of the invention, the compound of formula I has the structure shown in formula IV:
Figure BDA0003664464850000062
wherein G is selected from 3-8 membered heterocyclyl, e.g. G is selected from
Figure BDA0003664464850000063
X is the same or different and is independently selected from C, CH, N, NH, O, S; g may be selected in particular from the following groups:
Figure BDA0003664464850000064
Figure BDA0003664464850000071
said 3-8 membered heterocyclyl is unsubstituted or optionally substituted with one, two or more R b1 Substituted heterocyclyl radical, R a M and R b1 Having the definitions as described above.
According to an embodiment of the invention, said R is selected from the group consisting of:
Figure BDA0003664464850000072
Figure BDA0003664464850000081
according to an embodiment of the present invention, the
Figure BDA0003664464850000082
Selected from the group consisting of:
Figure BDA0003664464850000083
Figure BDA0003664464850000091
according to an embodiment of the invention, the structure of the compound of formula I is as follows:
Figure BDA0003664464850000092
Figure BDA0003664464850000101
Figure BDA0003664464850000111
Figure BDA0003664464850000121
Figure BDA0003664464850000131
the compounds of formula I of the present invention also exist as resonance structures represented by formula IA below, it being understood by those skilled in the art that resonance structure IA represents the same compound as formula I:
Figure BDA0003664464850000132
the present invention also provides a process for the preparation of a compound of formula I, comprising the steps of:
reacting the compound 1 under the action of alkali to obtain a compound shown in a formula I;
Figure BDA0003664464850000141
wherein A and R have the definitions described above; r is 0 Identical or different, independently of one another, from C 1-6 Alkyl groups such as methyl, ethyl, propyl;
according to an embodiment of the present invention, the base in scheme 1 may be an inorganic base, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide;
according to an embodiment of the present invention, the reaction may be performed in the presence of a solvent such as an organic solvent or a mixed solvent of an organic solvent and water. For example, the organic solvent may be selected from at least one of the following: alcohols such as methanol, ethanol, isopropanol, n-butanol; ethers such as ethyl propyl ether, n-butyl ether, anisole, phenetole, cyclohexylmethyl ether, dimethyl ether, diethyl ether, dimethyl glycol, diphenyl ether, propyl ether, isopropyl ether, isobutyl ether, isoamyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, methyl tert-butyl ether, tetrahydrofuran, methyl tetrahydrofuran, dioxane, dichlorodiethyl ether, and polyethers of ethylene oxide and/or propylene oxide; aliphatic, cycloaliphatic or aromatic hydrocarbons, such as pentane, hexane, heptane, octane, nonane, and hydrocarbons which may be substituted by fluorine and/or chlorine atoms, such as methylene chloride, trichloromethane, carbon tetrachloride, fluorobenzene, chlorobenzene or dichlorobenzene; cyclohexane, methylcyclohexane, petroleum ether, acetone, octane, benzene, toluene, chlorobenzene, bromobenzene, and xylene; esters such as methyl acetate, ethyl acetate, butyl acetate, isobutyl acetate and dimethyl carbonate, dibutyl carbonate or ethylene carbonate.
The invention also provides a pharmaceutical composition, which comprises at least one of a therapeutically effective amount of compound shown in formula I, racemate, stereoisomer, tautomer, isotopic label, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof.
According to an embodiment of the invention, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.
According to an embodiment of the invention, the pharmaceutical composition may further comprise one or more additional therapeutic agents.
The present invention also provides a method of treating myeloperoxidase-related diseases, comprising administering to a patient a prophylactically or therapeutically effective amount of at least one compound of formula I, its racemate, stereoisomer, tautomer, isotopic label, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound thereof.
The present invention also provides a method for treating myeloperoxidase-related diseases, which comprises administering to a patient a prophylactically or therapeutically effective amount of the above-described pharmaceutical composition.
The myeloperoxidase-associated diseases include neurodegenerative diseases (including but not limited to dementia, parkinson, multiple sclerosis, huntington's disease, amyotrophic lateral sclerosis, multiple system atrophy, aphasia), stroke, epilepsy, depression, traumatic brain injury, cardiovascular diseases (including but not limited to heart failure, atrial fibrillation, atherosclerosis, thrombosis, acute coronary syndrome, pulmonary hypertension, diabetes), novel coronavirus-associated disorders.
In some embodiments, the patient comprises a mammal, preferably a human.
The invention also provides at least one of the compounds shown in the formula I, racemates, stereoisomers, tautomers, isotopic labels, solvates, polymorphs, pharmaceutically acceptable salts or prodrug compounds thereof, or a pharmaceutical composition thereof, which is used for diseases related to myeloperoxidase.
The invention also provides application of at least one of the compounds shown in the formula I, racemates, stereoisomers, tautomers, isotopic labels, solvates, polymorphs, pharmaceutically acceptable salts or prodrug compounds thereof in preparing medicines.
According to an embodiment of the invention, the use may be in the manufacture of a medicament for the treatment of myeloperoxidase-related diseases, such as in the manufacture of a medicament for MPO inhibitors.
According to embodiments of the invention, the use may be in the manufacture of a medicament for the treatment or prevention of neurodegenerative diseases (including but not limited to dementia, parkinson, multiple sclerosis, huntington's chorea, amyotrophic lateral sclerosis, multiple system atrophy, aphasia), stroke, epilepsy, depression, traumatic brain injury, cardiovascular diseases (including but not limited to heart failure, atrial fibrillation, atherosclerosis, thrombosis, acute coronary syndrome, pulmonary hypertension, diabetes), novel coronavirus related disorders.
The medicament can be used for diseases related to myeloperoxidase.
Advantageous effects
The compound provided by the invention has good MPO inhibition effect, and can be used for treating or preventing myeloperoxidase diseases and disorders and preparing medicaments for the diseases and disorders.
Definition and description of terms
Unless otherwise indicated, the definitions of groups and terms described in the specification and claims of the present application, including definitions thereof as examples, exemplary definitions, preferred definitions, definitions described in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and coupled with each other. Such combinations and definitions of groups and structures of compounds after combination are to be understood as being within the scope of the present description and/or claims.
Unless otherwise indicated, the numerical ranges set forth in the specification and claims are equivalent to at least each specific integer recited therein. For example, a numerical range of "1 to 40" is equivalent to reciting each of the integer values in the numerical range of "1 to 10", i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and each of the integer values in the numerical range of "11 to 40", i.e., 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40. Further, when certain numerical ranges are defined as "numbers," it should be understood that the two endpoints of the range, each integer within the range, and each decimal within the range are recited. For example, "a number of 0 to 10" should be understood to recite not only each integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, but also at least the sum of each integer thereof with 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, respectively.
It should be understood that in describing 1,2 or more herein, "more" shall mean an integer greater than 2, e.g., greater than or equal to 3, e.g., 3, 4, 5, 6, 7, 8, 9, or 10.
The term "halogen" denotes fluorine, chlorine, bromine and iodine.
The term "C 1-40 Alkyl "is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having from 1 to 40 carbon atoms. For example, "C 1-10 Alkyl "denotes straight-chain and branched alkyl groups having 1,2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms," C 1-8 Alkyl "denotes straight and branched chain alkyl groups having 1,2, 3, 4, 5, 6, 7, or 8 carbon atoms," C 1-6 Alkyl "denotes straight-chain and branched alkyl groups having 1,2, 3, 4, 5 or 6 carbon atoms. The alkyl group is, for example, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, an isopropyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an isopentyl group, a 2-methylbutyl group, a 1-ethylpropyl group, a 1, 2-dimethylpropyl group, a neopentyl group, a 1, 1-dimethylpropyl group, a 4-methylpentyl group, a 3-methylpentyl group, a 2-methylpentyl group, a 1-methylpentyl group, a 2-ethylbutyl group, a 1-ethylbutyl group, a 3, 3-dimethylbutyl group, a 2, 2-dimethylbutyl group, a 1, 1-dimethylbutyl group, a 2, 3-dimethylbutyl group, a 1, 3-dimethylbutyl group or a 1, 2-dimethylbutyl group, or the like, or isomers thereof.
The term "C 2-40 Alkenyl "is understood to mean a straight-chain or branched monovalent hydrocarbon radical comprising one or more double bonds and having from 2 to 40 carbon atoms, preferably" C 2-10 Alkenyl ". "C 2-10 Alkenyl "is understood to preferably mean a straight-chain or branched monovalent hydrocarbon radical which contains one or more double bonds and has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, more preferably" C 2-8 Alkenyl ". "C 2-10 Alkenyl "is understood to preferably mean a straight-chain or branched monovalent hydrocarbon radical comprising one or more double bonds and having 2, 3, 4, 5, 6, 7 or 8 carbon atoms, for example having 2, 3, 4, 5 or 6 carbon atoms (i.e. C) 2-6 Alkenyl) having 2 or 3 carbon atoms (i.e., C) 2-3 Alkenyl). It is to be understood that where the alkenyl group comprises more than one double bond, the double bonds may be separated from each otherIonic or conjugated. The alkenyl group is, for example, vinyl, allyl, (E) -2-methylvinyl, (Z) -2-methylvinyl, (E) -but-2-enyl, (Z) -but-2-enyl, (E) -but-1-enyl, (Z) -but-1-enyl, pent-4-enyl, (E) -pent-3-enyl, (Z) -pent-3-enyl, (E) -pent-2-enyl, (Z) -pent-2-enyl, (E) -pent-1-enyl, (Z) -pent-1-enyl, hex-5-enyl, (E) -hex-4-enyl, (Z) -hex-4-enyl, (E) -hex-3-enyl, (Z) -hex-3-enyl, (E) -hex-2-enyl, (Z) -hex-2-enyl, (E) -hex-1-enyl, (Z) -hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E) -1-methylprop-1-enyl, (Z) -1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E) -2-methylbut-2-enyl, (Z) -2-methylbut-2-enyl, (E) -1-methylbut-2-enyl, (Z) -1-methylbut-2-enyl, (E) -3-methylbut-1-enyl, (Z) -3-methylbut-1-enyl, (E) -2-methylbut-1-enyl, (Z) -2-methylbut-1-enyl, (E) -1-methylbut-1-enyl, (Z) -1-methylbut-1-enyl, 1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.
The term "C 2-40 Alkynyl "is understood to mean a straight-chain or branched monovalent hydrocarbon radical comprising one or more triple bonds and having from 2 to 40 carbon atoms, preferably" C 2-10 Alkynyl ". The term "C 2-10 Alkynyl "is understood as preferably meaning a straight-chain or branched, monovalent hydrocarbon radical which contains one or more triple bonds and has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, for example 2, 3, 4, 5, 6, 7 or 8 carbon atoms (i.e." C ") 2-8 Alkynyl ") having 2, 3, 4, 5, or 6 carbon atoms (i.e.," C ") 2-6 Alkynyl ") having 2 or 3 carbon atoms (" C) 2-3 Alkynyl "). The alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2-dimethylbut-3-ynyl, 1-dimethylbut-2-ynyl or 3, 3-dimethylbut-1-ynyl. In particular, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.
The term "C 3-40 Cycloalkyl "is understood to mean a saturated monovalent monocyclic, bicyclic (e.g. fused, bridged, spiro) hydrocarbon or tricyclic hydrocarbon ring having 3 to 40 carbon atoms, preferably" C 3-10 Cycloalkyl ", more preferably" C 3-8 Cycloalkyl groups ". The term "C 3-10 Cycloalkyl "is understood to mean a saturated monovalent monocyclic, bicyclic (e.g. bridged, spiro) hydrocarbon ring or tricycloalkane having 3,4, 5, 6, 7, 8, 9 or 10 carbon atoms. Said C is 3-10 Cycloalkyl can be monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or bicyclic, such as bornyl, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo [2.1.1]Hexyl, bicyclo [2.2.1]Heptyl, bicyclo [2.2.1]Heptenyl, 6-dimethylbicyclo [3.1.1]Heptyl, 2, 6-trimethylbicyclo [3.1.1]Heptyl, bicyclo [2.2.2]Octyl, 2, 7-diazaspiro [3,5 ]]Nonanyl, 2, 6-diazaspiro [3,4 ]]An octyl group, or a tricyclic hydrocarbon group such as an adamantyl group.
Unless otherwise defined, the term "3-20 membered heterocyclyl" means a saturated or unsaturated non-aromatic ring or ring system, e.g., which is a 4-, 5-, 6-or 7-membered monocyclic, 7-, 8-, 9-, 10-, 11-or 12-membered bicyclic (e.g., fused, bridged, spiro) or 10-, 11-, 12-, 13-, 14-or 15-membered tricyclic ring system, and contains at least one, e.g., 1, 2, 3,4, 5 or more heteroatoms selected from O, S and N, wherein N and S may also be optionally oxidized to various oxidation states to form nitroxides, -S (O) -or-S (O) 2 -state of (c). Preferably, the heterocyclic group may be selected from "3-10 membered heterocyclic group". The term "3-10 membered heterocyclyl" means a saturated or unsaturated non-aromatic ring or ring system and contains at least one heteroatom selected from O, S and N. The heterocyclic group may be attached to the rest of the molecule through any of the carbon atoms or the nitrogen atom (if present). The heterocyclic group may include fused or bridged rings as well as spiro rings. In particular, the heterocyclic group may include, but is not limited to: 4-membered rings such as azetidinyl, oxetanyl; 5-membered rings such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or a 7-membered ring such as diazepanyl. Optionally, the heterocyclic group may be benzo-fused. The heterocyclic group may be bicyclic, for example but not limited to a 5,5 membered ring, such as hexahydrocyclopenta [ c ]]Pyrrole-2 (1H) -cyclic rings, or 5,6 membered bicyclic rings, e.g. hexahydropyrrolo [1,2-a ]]A pyrazin-2 (1H) -yl ring. The heterocyclyl group may be partially unsaturated, i.e. it may contain one or more double bonds, such as, but not limited to, dihydrofuranyl, dihydropyranyl, 2, 5-dihydro-1H-pyrrolyl, 4H- [1,3,4 ]Thiadiazinyl, 1,2,3, 5-tetrahydrooxazolyl or 4H- [1,4]Thiazinyl, or it can be benzo-fused, such as but not limited to dihydroisoquinolinyl. When the 3-20 membered heterocyclic group is connected with other groups to form the compound of the present invention, the carbon atom on the 3-20 membered heterocyclic group may be connected with other groups, or the heterocyclic atom on the 3-20 membered heterocyclic ring may be connected with other groups. For example, when the 3-20 membered heterocyclyl group is selected from piperazinyl, it may be that the nitrogen atom on the piperazinyl is attached to another group. Or when the 3-20 membered heterocyclyl group is selected from piperidinyl, it may be that the nitrogen atom on the piperidinyl ring and the carbon atom in the para position thereof are attached to other groups.
The term "C 6-20 Aryl "is understood to preferably mean a monocyclic, bicyclic (e.g. fused, bridged, spiro) or tricyclic hydrocarbon ring of monovalent or partial aromaticity having 6 to 20 carbon atoms, which may be monoaromatic or polyaromatic which is fused togetherGroup ring, preferably "C 6-14 Aryl ". The term "C 6-14 Aryl "is understood as preferably meaning a monocyclic, bicyclic or tricyclic hydrocarbon ring of monovalent or partial aromaticity having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms (" C) 6-14 Aryl group "), in particular a ring having 6 carbon atoms (" C 6 Aryl "), such as phenyl; or biphenyl, or is a ring having 9 carbon atoms ("C 9 Aryl), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 Aryl radicals), such as tetralinyl, dihydronaphthyl or naphthyl, or rings having 13 carbon atoms ("C 13 Aryl radicals), such as the fluorenyl radical, or a ring having 14 carbon atoms ("C) 14 Aryl), such as anthracenyl. When said C is 6-20 When the aryl group is substituted, it may be mono-or polysubstituted. And, the substitution site thereof is not limited, and may be, for example, ortho-, para-or meta-substitution.
The term "5-20 membered heteroaryl" is understood to include such monovalent monocyclic, bicyclic (e.g., fused, bridged, spiro) or tricyclic aromatic ring systems: having 5 to 20 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O and S, e.g., "5-14 membered heteroaryl". The term "5-14 membered heteroaryl" is understood to include such monovalent monocyclic, bicyclic or tricyclic aromatic ring systems: which has 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and which comprises 1 to 5, preferably 1 to 3, heteroatoms each independently selected from N, O and S and, in addition, can in each case be benzo-fused. "heteroaryl" also refers to a group in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclic rings, wherein the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include 1-, 2-, 3-, 5-, 6-, 7-or 8-indolizinyl, 1-, 3-, 4-, 5-, 6-or 7-isoindolyl, 2-, 3-, 4-, 5-, 6-or 7-indolyl, 2-, 3-, 4-, 5-, 6-or 7-indazolyl, 2-, 4-, 5-, 6-, 7-or 8-purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-or 9-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 7-or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7-or 8-isoquinolinyl, 1-, 4-, 5-, 6-, 7-or 8-phthalazinyl (phthalazinyl), 2-, 3-, 4-, 5-or 6-naphthyridinyl, 2-, 3-, 5-, 6-, 7-or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7-or 8-cinnolinyl, 2-, 4-, 6-or 7-pteridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-or 8-4 aH-carbazolyl, 1-, 2-, 3-, or, 4-, 5-, 6-, 7-or 8-carbazolylcarbazolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-or 9-carbolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-or 10-phenanthridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-or 9-pyridyl, 2-, 3-, 4-, 5-, 6-, 8-, 9-or 10-phenanthrolinyl, 1-, 6-, 7-, 8-or 10-phenanthrolinyl 2-, 3-, 4-, 6-, 7-, 8-or 9-phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-or 10-phenothiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-or 10-phenazinyl, 2-, 3-, 4-, 5-, 6-or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9-or 10-benzisoquinolinyl, 2-, 3-, 4-or thieno [2,3-b ] furyl, 2-, 3-, 5-, (a) a salt thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, <xnotran> 6-, 7-, 8-, 9-, 10- 11-7H- [2,3-c ] ,2-, 3-, 5-, 6- 7-2H- [3,2-b ] - ,2-, 3-, 4-, 5-, 7- 8-5H- [2,3-d ] - - ,1-, 3- 5-1H- [4,3-d ] - ,2-, 4- 54H- [4,5-d ] ,3-, 5- 8- [2,3-d ] ,2-, 3-, 5- 6- [2,1-b ] ,1-, 3-, 6-, 7-, 8- 9- [3,4-c ] ,1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10 11-4H- [2,3-c ] ,2-, 3-, 6- 7- [1,2-b ] [1,2,4] , 7- [ b ] ,2-, 4-, 5-, 6- 7- ,2-, 4-, 5-, 6- 7- ,2-, 4-, 4-, 5-, 6- 7- , </xnotran> 1-, 2-, 4-, 5-, 6-, 7-, 8-or 9-benzoxazinyl (benzoxapinyl), 2-, 4-, 5-, 6-, 7-or 8-benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-or 11-4H-pyrrolo [1,2-b ] [2] benzazepinyl. Typical fused heteroaryl groups include, but are not limited to, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo [ b ] thienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, and 2-, 4-, 5-, 6-, or 7-benzothiazolyl. . When the 5-20 membered heteroaryl group is linked to another group to form the compound of the present invention, the carbon atom on the 5-20 membered heteroaryl ring may be linked to another group, or the heteroatom on the 5-20 membered heteroaryl ring may be linked to another group. When the 5-20 membered heteroaryl group is substituted, it may be mono-or poly-substituted. Also, there is no limitation on the substitution site thereof, and for example, hydrogen attached to a carbon atom on a heteroaryl ring may be substituted, or hydrogen attached to a heteroatom on a heteroaryl ring may be substituted.
The term "spiro" refers to a ring system in which two rings share 1 ring atom.
The term "fused ring" refers to a ring system in which two rings share 2 ring atoms.
The term "bridged ring" refers to a ring system in which two rings share more than 3 ring-forming atoms.
Unless otherwise indicated, heterocyclyl, heteroaryl or heteroarylene include all possible isomeric forms thereof, e.g., positional isomers thereof. Thus, for some illustrative non-limiting examples, forms may be included that are substituted at 1, 2 or more of their 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-positions, etc. (if present) or bonded to other groups, including pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, and pyridin-4-yl; thienyl or thienylene groups include thien-2-yl, thien-3-yl, and thien-3-yl; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, and pyrazol-5-yl.
The term "oxo" refers to an oxy substitution (= O) formed when a carbon atom, a nitrogen atom, or a sulfur atom in a substituent is oxidized.
The term "thio" refers to an oxy substitution (= S) formed after oxidation of a carbon atom or a nitrogen atom in a substituent.
The term "alkylamino" refers to-NH- (alkyl), wherein alkyl is as defined above. Non-limiting examples of alkylamino groups include: methylamino, ethylamino, propylamino, isopropylamino, butylamino and the like.
Term "(alkyl) 2 Amino group"means-N- (alkyl) 2 Wherein alkyl is as defined above. (alkyl group) 2 Non-limiting examples of amino groups include: dimethylamino, methylethylamino, diethylamino, dipropylamino, methylpropylamino, diisopropylamino, dibutylamino and the like.
The term "alkyloxy (alkoxy)" refers to-O- (alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkyloxy, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy or heterocycloalkyloxy.
"haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
It will be appreciated by those skilled in the art that the compounds of formula (I) may exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form base addition salts; these compounds may also form inner salts if they contain both an acidic centre (e.g. carboxyl) and a basic centre (e.g. amino).
The compounds of the invention may be present in the form of solvates, such as hydrates, wherein the compounds of the invention comprise as structural element of the crystal lattice of the compound a polar solvent, such as in particular water, methanol or ethanol. The amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric proportions.
Depending on their molecular structure, the compounds of the invention may be chiral and may therefore exist in various enantiomeric forms. These compounds may thus be present in racemic or optically active form. The compound of the invention covers isomers or mixtures and racemates thereof, wherein each chiral carbon is in R or S configuration. The compounds of the invention or intermediates thereof may be separated into enantiomeric compounds by chemical or physical methods well known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are prepared from mixtures by reaction with optically active resolving agents. Examples of suitable resolving agents are optically active acids such as tartaric acid in the R and S forms, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g. N-benzoylproline or N-benzenesulfonylproline) or various optically active camphorsulfonic acids. Chromatographic enantiomeric resolution can also advantageously be carried out with the aid of optically active resolving agents, such as dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chirally derivatized methacrylate polymers, which are immobilized on silica gel. Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example hexane/isopropanol/acetonitrile.
The corresponding stable isomers can be isolated according to known methods, for example by extraction, filtration or column chromatography.
The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses or primates, most preferably humans.
The term "therapeutically effective amount" means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought by a researcher, veterinarian, medical doctor or other clinician in a tissue, system, animal, individual, or human, which includes one or more of the following: (1) prevention of diseases: for example, preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but has not experienced or developed disease pathology or symptomatology. (2) inhibition of diseases: for example, inhibiting the disease, disorder or condition (i.e., arresting the further development of the pathology and/or condition) in an individual who is experiencing or presenting the pathology or condition of the disease, disorder or condition. (3) relieving the diseases: for example, relieving the disease, disorder or condition (i.e., reversing the pathology and/or symptomatology) in an individual who is experiencing or presenting with the pathology or symptomatology of the disease, disorder or condition.
Detailed Description
The technical solution of the present invention will be further described in detail with reference to specific embodiments. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.
Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.
The present invention is further described below with reference to examples, which are not intended to limit the scope of the present invention.
The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) and/or liquid mass chromatography (LC-MS). NMR chemical shifts (x) are given in parts per million (ppm). NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated methanol (CD) 3 OD) and deuterated chloroform (CDCl) 3 ) Internal standard is Tetramethylsilane (TMS).
LC-MS was measured using an Agilent 1200Infinity Series Mass spectrometer. HPLC was carried out using an Agilent 1200DAD high performance liquid chromatograph (Sunfire C18X 4.6mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18X 4.6mm column).
The thin layer chromatography silica gel plate is prepared from HSGF254 of tobacco yellow sea or GF254 of Qingdao, TLC is 0.15-0.20 mm, and the thin layer chromatography separation and purification product is 0.4-0.5 mm. The column chromatography is carried out by using 200-300 mesh silica gel of Taiwan yellow sea as carrier.
The starting materials in the examples of the present invention are known and commercially available, or may be synthesized using or according to methods known in the art.
Example 1
6-chloro-1- (2-isopropoxyethyl) -2-thioxo-1, 2,3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000191
First step of
Preparation of ethyl 3- ((tert-butoxycarbonyl) amino) -1H-pyrrole-2-carboxylate
Ethyl 3-amino-1H-pyrrole-2-carboxylate Cpd-001A (1.0g, 6.5mmol) and di-tert-butyl dicarbonate (2.8g, 13.0mmol) were dissolved in methanol (20 mL), and the mixture was stirred at reflux for 4 hours. After the reaction is finished, the reaction liquid is cooled to room temperature, and the crude product is obtained by decompression and concentration. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to give compound 3- ((tert-butoxycarbonyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-001B (1.7 g, white solid), yield: 99 percent.
MS m/z(ESI):255[M+1] + .
Second step of
Preparation of ethyl 3- ((tert-butoxycarbonyl) amino) -5-chloro-1H-pyrrole-2-carboxylate
Ethyl 3- ((tert-butoxycarbonyl) amino) -1H-pyrrole-2-carboxylate Cpd-001B (500mg, 2.0 mmol) was dissolved in chloroform (10 mL) and N-chlorosuccinimide (276mg, 2.1mmol) was added. The reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate/= 10/1) to give the compound 3- ((tert-butoxycarbonyl) amino) -5-chloro-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-001C (456 mg, light yellow oil), yield: 76 percent.
MS m/z(ESI):289[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.42(s,1H),8.36(s,1H),6.48(s,1H),4.25(q,J＝7.1Hz,2H),1.45(s,9H),1.28(t,J＝7.1Hz,3H).
The third step
Preparation of 3-amino-5-chloro-1H-pyrrole-2-carboxylic acid ethyl ester
3- ((tert-Butoxycarbonyl) amino) -5-chloro-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-001C (200mg, 25mmol) was dissolved in hydrochloric acid methanol solution (1 mol/L,5 mL), stirred at room temperature for 2 hours, after completion of the reaction, the reaction solution was neutralized with aqueous sodium bicarbonate solution, extracted with ethyl acetate, and the organic layer was washed with anhydrous sodium sulfateDried and concentrated. To give ethyl 3-amino-5-chloro-1H-pyrrole-2-carboxylate Cpd-001D (120 mg, white solid) in yield: 92 percent. MS m/z (ESI) 189[ cm ], [ M ] +1] + .
The fourth step
Preparation of ethyl 3- ((2-isopropoxyethyl) amino) -5-chloro-1H-pyrrole-2-carboxylate
Ethyl 3-amino-5-chloro-1H-pyrrole-2-carboxylate Cpd-001D (120mg, 0.64mmol) was dissolved in methanol (3 mL), and acetic acid (38mg, 0.64mmol) and 2-isopropoxyacetaldehyde (65mg, 0.64mmol) were added in this order and stirred at room temperature for half an hour. Sodium cyanoborohydride (40mg, 0.64mmol) was then added portionwise, followed by stirring at room temperature for 16 hours. After the reaction is finished, adding 5mL of water for quenching, extracting by ethyl acetate, washing an organic phase by saturated sodium chloride, drying by anhydrous sodium sulfate, carrying out rotary evaporation to obtain a crude product, and purifying by a column to obtain 3- ((2-isopropoxyethyl) amino) -5-chloro-1H-pyrrole-2-ethyl formate Cpd-001E (60 mg, light brown oily substance), wherein the yield is as follows: 34 percent.
MS m/z(ESI):275[M+1] + .
The fifth step
Preparation of ethyl 3- (3- (ethoxycarbonyl) -1- (2-isopropoxyethyl) thioureido) -5-chloro-1H-pyrrole-2-carboxylate
Ethyl 3- ((2-isopropoxyethyl) amino) -5-chloro-1H-pyrrole-2-carboxylate Cpd-001E (60mg, 0.22mmol) was dissolved in dichloromethane (5 mL), cooled to 0 ℃ and to this was added ethyl isothiocyanatecarboxylate (72mg, 0.26mmol), followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction mixture was washed once with water (5 mL), and the organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was separated and purified by silica gel column (petroleum ether/ethyl acetate = 3/1) to give ethyl 3- (3- (ethoxycarbonyl) -1- (2-isopropoxyethyl) thioureido) -5-chloro-1H-pyrrole-2-carboxylate Cpd-001F (40 mg, light brown oil), yield: 45 percent.
MS m/z(ESI):406[M+1] + .
The sixth step
Preparation of 1- (2-isopropoxyethyl) -2-thioxo-1, 2,3, 5-tetrahydro-5-chloro-pyrrolo [3,2-d ] pyrimidin-4-one
Ethyl 3- (3- (ethoxycarbonyl) -1- (2-isopropoxyethyl) thioureido) -5-chloro-1H-pyrrole-2-carboxylate Cpd-001F (40mg, 0.10 mmol) was dissolved in ethanol (3 mL), sodium ethoxide (13mg, 0.20mmol) was added thereto, and the reaction mixture was heated to 90 ℃ to react for 1 hour. After the reaction was completed, it was cooled to room temperature and quenched with a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated, and the obtained residue was isolated by plate separation to give 1- (2-isopropoxyethyl) -2-thio-1, 2,3, 5-tetrahydro-6-chloro-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-001 (8 mg, white solid) in yield: 28 percent.
MS m/z(ESI):288[M+1] + .
1 H NMR(400MHz,DMSO-d 6 )δ13.30(s,1H),12.33(s,1H),6.44(s,1H),4.44(t,J＝6.0Hz,2H),3.70(t,J＝6.0Hz,2H),3.58-3.52(m,1H),1.01(d,J＝6.0Hz,6H).
Example 2
1- (2-Isopropoxyethyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyridinyl [3',2':4,5] pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000201
First step of
Preparation of ethyl (3-cyanopyridin-2-yl) glycinate
2-Chloronicotin, cpd-002A (10g, 72.2mmol), was dissolved in ethanol (100 mL) together with glycine ethyl ester hydrochloride (12.09g, 86.6mmol) and triethylamine (14.61g, 144.4 mmol). The reaction was carried out at 80 ℃ for 16 hours. After cooling to room temperature, the reaction was concentrated. The obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 10/1) to obtain (3-cyanopyridin-2-yl) glycine ethyl ester Cpd-002B (10.84 g, white solid), yield: 73 percent.
1 H NMR(400MHz,DMSO-d6)δ8.26(dd,J＝4.8,1.6Hz,1H),7.96(dd,J＝7.6,1.6Hz,1H),7.50(t,J＝6.0Hz,1H),6.72(dd,J＝7.6,4.8Hz,1H),4.17-3.89(m,4H),1.17(t,J＝7.2Hz,3H).
Second step of
Preparation of ethyl 3-amino-4H-pyrrolo [2,3-b ] pyridine-2-carboxylate
(3-Cyanopyridin-2-yl) glycine ethyl ester Cpd-002B (1g, 4.9mmol) was dissolved in N, N-dimethylformamide (5 mL), and potassium tert-butoxide (820mg, 7.35mmol) was added thereto. The reaction was carried out at 25 ℃ for 1 hour. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL. Times.3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to give ethyl 3-amino-4H-pyrrolo [2,3-b ] pyridine-2-carboxylate Cpd-002C (760 mg, yellow solid) in yield: and 76 percent.
1 H NMR(400MHz,DMSO-d6)δ10.93(s,1H),8.31(dd,J＝4.4,1.6Hz,1H),8.19(d,J＝8.0Hz,1H),6.96(dd,J＝8.0,4.4Hz,1H),5.86(s,2H),4.29(q,J＝7.2Hz,2H),1.32(t,J＝7.2Hz,3H).
The third step
Preparation of ethyl 3- ((2-isopropoxyethyl) amino) -4H-pyrrolo [2,3-b ] pyridine-2-carboxylate
Ethyl 3-amino-4H-pyrrolo [2,3-b ] pyridine-2-carboxylate Cpd-002C (60mg, 5.79mmol) was dissolved in methanol (3 mL) and 2-isopropoxyacetaldehyde (45mg, 0.44mmol) and glacial acetic acid (17mg, 0.29mmol) were added thereto. The reaction mixture was reacted at 25 ℃ for 1 hour. To the reaction solution was added sodium cyanoborohydride (18.37mg, 0.29mmol) and the reaction was continued for 16 hours. After the reaction was completed, methanol was removed by rotary evaporation, and the obtained residue was extracted with ethyl acetate (15 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give ethyl 3- ((2-isopropoxyethyl) amino) -4H-pyrrolo [2,3-b ] pyridine-2-carboxylate Cpd-002D (40 mg, yellow oil), yield: and 47 percent.
MS m/z(ESI):292.1[M+1] +
The fourth step
Preparation of 1- (2-isopropoxyethyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyridinyl [3',2':4,5] pyrrolo [3,2-d ] pyrimidin-4-one
Ethyl 3- ((2-isopropoxyethyl) amino) -4H-pyrrolo [2,3-b ] pyridine-2-carboxylate Cpd-002D (40mg, 0.13mmol) was dissolved in methylene chloride (2 mL), ethyl isothiocyanatecarboxylate (45.9 mg, 0.35mmol) was added thereto, and the reaction solution was reacted at 25 ℃ for 1 hour. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (15 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The obtained residue was dissolved in ethanol (2 mL), and sodium ethoxide (148.8mg, 0.43mmol) was added thereto to react the reaction solution at 100 ℃ for 10 minutes in a microwave reactor. After cooling, the ethanol was removed by rotary evaporation, methylene chloride (5 mL) was added thereto, a solid precipitated, and the solid was filtered off to give 1- (2-isopropoxyethyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyridinyl [3',2':4,5] pyrrolo [3,2-d ] pyrimidin-4-one Cpd-002 (10 mg, yellow solid) in yield: 23 percent.
MS m/z(ESI):305.1[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.85(br,2H),8.55(d,J＝3.9Hz,1H),8.50(d,J＝8.4Hz,1H),7.31(dd,J＝8.3,4.5Hz,1H),4.91(s,2H),3.86(t,J＝6.1Hz,2H),3.54(dt,J＝12.1,6.1Hz,1H),0.93(d,J＝6.0Hz,6H).
Example 3
5- (2-hydroxyethyl) -1- (2-isopropoxyethyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000211
First step of
Preparation of ethyl 3- ((tert-butoxycarbonyl) amino) -1H-pyrrole-2-carboxylate
3-amino-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-003A (1.1g, 7.1mmol) and (BOC) 2 O (3.1g, 14.2mmol) was dissolved in methanol (50 mL), heated to 60 ℃ under nitrogen and stirred for 12 hours. After completion of the reaction, the reaction liquid was concentrated, and the crude product was isolated and purified by a silica gel column (petroleum ether/ethyl acetate = 1/0-2/1) to give ethyl 3- ((tert-butoxycarbonyl) amino) -1H-pyrrole-2-carboxylate Cpd-003B (1.8 g, white solid) in yield: 99 percent.
MS m/z(ESI):255.0[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ11.52(s,1H),8.32(s,1H),6.89(s,1H),6.51(s,1H),4.25(q,J＝5.2Hz,2H),1.46(s,9H),1.29(t,J＝5.2Hz,3H).
Second step of
Preparation of ethyl 3- ((tert-butoxycarbonyl) amino) -1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -1H-pyrrole-2-carboxylate
Ethyl 3- ((tert-butoxycarbonyl) amino) -1H-pyrrole-2-carboxylate Cpd-003B (600mg, 2.36mmol) and cesium carbonate (1.5g, 4.71mmol) were dissolved in dimethyl sulfoxide (8 mL), followed by addition of (2-bromoethoxy) (tert-butyl) dimethylsilane (790mg, 3.30mmol) under nitrogen and stirring at room temperature for 1 hour. After the reaction, the reaction mixture was poured into ice water (100 mL), extracted with ethyl acetate (50 mL × 2), washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was separated and purified with a silica gel column (petroleum ether/ethyl acetate = 5/1) to obtain ethyl 3- ((tert-butoxycarbonyl) amino) -1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -1H-pyrrole-2-carboxylate Cpd-003C (900 mg, colorless oil) in yield: 92 percent.
MS m/z(ESI):413.0[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ8.58(s,1H),6.97(d,J＝2.8Hz,1H),6.49(s,1H),4.28-4.22(m,4H),3.76(t,J＝5.3Hz,2H),1.45(s,9H),1.28(t,J＝7.1Hz,3H),0.79(s,9H),-0.12(s,6H).
The third step
Preparation of 3-amino-1- (2-hydroxyethyl) -1H-pyrrole-2-carboxylic acid ethyl ester hydrochloride
Ethyl 3- ((tert-butoxycarbonyl) amino) -1- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -1H-pyrrole-2-carboxylate Cpd-003C (1g, 2.4 mmol) was dissolved in a solution of 3 moles per liter of methanol hydrochloride (15 mL) and stirred at 40 ℃ for half an hour. After completion of the reaction, the reaction solution was concentrated to give crude 3-amino-1- (2-hydroxyethyl) -1H-pyrrole-2-carboxylic acid ethyl ester hydrochloride Cpd-003D (0.5 g, white solid), yield: 89 percent.
1 H NMR(400MHz,DMSO-d6)δ9.80(br,2H),7.13(d,J＝2.8Hz,1H),6.23(d,J＝2.8Hz,1H),4.35-4.23(m,4H),3.61(t,J＝5.6Hz,2H),1.32(t,J＝7.2Hz,3H).
The fourth step
Preparation of ethyl 1- (2-hydroxyethyl) -3- ((2-isopropoxyethyl) amino) -1H-pyrrole-2-carboxylate
3-amino-1- (2-hydroxyethyl) -1H-pyrrole-2-carboxylic acid ethyl ester hydrochloride Cpd-003D (700mg, 3.53mmol), 2-isopropoxyacetaldehyde (721mg, 7.06mmol) was dissolved in methanol (15 mL), two drops of trifluoroacetic acid were added dropwise and stirred at room temperature under nitrogen for 2 hours followed by addition of sodium cyanoborohydride (900mg, 14.12mmol) and stirring at room temperature overnight. After completion of the reaction, the reaction solution was poured into water (200 mL), extracted twice with ethyl acetate (100 mL), washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was separated and purified with a silica gel column (petroleum ether/ethyl acetate = 2/1) to give ethyl 1- (2-hydroxyethyl) -3- ((2-isopropoxyethyl) amino) -1H-pyrrole-2-carboxylate Cpd-003E (1 g, colorless oil), yield: 40 percent.
MS m/z(ESI):285.0[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ6.85(d,J＝2.8Hz,1H),5.59(d,J＝2.8Hz,2H),4.71(t,J＝5.2Hz,1H),4.21-4.08(m,4H),3.60-3.46(m,5H),3.14(q,J＝5.6Hz,2H),1.26(t,J＝7.2Hz,3H),1.09(d,J＝6.0Hz,6H).
The fifth step
Preparation of ethyl 3- (3- (ethoxycarbonyl) -1- (2-isopropoxyethyl) thioureido) -1- (2-hydroxyethyl) -1H-pyrrole-2-carboxylate
Ethyl 1- (2-hydroxyethyl) -3- ((2-isopropoxyethyl) amino) -1H-pyrrole-2-carboxylate Cpd-003E (200mg, 0.70mmol) was dissolved in dichloromethane (7 mL) followed by the addition of ethyl thioisocyanoylcarboxylate (110mg, 0.84mmol) and stirring at 30 ℃ under nitrogen for 1 hour. After the reaction was completed, the reaction mixture was concentrated at room temperature, and the crude product was isolated and purified by wet-chromatography on a silica gel column (petroleum ether/ethyl acetate = 1/1) to give 3- (3- (ethoxycarbonyl) -1- (2-isopropoxyethyl) thioureido) -1- (2-hydroxyethyl) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-003F (280 mg, colorless oil) in yield: 96 percent.
MS m/z(ESI):416.0[M+1] + .
The sixth step
Preparation of 5- (2-hydroxyethyl) -1- (2-isopropoxyethyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
3- (3- (ethoxycarbonyl) -1- (2-isopropoxyethyl) thioureido) -1- (2-hydroxyethyl) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-003F (120mg, 0.289mmol) was dissolved in absolute ethanol (2 mL), and a 20% ethanol solution of sodium ethoxide (1.29g, 0.867mmol) was added and the reaction was carried out at 100 ℃ for 1 hour under nitrogen protection by microwave. After the reaction was completed, the reaction mixture was quenched by pouring into 1 mol/l diluted hydrochloric acid solution (100 mL), extracted twice with ethyl acetate (50 mL), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was isolated and purified by silica gel column (petroleum ether/ethyl acetate = 1/1) to give 5- (2-hydroxyethyl) -1- (2-isopropoxyethyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-003 (27 mg, white solid) in yield: 31 percent.
MS m/z(ESI):298.0[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.16(s,1H),7.37(d,J＝2.4Hz,1H),6.25(d,J＝2.4Hz,1H),4.85(t,J＝5.2Hz,1H),4.47(t,J＝6.0Hz,2H),4.31(t,J＝5.2Hz,2H),3.78-3.62(m,4H),3.58(dt,J＝12.0,6.0Hz,1H),1.03(d,J＝6.0Hz,6H).
Example 4
1- (Cyclopropoxyethyl) -2-thioxo-1, 2,3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000231
First step of
Preparation of 2-cyclopropoxyethanol
Under nitrogen atmosphere, magnesium powder (1.5g, 64mmol) and iodine simple substance (100 mg) were dispersed in anhydrous tetrahydrofuran (10 mL), the temperature was controlled at 40 ℃ to 55 ℃, a tetrahydrofuran (15 mL) solution of dibromoethane (8.1g, 43mmol) was slowly dropped, after completion of the addition, the temperature was maintained for 20 minutes, the reaction solution was cooled to room temperature, and a tetrahydrofuran (10 mL) solution of 2- (2-bromoethyl) -1, 3-dioxane Cpd-004A (1.8g, 10mmol) was slowly dropped, and the temperature was maintained at 50 ℃ overnight. After the reaction is finished, cooling the reaction solution to room temperature, adding saturated ammonium chloride aqueous solution (50 mL) for quenching, extracting by dichloromethane, washing an organic phase by saturated sodium chloride, drying by anhydrous sodium sulfate, carrying out rotary evaporation to obtain a crude product, and purifying by a column to obtain 2-cyclopropoxyethanol Cpd-004B (500 mg, colorless oily substance), wherein the yield is as follows: 49 percent.
1 H NMR(400MHz,CDCl 3 )δ3.74-3.68(m,2H),3.64-3.57(m,2H),3.32(tt,J＝6.0,3.0Hz,1H),1.92(s,1H),0.62-0.43(m,4H).
Second step of
Preparation of 2-cyclopropoxyethyl trifluoromethanesulfonic acid
2-Cyclopropoxyethanol Cpd-004B (100mg, 1.0 mmol) and triethylamine (303mg, 3.0 mmol) were dissolved in dry dichloromethane (5 mL). Cooling to 0 ℃, then slowly adding dichloromethane (1 mL) solution of trifluoromethanesulfonic anhydride (564mg, 2.0mmol), stirring for 1 hour at 0 ℃ after the addition is finished, after the reaction is finished, adding water (10 mL), extracting dichloromethane, washing an organic phase by saturated sodium chloride, drying anhydrous sodium sulfate to obtain a crude product, and purifying by a column to obtain 2-cyclopropoxy ethyl trifluoromethanesulfonic acid Cpd-004C (130 mg, light brown liquid), wherein the yield is as follows: 57 percent.
1 H NMR(400MHz,CDCl 3 )δ4.61(t,J＝4.0Hz,2H),3.82(t,J＝4.0Hz,2H),3.50-3.45(m,1H),0.62-0.60(m,2H),0.52-0.50(m,2H).
The third step
Preparation of ethyl 3- ((2-cyclopropyloxyethyl) amino) -1H-pyrrole-2-carboxylate
Ethyl 3-amino-1H-pyrrole-2-carboxylate (66mg, 0.427mmol) was dissolved in 1, 4-dioxane (4 mL), DIPEA (83mg, 0.64mmol) and Cpd-004C 2-cyclopropoxyethyltrifluoromethanesulfonate (100mg, 0.427mmol) were added in that order, and then heated to 80 ℃ for reaction for 2.5 hours. After the reaction is finished, 10mL of water is added for quenching, ethyl acetate is used for extraction, an organic phase is washed by saturated sodium chloride, dried by anhydrous sodium sulfate and evaporated in a rotary manner to obtain a crude product, and the crude product is purified by a column to obtain 3- ((2-cyclopropoxyethyl) amino) -1H-pyrrole-2-ethyl formate Cpd-004D (60 mg, colorless oily matter), wherein the yield is as follows: 59 percent.
1 H NMR(400MHz,DMSO-d 6 )δ10.76(s,1H),6.75(t,J＝3.0Hz,1H),5.66(t,J＝2.5Hz,1H),5.31(s,1H),4.17(q,J＝7.0Hz,2H),3.60-3.53(m,2H),3.48(t,J＝6.1Hz,1H),3.20-3.14(m,2H),1.25(t,J＝7.1Hz,3H),0.44-0.35(m,4H).
The fourth step
Preparation of ethyl 3- (3- (ethoxycarbonyl) -1- (2-cyclopropoxyethyl) thioureido) -1H-pyrrole-2-carboxylate
3- ((2-Cyclopropoxyethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-004D (60mg, 0.252mmol) was dissolved in dichloromethane (50 mL), cooled to 0 ℃ and to this was added isothiocyanatoethyl formate (40mg, 0.302mmol), followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction mixture was washed once with water (5 mL), and the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue obtained was isolated and purified by silica gel column (petroleum ether/ethyl acetate = 3/1) to give ethyl 3- (3- (ethoxycarbonyl) -1- (2-cyclopropoxyethyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-004E (60 mg, light brown oil) in yield: and 64 percent.
1 H NMR(400MHz,CDCl 3 )δ9.32(s,1H),7.50(s,1H),6.99(s,1H),6.21(s,1H),4.66(s,1H),4.30(q,J＝8.0Hz,2H),4.12(q,J＝8.0Hz,2H),4.04-3.79(m,2H),3.72(s,1H),3.24(s,1H),1.34(t,J＝7.1Hz,3H),1.26(t,J＝7.1Hz,3H),0.48-0.44(m,4H).
The fifth step
Preparation of 1- (2-Cyclopropoxyethyl) -2-thioxo-1, 2,3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one
3- (3- (ethoxycarbonyl) -1- (2-Cyclopropoxyethyl) thioureido) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-004E (60mg, 0.163mmol) was dissolved in ethanol (2 mL), sodium ethoxide (16.6 mg, 0.244mmol) was added thereto, and the reaction solution was heated to 90 ℃ to react for 1 hour. The reaction solution was cooled to room temperature, a saturated aqueous ammonium chloride solution (5 mL) was added, extraction was performed with ethyl acetate (10 mL. Times.3), and the organic layer was dried over anhydrous sodium sulfate and concentrated. The crude was isolated on a preparative silica gel plate (DCM/MeOH = 20/1) to give 1- (2-cyclopropoxyethyl) -2-thioxo-1, 2,3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-004 (8 mg, white solid) in yield: 20 percent.
MS m/z(ESI):252[M+1] + .
1 H NMR(400MHz,DMSO-d 6 )δ12.39(s,1H),12.23(s,1H),7.36(t,J＝4.0Hz,1H),6.28(t,J＝4.0Hz,1H),4.52(t,J＝6.0Hz,2H),3.80(t,J＝6.0Hz,2H),3.34(s,1H),0.40-0.38(m,4H).
Example 5
1- (4-chloro-2- (1-methylpyrrolidin-2-yl) benzyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000241
First step of
Preparation of 3- (2-bromo-5-chlorobenzoyl) -1-vinylpyrrolidin-2-one
Sodium hydride (3.00g, 73.90mmol, 60%) was added to toluene (150 mL), the temperature was raised to 110 ℃ under nitrogen, and a solution of methyl 2-bromo-5-chlorobenzoate, cpd-005A (15.00g, 56.90mmol), and 1-vinylpyrrolidin-2-one (6.32g, 56.90mmol) in toluene (50 mL) was added dropwise. After the completion of the dropwise addition, the reaction mixture was allowed to react at 110 ℃ for 3 hours. The reaction solution was cooled to room temperature and saturated aqueous ammonium chloride solution (50 mL) was added dropwise thereto, followed by extraction with toluene (250 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 2/1) to obtain 3- (2-bromo-5-chlorobenzoyl) -1-vinylpyrrolidin-2-one Cpd-005B (3.00 g, yellow solid), yield: 14 percent.
MS m/z(ESI):328[M+1] + .
Second step of
Preparation of 5- (2-bromo-5-chlorophenyl) -3, 4-dihydro-2H-pyrrole
3- (2-bromo-5-chlorobenzoyl) -1-vinylpyrrolidin-2-one Cpd-005B (2.2g, 6.1mmol) was added to a hydrochloric acid solution (20mL, 5mol/L), and the reaction mixture was reacted at 100 ℃ for 16 hours. The reaction solution was cooled to 0 deg.C, adjusted to pH 12-13 with 50% sodium hydroxide solution, the resulting aqueous phase was extracted with dichloromethane (100 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 3/1) to obtain 5- (2-bromo-5-chlorophenyl) -3, 4-dihydro-2H-pyrrole Cpd-005C (1.0 g, pale yellow oil), yield: 57 percent.
The third step
Preparation of 2- (2-bromo-5-chlorophenyl) pyrrolidine
5- (2-bromo-5-chlorophenyl) -3, 4-dihydro-2H-pyrrole Cpd-005C (1.0 g,3.9 mmol) was dissolved in methanol (8 mL) and water (2 mL) and sodium borohydride (290mg, 7.8 mmol) was added thereto, and the reaction solution was reacted at 25 ℃ for 16 hours. To the reaction mixture was added a saturated aqueous ammonium chloride solution (20 mL), and the resulting aqueous phase was extracted with dichloromethane (50 mL. Times.2). All organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give 2- (2-bromo-5-chlorophenyl) pyrrolidine Cpd-005D (0.67 g, light yellow oil), yield: 59 percent.
1 H NMR(400MHz,CDCl 3 )δ7.66(d,J＝2.4Hz,1H),7.42(d,J＝8.4Hz,1H),7.05(dd,J＝8.4,2.2Hz,1H),4.46(t,J＝7.4Hz,1H),3.34-2.94(m,2H),2.37(td,J＝13.7,7.8Hz,1H),1.85(tdd,J＝19.9,12.8,7.0Hz,4H),1.50(dt,J＝15.4,7.3Hz,1H).
The fourth step
Preparation of 2- (2-bromo-5-chlorophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester
2- (2-bromo-5-chlorophenyl) pyrrolidine Cpd-005D (600mg, 2.53mmol) was dissolved in methylene chloride (5 mL), and di-tert-butyl dicarbonate (552.84mg, 2.53mmol), and triethylamine (255.84mg, 2.53mmol) were added thereto and reacted at 25 ℃ for 5 hours. Dichloromethane was removed by rotation, and the resulting residue was isolated and purified on silica gel column (petroleum ether/ethyl acetate = 33/1) to give tert-butyl 2- (2-bromo-5-chlorophenyl) pyrrolidine-1-carboxylate Cpd-005E (600 mg, colorless oil), yield: 68 percent.
1 H NMR(400MHz,CDCl 3 )δ7.43(d,J＝8.5Hz,1H),7.17-7.00(m,2H),5.20-4.96(m,1H),3.74-3.43(m,2H),2.38(qd,J＝15.2,7.1Hz,1H),1.88(dt,J＝13.4,6.5Hz,2H),1.82-1.72(m,1H),1.46(s,3H),1.19(s,6H).
The fifth step
Preparation of tert-butyl 2- (5-chloro-2-formylphenyl) pyrrolidine-1-carboxylate
Tert-butyl 2- (2-bromo-5-chlorophenyl) pyrrolidine-1-carboxylate Cpd-005E (300mg, 0.83mmol) was dissolved in dimethyl sulfoxide (3 mL), followed by the addition of triethylsilane (337.59mg, 2.90mmol), N, N-diisopropylethylamine (160.81mg, 1.24mmol), and bis [ di-tert-butyl- (4-dimethylaminophenyl) phosphine ] palladium (II) dichloride (100 mg) in that order, carbon monoxide was passed through, and the reaction was heated to 90 ℃ for 16 hours. The reaction solution was cooled to room temperature, ethyl acetate (50 mL) was added, the reaction solution was washed once with a saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain a residue, which was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 5/1) to obtain tert-butyl 2- (5-chloro-2-formylphenyl) pyrrolidine-1-carboxylate Cpd-005F (130 mg, yellow oil), yield: 48 percent.
1 H NMR(400MHz,CDCl 3 )δ10.15(s,1H),7.75(d,J＝8.2Hz,1H),7.48-7.28(m,2H),5.77-5.60(m,1H),3.74-3.49(m,2H),2.52(d,J＝6.9Hz,1H),1.96-1.77(m,2H),1.74-1.66(m,1H),1.46(s,3H),1.17(s,6H).
The sixth step
Preparation of ethyl 3- ((4-chloro-3- (1-methylpyrrolidin-2-yl) benzyl) amino) -1H-pyrrole-2-carboxylate
Tert-butyl 2- (5-chloro-2-formylphenyl) pyrrolidine-1-carboxylate, cpd-005F (130mg, 0.41mmol), was dissolved in methanol (5 mL) and ethyl 3-amino-1H-pyrrole-2-carboxylate (70.94mg, 0.46mmol) was added. The reaction mixture was stirred at 25 ℃ for 30 minutes, sodium cyanoborohydride (39.43mg, 0.62mmol) was added, and stirring was continued at 25 ℃ for 4 hours. After the reaction was complete, the reaction was quenched with water (1 mL) and the ethanol was removed by rotary evaporation. Saturated sodium bicarbonate was added to the residue to adjust its pH to 8, followed by extraction with dichloromethane (50 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 5/1) to obtain ethyl 3- ((2- (1- (tert-butoxycarbonyl) pyrrolidin-2-yl) -4-chlorobenzyl) amino) -1H-pyrrole-2-carboxylate Cpd-005G (120 mg, yellow oil), yield: 57 percent.
MS m/z(ESI):448[M+1] +
Seventh step
Preparation of tert-butyl 2- (5-chloro-2- ((4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) methyl) phenyl) pyrrolidine-1-carboxylate
Ethyl 3- ((2- (1- (tert-butoxycarbonyl) pyrrolidin-2-yl) -4-chlorobenzyl) amino) -1H-pyrrole-2-carboxylate Cpd-005G (100mg, 0.22mmol) was dissolved in methanol (5 mL). Ethylisothiocyanatecarboxylate (35.05mg, 0.26mmol) was added. The reaction mixture was reacted at 25 ℃ for 12 hours. Cesium carbonate (217.68mg, 0.66mmol) was added to the reaction mixture, and the mixture was heated to 70 ℃ to react for 4 hours. The reaction was cooled to room temperature, ethyl acetate (10 mL) was added, the reaction was washed once with saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and concentrated, and the obtained residue was separated and purified with a silica gel column (petroleum ether/ethyl acetate = 6/1) to obtain Cpd-005H (50 mg, yellow oil), yield: 44 percent.
1 H NMR(400MHz,CDCl 3 )δ7.32(d,J＝2.6Hz,1H),7.18(d,J＝7.5Hz,1H),7.07(s,1H),6.76-6.64(m,1H),6.03-5.48(m,3H),5.14(s,1H),3.63(s,1H),3.47(s,1H),1.95-1.68(m,3H),1.42(s,3H),1.17(s,6H).
Eighth step
Preparation of 1- (4-chloro-2- (pyrrolidin-2-yl) benzyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one hydrochloride
Tert-butyl 2- (5-chloro-2- ((4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) methyl) phenyl) pyrrolidine-1-carboxylate Cpd-005H (50mg, 0.111mmol) was added to a solution of hydrochloric acid in methanol (2mL, 2mol/L) and the reaction was reacted at 25 ℃ for 4 hours. After the reaction was completed, the reaction solution was concentrated to give 1- (4-chloro-2- (pyrrolidin-2-yl) benzyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one hydrochloride Cpd-005I (30.0 mg, white solid), yield: 73 percent.
MS m/z(ESI):361[M+1] + .
The ninth step
Preparation of 1- (4-chloro-2- (1-methylpyrrolidin-2-yl) benzyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
1- (4-chloro-2- (pyrrolidin-2-yl) benzyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one hydrochloride Cpd-005I (20mg, 0.05mmol) was dissolved in methanol (2 mL), paraformaldehyde (9mg, 0.1mg) was added, stirring was performed at room temperature for 1 hour, sodium cyanoborohydride (6mg, 0.1mmol) was added, and stirring was performed at room temperature for 3 hours. The reaction was concentrated and plate-on-silica gel isolated (DCM/MeOH = 10/1) to give 1- (4-chloro-2- (1-methylpyrrolidin-2-yl) benzyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-005 (10 mg, white solid) in yield: 53 percent
MS m/z(ESI):375[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.50(s,1H),12.40(s,1H),7.56(s,1H),7.32(s,1H),7.16(d,J＝8.0Hz,1H),6.65(s,1H),5.94(s,1H),5.71(s,1H),3.50(t,J＝8.0Hz,1H),3.20(t,J＝8.0Hz,1H),2.33-2.30(m,2H),2.21(s,3H),1.84-1.82(m,2H),1.65-1.50(m,1H).
Example 6
1- (4-chloro-2- (1-methylpyrrolidin-2-yl) benzyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000261
First step of
Preparation of 3- (5-bromo-2-chlorobenzoyl) -1-vinylpyrrolidin-2-one
Sodium hydride (1.04g, 26.1mmol, 60%) was added to toluene (25 mL), warmed to 110 ℃ under nitrogen, and a mixture of ethyl 2-chloro-5-bromobenzoate Cpd-006A (5.0 g,20.0 mmol) and 1-vinylpyrrolidin-2-one (2.36g, 21.2 mmol) was added dropwise. After the completion of the dropwise addition, the reaction mixture was allowed to react at 110 ℃ for 3 hours. The reaction solution was cooled to room temperature and a saturated aqueous ammonium chloride solution (10 mL) was added dropwise thereto, followed by extraction with toluene (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The obtained residue was separated and purified by silica gel column (petroleum ether/ethyl acetate = 2/1) to obtain 3- (2-bromo-5-chlorobenzoyl) -1-vinylpyrrolidin-2-one Cpd-006B (3.00 g, brown oil), yield: 41 percent.
MS m/z(ESI):328[M+1] + .
Second step of
Preparation of 5- (2-chloro-5-bromophenyl) -3, 4-dihydro-2H-pyrrole
3- (2-chloro-5-bromobenzoyl) -1-vinylpyrrolidin-2-one Cpd-006B (3.0 g, 9.1mmol) was added to 5 mol/l hydrochloric acid solution (30 mL) and the reaction was stirred at 100 ℃ for 16 hours. The reaction solution was cooled to 0 deg.C, adjusted to pH 12-13 with 50% sodium hydroxide solution, the resulting aqueous phase was extracted with dichloromethane (100 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The resulting residue was separated and purified by silica gel column (petroleum ether/ethyl acetate = 10/1) to give 5- (2-chloro-5-bromophenyl) -3, 4-dihydro-2H-pyrrole Cpd-006C (1.7 g, pale yellow oil), yield: 65 percent.
1 H NMR(400MHz,CDCl 3 )δ7.76(d,J＝2.4Hz,1H),7.43(dd,J＝8.4,2.4Hz,1H),7.27-7.24(m,1H),4.07-4.02(m,2H),3.08-2.94(m,2H),2.10-2.01(m,2H).
The third step
Preparation of 2- (2-bromo-5-chlorophenyl) pyrrolidine
5- (2-chloro-5-bromophenyl) -3, 4-dihydro-2H-pyrrole Cpd-006C (1.7 g,6.6 mmol) was dissolved in methanol (20 mL) and water (4 mL), and sodium borohydride (0.5 g, 13.2mmol) was added thereto, and the reaction solution was reacted at 25 ℃ for 16 hours. After the reaction was complete, the reaction was quenched with water (10 mL) and the methanol was rotary evaporated. Saturated sodium bicarbonate was added to the residue to adjust its pH to 8, followed by extraction with dichloromethane (50 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The obtained residue was isolated and purified by silica gel column (petroleum ether/ethyl acetate = 10/1) to give 2- (2-bromo-5-chlorophenyl) pyrrolidine Cpd-006D (800 mg, yellow oil), yield: 57 percent.
1 H NMR(400MHz,CDCl 3 )δ7.84(d,J＝2.4Hz,1H),7.42(dd,J＝8.4,2.4Hz,1H),7.35(d,J＝8.4Hz,1H),4.35(t,J＝7.2Hz,1H),3.02-2.92(m,3H),2.32-2.23(m,1H),1.71(dd,J＝13.6,7.2Hz,2H),1.32(dd,J＝12.4,7.2Hz,1H).
The fourth step
Preparation of 2- (5-bromo-2-chlorophenyl) -1-methylpyrrolidine
2- (2-bromo-5-chlorophenyl) pyrrolidine Cpd-006D (800mg, 3.07mmol) was dissolved in methanol (20 mL), paraformaldehyde (147.37mg, 4.91mmol) was added thereto, and the reaction mixture was reacted at 25 ℃ for 1 hour. Sodium cyanoborohydride (308.7 mg, 4.91mmol) was added and stirring continued at 25 ℃ for 16 h. Ethyl acetate (100 mL) was added to the reaction solution, and the organic phase was washed with saturated sodium bicarbonate (50 mL), dried over anhydrous sodium sulfate, concentrated, and the resulting residue was separated and purified with silica gel column (petroleum ether/ethyl acetate = 10/1) to give (5-bromo-2-chlorophenyl) -1-methylpyrrolidine Cpd-006E (500 mg, colorless oil), yield: 46 percent.
1 H NMR(400MHz,CDCl 3 )δ7.77(d,J＝2.4Hz,1H),7.29-7.26(m,1H),7.18(d,J＝8.4Hz,1H),3.56(t,J＝8.4Hz,1H),3.28-3.20(m,1H),2.42-2.33(m,2H),2.23(s,3H)1.91-1.73(m,2H),1.55-1.47(m,1H).
The fifth step
Preparation of 4-chloro-3- (1-methylpyrrolidin-2-yl) benzaldehyde
(5-bromo-2-chlorophenyl) -1-methylpyrrolidine Cpd-006E (700mg, 2.55mmol) was dissolved in dimethyl sulfoxide (5 mL), and triethylsilane (1037 mg, 8.92mmol), N, N-diisopropylethylamine (494mg, 3.82mmol), and bis [ di-t-butyl- (4-dimethylaminophenyl) phosphine ] palladium (II) dichloride (100 mg) were sequentially added thereto, and carbon monoxide was introduced thereto, and the reaction mixture was heated to 90 ℃ to react for 16 hours. The reaction solution was cooled to room temperature, ethyl acetate (50 mL) was added, the reaction solution was washed once with a saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain a residue, which was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 5/1) to obtain 4-chloro-3- (1-methylpyrrolidin-2 yl) benzaldehyde Cpd-006F (100 mg, yellow oil), yield: 17 percent.
MS m/z(ESI):224[M+1] + .
The sixth step
Preparation of ethyl 3- ((4-chloro-3- (1-methylpyrrolidin-2-yl) benzyl) amino) -1H-pyrrole-2-carboxylate
4-chloro-3- (1-methylpyrrolidin-2-yl) benzaldehyde, cpd-006F (60mg, 0.27mmol), was dissolved in methanol (5 mL) and ethyl 3-amino-1H-pyrrole-2-carboxylate (45.48mg, 0.30mmol) was added. The reaction mixture was stirred at 25 ℃ for 30 minutes, sodium cyanoborohydride (25.28mg, 0.40mmol) was added, and stirring was continued for 4 hours. After the reaction was complete, the reaction was quenched with water (0.5 mL) and the ethanol was removed by rotary evaporation. Saturated sodium bicarbonate was added to the residue to adjust its pH to 8, followed by extraction with dichloromethane (30 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The obtained residue was isolated and purified by silica gel column (petroleum ether/ethyl acetate = 5/1) to give ethyl 3- ((4-chloro-3- (1-methylpyrrolidin-2-yl) benzyl) amino) -1H-pyrrole-2-carboxylate Cpd-006G (30 mg, yellow oil), yield: 30 percent.
MS m/z(ESI):362[M+1] + .
Seventh step
Preparation of 1- (4-chloro-3- (1-methylpyrrolidin-2-yl) benzyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Ethyl 3- ((4-chloro-3- (1-methylpyrrolidin-2-yl) benzyl) amino) -1H-pyrrole-2-carboxylate Cpd-006G (30mg, 0.08mmol) was dissolved in methanol (2 mL). Ethylisothiocyanatecarboxylate (13.02mg, 0.13mmol) was added. The reaction mixture was reacted at 25 ℃ for 12 hours. Cesium carbonate (161.66mg, 0.50mmol) was added to the reaction mixture, and the mixture was heated to 70 ℃ to react for 4 hours. The reaction was cooled to room temperature, ethyl acetate (10 mL) was added, the saturated sodium chloride solution was washed once, the organic phase was dried over anhydrous sodium sulfate, concentrated, and the resulting residue was isolated and purified on a preparative plate (dichloromethane/methanol = 20/1) to give 1- (4-chloro-3- (1-methylpyrrolidin-2-yl) benzyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-006 (10.0 mg, pale oil), yield: 16 percent.
MS m/z(ESI):375[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.57-12.17(m,2H),7.59(d,J＝1.6Hz,1H),7.32(dd,J＝8.4,5.6Hz,2H),7.12(dd,J＝8.0,2.0Hz,1H),6.11(d,J＝2.8Hz,1H),5.71(s,2H),3.43(t,J＝8.4Hz,1H),3.17-3.11(m,1H),2.27(dd,J＝16.8,8.0Hz,2H),2.07(s,3H),1.75(dd,J＝14.4,7.2Hz,2H),1.36(dd,J＝12.0,7.2Hz,1H).
Example 7
1- (2-Isopropoxyethyl) -2-thioxo-furo [3,2-d ] pyrimidin-4 (1H) -one
Figure BDA0003664464850000281
First step of
Preparation of methyl 3- ((2-isopropoxyethyl) amino) furan-2-carboxylate
Methyl 3-aminofuran-2-carboxylate Cpd-007A (460mg, 3.3mmol), N, N-diisopropylethylamine (1.26g, 9.8mmol) and isopropoxyethyl trifluoromethanesulfonate (924mg, 3.9mmol) were dissolved in dioxane (10 mL) and then heated to 90 ℃ under nitrogen and stirred for 2 hours. After completion of the reaction, the reaction solution was poured into water (100 mL), extracted twice with ethyl acetate (50 mL), washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was separated and purified with a silica gel column (petroleum ether/ethyl acetate = 5/1) to give methyl 3- ((2-isopropoxyethyl) amino) furan-2-carboxylate Cpd-007B (275 mg, colorless oil), yield: 37 percent.
MS m/z(ESI):228.0[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ7.62(d,J＝4.0Hz,1H),6.49(d,J＝4.0Hz,1H),5.74(s,1H),3.72(s,3H),3.60-3.53(m,1H),3.49-3.46(m,2H),3.33-3.25(m,2H),1.08(d,J＝8.0Hz,6H).
Second step of
Preparation of methyl 3- (3- (ethoxycarbonyl) -1- (2-isopropoxyethyl) thioureido) furan-2-carboxylate
Methyl 3- ((2-isopropoxyethyl) amino) furan-2-carboxylate, cpd-007B (200mg, 0.88mmol) and ethyl isothiocyanatecarboxylate (139mg, 1.06mmol) were dissolved in dichloromethane (5 mL) and stirred at room temperature under nitrogen for half an hour. After the reaction, the reaction mixture was concentrated to give a crude product, which was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 1/1) to give methyl 3- (3- (ethoxycarbonyl) -1- (2-isopropoxyethyl) thioureido) furan-2-carboxylate Cpd-007C (200 mg, brown oil), yield: and 63 percent.
MS m/z(ESI):359.0[M+1] +
The third step
Preparation of 1- (2-isopropoxyethyl) -2-thio-furo [3,2-d ] pyrimidin-4 (1H) -one
Methyl 3- (3- (ethoxycarbonyl) -1- (2-isopropoxyethyl) thioureido) furan-2-carboxylate, cpd-007C (70mg, 0.20mmol), was dissolved in ethanol (3 mL), followed by addition of sodium ethoxide (53mg, 0.78mmol) and microwave heating to 100 ℃ under nitrogen with stirring for half an hour. After the reaction was completed, the reaction solution was quenched with hydrochloric acid (2 mol/L,20 mL), extracted twice with ethyl acetate (50 mL), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was separated and purified with a silica gel column (petroleum ether/ethyl acetate = 2/1) to obtain 1- (2-isopropoxyethyl) -2-thio-furo [3,2-d ] pyrimidin-4 (1H) -one Cpd-007 (10 mg, white solid) in yield: 19 percent.
MS m/z(ESI):255.0[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.74(s,1H),8.19(d,J＝1.5Hz,1H),7.02(d,J＝1.7Hz,1H),4.48(t,J＝5.5Hz,2H),3.74(t,J＝5.5Hz,2H),3.52(dt,J＝12.1,6.0Hz,1H),0.98(d,J＝6.0Hz,6H).
Example 8
1- (3-cyclopropyl-2-yne-1-methylene) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000291
First step of
Preparation of 3-cyclopropyl-2-propyn-1-aldehyde
3-cyclopropyl-2-propyn-1-ol Cpd-008A (500mg, 5.20mmol) and manganese dioxide (3165mg, 36.40mmol) were dissolved in chloroform (10 mL), and the mixture was stirred at 40 ℃ for 1 hour under nitrogen protection. After the reaction is finished, the reaction solution is filtered by diatomite, filter residues are washed by dichloromethane, and the filtrate is concentrated at room temperature to obtain a crude product. After separation and purification by a silica gel column (petroleum ether/ethyl acetate = 10/1), 3-cyclopropyl-2-propyne-1-aldehyde Cpd-008B (330 mg, colorless oil) was obtained in yield: 67%.
1 H NMR(400MHz,DMSO-d6)δ9.11(d,J＝1.2Hz,1H),1.68-1.61(m,1H),1.09-1.03(m,2H),0.92-0.88(m,2H).
Second step of
Preparation of ethyl 3- ((3-cyclopropyl-2-alkynyl-1-methylene) amino) -1H-pyrrole-2-carboxylate
3-cyclopropyl-2-propyne-1-aldehyde (330mg, 3.50mmol) and ethyl 3-amino-1H-pyrrole-2-carboxylate Cpd-008B (541mg, 3.50mmol) were dissolved in methanol (5 mL), two drops of acetic acid were added dropwise, stirred at room temperature for 1 hour under nitrogen, followed by addition of sodium cyanoborohydride (661mg, 10.51mmol) and stirred for half an hour. The reaction was poured into water (100 mL), extracted twice with ethyl acetate (50 mL), the combined organic phases washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give crude product which was isolated and purified by silica gel column (petroleum ether/ethyl acetate = 4/1) to give 3- ((3-cyclopropyl-2-alkynyl-1-methylene) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-008C (360 mg, colorless oil), yield: 40 percent.
MS m/z(ESI):233.0[M+1] + .
The third step
Preparation of ethyl 3- (1- (3-cyclopropyl-2-yne-1-methylene) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate
3- (3-cyclopropyl-2-yn-1-methylene) amino-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-008C (230mg, 0.95mmol) was dissolved in dichloromethane (7 mL) and ethyl isothiocyanato formate (149mg, 1.14mmol) was added dropwise at room temperature, stirred under nitrogen for half an hour and concentrated after completion of the reaction at room temperature, and the crude product was wet-filtered directly through a silica gel column (petroleum ether/ethyl acetate = 1/2) to give 3- (1- (3-cyclopropyl-2-yn-1-methylene) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-008D (230 mg, colorless oil) yield: 67%.
MS m/z(ESI):364.0[M+1] + .
The fourth step
Preparation of 1- (3-cyclopropyl-2-yn-1-methylene) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
3- (1- (3-cyclopropyl-2-yne-1-methylene) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-008D (230mg, 0.63mmol) is dissolved in absolute ethyl alcohol (2 mL), 20% sodium ethoxide ethanol solution (295mg, 1.90mmol) is added, and the reaction is carried out under the protection of nitrogen by microwave at 100 ℃ for 1 hour. After the reaction was completed, it was quenched by pouring into dilute hydrochloric acid solution (100ml, 1mol/L), extracted twice with ethyl acetate (50 mL), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified with silica gel column (petroleum ether/ethyl acetate = 9/1) to give 1- (3-cyclopropyl-2-yne-1-methylene) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-008 (15 mg, white solid), yield: 13 percent.
MS m/z(ESI):246.0[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.65(s,1H),8.26(s,1H),7.52(t,J＝2.8Hz,1H),6.86(t,J＝2.4Hz,1H),2.73(d,J＝7.2Hz,2H),1.18-0.98(m,1H),0.68-0.52(m,2H),0.40-0.23(m,2H).
Example 9
2-thio-1- [2- (2, 2-trifluoroethoxy) ethyl ] -5H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000301
First step of
Preparation of ethyl 2- (2, 2-trifluoroethoxy) trifluoromethanesulfonate
2- (2, 2-trifluoroethoxy) ethanol Cpd-009A (300mg, 2.0mmol), N, N-diisopropylethylamine (800mg, 6.2mmol) was dissolved in anhydrous dichloromethane (20 mL), stirred at 0 ℃ under a nitrogen atmosphere, and trifluoromethanesulfonic anhydride (700mg, 2.5mmol) was added dropwise thereto. The reaction solution was stirred at room temperature for 1 hour. After completion of the reaction, ice water (20 mL) was added thereto, followed by extraction with methylene chloride (30 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product. The crude product obtained was isolated and purified by Flash column (petroleum ether/ethyl acetate = 10/1) to give the compound ethyl 2- (2, 2-trifluoroethoxy) trifluoromethanesulfonate Cpd-009B (359 mg, light yellow liquid), yield: and 63 percent.
1 H NMR(400MHz,DMSO-d6)δ4.55-4.42(m,2H),4.18(q,J＝9.2Hz,2H),3.87(dd,J＝5.2,3.2Hz,2H).
Second step of
Preparation of ethyl 3- { [2- (2, 2-trifluoroethoxy) ethyl ] amino } -1H-pyrrole-2-carboxylate
Ethyl 2- (2, 2-trifluoroethoxy) trifluoromethanesulfonate Cpd-009B (300mg, 1.1mmol), ethyl 3-amino-1H-pyrrole-2-carboxylate (200mg, 1.3mmol) and N, N-diisopropylethylamine (421mg, 3.3mmol) were dissolved in 1, 4-dioxane (20 mL) and the reaction mixture was stirred at 80 ℃ for 4 hours under a nitrogen atmosphere. The reaction solution was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate (30 mL × 3), the organic phases were combined and dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product obtained was isolated and purified by Flash column (petroleum ether/ethyl acetate = 85/15) to give the compound ethyl 3- { [2- (2, 2-trifluoroethoxy) ethyl ] amino } -1H-pyrrole-2-carboxylate Cpd-009C (200 mg, yellow liquid), yield: 66 percent.
MS m/z(ESI):281[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ10.77(s,1H),6.76(t,J＝3.0Hz,1H),5.68(t,J＝2.5Hz,1H),5.35(s,1H),4.17(q,J＝7.1Hz,2H),4.09(q,J＝9.4Hz,2H),3.72(t,J＝5.4Hz,2H),3.25(q,J＝5.5Hz,2H),1.25(t,J＝7.1Hz,3H).
The third step
Preparation of ethyl 3- (3- (ethoxycarbonyl) -1- (2, 2-trifluoroethoxy) ethyl) thioureido) -1H-pyrrole-2-carboxylate
Ethyl 3- { [2- (2, 2-trifluoroethoxy) ethyl ] amino } -1H-pyrrole-2-carboxylate Cpd-009C (200mg, 0.7mmol), ethyl isothiocyanato (112mmol, 0.8mmol) were dissolved in dichloromethane (20 mL) and the reaction mixture was reacted at room temperature under a nitrogen atmosphere for 1 hour. The reaction solution was quenched with water and extracted with ethyl acetate (30 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give the crude product. The crude product obtained was isolated and purified by Flash column (petroleum ether/ethyl acetate = 85/15) to give the compound ethyl 3- (3- (ethoxycarbonyl) -1- (2, 2-trifluoroethoxy) ethyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-009D (200 mg, yellow viscous liquid) in yield: 68 percent.
MS m/z(ESI):413[M+1] + .
The fourth step
Preparation of 2-thio-1- [2- (2, 2-trifluoroethoxy) ethyl ] -5H-pyrrolo [3,2-d ] pyrimidin-4-one
Ethyl 3- (3- (ethoxycarbonyl) -1- (2, 2-trifluoroethoxy) ethyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-009D (190mg, 0.4607mmol), sodium ethoxide (470mg, 20% in ethanol) was dissolved in ethanol (3 mL) in a microwave tube and microwave reacted at 100 ℃ for 30 minutes. After the reaction was completed, it was quenched with 5mL of a saturated aqueous ammonium chloride solution, and the precipitated solid was collected by filtration and washed with pure water several times to give the title compound 2-thio-1- [2- (2, 2-trifluoroethoxy) ethyl ] -5H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-009 (25 mg, white solid) in yield: 19 percent.
MS m/z(ESI):294[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.39(s,1H),12.24(s,1H),7.37(d,J＝2.8Hz,1H),6.32(d,J＝2.8Hz,1H),4.59(t,J＝5.6Hz,2H),4.10(q,J＝9.2Hz,2H),3.98(t,J＝5.6Hz,2H).
Example 10
2-thio-1- (4, 4-trifluoro-3-hydroxybutyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000311
First step of
Preparation of ethyl 3- ((tert-butyldimethylsilyl) hydroxy) -4, 4-trifluorobutyrate
Ethyl 3-hydroxy-4, 4-trifluorobutyrate (0.5g, 2.7 mmol) was dissolved in dry N, N-dimethylformamide (2 mL) and cooled to 0 ℃. Thereafter, imidazole (0.46g, 6.8mmol) and tert-butyldimethylsilyl chloride (0.49g, 3.3mmol) were added to the reaction solution. The reaction solution was slowly warmed to room temperature, stirred overnight, then diluted with ethyl acetate and washed twice with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1) to give the compound ethyl 3- ((tert-butyldimethylsilyl) hydroxy) -4, 4-trifluorobutanoate Cpd-010B (610 mg, colorless oil), yield: 67%.
1 H NMR(400MHz,DMSO-d6)δ4.66-4.54(m,1H),4.16-4.03(m,2H),2.82(dd,J＝15.6,3.2Hz,2H),1.20(t,J＝7.2Hz,3H),0.83(s,9H),0.11(s,3H),0.06(s,3H).
Second step of
Preparation of 3- ((tert-butyldimethylsilyl) hydroxy) -4, 4-trifluoro-1-butanol
Ethyl 3- ((tert-butyldimethylsilyl) hydroxy) -4, 4-trifluorobutanoate Cpd-010B (500mg, 1.7 mmol) and lithium chloride (280mg, 6.7 mmol) were dispersed in dry ethanol (20 mL), cooled to 0 deg.C and stirred for 1 h, followed by the slow addition of sodium borohydride (250mg, 6.7 mmol). The reaction was slowly warmed to room temperature and stirred overnight. After completion of the reaction, water (10 mL) was added, followed by extraction with ethyl acetate (50 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound 3- ((tert-butyldimethylsilyl) hydroxy) -4, 4-trifluoro-1-butanol Cpd-010C (430 mg, colorless oil) in yield: 70 percent.
The third step
Preparation of 3- ((tert-butyldimethylsilyl) hydroxy) -4, 4-trifluorobutanal
3- ((tert-Butyldimethylsilyl) hydroxy) -4, 4-trifluoro-1-butanol Cpd-010C (430mg, 1.7mmol) was dissolved in dichloromethane (25 mL) and cooled to 0 deg.C, followed by slow addition of Des-Martin oxidant (470mg, 1.7mmol). The reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was washed with a saturated sodium thiosulfate solution (10 mL × 2) and a saturated sodium bicarbonate solution (10 mL × 2), the organic phase was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, the residue was again dispersed in a mixed solvent of petroleum ether/ethyl acetate =5/1, suction filtration was performed, the filtrate was collected and concentrated under reduced pressure to obtain the title compound 3- ((tert-butyldimethylsilyl) hydroxy) -4, 4-trifluorobutanal Cpd-010D (440 mg, yellow oil), yield: 61 percent.
The fourth step
Preparation of ethyl 3- ((3- ((tert-butyldimethylsilyl) hydroxy) -4, 4-trifluorobutyl) amino) -1H-pyrrole-2-carboxylate
Ethyl 3-amino-1H-pyrrole-2-carboxylate (250mg, 1.7 mmol) was dissolved in methanol (10 mL) before the addition of 3- ((tert-butyldimethylsilyl) hydroxy) -4, 4-trifluorobutanal Cpd-010D (430mg, 1.7 mmol), acetic acid (100mg, 1.7 mmol) and sodium cyanoborohydride (105mg, 1.7 mmol) in that order. The reaction was stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to give the title compound, ethyl 3- ((3- ((tert-butyldimethylsilyl) hydroxy) -4, 4-trifluorobutyl) amino) -1H-pyrrole-2-carboxylate Cpd-010E (330 mg, colorless oil), yield: and 47 percent.
MS m/z(ESI):395[M+1] +
1 H NMR(400MHz,DMSO-d6)δ10.80(s,1H),6.78(d,J＝2.4Hz,1H),5.62(s,1H),5.29(s,1H),4.33(s,1H),4.18(q,J＝7.2Hz,2H),3.18(d,J＝6.4Hz,2H),1.91(dd,J＝13.2,3.6Hz,1H),1.75(td,J＝14.0,7.2Hz,1H),1.25(t,J＝7.2Hz,3H),0.88(s,9H),0.10(d,J＝5.6Hz,6H).
The fifth step
Preparation of ethyl 3- (1- (3- ((tert-butyldimethylsilyl) hydroxy) -4, 4-trifluorobutyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate
Ethyl- ((3- ((tert-butyldimethylsilyl) hydroxy) -4, 4-trifluorobutyl) amino) -1H-pyrrole-2-carboxylate Cpd-010E (150mg, 0.38mmol) was dissolved in dichloromethane (10 mL) followed by the addition of ethyl isothiocyanatecarboxylate (60mg, 0.46mmol). The reaction was stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was separated on a silica gel preparation plate (dichloromethane/methanol = 20/1) to give the title compound ethyl 3- (1- (3- ((tert-butyldimethylsilyl) hydroxy) -4, 4-trifluorobutyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-010F (177 mg, yellow solid) in yield: 84 percent.
MS m/z(ESI):526[M+1] + .
The sixth step
Preparation of 2-thioxo-1- (4, 4-trifluoro-3-hydroxybutyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Ethyl 3- (1- (3- ((tert-butyldimethylsilyl) hydroxy) -4, 4-trifluorobutyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-010F (100mg, 0.19mmol) was dissolved in methanol (25 mL) and cesium carbonate (310mg, 0.95mmol) was added and stirred at 65 ℃ for 4H. After the reaction was complete, water (10 mL) and ethyl acetate (10 mL) were added, and the aqueous phase was extracted with ethyl acetate (10 mL. Times.3). The organic phases were combined and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated on silica gel preparation plates (dichloromethane/methanol = 20/1) to give the title compound 2-thio-1- (4, 4-trifluoro-3-hydroxybutyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-010 (70 mg, white solid) in yield: 97 percent.
MS m/z(ESI):294[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.45(s,1H),12.20(s,1H),7.40(t,J＝2.8Hz,1H),6.43(d,J＝6.4Hz,1H),6.32(s,1H),4.58-4.41(m,2H),4.19(dd,J＝14.0,7.2Hz,1H),2.12-1.98(m,1H),1.89-1.84(m,1H).
Example 11
1- ((2-azabicyclo [2.2.2] octan-3-yl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000331
First step of
Preparation of ethyl 2-tolyl-2-azabicyclo [2.2.2] oct-5-ene-3-carboxylate
Ethyl 2-oxyacetate Cpd-011A (7.86g, 77.00mmol) and 4-toluenesulfonylisocyanate (7.60g, 38.50mmol) were dissolved in dry toluene (25 mL) and the reaction was reacted at 105 ℃ for 24 hours, followed by addition of 1, 3-cyclohexadiene (4.63g, 57.75mmol) and continued reaction at 105 ℃ for 18 hours. After the reaction is finished, the reaction product is cooled to 0 ℃, a large amount of solid is discharged, the reaction product is filtered, a filter cake is pulped by a mixed solution of petroleum ether/ethyl acetate =10/1, and the secondary filtration is carried out to obtain 2-tolyl-2-azabicyclo [2.2.2] oct-5-ene-3-carboxylic acid ethyl ester Cpd-011B (4.60 g, white solid), wherein the yield is as follows: 36 percent.
MS m/z(ESI):335.9[M+1] + .
Second step of
Preparation of ethyl 2-tolyl-2-azabicyclo [2.2.2] octane-3-carboxylate
Dissolving ethyl 2-tolyl-2-azabicyclo [2.2.2] oct-5-ene-3-carboxylate Cpd-011B (4.60g, 13.67mmol) in a mixed solvent of ethanol (50 mL) and ethyl acetate (250 mL), adding 10% palladium on carbon (460 mg), reacting at room temperature for 18 hours under a hydrogen atmosphere, filtering off the palladium on carbon after the reaction is finished, and concentrating the mother liquor to obtain ethyl 2-tolyl-2-azabicyclo [2.2.2] octane-3-carboxylate Cpd-011C (4.50 g, white solid), yield: 97 percent.
MS m/z(ESI):337.9[M+1] + .
The third step
Preparation of ethyl 2-azabicyclo [2.2.2] octane-3-carboxylate
Ethyl 2-tolyl-2-azabicyclo [2.2.2] octane-3-carboxylate Cpd-011C (2.00g, 5.90mmol) and phenol (5.55g, 59.00mmol) were dissolved in ethyl acetate (50 mL), followed by addition of acetic acid solution of hydrogen bromide (30%, 50 mL) and reaction at room temperature for 18 hours. After the reaction is finished, acetic acid is removed by rotary evaporation, then ethyl acetate (30 mL multiplied by 3) and saturated sodium bicarbonate water solution (30 mL) are used for extraction, organic phase is dried and concentrated to obtain 2-azabicyclo [2.2.2] octane-3-ethyl formate Cpd-011D (1.00 g, light yellow oily substance), and the yield: 93 percent.
MS m/z(ESI):183.9[M+1] + .
The fourth step
Preparation of 2-azabicyclo [2.2.2] octane-2-carboxylic acid tert-butyl ester-3-carboxylic acid ethyl ester
By reacting 2-azabicyclo [2.2.2]Octane-3-carboxylic acid Ethyl ester Cpd-011D (1.00g, 5.50mmol) was dissolved in dichloromethane (50 mL) and added (Boc) 2 O (1.80g, 8.25mmol) and DIEA (1.42g, 11.00mmol) were reacted at room temperature for 18 hours. After the reaction, methylene chloride was removed by rotary evaporation, and the mixture was extracted with ethyl acetate (50 mL × 3) and a saturated aqueous potassium hydrogen sulfate solution (30 mL), and the organic phase was concentrated by drying, and the obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 4/1) to obtain 2-azabicyclo [2.2.2]Octane-2-carboxylic acid tert-butyl ester-3-carboxylic acid ethyl ester Cpd-011E (1.00 g, colorless oil), yield: and 64 percent.
MS m/z(ESI):228.0(M-56+1).
The fifth step
Preparation of 3- (hydroxymethyl) -2-azabicyclo [2.2.2] octane-2-carboxylic acid tert-butyl ester
2-azabicyclo [2.2.2] octane-2-carboxylic acid tert-butyl ester-3-carboxylic acid ethyl ester Cpd-011E (1.00g, 3.50mmol) was dissolved in tetrahydrofuran (10 mL), followed by careful dropwise addition of an aluminum lithium hydrogen tetrahydrofuran solution (17.50mL, 17.50mmol, 1M) under ice-bath, reaction at room temperature for 18 hours, addition of sodium sulfate decahydrate after completion of the reaction, stirring for half an hour, filtration, drying and concentration of the mother liquor to give 3- (hydroxymethyl) -2-azabicyclo [2.2.2] octane-2-carboxylic acid tert-butyl ester Cpd-011F (0.55 g, colorless oil), yield: 67%.
MS m/z(ESI):242.2[M+1] + .
The sixth step
Preparation of 3-formyl-2-azabicyclo [2.2.2] octane-2-carboxylic acid tert-butyl ester
Dissolving 3- (hydroxymethyl) -2-azabicyclo [2.2.2] octane-2-carboxylic acid tert-butyl ester Cpd-011F (550mg, 2.28mmol) in dichloromethane (20 mL), adding Dess-Martin reagent (1.93g, 4.56mmol), reacting at room temperature for 18 hours, filtering after the reaction is finished, washing mother liquor with saturated sodium bicarbonate solution and saturated sodium bisulfite solution in sequence, removing dichloromethane by spinning, and separating and purifying the obtained residue with a silica gel column (petroleum ether/ethyl acetate = 100/10) to obtain 3-formyl-2-azabicyclo [2.2.2] octane-2-carboxylic acid tert-butyl ester Cpd-011G (400 mg, colorless oily substance) with yield: 73 percent.
MS m/z(ESI):184.0(M-56+1).
Step seven
Preparation of tert-butyl 3- ((2- (ethoxycarbonyl) -1H-pyrrol-3-yl) amino) methyl-2-azabicyclo [2.2.2] octane-2-carboxylate
3-formyl-2-azabicyclo [2.2.2] octane-2-carboxylic acid tert-butyl ester Cpd-011G (400mg, 1.67mmol) was dissolved in anhydrous methanol (20 mL), followed by the addition of ethyl 3-amino-1H-pyrrole-2-carboxylate (309mg, 2.01mmol), sodium cyanoborohydride (315mg, 5.01mmol) and acetic acid (3 drops) in that order, and stirred at room temperature for 3 hours. After the reaction was completed, methanol was removed by rotary evaporation, and the obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 100/10) to obtain tert-butyl 3- ((2- (ethoxycarbonyl) -1H-pyrrol-3-yl) amino) methyl-2-azabicyclo [2.2.2] octane-2-carboxylate Cpd-011H (600 mg, colorless oil) in yield: 95 percent.
MS m/z(ESI):378.1[M+1] + .
The eighth step
Preparation of tert-butyl 3- ((2-thio-4-oxo-1, 2,3, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) methyl) -2-azabicyclo [2.2.2] octane-2-carboxylate
Tert-butyl 3- ((2- (ethoxycarbonyl) -1H-pyrrol-3-yl) amino) methyl-2-azabicyclo [2.2.2] octane-2-carboxylate Cpd-011H (600mg, 1.59mmol) was dissolved in anhydrous methanol (20 mL), followed by addition of oxyethyl isothiocyanate (250mg, 1.91mmol) and stirring at room temperature for 8 hours. Cesium carbonate (1.56g, 4.77mmol) was added, the reaction was allowed to warm to 65 ℃ for 3 hours, after completion of the reaction, ethyl acetate (50 mL × 3) and a saturated aqueous solution of sodium chloride (30 mL) were extracted, and the organic phase was concentrated to give tert-butyl 3- ((2-thio-4-oxo-1, 2,3, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) methyl) -2-azabicyclo [2.2.2] octane-2-carboxylate Cpd-011I (400 mg, white solid), yield: 65 percent.
MS m/z(ESI):391.1[M+1] + .
The ninth step
Preparation of 1- ((2-azabicyclo [2.2.2] octan-3-yl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
3- ((2-thio-4-oxo-1, 2,3, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) methyl) -2-azabicyclo [2.2.2] octane-2-carboxylic acid tert-butyl ester Cpd-011I (300mg, 0.77mmol) was dissolved in anhydrous methanol (10 mL) and then added with a solution of hydrochloric acid in methanol (1.93mL, 7.70mmol, 4M) and stirred at 65 ℃ for 2 hours. After the reaction was completed, methanol was distilled off, the resulting solid was slurried with ethyl acetate, filtered, the filter cake was washed with an aqueous sodium bicarbonate solution, extracted with ethyl acetate and dried to give Cpd-011 (150 mg, white solid) with yield: 67 percent
MS m/z(ESI):291.0[M+1] + .
Example 12
2-thio-1- ((2-methyl-2-azabicyclo [2.2.2] octan-3-yl) methyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000351
1- ((2-azabicyclo [2.2.2] oct-3-yl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-011 (50mg, 0.17mmol) was dissolved in methanol (10 mL), paraformaldehyde (15mg, 0.52mmol) and sodium cyanoborohydride (33mg, 0.52mmol) were added in this order, and after 1 hour of reaction at room temperature, methanol was removed by spinning off, and the residue was purified by preparation (aqueous solution/acetonitrile =100/25 (formic acid 1 ‰)) to give 2-thioxo-1- ((2-methyl-2-azabicyclo [2.2.2] oct-3-yl) methyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-012 (5 mg, white solid) in yield: 10 percent.
MS m/z(ESI):304.9[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.40(s,1H),12.16(s,1H),8.20(s,1H),7.36(s,1H),6.25(d,J＝2.4Hz,1H),4.48-4.35(m,1H),4.25-4.22(m,1H),2.81-2.78(m,1H),2.33-2.32(m,4H),2.02-1.78(m,4H),1.47-1.29(m,5H).
Example 13
1- (Quinulin-4-ylmethyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000352
First step of
Preparation of quinine-4-methanol
Quinine-4-carboxylate Cpd-013A (500mg, 2.73mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) under a nitrogen atmosphere, controlled at 0 deg.C-10 deg.C, and slowly added lithium aluminum hydride (4.1mL, 4.1mmol,1M in THF) and allowed to react at 70 deg.C for 2 h. After the reaction was completed, the reaction solution was cooled to 0 ℃, and then aqueous sodium hydroxide (1m, 0.5 mL) and water (0.5 mL) were slowly added to quench, followed by addition of anhydrous magnesium sulfate, filtration, and concentration of the filtrate to obtain Cpd-013B (300 mg, white solid), yield: and 78 percent.
1 H NMR(400MHz,CDCl 3 )δ3.29(s,2H),2.91(t,J＝8.0Hz,6H),1.40(t,J＝8.0Hz,6H).
Second step of
Preparation of quinine-4-carbaldehyde
Quinine-4-methanol Cpd-013B (100mg, 0.71mmol) was dissolved in dry dichloromethane (5 mL). Cooling to 0 ℃, then adding dess-martin oxidant (361mg, 0.85mmol) in batches, stirring for 1 hour at room temperature after the addition is finished, adding 10mL of water after the reaction is finished, taking the water phase, washing with dichloromethane, and freeze-drying the water phase to obtain the product Cpd-013C (80 mg, white solid), wherein the yield is: 80 percent.
The third step
Preparation of 3- (quinine-4-methylamino) -1H-pyrrole-2-carboxylic acid ethyl ester
Ethyl 3-amino-1H-pyrrole-2-carboxylate (88.5mg, 0.575mmol) was dissolved in methanol (3 mL), and acetic acid (34.5mg, 0.575mmol) and Cpd-013C (80mg, 0.575mmol) were added in this order and stirred at room temperature for 0.5 hour. Sodium cyanoborohydride (36mg, 0.575 mmol) was then added in portions and stirred at room temperature for 16 hours. After the reaction is finished, 5mL of water is added for quenching, ethyl acetate is used for extraction, an organic phase is washed by saturated sodium chloride, dried by anhydrous sodium sulfate and rotary evaporated to obtain a crude product, and the crude product is purified by a column to obtain 3- (quinine-4-methylamino) -1H-pyrrole-2-ethyl formate Cpd-013D (60 mg, light brown oily substance), yield: 38 percent.
MS m/z(ESI):278[M+1] + .
The fourth step
Preparation of 3- (3- (ethoxycarbonyl) -1- (quinine-4-methyl) thioureido) -1H-pyrrole-2-carboxylic acid ethyl ester
3- (quinine-4-methylamino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-013D (60mg, 0.217mmol) was dissolved in dichloromethane (5 mL) and ethyl isothiocyanatecarboxylate (34mg, 0.260mmol) was added thereto, followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction mixture was washed once with water (5 mL), and the organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was isolated and purified by silica gel column (petroleum ether/ethyl acetate = 3/1) to give ethyl 3- (3- (ethoxycarbonyl) -1- (quinine-4-methyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-013E (70 mg, light brown oil), yield: 79 percent.
MS m/z(ESI):409[M+1] + .
The fifth step
Preparation of 1- (quinine-4-methyl) -2-thioxo-1, 2,3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one
Ethyl 3- (3- (ethoxycarbonyl) -1- (quinine-4-methyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-013E (70mg, 0.171mmol) was dissolved in methanol (2 mL), cesium carbonate (167mg, 0.515mmol) was added thereto, and the reaction mixture was heated to 65 ℃ for reaction for 3 hours. The reaction was cooled to room temperature, saturated aqueous ammonium chloride was added, DCM/MeOH (10/1) (10 mL. Times.3) was added, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The crude was isolated on a preparative silica gel plate (DCM/MeOH = 10/1) to give 1- (quinine-4-methyl) -2-thioxo-1, 2,3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-013 (30 mg, white solid), yield: 60 percent.
MS m/z(ESI):291[M+1] + .
1 H NMR(400MHz,DMSO-d 6 )δ12.39(s,1H),12.10(s,1H),7.33(s,1H),6.33(s,1H),5.06(s,1H),3.69(s,1H),2.76(t,J＝8.0Hz,6H),1.59-1.51(m,6H).
Example 14
(S) -1- (2-amino-4-methylpentyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000361
First step of
Preparation of (S) - (4-methyl-1-oxopentan-2-yl) carbamic acid tert-butyl ester
(S) - (1-hydroxy-4-methylpentane-2-yl) carbamic acid tert-butyl ester Cpd-014A (1.6 g, 7.3mmol) was dissolved in dichloromethane (20 mL), dessimidine (3.7 g, 8.8mmol) was added in portions under ice-bath, and then the ice-bath was removed and naturally returned to room temperature and stirred for 1 hour under nitrogen protection. After the reaction was completed, the reaction turbid solution was filtered with celite, the residue was washed with dichloromethane, and the resulting mother liquor was concentrated to give a crude product, which was separated and purified with a silica gel column (petroleum ether/ethyl acetate = 6/1) to give (S) - (4-methyl-1-oxopentan-2-yl) carbamic acid tert-butyl ester Cpd-014B (1.2 g, colorless oily substance) in yield: 73 percent.
1 H NMR(400MHz,DMSO-d6)δ9.43(s,1H),7.27(d,J＝7.5Hz,1H),3.92-3.80(m,1H),1.63(td,J＝13.4,6.6Hz,1H),1.41-1.34(m,11H),0.87(dd,J＝10.1,6.6Hz,6H).
Second step of
Preparation of ethyl (S) -3- ((2- ((tert-butoxycarbonyl) amino) -4-methylpentyl) amino) -1H-pyrrole-2-carboxylate
Tert-butyl (S) - (4-methyl-1-oxopentan-2-yl) carbamate, cpd-014B (1.1g, 5.3 mmol), ethyl 3-amino-1H-pyrrole-2-carboxylate (0.8g, 5.3 mmol) and two drops of acetic acid were dissolved in methanol (15 mL), stirred at room temperature under nitrogen for 1 hour, followed by addition of sodium cyanoborohydride (213mg, 3.4 mmol) and stirring at room temperature overnight. After completion of the reaction, the reaction solution was poured into water (100 mL), extracted with ethyl acetate (50 mL), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was separated and purified with a silica gel column (petroleum ether/ethyl acetate = 2/1) to give (S) -3- ((2- ((tert-butoxycarbonyl) amino) -4-methylpentyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-014C (1.5 g, colorless oil) in yield: 75 percent.
MS m/z(ESI):354[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ10.69(s,1H),6.74(d,J＝8Hz,1H),6.68(d,J＝8Hz,1H),5.67(s,1H),5.34(s,1H),4.17-1.14(m,2H),3.62(s,1H),3.12-2.89(m,2H),1.70-1.54(m,1H),1.37(s,9H),1.36-1.26(m,5H),0.85-0.82(m,6H).
The third step
Preparation of ethyl (S) -3- (1- (2- ((tert-butoxycarbonyl) amino) -4-methylpentyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate
Ethyl (S) -3- ((2- ((tert-butoxycarbonyl) amino) -4-methylpentyl) amino) -1H-pyrrole-2-carboxylate Cpd-014C (1.3g, 3.7 mmol) and ethoxycarbonyl isothiocyanate (0.5g, 4.1mmol) were dissolved in dichloromethane (20 mL) and stirred at room temperature under nitrogen for half an hour. After completion of the reaction, the crude product obtained by concentrating the reaction mixture was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 1/2) to obtain ethyl (S) -3- (1- (2- ((tert-butoxycarbonyl) amino) -4-methylpentyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-014D (1.5 g, colorless oil), yield: 78 percent.
MS m/z(ESI):485[M+1] + .
The fourth step
Preparation of (S) - (4-methyl-1- (4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) pentan-2-yl) carbamic acid tert-butyl ester
Ethyl (S) -3- (1- (2- ((tert-butoxycarbonyl) amino) -4-methylpentyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-014D (1.5g, 3.0 mmol) was dissolved in ethanol (10 mL), followed by addition of sodium ethoxide (3.1g, 9.0 mmol) and microwave heating to 100 ℃ under nitrogen with stirring for half an hour. After completion of the reaction, the reaction solution was quenched with an aqueous ammonium chloride solution (200 mL), the mixed solvent (dichloromethane/methanol =10/1, 100mL × 2) was extracted, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated, and the obtained crude product was separated and purified with a silica gel column (petroleum ether/ethyl acetate = 1/1) to obtain (S) - (4-methyl-1- (4-oxo-2-thio-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) pentan-2-yl) carbamic acid tert-butyl ester Cpd-014E (0.8 g, white solid) with a yield: 70 percent.
MS m/z(ESI):367[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.26(s,1H),12.09(s,1H),7.35(t,J＝2.8Hz,1H),6.60(d,J＝9.4Hz,1H),6.40(s,1H)4.65(d,J＝11.1Hz,1H),4.36-4.13(m,1H),3.83(s,1H),1.64-1.59(m,1H),1.51-1.39(m,1H),1.27-1.18(m,1H),1.11-1.08(m,9H),0.94-0.79(m,6H).
The fifth step
Preparation of (S) -1- (2-amino-4-methylpentyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Tert-butyl (S) - (4-methyl-1- (4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) pentan-2-yl) carbamate Cpd-014E (400mg, 1.1mmol) was dissolved in methanol hydrochloride (10mL, 3M), and the reaction mixture was heated to 30 ℃ and stirred for half an hour under nitrogen protection. After the reaction was completed, the reaction solution was concentrated, and the crude product was purified by a C18 reverse phase column (methanol/water (1 ‰ FA) = 3/7-7/3) to give (S) -1- (2-amino-4-methylpentyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-014 (100 mg, white solid), yield: 34 percent.
MS m/z(ESI):267[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ7.37(d,J＝2.8Hz,1H),6.41(d,J＝2.8Hz,1H),4.48(dd,J＝13.6,4.7Hz,1H),4.28-4.14(m,1H),3.62-3.54(m,1H),1.95-1.73(m,1H),1.47-1.23(m,2H),0.86(dd,J＝38.4,6.5Hz,6H).
Example 15
(S) -1- (2- (dimethylamino) -4-methylpentyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000381
First step of
Preparation of (S) -1- (2- (dimethylamino) -4-methylpentyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
(S) -1- (2-amino-4-methylpentyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-014 (50mg, 0.18mmol) was dissolved in methanol (3 mL), followed by addition of paraformaldehyde (322mg, 3.75mmol) and two drops of acetic acid, followed by addition of sodium cyanoborohydride (94mg, 1.50mmol) at room temperature and stirring at room temperature for half an hour. After completion of the reaction, the reaction solution was diluted with water (100 mL), extracted with ethyl acetate (50 mL × 2), the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the resulting crude product was separated and purified with a silica gel column (petroleum ether/ethyl acetate = 1/1) to give (S) -1- (2- (dimethylamino) -4-methylpentyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-015 (11 mg, white solid), yield: 19 percent.
MS m/z(ESI):295[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.36(s,1H),12.11(s,1H),7.36(s,1H),6.29(s,1H),4.35(s,2H),3.41(s,1H),2.23(s,6H),1.66(s,1H),1.48-1.35(m,1H),1.02(d,J＝5.8Hz,1H),0.81(dd,J＝31.0,5.0Hz,6H).
Example 16
(S) -1- (4-methyl-2- (methylamino) pentyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000382
First step preparation of (S, E) -N, N-dimethyl-N' - (4-methyl-1- (4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) pentan-2-yl) carboxamide
Prepare for
(S) -1- (2-amino-4-methylpentyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one, cpd-014 (70mg, 0.26mmol) and N, N-dimethylformamide dimethyl acetal (94mg, 0.78mmol) were dissolved in N, N-dimethylformamide (2 mL) and stirred at room temperature under a nitrogen atmosphere for 2 hours. After the reaction was completed, the reaction solution was quenched with water (100 mL), extracted with ethyl acetate (50 mL × 2), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give (S, E) -N, N-dimethyl-N' - (4-methyl-1- (4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) pentan-2-yl) carboxamide Cpd-016A (70 mg, white solid), yield: 58 percent.
MS m/z(ESI):322[M+1] + .
Second step of
Preparation of (S) -1- (4-methyl-2- (methylamino) pentyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
(S, E) -N, N-dimethyl-N' - (4-methyl-1- (4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) pentan-2-yl) carboxamide Cpd-016A (45mg, 0.14mmol) was dissolved in absolute ethanol (2 mL), and sodium borohydride (53mg, 1.40mmol) was added portionwise under ice bath followed by stirring for half an hour under nitrogen blanket. After the reaction was completed, the reaction solution was diluted with water (100 mL), extracted with ethyl acetate (50 mL. Times.2), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated for Prep-HPLC to afford (S) -1- (4-methyl-2- (methylamino) pentyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-016 (5 mg, white solid) with a yield: 12 percent.
MS m/z(ESI):281[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.29(br,2H),7.35(d,J＝2.7Hz,1H),6.32(d,J＝2.7Hz,1H),4.29(s,2H),3.26-3.17(m,1H),2.24(s,3H),1.72(dt,J＝13.3,6.5Hz,1H),1.37(dt,J＝13.7,6.9Hz,1H),1.16-1.06(m,1H),0.92-0.75(m,6H).
Example 17
1- (spiro [3.3] heptane-2-methyl) -2-thioxo-1, 2,3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000391
First step of
Preparation of spiro [3.3] heptane-2-methanol
Dissolving spiro [3.3] heptane-2-carboxylic acid Cpd-017A (300mg, 2.14mmol) in tetrahydrofuran (5 mL), cooling to 0 ℃, slowly adding borane tetrahydrofuran complex (10.7ml, 10.7mmol, 1m), standing overnight at room temperature, after the reaction is finished, cooling to 0 ℃, slowly adding methanol for quenching, concentrating the reaction solution, directly carrying out the next step of Cpd-017B (250 mg, white solid) without purification, wherein the yield is as follows: 92 percent.
1 H NMR(400MHz,CDCl 3 )δ3.55(d,J＝8.0Hz,2H),2.37-2.27(m,1H),2.09-2.05(m,2H),2.02-1.96(m,2H),1.91-1.87(m,2H),1.82-1.77(m,2H),1.71-1.67(m,2H).
Second step of
Preparation of spiro [3.3] heptane-2-carbaldehyde
Dissolving spiro [3.3] heptane-2-methanol Cpd-017B (100mg, 0.79mmol) in dry dichloromethane (5 mL), adding sodium bicarbonate (80mg, 0.95mmol), cooling to 0 ℃, then slowly dropping dess-Martin oxidant (402mg, 0.95mmol) in batches, stirring at room temperature for 1 hour after the addition is finished, filtering after the reaction is finished, washing the filtrate with an aqueous solution of sodium bicarbonate and an aqueous solution of sodium thiosulfate, washing an organic phase with saturated sodium chloride, drying anhydrous sodium sulfate to obtain a crude product, and purifying with a column to obtain spiro [3.3] heptane-2-formaldehyde Cpd-017C (80 mg, colorless oily substance), wherein the yield: 81 percent.
The third step
Preparation of ethyl 3- (spiro [3.3] heptane-2-methylamino) -1H-pyrrole-2-carboxylate
Ethyl 3-amino-1H-pyrrole-2-carboxylate Cpd-017C (99mg, 0.645 mmol) was dissolved in methanol (50 mL), and acetic acid (38.7 mg,0.645 mmol) and spiro [3.3] heptane-2-carbaldehyde (80mg, 0.645 mmol) were added in this order, followed by stirring at room temperature for 0.5 hour. Sodium cyanoborohydride (40.5mg, 0.645mmol) was then added in portions and stirred at room temperature for 16 hours. After the reaction is finished, adding 5mL of water for quenching, extracting by ethyl acetate, washing an organic phase by saturated sodium chloride, drying by anhydrous sodium sulfate, carrying out rotary evaporation to obtain a crude product, and purifying by a column to obtain 3- (spiro [3.3] heptane-2-methylamino) -1H-pyrrole-2-ethyl formate Cpd-017D (80 mg, light brown oily substance), wherein the yield is as follows: and 47 percent.
MS m/z(ESI):263[M+1] + .
The fourth step
Preparation of ethyl 3- (3- (ethoxycarbonyl) -1- (spiro [3.3] heptane-2-methyl) thioureido) -1H-pyrrole-2-carboxylate
3- (Spiro [3.3] heptane-2-methylamino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-017D (80mg, 0.305mmol) was dissolved in dichloromethane (5 mL), cooled to 0 ℃ and ethyl isothiocyanatocarboxylate (48mg, 0.366mmol) was added thereto, followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction mixture was washed once with water (5 mL), and the organic layer was dried over anhydrous sodium sulfate and concentrated. The obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 3/1) to obtain ethyl 3- (3- (ethoxycarbonyl) -1- (spiro [3.3] heptane-2-methyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-017E (40 mg, light brown oil), yield: 33 percent.
1 H NMR(400MHz,CDCl 3 )δ9.28(s,1H),7.40(s,1H),7.01(t,J＝3.1Hz,1H),6.16(t,J＝2.8Hz,1H),4.41-4.27(m,3H),4.15-4.10(m,2H),4.04-3.92(m,1H),2.58-2.48(m,1H),1.97-1.88(m,4H),1.84-1.80(m,2H),1.75-1.70(m,2H),1.63-1.56(m,2H),1.35(t,J＝7.1Hz,3H),1.20(t,J＝7.1Hz,3H).
The fifth step
Preparation of 1- (spiro [3.3] heptane-2-methyl) -2-thioxo-1, 2,3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one
Ethyl 3- (3- (ethoxycarbonyl) -1- (spiro [3.3] heptane-2-methyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-017E (20mg, 0.051mmol) was dissolved in ethanol (2 mL), sodium ethoxide (5.2mg, 0.076mmol) was added thereto, and the reaction mixture was heated to 90 ℃ for reaction for 1 hour. The reaction solution was cooled to room temperature, a saturated aqueous solution of ammonium chloride was added, extraction was performed with ethyl acetate (10 mL × 3), and the organic layer was dried over anhydrous sodium sulfate and concentrated. The crude was isolated on preparative silica gel plates (DCM/MeOH = 20/1) to give 1- (spiro [3.3] heptane-2-methyl) -2-thio-1, 2,3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-017 (8 mg, white solid) in yield: 57 percent.
MS m/z(ESI):276[M+1] + .
1 H NMR(400MHz,DMSO-d 6 )δ12.39(s,1H),12.12(s,1H),7.35(s,1H),6.33(s,1H),4.42(d,J＝6.8Hz,2H),2.87-2.63(m,1H),2.02-1.84(m,8H),1.79-1.58(m,2H).
Example 18
1- ((hexahydrocyclopent [ c ] pyrrol-5-yl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000401
First step of
Preparation of 5-Methylenehexahydrocyclopent [ c ] pyrrole-2- (1H) -carboxylic acid tert-butyl ester
Methyl triphenyl phosphonium bromide Cpd-018A (1600mg, 4.44mmol) is dispersed in 10mL of anhydrous ether under an ice bath, potassium tert-butoxide (500mg, 4.44mmol) is added, after stirring for one hour, an ether solution (5 mL) of tert-butyl 5-oxohexahydrocyclopentylpyrrole [ c ] pyrrole-2- (1H) -carboxylate (500mg, 2.22mmol) is added to a reaction flask, and reacted for 1 hour under an ice bath, then stirred at room temperature for 3 hours, 20mL of water is added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the resulting residue after concentration under reduced pressure is subjected to column chromatography (petroleum ether/ethyl acetate = 5/1) to give tert-butyl 5-methylenehexahydrocyclopentylpyrrole-2- (1H) -carboxylate (332 mg, colorless oil), yield: 67 percent.
1 H NMR(400MHz,CDCl 3 )δ4.90-4.87(m,2H),3.55-3.50(m,2H),3.13-3.09(m,2H),2.70-2.65(m,2H),2.59-2.52(m,2H),2.21-2.16(m,2H),1.45(s,9H).
Second step of
Preparation of 5- (hydroxymethyl) hexahydrocyclopenta [ c ] pyrrole-2- (1H) -carboxylic acid tert-butyl ester
After 2 hours of reaction, 1mol/L sodium oxyhydroxide solution 1.5mL was added dropwise slowly at-15 ℃ to a diethyl ether (10 mL) solution of 5-methylenehexahydrocyclopentyl [ C ] pyrrole-2- (1H) -carboxylic acid tert-butyl ester Cpd-018B (330mg, 1.5 mmol), and after 1 hour of reaction, 30% hydrogen peroxide solution 0.5mL was added dropwise to the reaction system, and the mixture was stirred at room temperature for 1 hour, the solvent was concentrated under reduced pressure and extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the residue obtained after concentration under reduced pressure was subjected to column chromatography (petroleum ether/ethyl acetate = 1/2) to give 5- (hydroxymethyl) hexahydrocyclopentyl [ C ] pyrrole-2- (1H) -carboxylic acid tert-butyl ester Cpd-018C (200 mg, colorless oil) in yield: 56 percent.
MS m/z(ESI):242.0[M+1] + .
The third step
Preparation of 5- (formaldehyde) hexahydrocyclopentyl [ c ] pyrrole-2- (1H) -tert-butyl formate
5- (hydroxymethyl) hexahydrocyclopenty [ C ] pyrrole-2- (1H) -carboxylic acid tert-butyl ester Cpd-018C (200mg, 0.83mmol) was dissolved in dichloromethane (10 mL), dess-Martine oxidant (424mg, 1.0 mmol) was added in portions and reacted at room temperature for 1 hour. The reaction solution was filtered, and the filtrate was washed with an aqueous sodium bicarbonate solution, an aqueous sodium thiosulfate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was subjected to column chromatography (petroleum ether/ethyl acetate = 4/1) to give 5- (formaldehyde-based) hexahydrocyclopentyl [ c ] pyrrole-2- (1H) -carboxylic acid tert-butyl ester Cpd-018D (120 mg, colorless oil), yield: 60 percent.
1 H NMR(400MHz,CDCl 3 )δ9.64(s,1H),3.51-3.46(m,2H),3.21-3.14(m,2H),2.89-2.82(m,1H),2.71-2.65(m,2H),2.18-2.10(m,2H),1.46(s,9H).
The fourth step
Preparation of ethyl 3- ((5- (methoxy) hexahydrocyclopenta [ c ] pyrrole-2- (1H) -carboxylate) amino) -1H-pyrrole-2-carboxylate
Ethyl 3-amino-1H-pyrrole-2-carboxylate (77mg, 0.5 mmol) was dissolved in methanol (5 mL), and acetic acid (30mg, 0.5 mmol) and 5- (carboxaldehyde) hexahydrocyclopentyl [ c ] pyrrole-2- (1H) -carboxylic acid tert-butyl ester Cpd-018D (120mg, 0.5 mmol) were added in this order and stirred at room temperature for 0.5 hour. Sodium cyanoborohydride (31mg, 0.5 mmol) was then added in portions and stirred at room temperature for 16 hours. After the reaction is finished, 5mL of water is added for quenching, ethyl acetate is used for extraction, an organic phase is washed by saturated sodium chloride, dried by anhydrous sodium sulfate and evaporated in a rotary manner to obtain a crude product, and the crude product is purified by a column to obtain 5- ((((2- (ethoxycarbonyl) -1H-pyrrole-3-yl) amino) methyl) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -tert-butyl formate Cpd-018E (70 mg, light brown oily substance) with the yield of 48%.
MS m/z(ESI):378.0[M+1] + .
The fifth step
Preparation of ethyl 3- [ 3-ethoxycarbonyl-1- (5- (methoxy) hexahydrocyclopenta [ c ] pyrrole-2- (1H) -carboxylate) ] -1H-pyrrole-2-carboxylate
5- ((((2- (ethoxycarbonyl) -1H-pyrrol-3-yl) amino) methyl) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester Cpd-018E (70mg, 0.185mmol) was dissolved in dichloromethane (5 mL), cooled to 0 ℃ and to which ethyl isothiocyanatecarboxylate (29mg, 0.223mmol) was added, followed by stirring at room temperature for 3 hours after the reaction was complete, the reaction was directly concentrated, and the residue was washed with petroleum ether to give 5- (((3- (ethoxycarbonyl) -1- (2- (ethoxycarbonyl) -1H-pyrrol-3-yl) thioureido) methyl) tert-butylcyclopentyl [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester Cpd-018F (50 mg, light brown oil) in 53% yield.
MS m/z(ESI):509.0[M+1] + .
The sixth step
Preparation of 1- (5- (methoxy) hexahydrocyclopenta [ c ] pyrrole-2- (1H) -carboxylic acid tert-butyl ester) -2-thioxo-1, 2,3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one
5- (((3- (ethoxycarbonyl) -1- (2- (ethoxycarbonyl) -1H-pyrrol-3-yl) thioureido) methyl) tert-butylcyclopentyl [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester Cpd-018F (50mg, 0.1mmol) was dissolved in methanol (2 mL), to which was added cesium carbonate (100mg, 0.3mmol), the reaction was heated to 65 ℃ for 3 hours, the reaction was cooled to room temperature, saturated aqueous ammonium chloride (5 mL) was added, ethyl acetate (10 mL. Times.3) was extracted, the organic layer was dried over anhydrous sodium sulfate and concentrated, the crude product was separated over preparative silica gel plate (DCM/MeOH = 20/1) to give 5- (((4-oxo-2-thioxo 2,3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) methyl) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester Cpd-018G (18 mg, white solid) in yield: 47%.
MS m/z(ESI):391[M+1] + .
Seventh step
Preparation of 1- ((hexahydrocyclopent [ c ] pyrrol-5-yl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
5- (((4-oxo-2-thioxooxy 2,3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) methyl) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester Cpd-018G (18mg, 0.046 mmol) was dissolved in hydrogen chloride in dioxane (4M, 2mL) and stirred at room temperature for 3 hours after completion of the reaction, concentrated, neutralized with saturated sodium bicarbonate, DCM/MeOH =10/1 extracted, the organic phase dried over anhydrous sodium sulfate and concentrated, and separated by preparative silica gel plates (DCM/MeOH = 10/1) to give 1- ((hexahydrocyclopenta [ c ] pyrrol-5-yl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-018% (10mg, 75%).
MS m/z(ESI):291[M+1] + .
1 H NMR(400MHz,DMSO-d 6 )δ10.30(br,2H),7.37(s,1H),6.44-6.36(m,1H),4.37(s,2H),3.17-3.13(m,1H),2.86(s,2H),2.74-2.60(m,2H),2.58-2.51(m,2H),1.90-1.84(m,1H),1.67-1.63(m,1H),1.50-1.48(m,1H),1.37-1.34(m,1H).
Example 19
1- ((2-methylhexahydropentyl [ c ] pyrrol-5-yl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000421
1- ((hexahydrocyclopent [ c ] pyrrol-5-yl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one (8mg, 0.027mmol) was dissolved in methanol (2 mL), paraformaldehyde (5mg, 0.055mol) was added, stirring was performed at room temperature for 1 hour, sodium cyanoborohydride (3.5mg, 0.055mmol) was added, and stirring was performed at room temperature for 3 hours. The reaction was concentrated and plate-separated on silica gel (DCM/MeOH = 10/1) to give 1- ((2-methylhexahydropentyl [ c ] pyrrol-5-yl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-019 (5mg, 59%).
MS m/z(ESI):305[M+1] + .
1 H NMR(400MHz,DMSO-d 6 )δ12.42(s,1H),12.15(s,1H),7.39(s,1H),6.37(s,1H),4.41(s,2H),3.39-3.29(m,2H),3.23-2.98(m,3H),2.93-2.75(m,2H),2.74(s,3H),1.68-1.54(m,2H),1.45-1.41(m,2H).
Example 20
1- (bicyclo [2.2.2] octan-1-ylmethyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000422
First step of
Preparation of bicyclo [2.2.2] octane-1-methanol
Bicyclo [2.2.2] octane-1-carboxylic acid Cpd-020A (200mg, 1.3 mmol) was dissolved in dry tetrahydrofuran (5 mL), and borane-tetrahydrofuran solution (6.5 mL,1.3 mmol) was slowly added. The reaction was stirred at 30 ℃ overnight. After the reaction was completed, methanol (3 mL) was added to quench the reaction, and then the reaction solution was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to give bicyclo [2.2.2] octane-1-methanol Cpd-020B (160 mg, colorless oil) in yield: 83 percent.
1 H NMR(400MHz,DMSO-d6)δ4.25(t,J＝5.4Hz,1H),2.97(d,J＝5.4Hz,2H),1.48(dd,J＝9.2,6.0Hz,7H),1.28(dd,J＝10.0,5.6Hz,6H).
Second step of
Preparation of bicyclo [2.2.2] octane-1-carbaldehyde
Bicyclo [2.2.2] octane-1-methanol Cpd-020B (160mg, 1.1mmol) was dissolved in dichloromethane (20 mL) and cooled to 0 ℃, followed by slow addition of dessimutan oxidant (580 mg,1.4 mmol) and the reaction mixture stirred at room temperature for 1h. After the reaction was completed, the reaction solution was washed with a saturated sodium thiosulfate solution (10 mL × 2) and a saturated sodium bicarbonate solution (10 mL × 2), the organic phase was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, the residue was again dispersed in a mixed solvent of petroleum ether/ethyl acetate =5/1, suction filtration was performed, the filtrate was collected and concentrated under reduced pressure to obtain bicyclo [2.2.2] octane-1-formaldehyde Cpd-020C (145 mg, yellow oily substance), yield: 45 percent.
The third step
Preparation of ethyl 3- ((bicyclo [2.2.2] octane-1-methyl) amino) -1H-pyrrole-2-carboxylate
Ethyl 3-amino-1H-pyrrole-2-carboxylate (110mg, 0.7 mmol) was dissolved in methanol (5 mL), after which bicyclo [2.2.2] octane-1-carbaldehyde Cpd-020C (100mg, 0.7 mmol), acetic acid (40mg, 0.7 mmol) and sodium cyanoborohydride (45mg, 0.7 mmol) were added in this order. The reaction was stirred at room temperature overnight and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to give the title compound ethyl 3- ((bicyclo [2.2.2] octane-1-methyl) amino) -1H-pyrrole-2-carboxylate Cpd-020D (85 mg, colorless oil) in yield: 40 percent.
MS m/z(ESI):277[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ10.66(s,1H),6.72(d,J＝2.8Hz,1H),5.60(t,J＝2.4Hz,1H),5.50-4.86(m,1H),4.18(q,J＝7.2Hz,2H),2.74(d,J＝6.4Hz,2H),1.57-1.46(m,7H),1.36(dd,J＝10.0,5.2Hz,6H),1.26(t,J＝7.2Hz,3H).
The fourth step
Preparation of ethyl 3- (1- (bicyclo [2.2.2] octane-1-methyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate
Ethyl 3- ((bicyclo [2.2.2] octane-1-methyl) amino) -1H-pyrrole-2-carboxylate Cpd-020D (80mg, 0.29mmol) was dissolved in dichloromethane (10 mL), followed by the addition of ethyl isothiocyanatecarboxylate (38mg, 0.29mmol). The reaction was stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was separated on a silica gel preparation plate (dichloromethane/methanol = 20/1) to obtain the title compound ethyl 3- (1- (bicyclo [2.2.2] octane-1-methyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-020E (40 mg, white solid), yield: 32 percent.
MS m/z(ESI):408[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ11.91(s,1H),9.05(s,1H),6.97(t,J＝2.9Hz,1H),6.22(d,J＝2.5Hz,1H),4.23(d,J＝8.5Hz,2H),4.18-4.03(m,2H),2.69(s,2H),1.48-1.28(m,13H),1.25(t,J＝7.1Hz,3H),1.07(t,J＝7.1Hz,3H).
The fifth step
Preparation of 1- (bicyclo [2.2.2] octane-1-methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Ethyl 3- (1- (bicyclo [2.2.2] octane-1-methyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-020E (40mg, 0.1mmol) was dissolved in methanol (5 mL) and cesium carbonate (160mg, 0.5 mmol) was added. The reaction solution was heated to 65 ℃ and stirred for 4 hours. After the reaction was complete, water (10 mL) and ethyl acetate (10 mL) were added, and the aqueous phase was extracted with ethyl acetate (10 mL. Times.3). The organic phases were combined and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated on silica gel preparation plates (dichloromethane/methanol = 20/1) to give the title compound 1- (bicyclo [2.2.2] octane-1-methyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-020 (6 mg, white solid) in yield: 20 percent.
MS m/z(ESI):290[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.34(s,1H),12.11(s,1H),7.32(d,J＝2.8Hz,1H),6.30(d,J＝2.8Hz,1H),5.00(s,1H),3.58(s,1H),1.46(s,13H).
Example 21
1- (2-Isopropoxyethyl) -2-thioxo-7-methyl-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000441
First step of
Preparation of ethyl 3- ((tert-butoxycarbonyl) amino) -1H-pyrrole-2-carboxylate
Ethyl 3-amino-1H-pyrrole-2-carboxylate Cpd-021A (5g, 32.4mmol) and di-tert-butyl dicarbonate (14.14g, 64.8mmol) were dissolved in methanol (50 mL) and reacted at 70 ℃ for 6 hours. The reaction solution is cooled to room temperature, and methanol is removed by rotary evaporation. The obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 4/1) to obtain ethyl 3- ((tert-butoxycarbonyl) amino) -1H-pyrrole-2-carboxylate Cpd-021B (7.6 g, white solid) in yield: 87 percent.
MS m/z(ESI):255[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ11.50(s,1H),8.31(s,1H),6.89(t,J＝3.2Hz,1H),6.51(s,1H),4.26(q,J＝7.2Hz,2H),1.46(s,9H),1.29(t,J＝7.2Hz,3H).
Second step of
Preparation of ethyl 3- ((tert-butoxycarbonyl) amino) -4-iodo-1H-pyrrole-2-carboxylate
Ethyl 3- ((tert-butoxycarbonyl) amino) -1H-pyrrole-2-carboxylate Cpd-021B (3g, 11.8mmol) was dissolved in chloroform (30 mL) and N-iodosuccinimide (2.79g, 12.4 mmol) was added thereto. The reaction mixture was reacted at 25 ℃ for 16 hours. The chloroform was removed by rotary evaporation, and the resulting residue was isolated and purified by silica gel column (petroleum ether/ethyl acetate = 5/1) to give ethyl 3- ((tert-butoxycarbonyl) amino) -4-iodo-1H-pyrrole-2-carboxylate Cpd-021C (1.94 g, yellow solid), yield: 41 percent.
MS m/z(ESI):381[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.04(s,1H),8.15(s,1H),7.06(d,J＝3.3Hz,1H),4.19(q,J＝7.1Hz,2H),1.41(s,9H),1.25(t,J＝7.1Hz,3H).
The third step
Preparation of ethyl 3- ((tert-butoxycarbonyl) amino) -4-methyl-1H-pyrrole-2-carboxylate
Ethyl 3- ((tert-butoxycarbonyl) amino) -4-iodo-1H-pyrrole-2-carboxylate Cpd-021C (300mg, 0.78mmol) was dissolved in a mixed solution of acetone (10 mL) and water (3 mL), and methylboronic acid (51.96mg, 0.86mmol), potassium carbonate (273mg, 1.97mmol) and palladium acetate (18mg, 0.08mmol) were added thereto. The reaction solution was reacted at 40 ℃ for 16 hours under nitrogen protection. The reaction solution was cooled to room temperature and the solvent was removed by rotary evaporation, and the obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 9/1) to give ethyl 3- ((tert-butoxycarbonyl) amino) -4-methyl-1H-pyrrole-2-carboxylate Cpd-021D (115 mg, white solid) in yield: 52 percent.
MS m/z(ESI):269[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ11.30(s,1H),7.97(s,1H),6.69(d,J＝3.2Hz,1H),4.17(q,J＝7.2Hz,2H),1.86(s,3H),1.41(s,9H),1.25(t,J＝7.2Hz,3H).
The fourth step
Preparation of ethyl 3-amino-4-methyl-1H-pyrrole-2-carboxylate
Ethyl 3- ((tert-butoxycarbonyl) amino) -4-methyl-1H-pyrrole-2-carboxylate Cpd-021D (230mg, 0.85mmol) was dissolved in methanol (3 mL), a 3M methanol hydrochloride solution (3 mL) was added thereto, and the reaction mixture was reacted at 25 ℃ for 16 hours. The acid was neutralized with saturated sodium bicarbonate solution, the methanol was then removed by rotary evaporation, and the residue was extracted with ethyl acetate (15 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give ethyl 3-amino-4-methyl-1H-pyrrole-2-carboxylate Cpd-021E (126 mg, yellow solid) in yield: 79 percent.
MS m/z(ESI):169[M+1] + .
The fifth step
Preparation of ethyl 3- ((2-isopropoxyethyl) amino) -4-methyl-1H-pyrrole-2-carboxylate
Ethyl 3-amino-4-methyl-1H-pyrrole-2-carboxylate Cpd-021E (80mg, 0.48mmol) was dissolved in methanol (3 mL) and 2-isopropoxyacetaldehyde (48mg, 0.48mmol) and glacial acetic acid (28.5mg, 0.48mmol) were added thereto. The reaction mixture was reacted at 25 ℃ for 1 hour. To the reaction solution was added sodium cyanoborohydride (29.8mg, 0.48mmol) and the reaction was continued for 16 hours. After the reaction was complete, methanol was removed by rotary evaporation and the resulting residue was extracted with ethyl acetate (15 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give crude 3- ((2-isopropoxyethyl) amino) -4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-021F (100 mg, yellow oil) in yield: 50 percent.
MS m/z(ESI):255[M+1] + .
The sixth step
Preparation of ethyl 3- (3- (ethoxycarbonyl) -1- (2-isopropoxyethyl) thioureido) -4-methyl-1H-pyrrole-2-carboxylate
Crude ethyl 3- ((2-isopropoxyethyl) amino) -4-methyl-1H-pyrrole-2-carboxylate Cpd-021F (100mg, 0.39mmol) was dissolved in dichloromethane (5 mL), and ethyl isothiocyanatecarboxylate (62mg, 0.47mmol) was added thereto to react at 25 ℃ for 2 hours. After the reaction was completed, dichloromethane was removed by rotary evaporation, and the obtained residue was isolated and purified using a preparative plate (petroleum ether/ethyl acetate = 2/1) to give 3- (3- (ethoxycarbonyl) -1- (2-isopropoxyethyl) thioureido) -4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-021G (35 mg, colorless oil), yield: 21 percent.
MS m/z(ESI):386[M+1] + .
Seventh step
Preparation of 1- (2-isopropoxyethyl) -2-thioxo-7-methyl-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Ethyl 3- (3- (ethoxycarbonyl) -1- (2-isopropoxyethyl) thioureido) -4-methyl-1H-pyrrole-2-carboxylate, cpd-021G (35mg, 0.03mmol), was dissolved in methanol (3 mL), and cesium carbonate (89mg, 0.27mmol) was added thereto. After the reaction solution was heated to 65 ℃ for 6 hours, the reaction solution was cooled to room temperature to remove methanol by rotary evaporation, water was added to the obtained residue, the mixture was allowed to stand and filtered, and the filter cake was dried to obtain 1- (2-isopropoxyethyl) -2-thio-7-methyl-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-021 (10 mg, pale yellow solid) in yield: 39 percent.
MS m/z(ESI):268[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.20(s,1H),12.13(s,1H),7.17(d,J＝2.4Hz,1H),4.65(s,2H),3.72(t,J＝6.4Hz,2H),3.54-3.51(m,1H),2.31(s,3H),1.02(d,J＝6.0Hz,6H).
Example 22
5-hydroxy-1- (2-isopropoxyethyl) -7-methoxy-2-thioxo-2, 3-dihydroquinazolin-4 (1H) -one
Figure BDA0003664464850000451
First step of
Preparation of methyl 2-amino-4, 6-dimethoxybenzoate
2-amino-4, 6-dimethoxybenzoic acid Cpd-022A (400mg, 2.03mmol) was dissolved in DMF (10 mL), potassium carbonate (308mg, 2.23mmol) and iodomethane (317mg, 2.23mmol) were added in this order, the reaction was allowed to react at room temperature for 2 hours, after completion of the reaction, the reaction was quenched with a saturated aqueous ammonium chloride solution, extracted with ethyl acetate (50 mL. Times.3), the organic phase was concentrated by drying, and the resulting residue was separated and purified with a silica gel column (petroleum ether/ethyl acetate = 4/1) to obtain methyl 2-amino-4, 6-dimethoxybenzoate Cpd-022B (300 mg, white solid) in yield: 70 percent.
MS m/z(ESI):212.0[M+1] + .
Second step of
Preparation of methyl 2- ((2-isopropoxyethyl) amino) -4, 6-dimethoxybenzoate
Methyl 2-amino-4, 6-dimethoxybenzoate Cpd-022B (300mg, 1.42mmol) was dissolved in anhydrous methanol (10 mL), followed by the addition of 2-isopropoxyacetaldehyde (174mg, 1.70mmol), sodium cyanoborohydride (268mg, 4.26mmol) and acetic acid (3 drops) in that order, and stirred at room temperature for 3 hours. After completion of the reaction, methanol was removed by rotary evaporation, and the obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 100/15) to obtain methyl 2- ((2-isopropoxyethyl) amino) -4, 6-dimethoxybenzoate Cpd-022C (300 mg, pale yellow oil), yield: 71 percent.
MS m/z(ESI):298.1[M+1] + .
The third step
Preparation of methyl 2- (3- (ethoxycarbonyl) -1- (2-isopropoxyethyl) thioureido) -4, 6-dimethoxybenzoate
Methyl 2- ((2-isopropoxyethyl) amino) -4, 6-dimethoxybenzoate Cpd-022C (60mg, 0.20mmol) was dissolved in methanol (10 mL), and ethyl isothiocyanatecarboxylate (32mg, 0.24mmol) was added and reacted at room temperature for 1 hour, and after completion of the reaction, the reaction solution was used in the next step as it was.
MS m/z(ESI):429.3[M+1] + .
The fourth step
Preparation of 1- (2-isopropoxyethyl) -5, 7-dimethoxy-2-thioxo-2, 3-dihydroquinazolin-4 (1H) -one
Cesium carbonate (114mg, 0.35mmol) was added to methyl 2- (3- (ethoxycarbonyl) -1- (2-isopropoxyethyl) thioureido) -4, 6-dimethoxybenzoate Cpd-022D (50mg, 0.12mmol) in methanol (10 mL), heated to 65 ℃ and stirred for 3 hours, after completion of the reaction, methanol was removed by rotary evaporation, and the resulting residue was isolated and purified by a silica gel column (petroleum ether/ethyl acetate = 1/1) to give 1- (2-isopropoxyethyl) -5, 7-dimethoxy-2-thio-2, 3-dihydroquinazolin-4 (1H) -one Cpd-022E (15 mg, white solid) in yield: 39 percent.
MS m/z(ESI):324.9[M+1] + .
The fifth step
Preparation of 5-hydroxy-1- (2-isopropoxyethyl) -7-methoxy-2-thioxo-2, 3-dihydroquinazolin-4 (1H) -one
1- (2-Isopropoxyethyl) -5, 7-dimethoxy-2-thio-2, 3-dihydroquinazolin-4 (1H) -one Cpd-022E (10mg, 0.03mmol) was added to pyridine (1 mL), followed by magnesium bromide (28mg, 0.15mmol), the temperature was raised to 105 ℃ to react for 2 hours, after completion of the reaction, pyridine was removed by rotary evaporation, and the obtained residue was separated and purified with a silica gel column (petroleum ether/ethyl acetate = 4/1) to give 5-hydroxy-1- (2-isopropoxyethyl) -7-methoxy-2-thio-2, 3-dihydroquinazolin-4 (1H) -one Cpd-022 (4 mg, white solid) in yield: 41 percent.
MS m/z(ESI):311.0[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.92(s,1H),12.10(d,J＝1.2Hz,1H),6.60(s,1H),6.41(s,1H),4.71(s,2H),3.87(d,J＝0.8Hz,3H),3.71(t,J＝6.0Hz,2H),3.62-3.56(m,1H),1.05(dd,J＝6.0,1.2Hz,6H).
Example 23
1- (2-Isopropoxyethyl) -7-methoxy-2-thioxo-2, 3-dihydroquinazolin-4 (1H) -one
Figure BDA0003664464850000461
First step of
Preparation of methyl 2- ((2-isopropoxyethyl) amino) -4-methoxybenzoate
Methyl 2-amino-4-methoxybenzoate Cpd-023A (100mg, 0.55mmol) was dissolved in methanol (2 mL) and 2-isopropoxyacetaldehyde (67.6 mg, 0.81mmol) and glacial acetic acid (33.1mg, 0.55mmol) were added thereto. The reaction mixture was reacted at 25 ℃ for 1 hour. To the reaction solution was added sodium cyanoborohydride (34.6 mg, 0.55mmol) and the reaction was continued for 16 hours. After completion of the reaction, methanol was removed by rotary evaporation, and the obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 9/1) to obtain methyl 2- ((2-isopropoxyethyl) amino) -4-methoxybenzoate Cpd-023B (90 mg, colorless oil), yield: and 55 percent.
MS m/z(ESI):268[M+1] + .
Second step of
Preparation of methyl 2- (3- (ethoxycarbonyl) -1- (2-isopropoxyethyl) thioureido) -4-methoxybenzoate
Methyl 2- ((2-isopropoxyethyl) amino) -4-methoxybenzoate Cpd-023B (80mg, 0.29mmol) was dissolved in dichloromethane (5 mL), and ethyl isothiocyanatecarboxylate (117.7 mg, 0.89mmol) was added thereto to react at 30 ℃ for 24 hours. After the completion of the reaction, methylene chloride was removed by rotary evaporation, and the obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 2/1) to obtain methyl 2- (3- (ethoxycarbonyl) -1- (2-isopropoxyethyl) thioureido) -4-methoxybenzoate Cpd-023C (57 mg, colorless oil) in yield: 45 percent.
MS m/z(ESI):399[M+1] + .
The third step
Preparation of 1- (2-isopropoxyethyl) -7-methoxy-2-thioxo-2, 3-dihydroquinazolin-4 (1H) -one
Methyl 2- (3- (ethoxycarbonyl) -1- (2-isopropoxyethyl) thioureido) -4-methoxybenzoate Cpd-023C (50mg, 0.12mmol) was dissolved in methanol (2 mL) and cesium carbonate (122.6 mg, 0.37mmol) was added thereto. The reaction mixture was heated to 65 ℃ and reacted for 6 hours. After the reaction was completed, the reaction solution was cooled to room temperature to remove methanol by rotary evaporation, and the obtained residue was isolated and purified using a preparative plate (petroleum ether/ethyl acetate = 4/1) to give 1- (2-isopropoxyethyl) -7-methoxy-2-thio-2, 3-dihydroquinazolin-4 (1H) -one Cpd-023 (35 mg, pale yellow solid) in yield: 90 percent.
MS m/z(ESI):295[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.58(s,1H),7.96(d,J＝8.8Hz,1H),7.15(d,J＝2.0Hz,1H),7.00(dd,J＝8.8,2.0Hz,1H),4.80(s,2H),3.92(s,3H),3.77(t,J＝6.0Hz,2H),3.59(dt,J＝12.0,6.0Hz,1H),1.04(d,J＝6.0Hz,6H).
Example 24
1- (2-Isopropoxyethyl) -5- (phenylamino) -2-thioxo-2, 3-dihydropyrimidin-4 (1H) -one
Figure BDA0003664464850000471
First step of
Preparation of 5-iodo-2- (methylthio) pyrimidin-4 (3H) -one
2- (methylthio) -3H-pyrimidin-4-one Cpd-024A (1.0 g,7.0 mmol) and iodosuccinimide (1.7 g,7.7 mmol) were dissolved in tetrahydrofuran (100 mL), followed by reaction at 70 ℃ for two hours under nitrogen. After the reaction is finished, the reaction solution is concentrated, ethyl acetate (50 mL) and water (50 mL) are added into the crude product, stirring and pulping are carried out, filtering is carried out, the filter cake is rinsed by ethyl acetate, and the compound 5-iodo-2- (methylthio) pyrimidin-4 (3H) -one 043B (1.5 g, white solid) is obtained, and the yield: 80 percent.
MS m/z(ESI):269[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ13.15(s,1H),8.32(s,1H),2.48(s,3H).
Second step of
Preparation of 5-iodo-1- (2-isopropoxyethyl) -2- (methylthio) pyrimidin-4-one
5-iodo-2- (methylthio) -3H-pyrimidin-4-one Cpd-024B (0.8g, 3.0mmol) and N, N-diisopropylethylamine (0.8g, 6.0mmol) were dissolved in dichloromethane (15 mL), followed by dropwise addition of isopropoxyethyl trifluoromethanesulfonate (0.9g, 3.6mmol) in an ice bath, after which it was stirred at room temperature for half an hour under nitrogen atmosphere. After completion of the reaction, the reaction solution was diluted with dilute hydrochloric acid (100ml, 1m), extracted with dichloromethane (50 mL × 2), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 10/1) to obtain 5-iodo-1- (2-isopropoxyethyl) -2- (methylthio) pyrimidin-4-one Cpd-024C (1.5 g, colorless oil) in yield: 75 percent.
MS m/z(ESI):355[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ8.20(s,1H),4.03(t,J＝5.3Hz,2H),3.64(t,J＝5.3Hz,2H),3.53(dt,J＝12.1,6.1Hz,1H),2.49(s,3H),1.04(d,J＝6.1Hz,6H).
The third step
Preparation of 1- (2-isopropoxyethyl) -2- (methylthio) -5- (phenylamino) pyrimidin-4-one
5-iodo-1- (2-isopropoxyethyl) -2- (methylthio) pyrimidin-4-one Cpd-024C (560mg, 1.6 mmol), aniline (294mg, 3.2mmol), tris (dibenzylideneacetone) dipalladium (72mg, 0.08mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (91mg, 0.16mmol) and cesium carbonate (1.0 g, 3.2mmol) were dissolved in anhydrous dioxane (80 mL) and reacted at 90 ℃ for 4 hours under nitrogen. After completion of the reaction, the reaction solution was filtered through celite, the filtrate was concentrated, and the obtained crude product was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 1/1) to obtain 1- (2-isopropoxyethyl) -2- (methylthio) -5- (phenylamino) pyrimidin-4-one Cpd-024D (1.2 g, white solid) in yield: 83 percent.
MS m/z(ESI):320[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ7.62(s,1H),7.35(s,1H),7.28-7.16(m,4H),6.86(t,J＝6.8Hz,1H),4.10(t,J＝5.1Hz,2H),3.69(t,J＝5.2Hz,2H),3.58(dt,J＝12.2,6.1Hz,1H),2.53(s,3H),1.07(d,J＝6.1Hz,6H).
The fourth step
Preparation of 1- (2-isopropoxyethyl) -5- (phenylamino) -2-thioxo-2, 3-dihydropyrimidin-4 (1H) -one
1- (2-Isopropoxyethyl) -2- (methylthio) -5- (phenylamino) pyrimidin-4-one Cpd-024D (100mg, 0.31mmol) and sodium hydrosulfide solid (88mg, 1.56mmol) were dissolved in N-methylpyrrolidinone (2 mL), followed by heating to 100 ℃ under nitrogen and stirring for 1 hour. After completion of the reaction, the reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (50 mL × 2), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was separated and purified with a silica gel column (petroleum ether/ethyl acetate = 1/1) to give 1- (2-isopropoxyethyl) -5- (phenylamino) -2-thio-2, 3-dihydropyrimidin-4 (1H) -one Cpd-024 (50 mg, white solid) in yield: and 52 percent.
MS m/z(ESI):306[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.81(s,1H),7.62(s,1H),7.48(s,1H),7.21(t,J＝7.8Hz,2H),7.11(d,J＝7.9Hz,2H),6.83(t,J＝7.2Hz,1H),4.35(t,J＝5.0Hz,2H),3.71(t,J＝5.0Hz,2H),3.57(dt,J＝12.2,6.1Hz,1H),1.07(d,J＝6.1Hz,6H).
Example 25
1- (1-adamantylmethyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000491
First step of
Preparation of 1-adamantane formaldehyde
1-Adamantanemethanol, cpd-025A (300mg, 1.8mmol), was dissolved in anhydrous dichloromethane (20 mL) and dess-martin oxidant (918mg, 2.2mmol) was slowly added. The reaction solution was stirred at room temperature for 1 hour. After completion of the reaction, a saturated sodium thiosulfate solution (30 mL) was added to quench, and the organic phase was washed with a saturated sodium carbonate solution (30 mL. Times.2), dried over anhydrous sodium sulfate, and filtered through celite. The filtrate was concentrated under reduced pressure to give the title compound 1-adamantanecarboxaldehyde, cpd-025B (274 mg, pale yellow liquid), yield: 92 percent. The crude product was used in the next reaction without further treatment.
1 H NMR(400MHz,DMSO-d6)δ9.29(s,1H),2.02(s,4H),1.74-1.63(m,12H).
Second step of
Preparation of ethyl 3- ((1-adamantylmethyl) amino) -1H-pyrrole-2-carboxylate
1-Adamantaldehyde Cpd-025B (270mg, 1.6 mmol), ethyl 3-amino-1H-pyrrole-2-carboxylate (200mg, 1.3 mmol), acetic acid (78mg, 1.3 mmol) and methanol (5 mL) were added to the flask, stirred at room temperature for 1 hour under a nitrogen atmosphere, followed by addition of sodium cyanoborohydride (413mg, 6.6 mmol) to the flask and reaction continued for 1 hour. After the reaction, the reaction solution was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate (30 mL × 3), the organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was isolated and purified on a Flash column (petroleum ether/ethyl acetate = 85/15) to give ethyl 3- ((1-adamantylmethyl) amino) -1H-pyrrole-2-carboxylate Cpd-025C (256 mg, yellow liquid), yield: 51 percent.
MS m/z(ESI):303[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ10.65(s,1H),6.72(s,1H),5.76(d,J＝0.7Hz,1H),5.62(t,J＝2.3Hz,1H),4.18(q,J＝7.2Hz,2H),2.74(d,J＝6.2Hz,2H),1.73-1.55(m,9H),1.50(s,6H),1.26(t,J＝7.2Hz,3H).
The third step
Preparation of ethyl 3- (1-adamantylmethyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate
Ethyl 3- ((1-adamantylmethyl) amino) -1H-pyrrole-2-carboxylate Cpd-025C (150mg, 0.5 mmol), ethyl isothiocyanatecarboxylate (98mg, 0.7 mmol) were dissolved in dichloromethane (20 mL) and the reaction mixture was reacted at room temperature under a nitrogen atmosphere for 1 hour. After the reaction, the reaction solution was quenched with water, extracted with ethyl acetate (30 mL × 3), the organic phases were combined and dried over anhydrous sodium sulfate, and concentrated to give a crude product. The crude product was isolated and purified on a Flash column (petroleum ether/ethyl acetate = 85/15) to give 3- (1-adamantylmethyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-025D (180 mg, yellow viscous liquid), yield: 84 percent.
MS m/z(ESI):434[M+1] + .
The fourth step
Preparation of 1- (1-adamantylmethyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Ethyl 3- (1-adamantylmethyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-025D (65mg, 0.15mmol), sodium ethoxide (153mg, 20% in ethanol) was dissolved in ethanol (1 mL) in a microwave tube and reacted at 100 ℃ for 30 minutes with a microwave. Quenched with 5mL of a saturated aqueous ammonium chloride solution, and the precipitated solid was collected by filtration and washed with purified water several times to give the title compound 1- (1-adamantylmethyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-025 (8 mg, white solid) in yield: 17 percent.
MS m/z(ESI):316[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.34(s,1H),12.11(s,1H),7.31(s,1H),6.33(s,1H),5.01(d,J＝10.4Hz,1H),3.55(d,J＝10.8Hz,1H),1.89(s,3H),1.73(s,3H),1.59(s,9H).
Example 26
1- (2-1, 1-Trifluoroisopropoxyethyl) -2-thioxo-1, 2,3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one (Cpd-026)
(R) -1- (2-1, 1-Trifluoroisopropoxyethyl) -2-thioxo-1, 2,3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one (Cpd-026R)
(S) -1- (2-1, 1-Trifluoroisopropoxyethyl) -2-thioxo-1, 2,3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one (Cpd-026S)
Figure BDA0003664464850000501
First step of
Preparation of (2- (1, 1-trifluoroisopropoxy) ethoxy) -tert-butyldimethylsilane
1, 1-trifluoroisopropanol Cpd-026A (1g, 8.77mmol) was dissolved in dry DMF (10 mL), cooled to 0 deg.C, added sodium hydride (421mg, 10.5 mmol) in portions, reacted at 0 deg.C for 1 hour, then (2-bromoethoxy) -tert-butyldimethylsilane (2.3g, 9.65mmol) was slowly added dropwise, and after the addition was complete, stirred at room temperature for 16 hours. After the reaction was completed, the reaction was quenched with saturated aqueous ammonium chloride (50 mL), extracted with dichloromethane, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and rotary evaporated to give crude product, which was directly purified in the next step, cpd-026B (1 g, light brown oil), yield: 42 percent.
1 H NMR(400MHz,CDCl 3 )δ3.91-3.82(m,1H),3.80-3.71(m,3H),3.67-3.61(m,1H),1.32(d,J＝8.0Hz,3H),0.89(s,9H),0.06(s,6H).
Second step of
Preparation of 2- (1, 1-Trifluoroisopropoxy) -ethanol
Dissolving (2- (1, 1-trifluoroisopropoxy) ethoxy) -tert-butyldimethylsilane Cpd-026B (1g, 3.67mmol) in tetrahydrofuran solution (1M, 10mL) of TBAF, stirring at room temperature for 1 hour, after the reaction, adding water (20 mL), extracting with dichloromethane, washing an organic phase with saturated sodium chloride, drying over anhydrous sodium sulfate to obtain a crude product, and purifying with a column to obtain 2- (1, 1-trifluoroisopropoxy) -ethanol Cpd-026C (230 mg, light yellow liquid), wherein the yield: 40 percent.
1 H NMR(400MHz,CDCl 3 )δ3.83-3.69(m,5H),1.88(s,1H),1.35(d,J＝8.0Hz,3H).
The third step
Preparation of ethyl 2- (1, 1-trifluoroisopropoxy) -trifluoromethanesulfonate
Under nitrogen atmosphere, 2- (1, 1-trifluoroisopropoxy) -ethanol Cpd-026C (100mg, 0.63mmol) and pyridine (75mg, 0.94mmol) were dissolved in dry dichloromethane (5 mL), cooled to 0 ℃, trifluoromethanesulfonic anhydride (213mg, 0.75mmol) was slowly added, after completion of the addition, reacted at 0 ℃ for 1 hour, after completion of the reaction, water (10 mL) was added thereto, dichloromethane was extracted, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated to give the product, which was directly purified in the next step Cpd-026D (150 mg, light brown liquid), yield: 82 percent.
The fourth step
Preparation of ethyl 3- ((1, 1-trifluoroisopropoxyethyl) amino) -1H-pyrrole-2-carboxylate
Ethyl 3-amino-1H-pyrrole-2-carboxylate (80mg, 0.517 mmol) was dissolved in 1, 4-dioxane (4 mL), DIPEA (100mg, 0.776mmol) and ethyl 2- (1, 1-trifluoroisopropoxy) -trifluoromethanesulfonate Cpd-026D (150mg, 0.517 mmol) were added in this order, followed by heating to 80 ℃ for 2.5 hours. After the reaction is finished, 10mL of water is added for quenching, ethyl acetate is used for extraction, an organic phase is washed by saturated sodium chloride, dried by anhydrous sodium sulfate and evaporated in a rotary manner to obtain a crude product, and the crude product is purified by a column to obtain 3- ((1, 1-trifluoro isopropoxyethyl) amino) -1H-pyrrole-2-ethyl formate Cpd-026E (70 mg, colorless oily substance), and the yield: 46 percent.
MS m/z(ESI):295[M+1] + .
The fifth step
Preparation of ethyl 3- (3- (ethoxycarbonyl) -1- (1, 1-trifluoroisopropoxyethyl) thioureido) -1H-pyrrole-2-carboxylate
Ethyl 3- ((1, 1-trifluoroisopropoxyethyl) amino) -1H-pyrrole-2-carboxylate Cpd-026E (70mg, 0.238mmol) was dissolved in methylene chloride (5 mL), cooled to 0 ℃ and ethyl isothiocyanatecarboxylate (37mg, 0.286mmol) was added thereto, followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction mixture was washed once with water (5 mL), and the organic layer was dried over anhydrous sodium sulfate and concentrated. The obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 3/1) to obtain ethyl 3- (3- (ethoxycarbonyl) -1- (1, 1-trifluoroisopropoxyethyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-026F (80 mg, light brown oil), yield: 79 percent.
MS m/z(ESI):426[M+1] + .
The sixth step
Preparation of 1- (2-1, 1-trifluoroisopropoxyethyl) -2-thioxo-1, 2,3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one
Ethyl 3- (3- (ethoxycarbonyl) -1- (1, 1-trifluoroisopropoxyethyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-026F (80mg, 0.188mmol) was dissolved in methanol (2 mL), cesium carbonate (184mg, 0.564mmol) was added thereto, and the reaction was heated to 65 ℃ for 3 hours. The reaction solution was cooled to room temperature, a saturated aqueous ammonium chloride solution (5 mL) was added, extraction was performed with ethyl acetate (10 mL. Times.3), and the organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was isolated on preparative silica gel plates (DCM/MeOH = 20/1) to give 1- (2-1, 1-trifluoroisopropoxyethyl) -2-thio-1, 2,3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-026 (30 mg, white solid) in yield: and 52 percent.
MS m/z(ESI):308[M+1] + .
1 H NMR(400MHz,DMSO-d 6 )δ12.38(s,1H),12.24(s,1H),7.36(s,1H),6.31(d,J＝2.7Hz,1H),4.63-4.46(m,2H),4.22-4.10(m,1H),3.98(t,J＝5.9Hz,2H),1.15(d,J＝6.5Hz,3H).
The example compound Cpd-026 was subjected to chiral resolution to afford (R) -1- (2-1, 1-trifluoroisopropoxyethyl) -2-thioxo-1, 2,3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one (Cpd-026R) and (S) -1- (2-1, 1-trifluoroisopropoxyethyl) -2-thioxo-1, 2,3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one (Cpd-026S). The chiral resolution conditions were as follows:
instrument LC-30AD SFC.
Chromatographic column, daicel CHIRALPAK AD-H250 mm × 20mm I.D.,5 μmm.
Mobile phase of CO 2 /EtOH＝77/23.
The flow rate was 38.0mL/min.
The wavelength is UV 214nm and 254nm.
The column temperature was 40 ℃.
Cpd-026R：
t R :4.644min.
1 H NMR(400MHz,DMSO-d6)δ12.28(s,2H),7.35(s,1H),6.30(s,1H),4.69-4.43(m,2H),4.27-4.08(m,1H),3.98(t,J＝5.6Hz,2H),1.15(d,J＝6.4Hz,3H).
Cpd-026S：
t R :5.289min.
1 H NMR(400MHz,DMSO-d6)δ12.26(s,2H),7.36(s,1H),6.30(s,1H),4.63-4.46(m,2H),4.23-4.09(m,1H),3.98(t,J＝5.8Hz,2H),1.15(d,J＝6.4Hz,3H).
Example 27
1- [2- (2-trifluoromethyl-2-propoxyethyl) ] -2-thioxo-1, 2,3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000521
First step of
Preparation of (2- (2-trifluoromethyl-2-propoxy) ethoxy) -tert-butyldimethylsilane
2-trifluoromethyl-2-propanol Cpd-027A (1g, 7.81mmol) was dissolved in dry DMF (10 mL), cooled to 0 deg.C, added sodium hydride (375mg, 9.37mmol) in portions, reacted at 0 deg.C for 1 h, then (2-bromoethoxy) -tert-butyldimethylsilane (2.05g, 8.59mmol) was slowly added dropwise, and after the addition was complete, stirred at room temperature for 16 h. After the reaction was complete, quenched with saturated aqueous ammonium chloride (50 mL), extracted with dichloromethane, the organic phase washed with saturated sodium chloride, dried over anhydrous sodium sulfate and rotary evaporated to give crude product which was purified directly to the next step Cpd-027B (1.5 g, light brown oil), yield: 68 percent.
1 H NMR(400MHz,CDCl 3 )δ3.88(t,J＝6.0Hz,1H),3.71(t,J＝4.0Hz,1H),3.55(t,J＝6.0Hz,1H),3.38(t,J＝6.0Hz,1H),0.89(s,9H),0.85(s,6H),0.05(s,6H).
Second step of
Preparation of 2- (2-trifluoromethyl-2-propoxy) -ethanol
Dissolving (2- (2-trifluoromethyl-2-propoxy) ethoxy) -tert-butyldimethylsilane Cpd-027B (1.0 g,3.5 mmol) in TBAF tetrahydrofuran solution (1M, 10mL), stirring at room temperature for 1 hour, after the reaction is finished, adding water (20 mL), extracting with dichloromethane, washing an organic phase with saturated sodium chloride, drying with anhydrous sodium sulfate to obtain a crude product, and purifying with a column to obtain 2- (2-trifluoromethyl-2-propoxy) -ethanol Cpd-027C (180 mg, light yellow liquid), wherein the yield is as follows: 30 percent.
1 H NMR(400MHz,CDCl 3 )δ3.75-3.71(m,2H),3.62(t,J＝4.0Hz,2H),1.93(s,1H),1.38(s,6H).
The third step
Preparation of ethyl 2- (2-trifluoromethyl-2-propoxy) -trifluoromethanesulfonate
Under nitrogen atmosphere, 2- (2-trifluoromethyl-2-propoxy) -ethanol Cpd-027C (100mg, 0.58mmol) and pyridine (70mg, 0.87mmol) were dissolved in dry dichloromethane (5 mL), cooled to 0 ℃, trifluoromethanesulfonic anhydride (200mg, 0.70mmol) was slowly added, and after completion of addition, reaction was carried out at 0 ℃ for 1 hour, after completion of reaction, water (10 mL) was added thereto, dichloromethane was extracted, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated to give the product, which was directly purified by the next step Cpd-027D (157 mg, light brown liquid), yield: 89 percent.
The fourth step
Preparation of ethyl 3- ((2-trifluoromethyl-2-propoxyethyl) amino) -1H-pyrrole-2-carboxylate
Ethyl 3-amino-1H-pyrrole-2-carboxylate (80mg, 0.517mmol) was dissolved in 1, 4-dioxane (4 mL), DIPEA (100mg, 0.776mmol) and ethyl 2- (2-trifluoromethyl-2-propoxy) -trifluoromethanesulfonate Cpd-027D (157mg, 0.517mmol) were added in that order, and then heated to 80 ℃ for 2.5 hours. After the reaction is finished, 10mL of water is added for quenching, ethyl acetate is used for extraction, an organic phase is washed by saturated sodium chloride, dried by anhydrous sodium sulfate and evaporated in a rotary manner to obtain a crude product, and the crude product is purified by a column to obtain 3- ((2-trifluoromethyl-2-propoxyethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-027E (70 mg, colorless oily substance), yield: 43.7 percent.
MS m/z(ESI):309[M+1] + .
The fifth step
Preparation of ethyl 3- (3- (ethoxycarbonyl) -1- (2-trifluoromethyl-2-propoxyethyl) thioureido) -1H-pyrrole-2-carboxylate
Ethyl 3- ((2-trifluoromethyl-2-propoxyethyl) amino) -1H-pyrrole-2-carboxylate Cpd-027E (70mg, 0.227mmol) was dissolved in dichloromethane (5 mL), cooled to 0 ℃ and ethyl isothiocyanatecarboxylate (35.7mg, 0.273mmol) was added thereto, followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction mixture was washed once with water (5 mL), and the organic layer was dried over anhydrous sodium sulfate and concentrated. The obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 3/1) to obtain ethyl 3- (3- (ethoxycarbonyl) -1- (2-trifluoromethyl-2-propoxyethyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-027F (80 mg, light brown oil), yield: 80 percent.
MS m/z(ESI):440[M+1] + 。
The sixth step
Preparation of 1- (2-2-trifluoromethyl-2-propoxyethyl) -2-thioxo-1, 2,3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one
Ethyl 3- (3- (ethoxycarbonyl) -1- (2-trifluoromethyl-2-propoxyethyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-027F (80mg, 0.182mmol) was dissolved in methanol (2 mL), cesium carbonate (178mg, 0.546mmol) was added thereto, and the reaction mixture was heated to 65 ℃ for 3 hours. The reaction solution was cooled to room temperature, a saturated aqueous ammonium chloride solution (5 mL) was added, extraction was performed with ethyl acetate (10 mL. Times.3), and the organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was isolated on a preparative silica gel plate (DCM/MeOH = 20/1) to give 1- (2-2-trifluoromethyl-2-propoxyethyl) -2-thioxo-1, 2,3, 5-tetrahydro-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-027 (20 mg, white solid) in yield: 34 percent.
MS m/z(ESI):322[M+1] + .
1 H NMR(400MHz,DMSO-d 6 )δ12.36(s,1H),12.23(s,1H),7.36(s,1H),6.27(s,1H),4.51(t,J＝6.0Hz,2H),3.90(t,J＝4.0Hz,2H),1.22(s,6H).
Example 28
1- (2-Isopropoxyethyl) -2-thioxo-7-cyclopropyl-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000531
First step of
Preparation of ethyl 3- ((tert-butoxycarbonyl) amino) -4-cyclopropyl-1H-pyrrole-2-carboxylate
Ethyl 3- ((tert-butoxycarbonyl) amino) -4-iodo-1H-pyrrole-2-carboxylate Cpd-028A (500mg, 1.3 mmol) was dissolved in dioxane (5 mL). And cyclopropylboronic acid (565mg, 6.8mmol), potassium carbonate (454mg, 3.3mmol), palladium acetate (30mg, 0.1mmol) and tricyclohexylphosphorus (74mg, 0.3mmol) were added thereto. The reaction solution is subjected to microwave reaction for 1 hour at the temperature of 120 ℃ under the protection of nitrogen. The reaction solution is cooled to room temperature, and the solvent is removed by rotary evaporation. The resulting residue was isolated and purified using preparative plates (petroleum ether/ethyl acetate = 4/1) to give ethyl 3- ((tert-butoxycarbonyl) amino) -4-cyclopropyl-1H-pyrrole-2-carboxylate Cpd-028B (80 mg, brown oil) in yield: 16 percent.
MS m/z(ESI):295[M+1] + .
Second step of
Preparation of 3-amino-4-cyclopropyl-1H-pyrrole-2-carboxylic acid ethyl ester
Ethyl 3- ((tert-butoxycarbonyl) amino) -4-cyclopropyl-1H-pyrrole-2-carboxylate Cpd-028B (80mg, 0.27mmol) was dissolved in dioxane (1 mL), 4M dioxane hydrochloride solution (1 mL) was added thereto, and the reaction mixture was reacted at 25 ℃ for 16 hours. The acid was neutralized with saturated sodium bicarbonate solution, the dioxane was removed, and the residue was extracted with ethyl acetate (3X 15 mL). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give ethyl 3-amino-4-cyclopropyl-1H-pyrrole-2-carboxylate Cpd-028C (18 mg, light yellow solid), yield: 32 percent.
MS m/z(ESI):195[M+1] + .
The third step
Preparation of ethyl 3- ((2-isopropoxyethyl) amino) -4-cyclopropyl-1H-pyrrole-2-carboxylate
Ethyl 3-amino-4-cyclopropyl-1H-pyrrole-2-carboxylate Cpd-028C (18mg, 0.09mmol) was dissolved in methanol (2 mL), and acetic acid (5.6 mg, 0.09mmol) and 2-isopropoxyacetaldehyde (10mg, 0.09mmol) were added in this order and the mixture was stirred at room temperature for 0.5 hour. Then, sodium cyanoborohydride (6 mg, 0.09mmol) was added in portions, and stirred at room temperature for 16 hours. After the reaction was finished, water (2 mL) was added for quenching, ethyl acetate was used for extraction, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, rotary evaporated to give a crude product, which was purified by column to give ethyl 3- ((2-isopropoxyethyl) amino) -4-cyclopropyl-1H-pyrrole-2-carboxylate Cpd-028D (20 mg, colorless oil), yield: 77 percent.
MS m/z(ESI):281[M+1] + .
The fourth step
Preparation of ethyl 3- (3- (ethoxycarbonyl) -1- (2-isopropoxyethyl) thioureido) -4-cyclopropyl-1H-pyrrole-2-carboxylate
Ethyl 3- ((2-isopropoxyethyl) amino) -4-cyclopropyl-1H-pyrrole- -2-carboxylate Cpd-028D (20mg, 0.07mmol) was dissolved in methylene chloride (2 mL), cooled to 0 ℃ and ethyl isothiocyanatecarboxylate (11.2mg, 0.09mmol) was added thereto, followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction mixture was washed once with water (2 mL), and the organic layer was dried over anhydrous sodium sulfate and concentrated. The obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 3/1) to obtain ethyl 3- (3- (ethoxycarbonyl) -1- (2-isopropoxyethyl) thioureido)) -4-cyclopropyl-1H-pyrrole-2-carboxylate Cpd-028E (18 mg, colorless oil), yield: 62 percent.
MS m/z(ESI):412[M+1] + .
The fifth step
Preparation of 1- (2-isopropoxyethyl) -2-thioxo-7-cyclopropyl-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Ethyl 3- (3- (ethoxycarbonyl) -1- (2-isopropoxyethyl) thioureido)) -4-cyclopropyl-1H-pyrrole-2-carboxylate, cpd-028E (18mg, 0.04mmol), was dissolved in methanol (3 mL) and cesium carbonate (43mg, 0.13mmol) was added thereto. The reaction mixture was heated to 65 ℃ and reacted for 6 hours. After the reaction was completed, the reaction solution was cooled to room temperature and quenched with ammonium chloride, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was plated to give 1- (2-isopropoxyethyl) -2-thioxo-7-cyclopropyl-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-028 (6 mg, white solid) in yield: and 47 percent.
MS m/z(ESI):294[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.22(s,1H),12.16(s,1H),7.13(s,1H),4.94(t,J＝6.4Hz,2H),3.78(t,J＝6.4Hz,2H),3.56-3.53(m,1H),2.02-1.93(m,1H),1.02(d,J＝6.0Hz,6H),0.87-0.8(m,2H),0.70-0.65(m,2H).
Example 29
2-thioxo-1- (2- ((1, 1-trifluoro-3- (methylamino) propan-2-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000551
First step of
Preparation of 1, 1-trifluoro-3- ((4-methoxybenzyl) amino) propan-2-ol
3-amino-1, 1-trifluoropropan-2-ol Cpd-029A (1.50g, 11.60mmol), p-methoxybenzyl chloride (1.91g, 12.18mmol) and triethylamine (2.35g, 23.2mmol) were sequentially added to acetonitrile (60 mL), heated to 70 ℃ for reaction for 2 hours, and after completion of the reaction, acetonitrile was removed by rotary evaporation, and the resulting residue was separated and purified with a silica gel column (petroleum ether/ethyl acetate = 2/1) to give 1, 1-trifluoro-3- ((4-methoxybenzyl) amino) propan-2-ol Cpd-029B (700 mg, colorless oil), yield: and 24 percent.
MS m/z(ESI):250.0[M+1] + .
Second step of
Preparation of 1, 1-trifluoro-3- ((4-methoxybenzyl) (methyl) amino) propan-2-ol
1, 1-trifluoro-3- ((4-methoxybenzyl) amino) propan-2-ol Cpd-029B (500mg, 2.01mmol) was dissolved in dry methanol (15 mL), and then paraformaldehyde (121mg, 4.02mmol) and sodium cyanoborohydride (252mg, 4.02mmol) were added and reacted at room temperature for 2 hours. After completion of the reaction, methanol was removed by rotary evaporation, and the obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 4/1) to obtain 1, 1-trifluoro-3- ((4-methoxybenzyl) (methyl) amino) propan-2-ol Cpd-029C (500 mg, white solid), yield: 94 percent.
1 H NMR(400MHz,DMSO-d6)δ7.21(d,J＝8.4Hz,2H),6.87(d,J＝8.4Hz,2H),6.13(d,J＝6.4Hz,1H),4.16-4.09(m,1H),3.73(s,3H),3.48(s,2H),2.60-2.51(m,2H),2.16(s,3H).
The third step
Preparation of 2- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) -3, 3-trifluoro-N- (4-methoxybenzyl) -N-methylpropan-1-amine
1, 1-trifluoro-3- ((4-methoxybenzyl) (methyl) amino) propan-2-ol Cpd-029C (500mg, 1.90mmol) was dissolved in anhydrous DMF (10 mL), cooled to zero, sodium hydrogen (91mg, 3.80mmol) was carefully added, reacted at room temperature for 10 minutes, (2-bromoethoxy) (tert-butyl) dimethylsilane (909 mg, 3.80mmol) was added, then the reaction was continued at room temperature for 2 hours, after the reaction was completed, the reaction was quenched with a saturated aqueous ammonium chloride solution, extracted with ethyl acetate (50 mL × 3), and the organic phase was dried and concentrated, and the resulting residue was purified with a silica gel column (petroleum ether/ethyl acetate = 10/1) to give 2- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) -3, 3-trifluoro-N- (4-methoxybenzyl) -N-methylpropan-1-Cpd-029D (500 mg, colorless oil) in yield: 62 percent.
MS m/z(ESI):422.2[M+1] + .
The fourth step
Preparation of 2- ((1, 1-trifluoro-3- ((4-methoxybenzyl) (methyl) amino) propan-2-yl) oxy) ethan-1-ol
2- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) -3, 3-trifluoro-N- (4-methoxybenzyl) -N-methylpropan-1-amine Cpd-029D (500mg, 1.19mmol) was dissolved in tetrahydrofuran (15 mL), followed by addition of a tetrahydrofuran solution of tetrabutylammonium fluoride (1M, 5.95mL, 5.95mmol) and allowed to react at room temperature for 2 hours, after completion of the reaction, quenching the reaction with a saturated aqueous ammonium chloride solution, extraction with ethyl acetate (50 mL. Times.3), and organic phase drying and concentration, and the resulting residue was isolated and purified with a silica gel column (petroleum ether/ethyl acetate = 2/1) to give 2- ((1, 1-trifluoro-3- ((4-methoxybenzyl) (methyl) amino) propan-2-yl) oxy) ethan-1-ol Cpd-029E (350 mg, colorless oil) in yield: 96 percent.
MS m/z(ESI):308.0[M+1] + .
The fifth step
Preparation of 2- ((1, 1-trifluoro-3- ((4-methoxybenzyl) (methyl) amino) propan-2-yl) oxy) acetaldehyde
Oxalyl chloride (496mg, 3.91mmol) was dissolved in dry dichloromethane (12 mL), to which was added dry dimethyl sulfoxide (610mg, 7.81mmol) dissolved in dichloromethane at-55 ℃ under nitrogen. After stirring for 10 min, 2- ((1, 1-trifluoro-3- ((4-methoxybenzyl) (methyl) amino) propan-2-yl) oxy) ethan-1-ol Cpd-029E (300mg, 0.98mmol) dissolved in dichloromethane was added thereto. After the reaction mixture was stirred at-55 ℃ for 30 minutes, triethylamine (790 mg, 7.81mmol) was added thereto. The reaction solution was stirred and returned to room temperature. After the reaction was complete, it was washed with water, dried over sodium sulfate and concentrated to give crude 2- ((1, 1-trifluoro-3- ((4-methoxybenzyl) (methyl) amino) propan-2-yl) oxy) acetaldehyde Cpd-029F (300 mg, yellow oil). Yield: 50 percent.
MS m/z(ESI):346.0(M+41).
The sixth step
Preparation of ethyl 3- ((2- ((1, 1-trifluoro-3- ((4-methoxybenzyl) (methyl) amino) propan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate
2- ((1, 1-trifluoro-3- ((4-methoxybenzyl) (methyl) amino) propan-2-yl) oxy) acetaldehyde Cpd-029F (300mg, 0.98mmol) was dissolved in methanol (5 mL) and ethyl 3-amino-1H-pyrrole-2-carboxylate (167mg, 1.08mmol) and glacial acetic acid (1 drop) were added thereto. The reaction mixture was reacted at 25 ℃ for 1 hour. To the reaction solution was added sodium cyanoborohydride (93mg, 1.47mmol) and the reaction was continued for 16 hours. After the completion of the reaction, methanol was removed by rotary evaporation, and the obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 1/1) to obtain ethyl 3- ((2- ((1, 1-trifluoro-3- ((4-methoxybenzyl) (methyl) amino) propan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-029G (80 mg, yellow oil) in yield: 16 percent.
MS m/z(ESI):444[M+1] + .
Step seven
Preparation of ethyl 3- ((2- ((1, 1-trifluoro-3- (methylamino) propan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate
Ethyl 3- ((2- ((1, 1-trifluoro-3- ((4-methoxybenzyl) (methyl) amino) propan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-029G (80 mg) was dissolved in methanol (5 mL) and Pd (OH) was added thereto 2 C (10 mg), under nitrogen atmosphere, at room temperature for 16 hours. The reaction was filtered, the filter cake was washed with a small amount of methanol, and the filtrate was concentrated to give ethyl 3- ((2- ((1, 1-trifluoro-3- (methylamino) propan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-029H (45 mg, yellow oil), yield: 61 percent.
MS m/z(ESI):324[M+1] + .
The eighth step
Preparation of ethyl 3- ((2- ((3- ((tert-butoxycarbonyl) (methyl) amino) -1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate
Ethyl 3- ((2- ((1, 1-trifluoro-3- (methylamino) propan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-029H (45mg, 0.14mmol) was dissolved in dichloromethane (1 mL) and di-tert-butyl dicarbonate (33mg, 0.15mmol) was added thereto, and reacted at room temperature for 16 hours. The reaction was concentrated, and to the residue was added a saturated sodium bicarbonate solution (2 mL), extracted with dichloromethane (5 mL × 3), dried over anhydrous sodium sulfate, ethyl 3- ((2- ((3- ((tert-butoxycarbonyl) (methyl) amino) -1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-029I (15 mg, yellow oil), yield: 25 percent.
MS m/z(ESI):424(M-100+1).
The ninth step
Preparation of ethyl 3- (1- (2- ((3- ((tert-butoxycarbonyl) (methyl) amino) -1, 1-trifluoropropan-2-yl) oxy) ethyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate
Ethyl 3- ((2- ((1- (tert-butoxycarbonyl) -3-methylpyrrolidin-3-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-029I (15mg, 0.035mmol) was dissolved in dichloromethane (1 mL), and ethyl isothiocyanatecarboxylate (9mg, 0.071mmol) was added thereto. The reaction mixture was reacted at 25 ℃ for 2 hours. After the reaction was completed, methylene chloride was removed by rotary evaporation. The resulting residue was extracted with ethyl acetate (3 × 5 mL), combined with the organic phase, dried over anhydrous sodium sulfate and concentrated to give the crude product, which was prepared to give ethyl 3- (1- (2- ((3- ((tert-butoxycarbonyl) (methyl) amino) -1, 1-trifluoropropan-2-yl) oxy) ethyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-029J (10 mg, yellow oil) yield: 46 percent.
MS m/z(ESI):555[M+1] + .
Preparation of methyl (3, 3-trifluoro-2- (2- (2-thioxo-4-oxo-1, 2,3, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) propyl) carbamic acid tert-butyl ester in the tenth step
Preparation of ethyl 3- (1- (2- ((3- ((tert-butoxycarbonyl) (methyl) amino) -1, 1-trifluoropropan-2-yl) oxy) ethyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-029J (10mg, 0.019mmol) was dissolved in methanol (0.5 mL), and cesium carbonate (12mg, 0.037mmol) was added thereto. The reaction mixture was heated to 65 ℃ and reacted for 6 hours. After completion of the reaction, methylene chloride (5 mL) was added to the reaction mixture, washed with water (2 mL) and saturated brine (2 mL) in this order, dried over anhydrous sodium sulfate, and concentrated to give Cpd-029K (10 mg, yellow oil) preparation of methyl (3, 3-trifluoro-2- (2- (2-thio-4-oxo-1, 2,3, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) propyl) carbamic acid tert-butyl ester: 100 percent.
MS m/z(ESI):459(M+23).
The eleventh step
Preparation of 2-thioxo-1- (2- ((1, 1-trifluoro-3- (methylamino) propan-2-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Methyl (3, 3-trifluoro-2- (2- (2-thio-4-oxo-1, 2,3, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) propyl) carbamic acid tert-butyl ester Cpd-029K was dissolved in methanol (0.5 mL) and 4N methanol hydrochloride solution (1 mL) was added thereto. The reaction solution was reacted at room temperature for 1 hour. After the reaction, the reaction solution was concentrated, neutralized with aqueous sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was concentrated, and the residue was purified by reverse phase preparative to give 2-thio-1- (2- ((1, 1-trifluoro-3- (methylamino) propan-2-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-029 (1.39 mg, white solid), yield: 2 percent.
MS m/z(ESI):337[M+1] + .
Example 30
1- (2- ((3-amino-1, 1-trifluoropropan-2-yl) oxy) ethyl) -2-mercapto-1, 5-dihydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000571
First step of
Preparation of 3- (bis (4-methoxybenzyl) amino) -1, 1-trifluoropropan-2-ol
3-amino-1, 1-trifluoropropan-2-ol Cpd-030A (4.00g, 31.00mmol), p-methoxybenzyl chloride (12.14g, 77.50mmol) and diisopropylethylamine (12.02g, 93.00mmol) were added sequentially to acetonitrile (100 mL), the temperature was raised to 75 ℃ to react for 18 hours, after completion of the reaction, acetonitrile was removed by rotary evaporation, and the residue obtained was separated and purified with a silica gel column (petroleum ether/ethyl acetate = 100/15) to give 3- (bis (4-methoxybenzyl) amino) -1, 1-trifluoropropan-2-ol Cpd-030B (2.00 g, colorless oil), yield: 17 percent.
MS m/z(ESI):370.1[M+1] + .
Second step of
Preparation of 2- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) -3, 3-trifluoro-N, N-bis (4-methoxybenzyl) propan-1-amine
3- (bis (4-methoxybenzyl) amino) -1, 1-trifluoropropan-2-ol Cpd-030B (2.00g, 5.40mmol) was dissolved in anhydrous DMF (15 mL), cooled to 0 deg.C, sodium hydrogen (390mg, 16.20mmol) was added carefully, after 10 minutes at room temperature, (2-bromoethoxy) (tert-butyl) dimethylsilane (1.94g, 8.10mmol) was added, and the reaction was continued at room temperature for 2 hours. After the reaction was completed, the reaction was quenched with a saturated aqueous ammonium chloride solution, extracted with ethyl acetate (50 mL × 3), and the organic phase was concentrated by drying, and the obtained residue was separated and purified with a silica gel column (petroleum ether/ethyl acetate = 10/1) to obtain 2- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) -3, 3-trifluoro-N, N-bis (4-methoxybenzyl) propan-1-amine Cpd-030C (2.00 g, white solid) in yield: 70 percent.
MS m/z(ESI):528.3[M+1] + .
The third step
Preparation of 2- ((3- (bis (4-methoxybenzyl) amino) -1, 1-trifluoropropan-2-yl) oxy) ethan-1-ol
2- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) -3, 3-trifluoro-N, N-bis (4-methoxybenzyl) propan-1-amine Cpd-030C (2.00g, 3.80mmol) was dissolved in tetrahydrofuran (50 mL), followed by addition of a tetrahydrofuran solution of tetrabutylammonium fluoride (1m, 7.60ml, 7.60mmol), reaction at room temperature for 2 hours, quenching with a saturated aqueous solution of ammonium chloride after completion of the reaction, extraction with ethyl acetate (50 mL × 3), organic phase drying and concentration, and the resulting residue was separated and purified with a silica gel column (petroleum ether/ethyl acetate = 4/1) to give 2- ((3- (bis (4-methoxybenzyl) amino) -1, 1-trifluoropropan-2-yl) oxy) ethan-1-ol Cpd-030D (1.10 g, white solid) yield: 70 percent.
MS m/z(ESI):414.1[M+1] + .
The fourth step
Preparation of 2- ((3- (bis (4-methoxybenzyl) amino) -1, 1-trifluoropropan-2-yl) oxy) acetaldehyde
Oxalyl chloride (690mg, 5.40mmol) was dissolved in dry dichloromethane (20 mL), the temperature was reduced to-78 ℃, then a solution of dimethyl sulfoxide (630mg, 8.10 mmol) in dichloromethane (5 mL) was slowly added, the temperature was controlled to be lower than-65 ℃, after the addition, the mixture was stirred at-78 ℃ for 30 minutes, then a solution of 2- ((3- (bis (4-methoxybenzyl) amino) -1, 1-trifluoropropan-2-yl) oxy) ethan-1-ol Cpd-030D (1.10g, 2.70mmol) in dichloromethane (5 mL) was added dropwise, and the mixture was kept warm for 2 hours after the addition. Triethylamine (1.64g, 16.20mmol) was then added dropwise, and after the addition, the temperature was slowly raised to 0 ℃ naturally, and water (100 mL) was added thereto, and the mixture was subjected to liquid separation, and the organic phase was washed with saturated sodium chloride and dried over anhydrous sodium sulfate to obtain 30mL of a dichloromethane solution containing 2- ((3- (bis (4-methoxybenzyl) amino) -1, 1-trifluoropropan-2-yl) oxy) acetaldehyde Cpd-030E, which was directly subjected to the next step without further treatment.
MS m/z(ESI):412.1[M+1] + .
The fifth step
Preparation of ethyl 3- ((2- ((3- (bis (4-methoxybenzyl) amino) -1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate
2- ((3- (bis (4-methoxybenzyl) amino) -1, 1-trifluoropropan-2-yl) oxy) acetaldehyde Cpd-030E (800mg, 1.94mmol) was dissolved in anhydrous methanol (20 mL), followed by the addition of ethyl 3-amino-1H-pyrrole-2-carboxylate (300mg, 1.94mmol), sodium cyanoborohydride (367mg, 5.83mmol) and acetic acid (3 drops) in that order, and stirred at room temperature for 3 hours. After the completion of the reaction, methanol was removed by rotary evaporation, and the obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 100/10) to obtain ethyl 3- ((2- ((3- (bis (4-methoxybenzyl) amino) -1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-030F (400 mg, light yellow solid) in yield: 38 percent.
MS m/z(ESI):550.2[M+1] + .
The sixth step
Preparation of ethyl 3- ((2- ((3-amino-1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate
Ethyl 3- ((2- ((3- (bis (4-methoxybenzyl) amino) -1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate, cpd-030F (400mg, 0.73mmol), was dissolved in methanol (20 mL), followed by addition of palladium on carbon (100 mg), displacement of hydrogen three times, warming to 65 ℃ for 18 hours, filtration of the catalyst after the end of the reaction, dry concentration to give ethyl 3- ((2- ((3-amino-1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate, cpd-030G (200 mg, light yellow oil), yield: 89 percent.
MS m/z(ESI):310.0[M+1] + .
Step seven
Preparation of ethyl 3- ((2- ((3- ((tert-butoxycarbonyl) amino) -1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate
Ethyl 3- ((2- ((3-amino-1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-030G (200mg, 0.65mmol) was dissolved in dichloromethane (20 mL) and then (Boc) was added 2 O (212mg, 0.97mmol) and triethylamine (196mg, 1.94mmol) were reacted at room temperature for 2 hours. After the reaction was completed, methylene chloride was removed by rotary evaporation, and the residue was extracted with ethyl acetate (20 mL × 3) and a saturated aqueous potassium hydrogensulfate solution (20 mL), and the organic phase was concentrated by drying, and the residue was separated and purified with a silica gel column (petroleum ether/ethyl acetate = 100/15) to give ethyl 3- ((2- ((3- ((tert-butoxycarbonyl) amino) -1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-030H (160 mg, colorless oil) in yield: 60 percent. MS m/z (ESI) 410.0[ m ] +1 ] + .
Eighth step
Preparation of ethyl 3- (1- (2- ((3- ((tert-butoxycarbonyl) amino) -1, 1-trifluoropropan-2-yl) oxy) ethyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate
Ethyl 3- ((2- ((3- ((tert-butoxycarbonyl) amino) -1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-030H (150mg, 0.37mmol) was dissolved in methanol (10 mL), followed by addition of ethyl isothiocyanatecarboxylate (58mg, 0.44mmol) and reaction at room temperature for 1 hour, after completion of the reaction mixture was used directly in the next step.
MS m/z(ESI):541.2[M+1] + .
Preparation of the ninth step (3, 3-trifluoro-2- (2- (2-thioxo-4-oxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) propyl) carbamic acid tert-butyl ester
Cesium carbonate (271mg, 0.83mmol) was added to a solution of 3- (1- (2- ((3- ((tert-butoxycarbonyl) amino) -1, 1-trifluoropropan-2-yl) oxy) ethyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-030I (150mg, 0.28mmol) in methanol (10 mL), heated to 65 ℃ and stirred for 3 hours, after the reaction was finished, methanol was removed by rotary evaporation, and the resulting residue was separated and purified with a silica gel column (petroleum ether/ethyl acetate = 1/1) to give tert-butyl (3, 3-trifluoro-2- (2- (2-thio-4-oxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) propyl) carbamate Cpd-030J (100 mg, white solid) yield: 85 percent.
MS m/z(ESI):423.1[M+1] + .
The tenth step
Preparation of 1- (2- ((3-amino-1, 1-trifluoropropan-2-yl) oxy) ethyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Tert-butyl (3, 3-trifluoro-2- (2- (2-thio-4-oxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) propyl) carbamate Cpd-030J (100mg, 0.24mmol) was added to methanol hydrochloride (5ml, 4m, 20.00mmol) and reacted at 50 ℃ for 2 hours, after completion of the reaction methanol was evaporated off, the residue was washed with aqueous sodium bicarbonate, dried after extraction with ethyl acetate, and the residue was purified by separation on a silica gel column (dichloromethane/methanol = 10/1) to give 1- (2- ((3-amino-1, 1-trifluoropropan-2-yl) oxy) ethyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-030 (50 mg, white solid) in yield: 65 percent.
MS m/z(ESI):323.0[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ7.37(d,J＝2.8Hz,1H),6.36(d,J＝2.8Hz,1H),4.71-4.51(m,2H),4.16-3.99(m,2H),3.93-3.82(m,1H),2.75-2.67(m,1H),2.59-2.53(m,1H).
Example 31
1- (2- ((3- (dimethylamino) -1, 1-trifluoropropan-2-yl) oxy) ethyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000601
1- (2- ((3-amino-1, 1-trifluoropropan-2-yl) oxy) ethyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-030 (15mg, 0.047mmol) was dissolved in anhydrous methanol (5 mL), and then paraformaldehyde (3mg, 0.094mmol) and sodium cyanoborohydride (6 mg, 0.094mmol) were added in this order and stirred at room temperature for 3 hours. After completion of the reaction, methanol was removed by rotary evaporation, and the obtained residue was separated and purified by a silica gel column (dichloromethane/methanol = 100/5) to obtain 1- (2- ((3- (dimethylamino) -1, 1-trifluoropropan-2-yl) oxy) ethyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-031 (4 mg, white solid), yield: 23 percent.
MS m/z(ESI):351.0[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.35(s,1H),12.21(s,1H),7.36(t,J＝2.8Hz,1H),6.30(s,1H),4.55(t,J＝5.6Hz,2H),4.21-4.17(m,1H),4.09(t,J＝5.6Hz,2H),2.38-2.37(m,2H),2.11(s,6H).
Example 32
1- (3-amino-2- (2, 2-trifluoroethoxy) propyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000602
First step of
Preparation of 3- (bis (4-methoxybenzyl) amino) propane-1, 2-diol
3-aminopropane-1, 2-diol Cpd-032A (1g, 11mmol), N, N-diisopropylethylamine (4.26g, 33mmol) and potassium iodide (0.37g, 2.2 mol) were dissolved in acetonitrile (20 mL) and subsequently heated to 90 ℃ under nitrogen for two hours with stirring. After completion of the reaction, the reaction solution was poured into water (200 mL), extracted with ethyl acetate (100 mL), and the combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product which was isolated and purified by silica gel column (petroleum ether/ethyl acetate = 1/1) to give 3- (bis (4-methoxybenzyl) amino) propane-1, 2-diol Cpd-032B (2.9 g, colorless oil) in yield: 80 percent.
MS m/z(ESI):332.0[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ7.23(d,J＝8.4Hz,4H),6.88(d,J＝8.4Hz,4H),4.41(t,J＝5.6Hz,1H),4.36(d,J＝4.4Hz,1H),3.73(s,6H),3.65(dd,J＝10.5,4.9Hz,1H),3.47(dd,J＝42.8,13.5Hz,4H),3.36-3.30(m,1H),3.16(dt,J＝11.2,5.8Hz,1H),2.42-2.48(m,2H).
Second step of
Preparation of 1- (bis (4-methoxybenzyl) amino) -3- ((tert-butyldimethylsilyl) oxy) propan-2-ol
3- (bis (4-methoxybenzyl) amino) propane-1, 2-diol Cpd-032B (2.94g, 8.9mmol) and imidazole (1.21g, 17.8mmol) were dissolved in tetrahydrofuran (40 mL), tert-butyldimethylchlorosilane (1.34g, 8.9mmol) was added in portions under ice-bath, stirred for ten minutes under nitrogen protection, and then stirred for 1 hour with ice-bath removed. After completion of the reaction, the reaction solution was poured into water (200 mL), extracted twice with ethyl acetate (100 mL), and the combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude 1- (bis (4-methoxybenzyl) amino) -3- ((tert-butyldimethylsilyl) oxy) propan-2-ol Cpd-032C (3.4 g, colorless oil) after separation and purification with silica gel column (petroleum ether/ethyl acetate = 4/1), yield: 85 percent.
MS m/z(ESI):446.0[M+1] + .
The third step
Preparation of 2-bromo-3- ((tert-butyldimethylsilyl) oxy) -N, N-bis (4-methoxybenzyl) propan-1-amine
1- (bis (4-methoxybenzyl) amino) -3- ((tert-butyldimethylsilyl) oxy) propan-2-ol Cpd-032C (500mg, 1.1mmol) and triphenylphosphine (382mg, 1.5mmol) were dissolved in dichloromethane (10 mL), carbon tetrabromide (484mg, 1.5mmol) was added in portions on ice, and then stirred for half an hour with the ice bath nitrogen blanketing removed. After the reaction was completed, the reaction solution was poured into 100mL of water, ethyl acetate (50 mL) was extracted twice, the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 10/1) to give 1- (bis (4-methoxybenzyl) amino) -3- ((tert-butyldimethylsilyl) oxy) propan-2-ol Cpd-032D (430 mg, colorless oily substance) with a yield: 75 percent.
MS m/z(ESI):508.0[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ7.25(d,J＝8.0Hz,4H),6.89(d,J＝8.0Hz,4H),4.22-4.12(m,1H),3.86-3.78(m,1H),3.74(s,6H),3.70-3.66(m,1H),3.57-3.43(m,4H),2.83-2.69(m,2H),0.82(s,9H),0.02-0.00(m,6H).
The fourth step
Preparation of 3- ((tert-butyldimethylsilyl) oxy) -N, N-bis (4-methoxybenzyl) -2- (2, 2-trifluoroethoxy) propan-1-amine
2-bromo-3- ((tert-butyldimethylsilyl) oxy) -N, N-bis (4-methoxybenzyl) propan-1-amine Cpd-032D (2.2g, 4.3mmol) was dissolved in trifluoroethanol (8.7g, 86mmol) and potassium tert-butoxide (0.97g, 8.6 mol) was added and heated at 70 ℃ for half an hour under nitrogen. After the reaction was completed, the reaction solution was poured into a saturated aqueous ammonium chloride solution (100 mL), ethyl acetate (50 mL) was extracted twice, the combined organic phases were washed with a saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was separated and purified with a silica gel column (petroleum ether/ethyl acetate = 10/1) to give 3- ((tert-butyldimethylsilyl) oxy) -N, N-bis (4-methoxybenzyl) -2- (2, 2-trifluoroethoxy) propane-1-amine Cpd-032E (2.0 g, colorless oil), yield: 79 percent.
MS m/z(ESI):528.0[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ7.23(d,J＝8.4Hz,4H),6.86(d,J＝8.1Hz,4H),4.16-3.94(m,2H),3.82-3.78(m,1H),3.76-3.66(m,9H),3.63(d,J＝2.1Hz,3H),3.52-3.39(m,1H),2.85-2.80(m,1H),0.85(s,9H),0.00(s,6H).
The fifth step
Preparation of 3- (bis (4-methoxybenzyl) amino) -2- (2, 2-trifluoroethoxy) propanol
3- ((tert-Butyldimethylsilyl) oxy) -N, N-bis (4-methoxybenzyl) -2- (2, 2-trifluoroethoxy) propan-1-amine Cpd-032E (2.0 g,3.7 mmol) was dissolved in tetrahydrofuran (15 mL), tetrabutylammonium fluoride (1M, 7.4mL, 7.4mmol) was added and stirred at room temperature for half an hour under nitrogen protection. After completion of the reaction, the reaction solution was poured into 100mL of an aqueous solution, ethyl acetate (50 mL) was extracted twice, the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 4/1) to give 3- (bis (4-methoxybenzyl) amino) -2- (2, 2-trifluoroethoxy) propanol Cpd-032F (1.3 g, colorless oil) in yield: 84 percent.
MS m/z(ESI):414.0[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ7.24(d,J＝8.5Hz,4H),6.86(d,J＝8.5Hz,4H),4.52-4.45(m,1H),4.06-3.96(m,2H),3.82(dd,J＝9.9,7.1Hz,1H),3.72(d,J＝5.3Hz,8H),3.62(s,3H),3.58-3.41(m,3H),2.86-2.76(m,1H).
The sixth step
Preparation of 3- (bis (4-methoxybenzyl) amino) -2- (2, 2-trifluoroethoxy) propanal
Oxalyl chloride (0.51g, 4.0 mmol) was dissolved in dichloromethane (15 mL) with anhydrous sodium sulfate (200 mg) under nitrogen, and a diluted anhydrous solution of dimethyl sulfoxide (0.63g, 8.1 mmol) in dichloromethane (0.5 mL) was added dropwise at-60 ℃. After 5 minutes, a solution of 3- (bis (4-methoxybenzyl) amino) -2- (2, 2-trifluoroethoxy) propanol Cpd-032F (1.1g, 2.7 mmol) dissolved in dichloromethane (3 mL) was added dropwise, maintaining the temperature no higher than-55 ℃. Stirring for half an hour while maintaining the same temperature, then adding triethylamine (1.09g, 10.8mmol) dropwise while maintaining the temperature at not higher than-55 ℃, and naturally raising the temperature to room temperature after completion of the dropwise addition and stirring for 10 minutes. After the reaction was completed, the reaction solution was poured into 100mL of an aqueous solution, dichloromethane (100 mL) was extracted twice, and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude 3- (bis (4-methoxybenzyl) amino) -2- (2, 2-trifluoroethoxy) propanal Cpd-032G (1.2G, colorless oil) which was used in the next reaction without further purification.
MS m/z(ESI):412.0[M+1] + .
Step seven
Preparation of ethyl 3- ((3- (bis (4-methoxybenzyl) amino) -2- (2, 2-trifluoroethoxy) propyl) amino) -1H-pyrrole-2-carboxylate
Ethyl 3-amino-1H-pyrrole-2-carboxylate (0.6g, 3.8mmol) and 3- (bis (4-methoxybenzyl) amino) -2- (2, 2-trifluoroethoxy) propanal Cpd-032G (1.2G, 2.9mmol) were dissolved in methanol (15 mL), two drops of glacial acetic acid were added dropwise under nitrogen and stirred at room temperature for half an hour, followed by sodium cyanoborohydride (0.7g, 11.6mmol) and stirred at room temperature for half an hour. After the reaction was completed, the reaction solution was poured into 100mL of water, ethyl acetate (50 mL) was extracted twice, and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product which was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 4/1) to give 3- ((3- (bis (4-methoxybenzyl) amino) -2- (2, 2-trifluoroethoxy) propyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-032H (1 g, colorless oil) in yield: 62 percent.
MS m/z(ESI):550.0[M+1] + .
The eighth step
Preparation of ethyl 3- ((3-amino-2- (2, 2-trifluoroethoxy) propyl) amino) -1H-pyrrole-2-carboxylate
Ethyl 3- ((3- (bis (4-methoxybenzyl) amino) -2- (2, 2-trifluoroethoxy) propyl) amino) -1H-pyrrole-2-carboxylate Cpd-032H (700mg, 1.27mmol) was dissolved in methanol (50 mL), palladium on carbon (70 mg) hydroxide was added, four times gas was replaced with a double-layer hydrogen balloon, and then the mixture was heated at 60 ℃ for two hours. After the reaction was complete, the reaction solution was filtered through celite, the filter residue was washed with methanol (20 mL. Times.2), and the combined organic phases were concentrated to give crude 3- ((3-amino-2- (2, 2-trifluoroethoxy) propyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-032I (330 mg, colorless oil) which was used in the next step without purification.
MS m/z(ESI):310.0[M+1] + .
The ninth step
Preparation of ethyl 3- ((3- ((tert-butoxycarbonyl) amino) -2- (2, 2-trifluoroethoxy) propyl) amino) -1H-pyrrole-2-carboxylate
Ethyl 3- ((3-amino-2- (2, 2-trifluoroethoxy) propyl) amino) -1H-pyrrole-2-carboxylate Cpd-032I (330mg, 1.1mmol), triethylamine (348mg, 1.6mmol) and Boc 2 O (348mg, 1.1mmol) was dissolved in methylene chloride (10 mL) and stirred at room temperature overnight under nitrogen. After the reaction was completed, the reaction mixture was poured into water (100 mL), ethyl acetate (50 mL) was extracted twice, the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 1/1) to give ethyl 3- ((3- ((tert-butoxycarbonyl) amino) -2- (2, 2-trifluoroethoxy) propyl) amino) -1H-pyrrole-2-carboxylate Cpd-032J (423 mg, none, and no content)A colored oil), yield: 97 percent.
MS m/z(ESI):410.0[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ10.73(s,1H),6.87(d,J＝8.0Hz,1H),6.76(s,1H),5.68-5.63(m,1H),5.40(s,1H),4.23-4.11(m,3H),3.77-3.70(m,1H),3.55(dd,J＝12.3,6.6Hz,2H),3.21-2.99(m,3H),1.37(s,9H),1.26(t,J＝6.0Hz,3H).
The tenth step
Preparation of ethyl 3- (1- (3- ((tert-butoxycarbonyl) amino) -2- (2, 2-trifluoroethoxy) propyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate
Ethyl 3- ((3- ((tert-butoxycarbonyl) amino) -2- (2, 2-trifluoroethoxy) propyl) amino) -1H-pyrrole-2-carboxylate Cpd-032J (420mg, 1.0 mmol) was dissolved in dichloromethane (7 mL), followed by dropwise addition of ethyl isothiocyanatecarboxylate (161mg, 1.2 mmol) at room temperature and stirring at room temperature for half an hour. After the reaction was complete, concentration gave crude ethyl 3- (1- (3- ((tert-butoxycarbonyl) amino) -2- (2, 2-trifluoroethoxy) propyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-032K (554 mg, colorless oil), yield: 100 percent.
MS m/z(ESI):541.0[M+1] + .
Preparation of the eleventh step tert-butyl (3- (2-thioxo-4-oxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-1-yl) -2- (2, 2-trifluoroethoxy) propyl) carbamate
Ethyl 3- (1- (3- ((tert-butoxycarbonyl) amino) -2- (2, 2-trifluoroethoxy) propyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-032K (450mg, 0.8mmol) was dissolved in methanol (10 mL) and cesium carbonate (2.7 g, 8.3mmol) was added and heated to 70 ℃ under nitrogen with stirring for 4 hours. After the reaction was completed, the reaction solution was poured into an aqueous ammonium chloride solution (100 mL), ethyl acetate (50 mL) was extracted twice, the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was separated and purified with a silica gel column (petroleum ether/ethyl acetate = 1/1) to give (3- (2-thio-4-oxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-1-yl) -2- (2, 2-trifluoroethoxy) propyl) carbamic acid tert-butyl ester Cpd-032L (278 mg, white solid) with yield: 79 percent.
MS m/z(ESI):423.0[M+1] + .
Twelfth step
Preparation of 1- (3-amino-2- (2, 2-trifluoroethoxy) propyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
The isolated and purified tert-butyl (3- (2-thio-4-oxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-1-yl) -2- (2, 2-trifluoroethoxy) propyl) carbamate, cpd-032L (278mg, 0.7 mmol), was dissolved in ethanol hydrochloride (10 mL) and stirred at 30 ℃ for 1 hour under nitrogen. After the reaction was completed, the reaction solution was concentrated, the obtained crude product was neutralized with a saturated aqueous sodium bicarbonate solution (100 mL), dichloromethane/methanol (10/1, 50 mL) was extracted three times, the combined organic phases were washed with a saturated brine (100 mL), dried with anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product which was separated and purified with a silica gel column (dichloromethane/methanol = 1/0-10/1) to obtain 1- (3-amino-2- (2, 2-trifluoroethoxy) propyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-032 (40 mg, white solid) with a yield: 19 percent.
MS m/z(ESI):323.0[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.36(s,1H),7.35(d,J＝2.7Hz,1H),6.34(d,J＝2.7Hz,1H),4.42(dd,J＝13.5,5.2Hz,1H),4.25(dd,J＝13.4,6.9Hz,1H),4.15-3.97(m,2H),3.63-3.42(m,3H).
Example 33
1- (3- (dimethylamino) -2- (2, 2-trifluoroethoxy) propyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000631
1- (3-amino-2- (2, 2-trifluoroethoxy) propyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one (hydrochloride) Cpd-032 (40mg, 0.12mmol), paraformaldehyde (37mg, 1.2mmol) was dissolved in methanol (3 mL) and a saturated aqueous solution of sodium bicarbonate (2 mL) and stirred at room temperature for half an hour. After the reaction was completed, the reaction solution was poured into water (100 mL), extracted twice with ethyl acetate (50 mL), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product which was isolated and purified with a silica gel column (dichloromethane/methanol = 1/0-14/1) to give 1- (3- (dimethylamino) -2- (2, 2-trifluoroethoxy) propyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-033 (25 mg, colorless oil) in yield: 53 percent.
MS m/z(ESI):351.0[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.38(s,1H),12.15(s,1H),7.37(s,1H),6.27(d,J＝2.1Hz,1H),4.47(dd,J＝13.5,7.3Hz,1H),4.35(dd,J＝13.6,6.6Hz,1H),4.06-3.92(m,2H),3.78(dd,J＝10.1,6.7Hz,1H),3.66(dd,J＝10.1,4.7Hz,1H),3.53-3.40(m,1H),2.32(s,6H).
Example 34
2-thio-1- (2, 2-trifluoro-1- (1H-imidazol-2-yl) ethoxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000641
First step of
Preparation of 1-trityl-1H-imidazole-2-carbaldehyde
1H-imidazole-2-carbaldehyde Cpd-034A (2.0 g, 20.8mmol) was dissolved in N, N-dimethylformamide (20 mL). And triphenylchloromethane (4.2g, 41.6 mmol) and triethylamine (6.4g, 22.8mmol) were added thereto. The reaction solution was reacted at room temperature for 3 hours. Water (50 mL) was added to the reaction solution, followed by extraction with ethyl acetate (3X 50 mL). The organic phases were combined and washed with water (3X 100 mL), dried over anhydrous sodium sulfate and concentrated. The obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 3/2) to obtain 1-trityl-1H-imidazole-2-carbaldehyde Cpd-034B (2.2 g, yellow solid), yield: 31 percent.
1 H NMR(400MHz,DMSO-d6)δ9.13(s,1H),7.40-7.35(m,10H),7.08-7.03(m,7H).
Second step of
Preparation of 2, 2-trifluoro-1- (1-trityl-1H-imidazol-2-yl) ethan-1-ol
1-trityl-1H-imidazole-2-carbaldehyde Cpd-034B (2.1g, 6.2mmol) was dissolved in tetrahydrofuran (20 mL), to which was added trimethyl (trifluoromethyl) silane (1.8g, 12.4 mmol), tetrabutylammonium fluoride (0.8g, 3.1mmol). The reaction mixture was reacted at 25 ℃ for 4 hours. The reaction was then concentrated, slurried with dichloromethane/methanol (20/1), filtered and the cake collected to give 2, 2-trifluoro-1- (1-trityl-1H-imidazol-2-yl) ethan-1-ol Cpd-034C (1.9 g, white solid), yield: 68 percent.
1 H NMR(400MHz,DMSO-d6)δ7.43-7.32(m,9H),7.13(d,J＝7.3Hz,6H),7.03(s,1H),6.83(s,1H),6.42(d,J＝3.0Hz,1H),4.31(s,1H).
The third step
Preparation of 2- (1- (2- (tert-butyldimethylsilyloxy) ethoxy) -2, 2-trifluoroethyl) -1-trityl-1H-imidazole
2, 2-trifluoro-1- (1-trityl-1H-imidazol-2-yl) ethan-1-ol Cpd-034C (1.9g, 4.7mmol) was dissolved in extra dry N, N-dimethylformamide (20 mL) and sodium hydride (280mg, 7.1mmol) was added to it. The reaction solution was stirred at 0 ℃ for half an hour under nitrogen protection. Then, (2-bromoethoxy) (tert-butyl) dimethylsilane (2.2g, 9.4 mmol) was added to the reaction solution, and the reaction was continued for 16 hours. After the reaction was completed, water was added to dilute, extracted with ethyl acetate (3 × 100 mL), the organic phases were combined and washed with water (4 × 100 mL), dried over anhydrous sodium sulfate and concentrated to give crude 2- (1- (2- (tert-butyldimethylsilyloxy) ethoxy) -2, 2-trifluoroethyl) -1-trityl-1H-imidazole Cpd-034D (2.1 g, yellow solid), yield: 66 percent.
1 H NMR(400MHz,DMSO-d6)δ7.44-7.37(m,9H),7.13(d,J＝7.3Hz,6H),7.06(s,1H),6.89(s,1H),4.26-4.21(m,1H),3.49-3.40(m,2H),3.25-3.20(m,1H),2.85-2.80(m,1H),0.82(s,9H),-0.01(d,J＝7.5Hz,6H).
The fourth step
Preparation of 2- (2, 2-trifluoro-1- (1-trityl-1H-imidazol-2-yl) ethoxy) ethan-1-ol
2- (1- (2- (tert-butyldimethylsilyloxy) ethoxy) -2, 2-trifluoroethyl) -1-trityl-1H-imidazole Cpd-034D (2.1g, 3.7 mmol) was dissolved in tetrahydrofuran (20 mL), and tetrabutylammonium fluoride (970mg, 3.7 mmol) was added thereto to react at 25 ℃ for 3 hours. After the reaction is finished, the tetrahydrofuran is removed by rotary evaporation. The obtained residue was extracted with ethyl acetate (3 × 50 mL), combined with organic phase, dried over anhydrous sodium sulfate and concentrated, and the obtained residue was isolated and purified with a silica gel column (petroleum ether/ethyl acetate = 3/2) to give 2- (2, 2-trifluoro-1- (1-trityl-1H-imidazol-2-yl) ethoxy) ethane-1-ol Cpd-034E (1.4 g, white solid) in yield: 76 percent.
1 H NMR(400MHz,DMSO-d6)δ7.47-7.37(m,9H),7.13(d,J＝7.2Hz,6H),7.05(s,1H),6.88(s,1H),4.63(t,J＝5.4Hz,1H),4.28-4.19(m,1H),3.28(s,2H),2.78(dt,J＝8.2,3.9Hz,1H).
The fifth step
Preparation of 2- (2, 2-trifluoro-1- (1-trityl-1H-imidazol-2-yl) ethoxy) acetaldehyde
Oxalyl chloride (700mg, 5.5 mmol) was dissolved in dry dichloromethane (10 mL), to which was added dry dimethyl sulfoxide (600mg, 7.7 mmol) dissolved in dichloromethane at-78 ℃ under nitrogen. After stirring for 10 minutes, 2- (2, 2-trifluoro-1- (1-trityl-1H-imidazol-2-yl) ethoxy) ethan-1-ol Cpd-034E (1g, 2.2mmol) dissolved in dichloromethane was added thereto. After the reaction mixture was stirred at-78 ℃ for 30 minutes, triethylamine (1.1g, 11mmol) was added thereto. The reaction solution was stirred and returned to room temperature. After the reaction was complete, it was washed with water, dried over sodium sulfate and concentrated to give crude 2- (2, 2-trifluoro-1- (1-trityl-1H-imidazol-2-yl) ethoxy) acetaldehyde Cpd-034F (1 g, yellow solid) in yield: 91 percent. The crude product was used directly in the next reaction without further treatment.
The sixth step
Preparation of ethyl 3- ((2- (2, 2-trifluoro-1- (1H-imidazol-2-yl) ethoxy) ethyl) amino) -1H-pyrrole-2-carboxylate
2- (2, 2-trifluoro-1- (1-trityl-1H-imidazol-2-yl) ethoxy) acetaldehyde Cpd-034F (1g, 2.3mmol) was dissolved in methanol (4 mL) and 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester (350mg, 2.3mmol) and glacial acetic acid (2 drops) were added thereto. The reaction mixture was reacted at 25 ℃ for 1 hour. Sodium cyanoborohydride (430mg, 6.9 mmol) was added to the reaction solution, and the reaction was continued for 16 hours. After the completion of the reaction, methanol was removed by rotary evaporation, and the obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 3/1) to obtain ethyl 3- ((2- (2, 2-trifluoro-1- (1H-imidazol-2-yl) ethoxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-034G (820 mg, colorless oil), yield: 52 percent.
MS m/z(ESI):347[M+1] + .
Seventh step
Preparation of ethyl 3- (3- (ethoxycarbonyl) -1- (2, 2-trifluoro-1- (1H-imidazol-2-yl) ethoxy) ethyl) thioureido) -1H-pyrrole-2-carboxylate
Ethyl 3- ((2- (2, 2-trifluoro-1- (1H-imidazol-2-yl) ethoxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-034G (400mg, 1.15mmol) was dissolved in dichloromethane (10 mL), and ethyl isothiocyanatecarboxylate (303mg, 2.3mmol) was added thereto to react at 25 ℃ for 2 hours. After the reaction was completed, methylene chloride was removed by rotary evaporation. The resulting residue was extracted with ethyl acetate (3 × 15 mL), combined with organic phase, dried over anhydrous sodium sulfate and concentrated to give crude 3- (3- (ethoxycarbonyl) -1- (2, 2-trifluoro-1- (1H-imidazol-2-yl) ethoxy) ethyl) thioureido) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-034H (500 mg, yellow oil) in yield: 72 percent.
MS m/z(ESI):478[M+1] + .
Eighth step
Preparation of 2-thioxo-1- (2, 2-trifluoro-1- (1H-imidazol-2-yl) ethoxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Ethyl 3- (3- (ethoxycarbonyl) -1- (2, 2-trifluoro-1- (1H-imidazol-2-yl) ethoxy) ethyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-034H (500mg, 1.0 mmol) was dissolved in methanol (10 mL), and cesium carbonate (1.4 g,4.2 mmol) was added thereto. The reaction mixture was heated to 65 ℃ and reacted for 6 hours. After the reaction was completed, the reaction solution was cooled to room temperature to remove methanol by rotary evaporation, and the obtained residue was roughly purified by a silica gel column (dichloromethane/methanol = 12/1), followed by further purification using a preparative plate (dichloromethane/methanol = 14/1) to obtain 2-thio-1- (2, 2-trifluoro-1- (1H-imidazol-2-yl) ethoxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-034 (120 mg, white solid), yield: 30 percent.
MS m/z(ESI):360[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.40(s,1H),12.35(s,1H),12.21(s,1H),7.34(t,J＝2.7Hz,1H),7.22(s,1H),6.96(s,1H),6.29(s,1H),5.38-5.33(m,1H),4.65-4.48(m,2H),3.96-3.74(m,2H).
Example 35
2-thioxo-1- (2- ((3- (trifluoromethyl) pyrrolidin-3-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000661
First step of
Preparation of 3-hydroxy-3- (trifluoromethyl) pyrrolidine-1-carboxylic acid tert-butyl ester
3-Oxopyrrolidine-1-carboxylic acid tert-butyl ester Cpd-035A (2.0g, 10.8mmol), trimethyl (trifluoromethyl) silane (3.1g, 21.6mmol) and tetrabutylammonium fluoride (1.2mL, 1.1mmol) were dissolved in dry tetrahydrofuran (15 mL). The reaction solution was reacted at room temperature overnight. To the reaction mixture was added a saturated sodium chloride solution (50 mL), followed by extraction with ethyl acetate (2X 50 mL). The organic phases were combined and dried over anhydrous sodium sulfate, concentrated and isolated and purified (petroleum ether/ethyl acetate = 5/1) to give 3-hydroxy-3- (trifluoromethyl) pyrrolidine-1-carboxylic acid tert-butyl ester Cpd-035B (2.5 g, white solid) yield: 90 percent.
1 H NMR(400MHz,DMSO-d6)δ3.67-3.48(m,4H),3.15(br,1H),2.26-2.17(m,1H),2.02-1.98(m,1H),1.45(s,9H).
Second step of
Preparation of 3- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) -3- (trifluoromethyl) pyrrolidine-1-carboxylic acid tert-butyl ester
3-hydroxy-3- (trifluoromethyl) pyrrolidine-1-carboxylic acid tert-butyl ester Cpd-035B (1.0 g,2.4 mmol) was dissolved in DMF (5 mL) and cooled to 0 ℃ in an ice bath. And thereto was added sodium hydride (212mg, 8.3mmol) and stirred for 30min. (2-Bromoethoxy) (tert-butyl) dimethylsilane (900mg, 2.9mmol) was added to the reaction solution, and the reaction mixture was reacted at 25 ℃ for 12 hours. The reaction mixture was washed with saturated aqueous sodium chloride (50 mL. Times.3). The organic phase was dried over anhydrous sodium sulfate to give tert-butyl 3- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) -3- (trifluoromethyl) pyrrolidine-1-carboxylate Cpd-035C (1.5 g, yellow oil) yield: 80 percent. The crude product was used directly in the next step without further purification.
The third step
Preparation of 3- (2-hydroxyethoxy) -3- (trifluoromethyl) pyrrolidine-1-carboxylic acid tert-butyl ester
3- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) -3- (trifluoromethyl) pyrrolidine-1-carboxylic acid tert-butyl ester Cpd-035C (1.0g, 3.3mmol) was dissolved in THF (5 mL) and tetrabutylammonium fluoride (0.33mL, 3.3mmol) was added thereto. The reaction mixture was reacted at 25 ℃ for 30 minutes. After the reaction was completed, tetrahydrofuran was removed by rotary evaporation, and the mixture was dissolved in ethyl acetate (5 mL), washed with saturated sodium chloride (10 mL. Times.3) and water, and the combined organic phases were dried over anhydrous sodium sulfate and concentrated. The obtained residue was separated and purified by silica gel column (petroleum ether/ethyl acetate = 1/2) to obtain 3- (2-hydroxyethoxy) -3- (trifluoromethyl) pyrrolidine-1-carboxylic acid tert-butyl ester Cpd-035D (200 mg, yellow oil), yield: 20 percent.
1 H NMR(400MHz,CDCl 3 )δ3.73-3.46(m,5H),3.35-3.31(m,1H),2.26-2.08(m,2H),1.66(s,2H),1.45(d,J＝3.1Hz,9H).
The fourth step
Preparation of 3- (2-carbonylethoxy) -3- (trifluoromethyl) pyrrolidine-1-carboxylic acid tert-butyl ester
3- (2-Hydroxyethoxy) -3- (trifluoromethyl) pyrrolidine-1-carboxylic acid tert-butyl ester Cpd-035D (100mg, 0.3 mmol) was dissolved in dry dichloromethane (2 mL) and placed in an ice-water bath to cool to 0 ℃. To this was added dessimutan reagent (170mg, 0.4 mmol) and reacted for 1 hour. The reaction solution was quenched with aqueous sodium thiosulfate (5 mL), and then washed with saturated aqueous sodium bicarbonate (10 mL. Times.3). The organic phase was dried over anhydrous sodium sulfate and rotary evaporated to give tert-butyl 3- (2-carbonylethoxy) -3- (trifluoromethyl) pyrrolidine-1-carboxylate Cpd-035E (80 mg, light brown solid) yield: 88 percent. The crude product was used in the next step without further purification.
The fifth step
Preparation of ethyl 3- ((2- ((1- (1- (tert-butoxycarbonyl) -3- (trifluoromethyl) pyrrolidin-3-yl) oxy) ethyl) amino) ethyl-1H-pyrrole-2-carboxylate
3- (2-carbonylethoxy) -3- (trifluoromethyl) pyrrolidine-1-carboxylic acid tert-butyl ester Cpd-035E (80mg, 0.2 mmol) was dissolved in methanol (2 mL) and then ethyl 3-amino-1H-pyrrole-2-carboxylate (26mg, 0.9 mmol) and acetic acid (0.5 mL) were added in that order. The reaction solution was reacted for 4 hours. Sodium cyanoborohydride (22mg, 0.4mmol) was added thereto and reacted for 1 hour. Methanol was removed by rotary evaporation, and the residue was dissolved in ethyl acetate (5 mL), washed with saturated brine (10 mL. Times.3), and dried over anhydrous sodium sulfate. Separation and purification on silica gel column (petroleum ether/ethyl acetate = 1/2) gave Cpd-035F (30 mg, oily liquid), yield: and 27 percent.
MS m/z(ESI):436[M+1] + .
The sixth step
Preparation of ethyl 3- (1- (2- (((1- (tert-butoxycarbonyl) -3- (trifluoromethyl) pyrrolidin-3-yl) oxy) ethyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate
Ethyl 3- ((2- ((1- (1- (tert-butoxycarbonyl) -3- (trifluoromethyl) pyrrolidin-3-yl) oxy) ethyl) amino) ethyl-1H-pyrrole-2-carboxylate Cpd-035F (30mg, 0.07mmol) was dissolved in DCM (2 mL), ethyl isothiocyanatocarboxylate (10mg, 0.08mmol) was added, and the reaction mixture was reacted at room temperature for 30 minutes, followed by rotary evaporation to give crude 3- (1- (2- (((1- (tert-butoxycarbonyl) -3- (trifluoromethyl) pyrrolidin-3-yl) oxy) ethyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-035G (30 mg, yellow oil) in 77% yield.
MS m/z(ESI):589[M+23] + .
Seventh step
Preparation of 3- (2- (2-thioxo-4-oxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) -3- (trifluoromethyl) pyrrolidine-1-carboxylic acid tert-butyl ester
3- (1- (2- (((1- (tert-butoxycarbonyl) -3- (trifluoromethyl) pyrrolidin-3-yl) oxy) ethyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-035G (30mg, 0.05mmol) was dissolved in anhydrous methanol (2 mL), cesium carbonate (60mg, 0.18mmol) was added and the reaction was placed in an oil bath pan at 65 ℃ for 12 hours, after the completion of the reaction, the reaction was cooled to room temperature and dried by spinning, and the plate (petroleum ether/ethyl acetate = 1/2) was climbed to give 3- (2- (2-thio-4-oxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) -3- (trifluoromethyl) pyrrolidine-1-carboxylic acid tert-butyl ester Cpd-035H (20 mg, yellow oil) in 84% yield.
MS m/z(ESI):471[M+23] + .
Eighth step
Preparation of 2-thioxo-1- (2- (((3- (trifluoromethyl) pyrrolidin-3-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
The resulting tert-butyl 3- (2- (2-thio-4-oxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) -3- (trifluoromethyl) pyrrolidine-1-carboxylate, cpd-035H (20mg, 0.04mmol), was dissolved in methanol (1 mL), followed by addition of a methanol solution (0.2 mL) of hydrochloric acid, reaction for 2 hours, and rotary evaporation to remove the methanol. Slurried with ethyl acetate provided 2-thio-1- (2- (((3- (trifluoromethyl) pyrrolidin-3-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-035 (15 mg, white solid) at 90% yield.
MS m/z(ESI):332[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.38(s,1H),12.25(s,1H),9.89(s,1H),9.72(s,1H),7.35(s,1H),6.43(s,1H),4.62-4.53(m,2H),4.02(s,2H),3.71-3.59(m,3H),3.26(s,1H),2.33-2.13(m,2H).
Example 36
2-thio-1- (2- (((1-methyl-3- (trifluoromethyl) pyrrolidinyl-3-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000681
2-thio-1- (2- (((3- (trifluoromethyl) pyrrolidin-3-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-035 (30mg, 0.09mmol) was dissolved in methanol (2 mL) and paraformaldehyde (10 mg) and two drops of acetic acid were added after 2 hours of reaction, sodium cyanoborohydride (20mg, 0.32mmol) was added and after 1 hour of reaction, methanol was removed by rotary column chromatography (DCM/MeOH = 10/1) to give 2-thio-1- (2- (((1-methyl-3- (trifluoromethyl) pyrrolidinyl-3-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-036 (20 mg, white solid) in 90% yield.
MS m/z(ESI):363[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.35(s,1H),12.25(s,1H),7.35(s,1H),6.30(s,1H),4.52(t,J＝5.2Hz,2H),3.99(dd,J＝12.3,5.5Hz,2H),2.69-2.51(m,2H),2.31(t,J＝6.7Hz,2H),2.12(s,3H),1.99-1.82(m,2H).
Example 37
2-thio-1- (4, 4-trifluoro-3-hydroxymethylbutyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000682
First step of
Preparation of ethyl 3-hydroxymethyl-4, 4-trifluorobutyrate
Ethyl 3-hydroxy-4,4, 4-trifluorobutyrate Cpd-037A (0.5g, 2.7 mmol) was dissolved in acetonitrile (10 mL), and cesium carbonate (1.7 g,5.4 mmol) and methyl iodide (0.8g, 5.4 mmol) were then added to the reaction solution. The reaction was stirred at room temperature overnight. After the reaction was completed, cesium carbonate was removed by suction filtration and then concentrated under reduced pressure to obtain the compound ethyl 3-hydroxymethyl-4, 4-trifluorobutyrate Cpd-037B (0.56 g, yellow oil) in yield: 74 percent.
1 H NMR(400MHz,DMSO-d6)δ4.34-4.21(m,1H),4.18-4.07(m,2H),3.48(s,3H),2.78(dd,J＝16.3,3.5Hz,1H),2.56(dd,J＝16.4,9.6Hz,1H),1.21(t,J＝7.1Hz,3H).
Second step of
Preparation of 3-hydroxymethyl-4, 4-trifluoro-1-butanol
Ethyl 3-hydroxymethyl-4, 4-trifluorobutyrate, cpd-037B (0.5g, 2.8mmol), was dissolved in 15mL dry tetrahydrofuran, cooled to 0 deg.C, and lithium aluminum hydride (0.1g, 2.8mmol) was added slowly. The reaction mixture was stirred at 0 ℃ for 1 hour. After the reaction was completed, the reaction was quenched by slowly dropping water (0.1 mL) and 15% sodium hydroxide solution (0.1 mL), after which water (0.3 mL) and anhydrous sodium sulfate were added, stirred at room temperature for 0.5 hour and then suction-filtered, the filtrate was collected and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1) to give compound 3-hydroxymethyl-4, 4-trifluoro-1-butanol Cpd-037C (0.49 g, yellow oil), yield: 73 percent.
1 H NMR(400MHz,DMSO-d6)δ4.71(t,J＝5.1Hz,1H),3.90(ddd,J＝9.8,7.1,2.7Hz,1H),3.62-3.40(m,5H),1.78-1.52(m,2H).
The third step
Preparation of 3-hydroxymethyl-4, 4-trifluorobutanal
Oxalyl chloride (150mg, 1.13mmol) was dissolved in dichloromethane and cooled to-65 ℃, followed by the slow addition of dimethyl sulfoxide (80mg, 1.04mmol). After stirring for 10 minutes, 3-hydroxymethyl-4, 4-trifluoro-1-butanol Cpd-037C (0.15g, 0.94mmol) was added slowly. After the reaction mixture was stirred at-65 ℃ for 1 hour, triethylamine (0.5g, 4.7 mmol) was slowly added thereto. After stirring for an additional 10 minutes, the temperature was slowly raised to room temperature and washed with water (2 mL). The organic phase was separated and collected and dried over anhydrous sodium sulfate to give a solution of compound 3-hydroxymethyl-4, 4-trifluorobutanal Cpd-037D in methylene chloride. The solution was used directly in the next reaction without further treatment.
The fourth step
Preparation of ethyl 3- ((3-hydroxymethyl-4, 4-trifluorobutyl) amino) -1H-pyrrole-2-carboxylate
Ethyl 3-amino-1H-pyrrole-2-carboxylate (140mg, 0.9mmol) was dissolved in methanol (5 mL) and 3-hydroxymethyl-4, 4-trifluorobutanal Cpd-037D (dichloromethane solution) and acetic acid (100mg, 1.7mmol) were added sequentially. After stirring at room temperature for half an hour, sodium cyanoborohydride (60mg, 0.9mmol) was added. The reaction was stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to give the title compound, ethyl 3- ((3-hydroxymethyl-4, 4-trifluorobutyl) amino) -1H-pyrrole-2-carboxylate Cpd-037E (170 mg, yellow oil), yield: 61 percent.
1 H NMR(400MHz,DMSO-d6)δ10.78(s,1H),6.77(t,J＝2.8Hz,1H),5.65(s,1H),5.39(s,1H),4.18(q,J＝7.1Hz,2H),3.97-3.87(m,1H),3.49(s,3H),3.29-3.17(m,2H),1.87(ddd,J＝14.5,8.7,5.9Hz,1H),1.70(dd,J＝14.8,8.7Hz,1H),1.27(d,J＝7.1Hz,3H).
The fifth step
Preparation of ethyl 3- (1- (3-hydroxymethyl-4, 4-trifluorobutyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate
3- ((3-hydroxymethyl-4, 4-trifluorobutyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-037E (30mg, 0.1mmol) was dissolved in dichloromethane (2 mL) followed by the addition of isothiocyanatoform (14mg, 0.1mmol). The reaction was stirred at room temperature overnight. After the reaction was completed, the reaction liquid was concentrated under reduced pressure, and the residue was separated on a silica gel preparation plate (petroleum ether/ethyl acetate = 3/1) to obtain the title compound ethyl 3- (1- (3-hydroxymethyl-4, 4-trifluorobutyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-037F (28 mg, yellow solid), yield: 61 percent.
MS m/z(ESI):426[M+1] + .
The sixth step
Preparation of 2-thioxo-1- (4, 4-trifluoro-3-hydroxymethylbutyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Ethyl 3- (1- (3-hydroxymethyl-4, 4-trifluorobutyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-037F (28mg, 0.07mmol) was dissolved in methanol (5 mL) followed by cesium carbonate (100mg, 0.33mmol). The reaction solution was heated to 65 ℃ and stirred for 8 hours. After the reaction was complete, water (10 mL) and ethyl acetate (10 mL) were added, and the aqueous phase was extracted with ethyl acetate (10 mL. Times.3). The organic phases were combined and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated on silica gel preparation plates (dichloromethane/methanol = 20/1) to give the compound 2-thio-1- (4, 4-trifluoro-3-hydroxymethylbutyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-037 (15 mg, light yellow solid), yield: 70 percent.
MS m/z(ESI):308[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.47(s,1H),12.23(s,1H),7.41(d,J＝2.4Hz,1H),6.29(d,J＝2.5Hz,1H),4.53(s,2H),4.17(s,1H),3.51(s,3H),2.11-1.89(m,2H).
Example 38
1- (4, 4-trifluoro-3- (methylamino) butyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000701
First step of
Preparation of ethyl 3-amino-4, 4-trifluorobutyrate
Thionyl chloride (1.2 g,10.2 mmol) was added dropwise to anhydrous ethanol (10 mL) in an ice bath, and after the dropwise addition was completed, 3-amino-4, 4-trifluorobutanoic acid Cpd-038A (0.4 g,2.5 mmol) was added to the reaction solution, followed by heating to 60 ℃ for two hours under nitrogen protection. After completion of the reaction, the reaction solution was concentrated, and after concentration, the remaining thionyl chloride was quenched thoroughly by adding water (20 mL), followed by lyophilization to give ethyl 3-amino-4, 4-trifluorobutyrate Cpd-038B (500 mg, white solid) in yield: 85 percent.
1 H NMR(400MHz,DMSO-d6)δ9.09(s,3H),4.50(dd,J＝14.1,7.0Hz,1H),4.15(q,J＝7.1Hz,2H),2.94(d,J＝6.3Hz,2H),1.22(t,J＝7.1Hz,3H).
Second step of
Preparation of ethyl 3- (((tert-butoxy) carbonyl) amino) -4, 4-trifluorobutyrate
Ethyl 3-amino-4, 4-trifluorobutyrate Cpd-038B (200mg, 0.9mmol) and triethylamine (365mg, 3.6mmol) were dissolved in ethanol (7 mL), followed by addition of di-tert-butyl dicarbonate (1.6 g, 7.2mmol), heating to 60 ℃ and stirring under nitrogen for 2 hours. After completion of the reaction, the reaction mixture was concentrated, diluted with water (100 mL), extracted with ethyl acetate (50 mL × 2), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by the concentration was separated and purified with a silica gel column (petroleum ether/ethyl acetate = 10/1) to obtain ethyl 3- (((tert-butoxy) carbonyl) amino) -4, 4-trifluorobutyrate Cpd-038C (263 mg, white solid) in yield: 102 percent.
1 H NMR(400MHz,DMSO-d6)δ7.66(d,J＝8.9Hz,1H),4.54(d,J＝5.4Hz,1H),4.15-3.99(m,2H),2.77(dd,J＝16.2,4.0Hz,1H),2.69-2.57(m,1H),1.18(t,J＝7.1Hz,3H).
The third step
Preparation of ethyl 3- (((tert-butoxy) carbonyl) methylamino) -4, 4-trifluorobutyrate
Ethyl 3- (((tert-butoxy) carbonyl) amino) -4, 4-trifluorobutyrate Cpd-038C (160mg, 0.56mmol), cesium carbonate (914mg, 2.80mmol) were dissolved in acetonitrile (3 mL) followed by dropwise addition of methyl iodide (239mg, 1.68mmol) at room temperature, after which the reaction mixture was heated to 30 ℃ with nitrogen blanket stirring for 12 hours. After completion of the reaction, the reaction mixture was filtered through celite, and the crude product obtained by concentrating the filtrate was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 10/1) to obtain ethyl 3- (((tert-butoxy) carbonyl) amino) -4, 4-trifluorobutyrate Cpd-038D (160 mg, white solid) in yield: 95 percent.
1 H NMR(400MHz,DMSO-d6)δ5.11(s,1H),4.10(s,2H),2.98-2.86(m,2H),2.74(d,J＝7.8Hz,3H),1.40(d,J＝8.1Hz,9H),1.17(s,3H).
The fourth step
Preparation of N-methyl-N- (1, 1-trifluoro-4-hydroxybutan-2-yl) carbamic acid tert-butyl ester
Ethyl 3- (((tert-butoxy) carbonyl) amino) -4, 4-trifluorobutyrate Cpd-038D (120mg, 0.40mmol) was dissolved in tetrahydrofuran (6 mL) and a solution of lithium aluminum tetrahydrofuran (1.2mL, 1.2mmol, 1M) was added dropwise with ice bath nitrogen blanketing. After the completion of the dropwise addition, stirring was continued for 10 minutes. After the reaction was completed, the reaction solution was diluted with tetrahydrofuran (50 mL), an aqueous sodium hydroxide solution (0.5ml, 2m) was dropped under ice bath, stirred for 10 minutes, then anhydrous sodium sulfate solid was added and stirred for half an hour, after quenching was completed, the reaction mixture solid was filtered with celite, and the crude product obtained by concentrating the filtrate was separated and purified with a silica gel column (petroleum ether/ethyl acetate = 2/1) to obtain N-methyl-N- (1, 1-trifluoro-4-hydroxybutan-2-yl) carbamic acid tert-butyl ester Cpd-038E (100 mg, white solid), yield: 97 percent.
1 H NMR(400MHz,DMSO-d6)δ4.90(s,1H),4.73-4.63(m,1H),3.55-3.40(m,1H),3.31-3.22(m,1H),2.72(d,J＝7.8Hz,3H),1.98-1.81(m,1H),1.80-1.70(m,1H),1.40(d,J＝10.6Hz,9H).
The fifth step
Preparation of N-methyl-N- (1, 1-trifluoro-4-oxobutan-2-yl) carbamic acid tert-butyl ester
N-methyl-N- (1, 1-trifluoro-4-hydroxybutan-2-yl) carbamic acid tert-butyl ester Cpd-038E (100mg, 0.39mmol) was dissolved in dichloromethane (5 mL) followed by the addition of dessimantin oxidant (330mg, 0.78mmol) under ice bath and stirring at room temperature under nitrogen for 1 hour. After the completion of the reaction, the reaction mixture was filtered with celite, the filtrate was concentrated at room temperature, and the crude product obtained by concentrating the filtrate was separated and purified with a silica gel column (petroleum ether/ethyl acetate = 4/1) to obtain N-methyl-N- (1, 1-trifluoro-4-hydroxybutan-2-yl) carbamic acid tert-butyl ester Cpd-038E (100 mg, white solid), yield: 100 percent.
1 H NMR(400MHz,DMSO-d6)δ9.61(d,J＝8.6Hz,1H),5.43-5.11(m,1H),3.25-3.05(m,1H),3.05-2.95(m,1H),2.70(d,J＝9.4Hz,3H),1.42(s,9H).
The sixth step
Preparation of ethyl 3- ((3- ((tert-butoxycarbonyl) methylamino) -4, 4-trifluorobutyl) amino) -1H-pyrrole-2-carboxylate
Tert-butyl N-methyl-N- (1, 1-trifluoro-4-hydroxybutan-2-yl) carbamate, cpd-038E (100mg, 0.39mmol), ethyl 3-amino-1H-pyrrole-2-carboxylate (72mg, 0.47mmol) and two drops of acetic acid were dissolved in methanol (5 mL) and stirred at room temperature for half an hour, followed by the addition of sodium cyanoborohydride (123mg, 1.95mmol) at room temperature and stirring for 12 hours. After completion of the reaction, the reaction mixture was diluted with water (200 mL), extracted with ethyl acetate (100 mL × 2), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was separated and purified with a silica gel column (petroleum ether/ethyl acetate = 4/1) to give 3- ((3- ((tert-butoxycarbonyl) methylamino) -4, 4-trifluorobutyl) amino) -1H-pyrrole-2-carboxylic acid ethyl Cpd-038F (93 mg, colorless oil) in yield: 60 percent.
MS m/z(ESI):394[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ10.77(s,1H),6.75(t,J＝2.8Hz,1H),5.64(s,1H),5.31(s,1H),4.90-4.72(m,1H),4.19(q,J＝7.1Hz,2H),3.22-2.94(m,2H),2.76(d,J＝8.6Hz,3H),2.02-1.87(m,2H),1.38(d,J＝39.7Hz,9H),1.26(t,J＝7.0Hz,3H).
Seventh step
Preparation of ethyl 3- (1- (3- ((tert-butoxycarbonyl) methylamino) -4, 4-trifluorobutyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate
Ethyl 3- ((3- ((tert-butoxycarbonyl) methylamino) -4, 4-trifluorobutyl) amino) -1H-pyrrole-2-carboxylate Cpd-038F (93mg, 0.24mmol) and ethoxycarbonyl isothiocyanate (46mg, 0.35mmol) were dissolved in methanol (5 mL) and then stirred at room temperature under nitrogen for 1 hour. After the reaction was complete, the reaction was concentrated to give crude ethyl 3- (1- (3- ((tert-butoxycarbonyl) methylamino) -4, 4-trifluorobutyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-038G (130 mg, colorless oil), yield: 104 percent. The crude product was used in the next step without further purification.
MS m/z(ESI):525[M+1] + .
Eighth step
Preparation of tert-butyl (1, 1-trifluoro-4- (4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) but-2-yl) methylcarbamate
The crude 3- (1- (3- ((tert-butoxycarbonyl) methylamino) -4, 4-trifluorobutyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-038G (130mg, 0.25mmol) and cesium carbonate (400mg, 1.24mmol) were dissolved in methanol (5 mL) and then heated to 60 ℃ under nitrogen and stirred for 5 hours. After completion of the reaction, the reaction solution was concentrated, quenched with saturated aqueous ammonium chloride (100 mL), extracted with ethyl acetate (50 mL × 2), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was separated and purified with a silica gel column (petroleum ether/ethyl acetate = 1/1) to obtain tert-butyl (1, 1-trifluoro-4- (4-oxo-2-thio-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) butan-2-yl) methylcarbamate Cpd-038H (80 mg, white solid), yield: 79 percent.
MS m/z(ESI):407[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.44(s,1H),12.23(s,1H),7.39(s,1H),6.49(d,J＝13.1Hz,1H),5.12-4.84(m,1H),4.56(s,1H),4.18(s,1H),2.86(d,J＝15.0Hz,3H),2.25(s,1H),2.08(s,1H),1.41(d,J＝19.1Hz,9H).
The ninth step
Preparation of 1- (4, 4-trifluoro-3- (methylamino) butyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Tert-butyl (1, 1-trifluoro-4- (4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) but-2-yl) methylcarbamate Cpd-038H (80mg, 0.20mmol) was dissolved in ethanol hydrochloride (5 mL) and heated to 30 ℃ for half an hour under nitrogen. After the reaction is finished, the reaction solution is concentrated, a C18 reverse column (methanol/water (1 ‰ formic acid) = 1/4) is purified, after concentration, the reaction solution is washed by sodium bicarbonate aqueous solution, and after ethyl acetate extraction, 1- (4, 4-trifluoro-3- (methylamino) butyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrole [3,2-d ] pyrimidine-4-one Cpd-038 (27 mg, white solid) is obtained, wherein the yield is as follows: 45 percent.
MS m/z(ESI):307[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.46(s,1H),12.21(s,1H),7.41(s,1H),6.38(s,1H),4.50(t,J＝7.5Hz,2H),3.30-3.20(m,1H),2.43(s,3H),2.11-1.99(m,1H),1.89-1.76(m,1H).
Example 39
1- (3- (dimethylamino) -4, 4-trifluorobutyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000721
First step of
Preparation of 1- (3- (dimethylamino) -4, 4-trifluorobutyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
1- (4, 4-trifluoro-3- (methylamino) butyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-038 (25mg, 0.08mmol) and paraformaldehyde (12mg, 0.41mmol) were dissolved in methanol (2 mL), followed by addition of sodium cyanoborohydride (51mg, 0.82mmol) at room temperature and stirring under nitrogen for half an hour at room temperature. After the reaction is finished, the reaction solution is diluted by water (100 mL), ethyl acetate (50 mL × 2) is extracted, the reaction solution is washed by saturated saline solution, dried by anhydrous sodium sulfate, filtered, and the concentrated crude product is separated, purified and concentrated by a C18 reverse phase column (methanol/water (1 ‰ formic acid) = 1/4), then washed by sodium bicarbonate aqueous solution, and the ethyl acetate is extracted to obtain 1- (3- (dimethylamino) -4, 4-trifluorobutyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrole [3,2-d ] pyrimidine-4-ketone Cpd-039 (10 mg, white solid), wherein the yield: 38 percent.
MS m/z(ESI):321[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.44(s,1H),12.22(s,1H),7.41(d,J＝2.8Hz,1H),6.33(d,J＝2.8Hz,1H),4.68-4.53(m,1H),4.35-4.21(m,1H),3.67-3.55(m,1H),2.45(s,6H),2.18-2.02(m,1H),1.95-1.80(m,1H).
Example 40
1- ((3- (aminomethyl) -4-chlorophenyl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000731
First step of
Preparation of tert-butyl (5-bromo-2-chlorobenzyl) carbamate
5-bromo-2-chloro-benzylamine Cpd-040A (0.9g, 4.1mmol) was dissolved in dichloromethane (50 mL), followed by di-tert-butyl dicarbonate (1.8g, 8.2 mmol) and triethylamine (1.2g, 12.2mmol) and stirring at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated, and the obtained crude product was purified by a silica gel column (petroleum ether/ethyl acetate = 9/1) to obtain (5-bromo-2-chlorobenzyl) carbamic acid tert-butyl ester Cpd-040B (1.5 g, white solid), yield: 97 percent.
1 H NMR(400MHz,DMSO-d6)δ7.52-7.35(m,4H),4.18(d,J＝5.9Hz,2H),1.41(s,9H).
Second step of
Preparation of tert-butyl (2-chloro-5-formylbenzyl) carbamate
Tert-butyl (5-bromo-2-chlorobenzyl) carbamate, cpd-040B (300mg, 0.93mmol), was dissolved in dimethyl sulfoxide (5 mL), triethylsilane (163mg, 1.40mmol), N, N-diisopropylethylamine (423mg, 3.27mmol), and bis (di-tert-butyl- (4-dimethylaminophenyl) phosphine) palladium (II) dichloride (130mg, 0.18mmol) were added in this order, carbon monoxide was passed through, and the reaction was heated to 90 ℃ for reaction for 2 hours. The reaction solution was cooled to room temperature, ethyl acetate (50 mL) was added, the reaction solution was washed with saturated brine once, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 5/1) to obtain (2-chloro-5-formylbenzyl) carbamic acid tert-butyl ester Cpd-040C (120 mg, pale yellow solid), yield: and 43 percent.
1 H NMR(400MHz,CDCl 3 )δ9.99(s,1H),7.89(s,1H),7.75(dd,J＝8.2,1.7Hz,1H),7.53(d,J＝8.2Hz,1H),5.05(s,1H),4.48(s,2H),1.47(s,9H).
The third step
Preparation of ethyl 3- ((3- (((tert-butoxycarbonyl) amino) methyl) -4-chlorobenzyl) amino) -1H-pyrrole-2-carboxylate
Ethyl 3-amino-1H-pyrrole-2-carboxylate (140mg, 0.9 mmol) was dissolved in methanol (15 mL), after which tert-butyl (2-chloro-5-formylbenzyl) carbamate Cpd-040C (250mg, 0.9 mmol), acetic acid (110mg, 1.8mmol) was added in that order. After stirring at room temperature for half an hour, sodium cyanoborohydride (60mg, 0.9mmol) was added. The reaction was stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain compound 3- ((3- (((tert-butoxycarbonyl) amino) methyl) -4-chlorobenzyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-040D (238 mg, colorless oil), yield: 60 percent.
1 H NMR(400MHz,DMSO-d6)δ10.75(s,1H),7.47-7.15(m,4H),6.67(s,1H),5.80(s,1H),5.51(s,1H),4.26(d,J＝6.0Hz,2H),4.23-4.08(m,4H),1.38(s,9H),1.26(t,J＝7.0Hz,3H).
The fourth step
Preparation of ethyl 3- (1- (3- ((tert-butoxycarbonyl) amino) methyl) -4-chlorobenzyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate
Ethyl 3- ((3- (((tert-butoxycarbonyl) amino) methyl) -4-chlorobenzyl) amino) -1H-pyrrole-2-carboxylate Cpd-040D (238mg, 0.58mmol) was dissolved in methanol (3 mL) and ethoxycarbonyl isothiocyanate (92mg, 0.70mmol) was added at room temperature and stirred under nitrogen for 1 hour. After the reaction was completed, the reaction solution was concentrated to give crude ethyl 3- (1- (3- ((tert-butoxycarbonyl) amino) methyl) -4-chlorobenzyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-040E (314 mg, colorless oil), yield: 99 percent.
MS m/z(ESI):539[M+1] + .
The fifth step
Preparation of tert-butyl (2-chloro-5- ((4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) methyl) benzyl) carbamate
The reaction was concentrated to give crude 3- (1- (3- ((tert-butoxycarbonyl) amino) methyl) -4-chlorobenzyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-040E (314mg, 0.58mmol) which was dissolved in methanol (8 mL) followed by addition of cesium carbonate (1328mg, 4.08mmol) and heating at 65 ℃ for four hours under nitrogen. After the reaction was completed, the reaction solution was concentrated, the residue was dispersed with an aqueous ammonium chloride solution (100 mL), ethyl acetate (50 mL × 2) was extracted, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by the concentration was slurried with methylene chloride to obtain tert-butyl (2-chloro-5- ((4-oxo-2-thio-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) methyl) benzyl) carbamate Cpd-040F (100 mg, white solid) in yield: 41 percent.
MS m/z(ESI):365[M-56+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.29(br,1H),7.38(d,J＝7.9Hz,2H),7.29(s,2H),7.23(d,J＝8.3Hz,1H),6.11(d,J＝2.0Hz,1H),5.68(s,2H),4.12(d,J＝5.8Hz,2H),1.36(s,9H).
The sixth step
Preparation of 1- ((3- (aminomethyl) -4-chlorophenyl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Tert-butyl (2-chloro-5- ((4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) methyl) benzyl) carbamate, cpd-040F (100mg, 0.23mmol) was dissolved in ethanol hydrochloride (10 mL) and then stirred for 1 hour at 30 ℃. After the reaction, the reaction solution was concentrated, and the obtained crude product was purified with a C18 reverse column (methanol/water (1 ‰ formic acid) = 1/4-3/2), washed with an aqueous solution of sodium bicarbonate after concentration, and extracted with ethyl acetate to obtain 1- ((3- (aminomethyl) -4-chlorophenyl) methyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-040 (35 mg, white solid) with a yield: 46 percent.
MS m/z(ESI):321[M+1] + .
EXAMPLE 41
1- (4-chloro-3- ((dimethylamino) methyl) benzyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000741
First step of
Preparation of 1- (4-chloro-3- ((dimethylamino) methyl) benzyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
1- ((3- (aminomethyl) -4-chlorophenyl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-040 (30mg, 0.08mmol) and paraformaldehyde (52mg, 0.84mmol) were dissolved in methanol (3 mL), followed by addition of sodium cyanoborohydride (42mg, 0.67mmol) at room temperature and stirring at room temperature for 1 hour. After the reaction is finished, the reaction solution is quenched by water (100 mL), ethyl acetate (50 mL × 2) is extracted, the reaction solution is washed by saturated brine, dried by anhydrous sodium sulfate, filtered, and the concentrated crude product is washed by a C18 reverse phase column (methanol/water (1 ‰ formic acid) = 1/4-1/1), concentrated and washed by a sodium bicarbonate aqueous solution, and extracted by ethyl acetate to obtain 1- (4-chloro-3- ((dimethylamino) methyl) benzyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrole [3,2-d ] pyrimidine-4-ketone Cpd-041 (10 mg, white solid), yield: 34 percent.
MS m/z(ESI):349[M+1] + .
Example 42
1- (2- (1- ((methylamino) methyl) cyclopropoxy) ethyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000751
First step of
Preparation of methyl 1- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) cyclopropane-1-carboxylate
Sodium hydrogen (0.9g, 22.4mmol) was dissolved in N, N-dimethylformamide (20 mL), the reaction was cooled to-40 deg.C, and methyl 1-hydroxycyclopropane-1-carboxylate Cpd-042A (2.0 g, 17.2mmol) was added thereto. The reaction mixture was stirred at-40 ℃ for 2 hours, and then (2-bromoethoxy) (tert-butyl) dimethylsilane (4.1g, 17.2mmol) was added thereto. The reaction solution was reacted at room temperature overnight. Water (50 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (50 mL. Times.3). The organic phases were combined and washed with water (100 mL × 3), dried over anhydrous sodium sulfate and concentrated at low temperature to give crude methyl 1- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) cyclopropane-1-carboxylate Cpd-042B (2.8 g, brown liquid), yield: 53.4 percent.
1 H NMR(400MHz,DMSO-d6)δ3.88(t,J＝5.7Hz,2H),3.64(s,3H),3.52(t,J＝5.7Hz,2H),1.21-1.11(m,4H),0.88(s,9H),0.07(s,6H).
Second step of
Preparation of (1- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) cyclopropyl) methanol
1- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) cyclopropane-1-carboxylic acid methyl ester Cpd-042B (2.5 g,9.5 mmol) was dissolved in tetrahydrofuran (10 mL), the reaction was cooled to 0 ℃ and a 1M suspension of aluminum lithium hydride in tetrahydrofuran (20 mL) was added slowly thereto. The reaction was allowed to react at 0 ℃ for 2 hours, then quenched at 0 ℃, filtered, and the filtrate was concentrated to give (1- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) cyclopropyl) methanol Cpd-042C (750 mg, yellow liquid), yield: 28.4 percent.
1 H NMR(400MHz,DMSO-d6)δ4.61(t,J＝5.8Hz,1H),3.61-3.56(m,2H),3.53(dd,J＝4.9,3.5Hz,2H),3.48(d,J＝5.8Hz,2H),0.85(s,9H),0.62(t,J＝5.7Hz,2H),0.51(t,J＝5.7Hz,2H),0.01(s,6H).
The third step
Preparation of 1- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) cyclopropane-1-carbaldehyde
Oxalyl chloride (515mg, 4.0 mmol) was dissolved in dry dichloromethane (5 mL), to which was added dry dimethyl sulfoxide (555mg, 7.1 mmol) dissolved in dichloromethane at-78 ℃ under nitrogen protection. After stirring for 10 minutes, (1- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) cyclopropyl) methanol, cpd-042C (500mg, 2.0 mmol) dissolved in dichloromethane, was added thereto. After the reaction mixture was stirred at-78 ℃ for 30 minutes, triethylamine (1.1g, 11mmol) was added thereto. The reaction solution was stirred and returned to room temperature. After the reaction was complete, it was washed with water, dried over sodium sulfate and concentrated to give crude 1- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) cyclopropane-1-carbaldehyde Cpd-042D (470 mg, colorless oil) in yield: 85 percent.
MS m/z(ESI):245[M+1] + .
The fourth step
Preparation of 1- (1- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) cyclopropyl) -N-methylmethanamine
1- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) cyclopropane-1-carbaldehyde Cpd-042D (470mg, 1.9mmol) was dissolved in methanol (5 mL) and a solution of methylamine in tetrahydrofuran (2.8mL, 5.7mmol) and glacial acetic acid (2 drops) were added thereto. The reaction mixture was reacted at 25 ℃ for 1 hour, and sodium cyanoborohydride (363mg, 5.7 mmol) was added thereto to continue the reaction for 16 hours. And after the reaction is finished, removing methanol by spinning to obtain a crude product 1- (1- (2- ((tert-butyl dimethyl silicon base) oxy) ethoxy) cyclopropyl) -N-methyl methylamine Cpd-042E which is directly used for the next reaction.
MS m/z(ESI):260[M+1] + .
The fifth step
Preparation of tert-butyl (1- (2- ((tert-butyldimethylsilyloxy) ethoxy) cyclopropyl) methyl) (methyl) carbamate
Crude 1- (1- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) cyclopropyl) -N-methylmethanamine Cpd-042E (500mg, 1.9mol) was dissolved in dichloromethane (10 mL) and di-tert-butyl dicarbonate (842mg, 3.9mmol) and triethylamine (585mg, 5.8mmol) were added thereto. The reaction mixture was reacted at 25 ℃ for 2 hours, then dichloromethane was removed by rotary evaporation, and the obtained residue was isolated and purified by silica gel column (petroleum ether/ethyl acetate = 9/1) to give (1- (2- ((tert-butyldimethylsilyloxy) ethoxy) cyclopropyl) methyl) (methyl) carbamic acid tert-butyl ester Cpd-042F (145 mg, colorless oil), yield: 19 percent.
MS m/z(ESI):360[M+1] + .
The sixth step
Preparation of tert-butyl (1- (2-hydroxyethoxy) cyclopropylmethyl (methyl) carbamate
Tert-butyl (1- (2- ((tert-butyldimethylsilyloxy) ethoxy) cyclopropyl) methyl) (methyl) carbamate, cpd-042F (145mg, 0.4 mmol), was dissolved in tetrahydrofuran (5 mL) and tetrabutylammonium fluoride (211mg, 0.8mmol) was added thereto. The reaction mixture was reacted at 25 ℃ for 2 hours. After the completion of the reaction, tetrahydrofuran was removed by rotary evaporation, and the obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 8/1) to obtain tert-butyl (1- (2-hydroxyethoxy) cyclopropylmethyl (methyl) carbamate Cpd-042G (74 mg, colorless oil) in a yield of 71%.
MS m/z(ESI):268[M+1] + .
Seventh step
Preparation of tert-butyl methyl ((1- (2-oxoethoxy) cyclopropyl) methyl) carbamate
Oxalyl chloride (115mg, 0.9 mmol) was dissolved in dry dichloromethane (4 mL), to which was added dry dimethyl sulfoxide (94mg, 1.2 mmol) dissolved in dichloromethane at-78 ℃ under nitrogen. After stirring for 10 minutes, t-butyl (1- (2-hydroxyethoxy) cyclopropylmethyl (methyl) carbamate Cpd-042G (74mg, 0.3mmol) dissolved in dichloromethane was added thereto, the reaction mixture was stirred at-78 ℃ for 30 minutes, triethylamine (182mg, 1.8mmol) was added thereto, the reaction mixture was stirred and returned to room temperature, after the reaction was completed, the mixture was washed with water, dried over sodium sulfate as an organic phase, and concentrated to give crude t-butyl methyl ((1- (2-oxoethoxy) cyclopropyl) methyl) carbamate Cpd-042H (70 mg, brown liquid) in a yield of 95%.
MS m/z(ESI):244[M+1] + .
Eighth step
Preparation of ethyl 3- ((2- (1- ((tert-butoxycarbonyl) methylamino) methyl) cyclopropane) ethyl) amino) -1H-pyrrole-2-carboxylate
Crude methyl tert-butyl ((1- (2-oxoethoxy) cyclopropyl) methyl) carbamate, cpd-042H (70mg, 0.8mmol), was dissolved in methanol (4 mL) and to this was added ethyl 3-amino-1H-pyrrole-2-carboxylate (53mg, 0.3mmol) and glacial acetic acid (2 drops). The reaction mixture was reacted at 25 ℃ for 1 hour. To the reaction solution was added sodium cyanoborohydride (54mg, 0.9mmol) and the reaction was continued for 16 hours. After the reaction was completed, methanol was removed by rotary evaporation, and the obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 4/1) to obtain ethyl 3- ((2- (1- ((tert-butoxycarbonyl) (methyl) amino) methyl) cyclopropane) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-042I (80 mg, colorless oil), yield: 73 percent.
MS m/z(ESI):382[M+1] + .
The ninth step
Preparation of ethyl 3- (1- (2- (1- ((tert-butoxycarbonyl) methylamino) methyl) cyclopropoxy) ethyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate
Ethyl 3- ((2- (1- ((tert-butoxycarbonyl) (methyl) amino) methyl) cyclopropane) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-042I (50mg, 0.1mmol) was dissolved in dichloromethane (4 mL), and ethyl isothiocyanatecarboxylate (34mg, 0.3mmol) was added thereto to react at 25 ℃ for 2 hours. After the reaction was completed, dichloromethane was removed by rotary evaporation. The resulting residue was extracted with ethyl acetate (3 × 15 mL), the organic phases combined, dried over anhydrous sodium sulfate and concentrated to give crude 3- (1- (2- (1- ((tert-butoxycarbonyl) methylamino) methyl) cyclopropoxy) ethyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-042J (60 mg, yellow oil) yield: 89 percent.
MS m/z(ESI):513[M+1] + .
The tenth step
Preparation of methyl ((1- (2- (4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) cyclopropyl) methylcarbamic acid tert-butyl ester
Ethyl 3- (1- (2- (1- ((tert-butoxycarbonyl) (methyl) amino) methyl) cyclopropoxy) ethyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-042J (80mg, 0.2mmol) was dissolved in methanol (4 mL) and cesium carbonate (152mg, 0.5 mmol) was added thereto. The reaction mixture was heated to 65 ℃ and reacted for 6 hours. After the reaction was completed, the reaction solution was cooled to room temperature, methanol was removed by rotary evaporation, and the obtained residue was purified using a preparative plate (dichloromethane/methanol = 20/1) to give methyl ((1- (2- (4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) cyclopropyl) carbamic acid tert-butyl ester Cpd-042K (50 mg, colorless oil) in 65% yield.
MS m/z(ESI):395[M+1] + .
The eleventh step
Preparation of 1- (2- (1- ((methylamino) methyl) cyclopropoxy) ethyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Methyl ((1- (2- (4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) cyclopropyl) methylcarbamate Cpd-042K (50mg, 0.12mmol) was dissolved in ethanol (2 mL), 3M ethanolic hydrochloric acid solution (2 mL) was added thereto, the reaction solution was reacted at 25 ℃ for 16 hours, then the acid therein was neutralized with saturated sodium bicarbonate solution, methanol was removed by centrifugation, the residue was extracted with ethyl acetate (15 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified with a C18 column (acetonitrile/water (containing 1 ‰ formic acid) of 4/1) to give 1- (2- (1- ((methylamino) methyl) cyclopropoxy) ethyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3, 2-Cpd ] pyrimidin-4-one-042 (1.45 mg, 042, 13.13 mg) solid yield, 13.13% yield.
MS m/z(ESI):295[M+1] + .
1 H NMR(400MHz,MeOD)δ8.53(s,1H),7.30(d,J＝2.4Hz,1H),6.27(d,J＝2.4Hz,1H),4.61(t,J＝5.4Hz,2H),4.02(t,J＝5.6Hz,2H),3.20(s,2H),2.73(s,3H),0.81(s,2H),0.70(s,2H).
Example 43
6, 7-dimethyl-2-thioxo-1- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000771
First step of
Preparation of ethyl (Z) - (3-cyano-2-en-2-yl) glycinate
2-methyl-3-oxobutanenitrile Cpd-043A (900mg, 9.27mmol) was dissolved in ethanol (20 mL) with glycine ethyl ester (1.24g, 12.05mmol) and triethylamine (1.41g, 13.90mmol) and reacted at room temperature for 8 hours. After completion of the reaction, ethanol was removed by evaporation, and the mixture was extracted with ethyl acetate (50 mL. Times.3) and saturated brine (50 mL), and the organic phase was concentrated by drying to give ethyl (Z) - (3-cyano-2-en-2-yl) glycinate Cpd-043B (1.2 g, yellow solid), yield: 58 percent.
MS m/z(ESI):183.1[M+1] + .
Second step of
Preparation of 3-amino-4, 5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester
(Z) - (3-cyano-2-en-2-yl) glycine ethyl ester Cpd-043B (1g, 5.50mmol) was dissolved in dry ethanol (20 mL), then sodium ethoxide (750mg, 11.00mmol) was added, the temperature was raised to 70 ℃ under nitrogen atmosphere to react for 2 hours, after the reaction was completed, ethanol was removed by rotary evaporation, then extraction was performed with ethyl acetate (50 mL. Times.3) and saturated brine (50 mL), the organic phase was concentrated by drying, and the obtained residue was separated and purified with a silica gel column (petroleum ether/ethyl acetate = 4/1) to obtain 3-amino-4, 5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-043C (650 mg, yellow solid) in yield: and 64 percent.
MS m/z(ESI):183.1[M+1] + .
The third step
Preparation of ethyl 4, 5-dimethyl-3- ((2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate
Ethyl 3-amino-4, 5-dimethyl-1H-pyrrole-2-carboxylate Cpd-043C (100mg, 0.55mmol) was dissolved in methanol (10 mL), followed by addition of 2- ((1, 1-trifluoropropan-2-yl) oxy) acetaldehyde (86mg, 0.55mmol) and sodium cyanoborohydride (69mg, 1.10 mmol), and reaction at room temperature for 1 hour. After the reaction was completed, methanol was removed by rotary evaporation, and the obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 10/1) to obtain ethyl 4, 5-dimethyl-3- ((2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-043D (100 mg, yellow solid), yield: 56 percent.
MS m/z(ESI):323.1[M+1] + .
The fourth step
Preparation of ethyl 3- (3- (ethoxycarbonyl) -1- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) thioureido) -4, 5-dimethyl-1H-pyrrole-2-carboxylate
Ethyl 4, 5-dimethyl-3- ((2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-043D (100mg, 0.31mmol) was dissolved in methanol (15 mL), then ethyl isothiocyanatecarboxylate (49mg, 0.37mmol) was added and reacted at room temperature for 1 hour, and the reaction solution was used directly in the next step after completion of the reaction.
MS m/z(ESI):454.0[M+1] + .
The fifth step
Preparation of 6, 7-dimethyl-2-thioxo-1- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Cesium carbonate (303mg, 0.93mmol) was added to ethyl 3- (3- (ethoxycarbonyl) -1- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) thioureido) -4, 5-dimethyl-1H-pyrrole-2-carboxylate Cpd-043E (141mg, 0.31mmol) in methanol (15 mL), heated to 65 ℃ and stirred for 3 hours, after completion of the reaction methanol was removed by rotary evaporation, and the residue obtained was separated and purified by a silica gel column (dichloromethane/methanol = 50/1) to give 6, 7-dimethyl-2-thio-1- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-043 (40 mg, white solid), yield: and 52 percent.
MS m/z(ESI):336.0[M+1] +
1 H NMR(400MHz,DMSO-d6)δ12.16(s,1H),12.09(s,1H),4.72(s,2H),4.20-4.14(m,1H),4.03-3.91(m,2H),2.21(d,J＝5.4Hz,6H),1.18(d,J＝6.4Hz,3H).
Example 44
7- ((dimethylamino) methyl) -2-thioxo-1- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000791
First step of
Preparation of ethyl 3- ((tert-butoxycarbonyl) amino) -4-formyl-1H-pyrrole-2-carboxylate
3- ((tert-Butoxycarbonylamino) -4-iodo-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-044A (500mg, 1.32mmol) was dissolved in DMSO (10 mL), pdAmphos (186mg, 0.26mmol), triethylsilane (535mg, 4.60mmol) and N, N-diisopropylethylamine (200mg, 1.97mmol) were added in this order, and the mixture was heated to 90 ℃ under a carbon monoxide atmosphere and reacted for 18 hours. After the completion of the reaction, the reaction mixture was extracted with ethyl acetate (50 mL × 3) and a saturated aqueous sodium chloride solution (50 mL), the organic phase was concentrated by drying, and the obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 7/3) to obtain ethyl 3- ((tert-butoxycarbonyl) amino) -4-formyl-1H-pyrrole-2-carboxylate Cpd-044B (130 mg, pale yellow solid), yield: 36 percent.
MS m/z(ESI):283.1[M+1] + .
Second step of
Preparation of ethyl 3- ((tert-butoxycarbonyl) amino) -4- ((dimethylamino) methyl) -1H-pyrrole-2-carboxylate
Ethyl 3- ((tert-butoxycarbonyl) amino) -4-formyl-1H-pyrrole-2-carboxylate Cpd-044B (130mg, 0.46mmol) was dissolved in methanol (10 mL), followed by addition of dimethylamine methanol solution (2M, 0.46mL, 0.92mmol) and sodium cyanoborohydride (58mg, 0.92mmol) and reaction at room temperature for 1 hour. After the reaction was completed, methanol was removed by rotary evaporation, and the obtained residue was separated and purified by a silica gel column (dichloromethane/methanol = 10/1) to obtain ethyl 3- ((tert-butoxycarbonyl) amino) -4- ((dimethylamino) methyl) -1H-pyrrole-2-carboxylate Cpd-044C (130 mg, colorless oil), yield: 91 percent.
MS m/z(ESI):312.0[M+1] + .
The third step
Preparation of ethyl 3-amino-4- ((dimethylamino) methyl) -1H-pyrrole-2-carboxylate hydrochloride
Ethyl 3- ((tert-butoxycarbonyl) amino) -4- ((dimethylamino) methyl) -1H-pyrrole-2-carboxylate Cpd-044C (130mg, 0.42mmol) was dissolved in methanol hydrochloride solution (4M, 5mL) and reacted at room temperature for 2 hours. After the reaction was completed, the methanol hydrochloride solution was removed by rotary evaporation, and then dissolved in methanol (10 mL), dried and concentrated to give 3-amino-4- ((dimethylamino) methyl) -1H-pyrrole-2-carboxylic acid ethyl ester hydrochloride Cpd-044D (100 mg, colorless oil), yield: 96 percent.
MS m/z(ESI):212.1[M+1] + .
The fourth step
Preparation of ethyl 4- ((dimethylamino) methyl) -3- ((2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate
3-amino-4- ((dimethylamino) methyl) -1H-pyrrole-2-carboxylic acid ethyl ester hydrochloride Cpd-044D (100mg, 0.40mmol) was dissolved in methanol (5 mL), followed by addition of 2- ((1, 1-trifluoropropan-2-yl) oxy) acetaldehyde (75mg, 0.48mmol) and sodium cyanoborohydride (30mg, 0.48mmol) and reaction at room temperature for 1 hour. After completion of the reaction, methanol was removed by rotary evaporation, and the obtained residue was separated and purified by a silica gel column (dichloromethane/methanol = 10/1) to obtain ethyl 4- ((dimethylamino) methyl) -3- ((2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-044E (50 mg, colorless oil), yield: 36 percent.
MS m/z(ESI):352.1[M+1] + .
The fifth step
Preparation of ethyl 4- ((dimethylamino) methyl) -3- (3- (ethoxycarbonyl) -1- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) thioureido) -1H-pyrrole-2-carboxylate
Ethyl 4- ((dimethylamino) methyl) -3- ((2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-044E (50mg, 0.14mmol) was dissolved in methanol (5 mL), followed by addition of ethyl isothiocyanatecarboxylate (22mg, 0.17mmol) and reaction at room temperature for 1 hour, after completion of the reaction, the reaction mixture was used directly in the next step.
MS m/z(ESI):483.1[M+1] + .
The sixth step
Preparation of 7- ((dimethylamino) methyl) -2-thioxo-1- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Cesium carbonate (228mg, 0.70mmol) was added to methanol (5 mL) of ethyl 5- ((dimethylamino) methyl) -3- (3- (ethoxycarbonyl) -1- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) thiourea) -1H-pyrrole-2-carboxylate Cpd-044F (68mg, 0.14mmol), warmed to 65 ℃ and stirred for 3 hours, and after completion of the reaction, methanol was removed by rotary evaporation, and the resulting residue was separated and purified with a silica gel column (dichloromethane/methanol = 100/6) to give 7- ((dimethylamino) methyl) -2-thio-1- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-044 (4 mg, white solid) yield: 8 percent.
MS m/z(ESI):365.0[M+1] +
1 H NMR(400MHz,DMSO-d6)δ12.30(s,2H),7.29(d,J＝2.0Hz,1H),5.00(s,2H),4.17-4.12(m,1H),4.04-3.93(m,2H),2.13(s,6H),1.17(d,J＝6.4Hz,3H).
Example 45
7-methoxy-2-thioxo-1- (2- (1, 1-trifluoroisopropoxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000801
First step of
(3- ((tert-Butoxycarbonyl) amino) -4- (phenyl-. Lamda.) - 3 Preparation of (E) -iodoalkyl) -1H-pyrrole-2-carboxylic acid ethyl ester
Ethyl 3- ((tert-butoxycarbonyl) amino) -1H-pyrrole-2-carboxylate Cpd-045A (1.00g, 3.93mmol) and iodobenzene acetate (1.39g, 4.32mmol) were dissolved in trifluoroethanol (15 mL) and reacted at room temperature for 3 hours. After the reaction is finished, the trifluoroethanol is removed by rotary evaporation, the obtained solid is pulped by ethyl acetate and filtered to obtain (3- ((tert-butyloxycarbonyl) amino) -4- (phenyl-lambda) 3 -iodoalkyl) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-045B (1.1 g, white solid), yield: 61 percent.
Second step of
Preparation of ethyl 3- ((tert-butoxycarbonyl) amino) -4-methoxy-1H-pyrrole-2-carboxylate
Reacting (3- ((tert-butyloxycarbonyl) amino) -4- (phenyl-lambda-ethyl) 3 -iodoalkyl) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-045B (500mg, 1.09mmol) was dissolved in dry methanol (15 mL) and sodium methoxide (177mg, 3.27mmol) and copper triflate (197mg, 0.55mmol) were added and the reaction was heated to 90 ℃ by microwave heating under nitrogen for 1 hour. After the reaction was completed, the reaction mixture was quenched by adding a saturated aqueous ammonium chloride solution (10 mL), extracted with ethyl acetate (50 mL × 3) and a saturated saline solution (50 mL), and the organic phase was concentrated by drying, and the obtained residue was separated and purified with a silica gel column (petroleum ether/ethyl acetate = 4/1) to obtain methyl 3- ((t-butoxycarbonyl) amino) -4-methoxy-1H-pyrrole-2-carboxylate Cpd-045C (50 mg, colorless oil), yield: 17 percent.
MS m/z(ESI):271.1[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ11.24(s,1H),7.90(s,1H),6.62(d,J＝3.2Hz,1H),3.69(s,3H),3.62(s,3H),1.39(s,9H).
The third step
Preparation of 3-amino-4-methoxy-1H-pyrrole-2-carboxylic acid ethyl ester hydrochloride
Methyl 3- ((tert-butoxycarbonyl) amino) -4-methoxy-1H-pyrrole-2-carboxylate Cpd-045C (50mg, 0.19mmol) was dissolved in methanol hydrochloride solution (4.0M, 5mL, 20.00mmol) and reacted at room temperature for 2 hours. After the reaction was completed, the methanol hydrochloride solution was removed by rotary evaporation, and then dissolved in methanol (10 mL), dried and concentrated to give methyl 3-amino-4-methoxy-1H-pyrrole-2-carboxylate hydrochloride Cpd-045D (25 mg, colorless oil), yield: and 64 percent.
MS m/z(ESI):171.1[M+1] + .
The fourth step
Preparation of ethyl 5-methoxy-3- ((2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate
Methyl 3-amino-4-methoxy-1H-pyrrole-2-carboxylate hydrochloride Cpd-045D (25mg, 0.12mmol) was dissolved in methanol (5 mL), followed by addition of 2- ((1, 1-trifluoropropan-2-yl) oxy) acetaldehyde (37mg, 0.24mmol) and sodium cyanoborohydride (15mg, 0.24mmol) and reaction at room temperature for 1 hour. After the reaction was completed, methanol was removed by rotary evaporation, and the obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 4/1) to obtain methyl 5-methoxy-3- ((2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-045E (20 mg, colorless oil), yield: 54 percent.
MS m/z(ESI):171.1[M+1] + .
The fifth step
Preparation of ethyl 3- (3- (ethoxycarbonyl) -1- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) thioureido) -4-methoxy-1H-pyrrole-2-carboxylate
Methyl 5-methoxy-3- ((2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-045E (20mg, 0.06mmol) was dissolved in methanol (5 mL), and ethyl isothiocyanatocarboxylate (12mg, 0.09mmol) was added thereto and reacted at room temperature for 1 hour, and the reaction solution was used in the next step as it was after completion of the reaction.
MS m/z(ESI):442.1[M+1] + .
The sixth step
Preparation of 7-methoxy-2-thioxo-1- (2- (1, 1-trifluoroisopropoxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Cesium carbonate (98mg, 0.30mmol) was added to methyl 3- (3- (ethoxycarbonyl) -1- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) thioureido) -4-methoxy-1H-pyrrole-2-carboxylate Cpd-045F (26mg, 0.06mmol) in methanol (5 mL), warmed to 65 ℃ and stirred for 3 hours, after the reaction was complete the methanol was removed by rotary evaporation and the residue was purified on a silica gel column (dichloromethane/methanol = 50/1) to give 7-methoxy-2-thio-1- (2- (1, 1-trifluoroisopropoxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-045 (6 mg, white solid) in yield: 30 percent.
MS m/z(ESI):338.0[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.23(s,1H),12.03(s,1H),7.21(d,J＝3.6Hz,1H),4.73(dd,J＝15.2,7.2Hz,2H),4.18-4.11(m,1H),3.91(t,J＝6.8Hz,2H),3.77(s,3H),1.20(d,J＝6.4Hz,3H).
Example 46
1- (3- (2, 2-trifluoroethoxy) propan-2-yl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000821
First step of
Preparation of 3- (bis (4-methoxybenzyl) amino) propane-1, 2-diol
3-aminopropane-1, 2-diol Cpd-046A (10.0g, 100mmol) was dissolved in dry dichloromethane (20 mL), diisopropylethylamine (15.4g, 120mmol) was added, and then PMBCl (18.7g, 120mmol) was added dropwise, followed by reaction at room temperature overnight. After the reaction was completed, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and rotary evaporated to give a crude product, which was subjected to column chromatography (petroleum ether/ethyl acetate = 4/1) to give 3- (bis (4-methoxybenzyl) amino) propane-1, 2-diol Cpd-046B (15 g, colorless oil) in yield: 45 percent.
MS m/z(ESI):331[M+1] + .
Second step of
Preparation of 1- (bis (4-methoxybenzyl) amino) -3- ((tert-butyldimethylsilyl) oxy) propan-2-ol
3- (bis (4-methoxybenzyl) amino) propane-1, 2-diol Cpd-046B (2.0 g,6.0 mmol) was dissolved in dry dichloromethane (10 mL) and imidazole (0.5 g,7.3 mmol) was added. The mixture was cooled to 0 ℃ on an ice bath, and TBSCl (1.1g, 7.3mmol) was added in portions. After 1 hour of reaction, spin-dried, and column chromatographed to give 1- (bis (4-methoxybenzyl) amino) -3- ((tert-butyldimethylsilyl) oxy) propan-2-ol Cpd-046C (2.2 g, colorless liquid) in yield: 82 percent.
MS m/z(ESI):446[M+1] + .
The third step
Preparation of 1- (bis (4-methoxybenzyl) amino) -3- ((tert-butyldimethylsilyl) oxy) propan-2-yl acetate
Preparation of 1- (bis (4-methoxybenzyl) amino) -3- ((tert-butyldimethylsilyl) oxy) propan-2-ol Cpd-046C (2.2 g,4.9 mmol) and triethylamine (997mg, 9.9 mmol) were dissolved in dry dichloromethane (5 mL), cooled to 0 ℃, acetic anhydride (604mg, 5.9 mmol) was slowly added, after completion of addition, reaction was carried out at 0 ℃ for 1 hour, after completion of the reaction, the solvent was removed by rotation, and the residue was subjected to column chromatography to give 1- (bis (4-methoxybenzyl) amino) -3- ((tert-butyldimethylsilyl) oxy) propan-2-yl acetate Cpd-046D (2.4 g, colorless liquid), yield: 92 percent.
MS m/z(ESI):488[M+1] + .
The fourth step
Preparation of 1- (bis (4-methoxybenzyl) amino) -3-hydroxypropyl-2-acetate
1- (bis (4-methoxybenzyl) amino) -3- ((tert-butyldimethylsilyl) oxy) propan-2-yl acetate Cpd-046D (2.4 g,4.5 mmol) was dissolved in tetrahydrofuran (4 mL) and reacted at room temperature for 2.5 hours with TBAF (2 mL). After the reaction is finished, 10mL of water is added for quenching, ethyl acetate is used for extraction, an organic phase is washed by saturated sodium chloride, dried by anhydrous sodium sulfate and rotary evaporated to obtain a crude product, and the crude product is purified by a column to obtain 1- (bis (4-methoxybenzyl) amino) -3-hydroxypropyl-2-acetate Cpd-046E (1.2 g, colorless oily substance), wherein the yield is as follows: 80 percent.
The fifth step
Preparation of 1- (bis (4-methoxybenzyl) amino) -3-bromopropan-2-yl acetate
1- (bis (4-methoxybenzyl) amino) -3-hydroxypropyl-2-acetate Cpd-046E (1.2g, 3.2mmol) was dissolved in dichloromethane (5 mL), cooled to 0 ℃ and carbon tetrabromide (1.6 g, 4.8mmol) and triphenylphosphine (1.2g, 4.8mmol) were added thereto. Then stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was washed once with water (5 mL), and the organic layer was dried over anhydrous sodium sulfate and concentrated. The obtained residue was isolated and purified by silica gel column (petroleum ether/ethyl acetate = 5/1) to give 1- (bis (4-methoxybenzyl) amino) -3-bromopropan-2-ylacetate Cpd-046F (800 mg, yellow oil), yield: 56 percent.
MS m/z(ESI):434[M+1] + .
The sixth step
Preparation of 1- (bis (4-methoxybenzyl) amino) -3- (2, 2-trifluoroethoxy) propan-2-yl acetate
1- (bis (4-methoxybenzyl) amino) -3-bromopropan-2-yl acetate Cpd-046F (800mg, 1.8mmol) was dissolved in trifluoroethanol (5 mL) followed by the addition of potassium tert-butoxide in tetrahydrofuran (2 mL). The reaction solution was heated to 65 ℃ and stirred overnight. After the reaction was completed, the solvent was removed under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2/1) to give 1- (bis (4-methoxybenzyl) amino) -3- (2, 2-trifluoroethoxy) propan-2-ylacetate Cpd-046G (600 mg, colorless oil), yield: 71 percent.
MS m/z(ESI):455[M+1] + .
Seventh step
Preparation of 1- (bis (4-methoxybenzyl) amino) -3- (2, 2-trifluoroethoxy) propanol
1- (bis (4-methoxybenzyl) amino) -3- (2, 2-trifluoroethoxy) propan-2-yl acetate Cpd-046G (800mg, 1.8mmol) was dissolved in methanol/water =1/1 (4 mL), to which was added lithium hydroxide (175mg, 7.3mmol), and the reaction was stirred at room temperature overnight. After the reaction was completed, methanol was removed by rotation, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The crude was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2/1) to give 1- (bis (4-methoxybenzyl) amino) -3- (2, 2-trifluoroethoxy) propanol Cpd-046H (400 mg, colorless oil), yield: 73 percent.
MS m/z(ESI):414[M+1] + .
Eighth step
Preparation of 2-bromo-N, N-bis (4-methoxybenzyl) -3- (2, 2-trifluoroethoxy) propan-1-amine
1- (bis (4-methoxybenzyl) amino) -3- (2, 2-trifluoroethoxy) propanol Cpd-046H (400mg, 1.0 mmol) was dissolved in dichloromethane (3 mL) and cooled to 0 ℃ followed by addition of carbon tetrabromide (480 mg,1.5 mmol) and triphenylphosphine (380mg, 1.5 mmol), and the reaction solution was stirred at room temperature for 1 hour. After the reaction, the reaction mixture was washed once with water (5 mL), and the organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 4/1) to give 2-bromo-N, N-bis (4-methoxybenzyl) -3- (2, 2-trifluoroethoxy) propan-1-amine Cpd-046I (250 mg, yellow oil), yield: and 54 percent.
MS m/z(ESI):478[M+1] + .
The ninth step
Preparation of ethyl 3- ((1- (bis (4-methoxybenzyl) amino) -3- (2, 2-trifluoroethoxy) propan-2-yl) amino) -1H-pyrrole-2-carboxylate
2-bromo-N, N-bis (4-methoxybenzyl) -3- (2, 2-trifluoroethoxy) propan-1-amine Cpd-046I (250mg, 0.5 mmol) was dissolved in acetonitrile (3 mL), ethyl 3-amino-1H-pyrrole-2-carboxylate (80mg, 0.5 mmol) and DIEA (101mg, 0.9 mmol) were added thereto, and the reaction solution was heated to 65 ℃ to react overnight. After the reaction was finished, the solvent was removed by rotary evaporation, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/1) to give ethyl 3- ((1- (bis (4-methoxybenzyl) amino) -3- (2, 2-trifluoroethoxy) propan-2-yl) amino) -1H-pyrrole-2-carboxylate Cpd-046J (200 mg, colorless oil), yield: 70 percent.
MS m/z(ESI):550[M+1] + .
The tenth step
Preparation of ethyl 3- ((1-amino-3- (2, 2-trifluoroethoxy) propan-2-yl) amino) -1H-pyrrole-2-carboxylate
Ethyl 3- ((1- (bis (4-methoxybenzyl) amino) -3- (2, 2-trifluorooxy) propan-2-yl) amino) -1H-pyrrole-2-carboxylate Cpd-046J (200mg, 0.4 mmol) was dissolved in methanol (2 mL), to which palladium hydroxide (98mg, 0.7 mmol) was added, followed by replacement of the internal atmosphere with hydrogen. The reaction was heated to 60 ℃ for 2H, then cooled to room temperature, the solid was filtered off and the solvent was removed under reduced pressure to give ethyl 3- ((1-amino-3- (2, 2-trifluoroethoxy) propan-2-yl) amino) -1H-pyrrole-2-carboxylate Cpd-046K (80 mg, colorless oil), yield: 71 percent.
MS m/z(ESI):310[M+1] + .
The eleventh step
Preparation of ethyl 3- ((1- ((tert-butoxycarbonyl) amino) -3- (2, 2-trifluoroethoxy) propan-2-yl) amino) -1H-pyrrole-2-carboxylate
Ethyl 3- ((1-amino-3- (2, 2-trifluorooxy) propan-2-yl) amino) -1H-pyrrole-2-carboxylate Cpd-046K (80mg, 0.3mmol) was dissolved in dichloromethane (2 mL), to which triethylamine (39mg, 0.4mmol) and di-tert-butyl dicarbonate were added to react (67mg, 0.3mmol), and reacted at room temperature for 2 hours. After the reaction was complete, the solvent was removed by rotary evaporation, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2/1) to give ethyl 3- ((1- ((tert-butoxycarbonyl) amino) -3- (2, 2-trifluoroethoxy) propan-2-yl) amino) -1H-pyrrole-2-carboxylate Cpd-046L (85 mg, colorless oil), yield: 77 percent. MS m/z (ESI) 410[ m ] +1] + .
The twelfth step
Preparation of ethyl 3- (1- (1- ((tert-butoxycarbonyl) amino) -3- (2, 2-trifluoroethoxy) propan-2-yl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-1-carboxylate-2-carboxylate
Ethyl 3- ((1- ((tert-butoxycarbonyl) amino) -3- (2, 2-trifluoroethoxy) propan-2-yl) amino) -1H-pyrrole-2-carboxylate Cpd-046L (85mg, 0.2mmol) was dissolved in dichloromethane (2 mL), cooled to 0 ℃ and then ethyl isothiocyanatocarboxylate (26mg, 0.2mmol) was added thereto and stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was washed once with water (5 mL), the organic layer was dried over anhydrous sodium sulfate and concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2/1) to give ethyl 3- (1- (1- ((tert-butoxycarbonyl) amino) -3- (2, 2-trifluoroethoxy) propan-2-yl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-1-carboxylate-2-carboxylate Cpd-046M (80 mg, colorless oil), yield: 70 percent.
MS m/z(ESI):541[M+1] + .
Thirteenth step
Preparation of tert-butyl 2- (4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) -3- (2, 2-trifluoroethoxy) propancarbamate
3- (1- (1- ((t-butoxycarbonyl) amino) -3- (2, 2-trifluoroethoxy) propan-2-yl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-1-carboxylic acid tert-butyl ester-2-carboxylic acid ethyl ester Cpd-046M (80mg, 0.14mmol) was dissolved in methanol (2 mL), cesium carbonate (91mg, 0.28mmol) was added thereto, and the reaction solution was heated to 65 ℃ for 3 hours. The reaction solution was cooled to room temperature, a saturated aqueous ammonium chloride solution (5 mL) was added, extraction was performed with ethyl acetate (10 mL. Times.3), and the organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified on preparative silica gel plate (dichloromethane/methanol = 20/1) to give tert-butyl 2- (4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) -3- (2, 2-trifluoroethoxy) propancarbamate Cpd-046N (40 mg, white solid), yield: 68 percent. MS M/z (ESI): 423 (M-100 + 1).
Fourteenth step
Preparation of 1- (1-amino-3- (2, 2-trifluoroethoxy) propan-2-yl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Tert-butyl (2- (4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) -3- (2, 2-trifluoroethoxy) propyl) carbamate Cpd-046N (40mg, 0.09mmol) was dissolved in methanol (1 mL), a methanol solution of hydrogen chloride (1 mL) was added thereto, and the reaction solution was heated to 60 ℃ for 1 hour. After the reaction solution was cooled to room temperature, the solvent was removed by spin-drying, the crude product was slurried with ethyl acetate, filtered, the filter cake was washed with aqueous sodium bicarbonate solution, extracted with ethyl acetate, concentrated and dried to give 1- (1-amino-3- (2, 2-trifluoroethoxy) propan-2-yl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-046 (20 mg, white solid) yield: 66 percent.
MS m/z(ESI):322[M+1] + .
Example 47
1- (1- (dimethylamino) -3- (2, 2-trifluoroethoxy) propan-2-yl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000851
1- (1-amino-3- (2, 2-trifluoroethoxy) propan-2-yl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-046 (10mg, 0.03mmol) was dissolved in methanol (1 mL), and paraformaldehyde (3mg, 0.09mmol), two drops of acetic acid, and sodium cyanoborohydride (2mg, 0.09mmol) were added thereto. The reaction solution was heated to 65 ℃ and reacted overnight. After the reaction was cooled to room temperature and concentrated, the crude product was isolated on preparative silica gel plates (dichloromethane/methanol = 20/1) to give 1- (1-dimethylamino-3- (2, 2-trifluoroethoxy) propan-2-yl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-047 (8 mg, white solid) in yield: 73 percent.
MS m/z(ESI):351[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.44(s,1H),12.21(s,1H),7.39(s,1H),6.32(s,1H),4.42(s,1H),4.04-3.81(m,4H),2.91(s,2H),1.23(s,6H).
Example 48
1- (((4-cyclopropylmorpholin-2-yl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000852
First step of
Preparation of morpholin-2-ylmethanol
Dissolving tert-butyl 2- (hydroxymethyl) morpholine-4-carboxylate Cpd-048A (2g, 9.2mmol) in dichloromethane (20 mL), then dropwise adding ethyl acetate hydrochloride (10 mL) solution at room temperature, stirring for 2 hours at room temperature after the addition, directly concentrating to obtain morpholine-2-yl methanol Cpd-048B (1 g, colorless oily liquid), yield: 100 percent.
MS m/z(ESI):118[M+1] + .
Second step of
Preparation of (4-cyclopropylmorpholin-2-yl) methanol
Morpholin-2-ylmethanol, cpd-048B (1g, 8.53mmol) was dissolved in methanol (25 mL), followed by the addition of (1-ethoxycyclopropoxy) trimethylsilane (1.48g, 8.53mmol), acetic acid (2 mL) and sodium cyanoborohydride (1.07g, 17.07mmol), and the reaction was heated to 50 ℃ and stirred for 5 hours. After the reaction was complete, the solution was cooled to room temperature, the pH was adjusted to basic with 2M aqueous sodium hydroxide, the solution was spun dry and dichloromethane (100 mL) was added, stirred at room temperature for 1 hour, dichloromethane was filtered, dried over anhydrous sodium sulfate and spun dry to give the product (4-cyclopropylmorpholin-2-yl) methanol Cpd-048C (800 mg, colorless oil), yield: and 54 percent.
MS m/z(ESI):158[M+1] + .
The third step
Preparation of 4-cyclopropylmorpholine-2-carbaldehyde
Oxalyl chloride (523.85mg, 4.2 mmol) is dissolved in dried dichloromethane (2 mL), the temperature of the solution is cooled to-70 ℃ under the protection of nitrogen, dimethyl sulfoxide (656mg, 8.4 mmol) is dissolved in dichloromethane (1 mL) and slowly added dropwise, the solution is kept at-70 ℃ and stirred for 30 minutes, then (4-cyclopropyl morpholin-2-yl) methanol Cpd-048C (600mg, 3.8 mmol) is slowly added dropwise, the mixed solution is stirred for 2 hours at-70 ℃, triethylamine (1.2 g,4.2 mmol) is added and stirred for 30 minutes, the temperature is slowly and naturally raised to 0 ℃, dichloromethane (20 mL) is added to the reaction solution for dilution, water (10 mL) is added into the reaction solution, the solution is separated, the organic phase is washed by saturated sodium chloride, and dried by anhydrous sodium sulfate to obtain dichloromethane Cpd-048D solution (20 mL) containing 4-cyclopropyl morpholine-2-formaldehyde, and the next step is carried out without treatment.
The fourth step
3- (((4-Cyclopropylmorpholin-2-yl) methyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester
Ethyl 3-amino-1H-pyrrole-2-carboxylate (664mg, 4.28mmol) was dissolved in methanol (5 mL), and acetic acid (23.37mg, 0.39mmol) and a solution of 4-cyclopropylmorpholine-2-carbaldehyde Cpd-048D in dichloromethane (20 mL) were added thereto and stirred at room temperature for 0.5 hour. Sodium cyanoborohydride (293mg, 4.67mmol) was then added portionwise and stirred at room temperature for 16 h. After the reaction is finished, adding 20mL of water for quenching, extracting by ethyl acetate, washing an organic phase by saturated sodium chloride, drying by anhydrous sodium sulfate, carrying out rotary evaporation to obtain a crude product, and purifying by a column to obtain 3- (((4-cyclopropyl morpholin-2-yl) methyl) amino) -1H-pyrrole-2-ethyl formate Cpd-048E (110 mg, light brown oily substance), wherein the yield is as follows: 9.6 percent.
MS m/z(ESI):294[M+1] + .
The fifth step
Preparation of ethyl 3- (1- (((4-cyclopropylmorpholin-2-yl) methyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate
Ethyl 3- (((4-cyclopropylmorpholin-2-yl) methyl) amino) -1H-pyrrole-2-carboxylate Cpd-048E (85mg, 0.28mmol) was dissolved in dichloromethane (5 mL), cooled to 0 ℃ and ethyl isothiocyanatocarboxylate (45.6 mg, 0.35mmol) was added thereto, followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction mixture was washed once with water (20 mL), and the organic layer was dried over anhydrous sodium sulfate and concentrated. The obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 1/1) to obtain ethyl 3- (1- (((4-cyclopropylmorpholin-2-yl) methyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-048F (90 mg, light brown oil) in 73% yield.
MS m/z(ESI):425[M+1] + .
The sixth step
Preparation of 1- (((4-cyclopropylmorpholin-2-yl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Ethyl 3- (1- (((4-cyclopropylmorpholin-2-yl) methyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-048F (90mg, 0.2mmol) was dissolved in methanol (5 mL), sodium methoxide (17mg, 0.3mmol) was added thereto, the reaction was heated to 90 ℃ for 2 hours, the reaction was cooled to room temperature and adjusted to pH =4-5 with dilute hydrochloric acid (1M), the solution was spun dry to give a crude product, which was isolated and purified by Prep-HPLC (acetonitrile/water (1 ‰ formate)) to give 1- (((4-cyclopropylmorpholin-2-yl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-048 (18 mg, white solid) in 28% yield.
MS m/z(ESI):307[M+1] + .
1 H NMR(400MHz,CDCl 3 )δ10.49(s,1H),9.56(s,1H),7.21(s,1H),6.27(s,1H),4.79(m,1H),4.14(s,2H),3.81(m,1H),3.52(s,1H),3.10(s,1H),2.82(s,1H),2.42(s,1H),2.25(s,1H),1.69(s,1H),0.49(s,4H).
Example 49
3-methyl-5-thioxo-4- (2- ((1, 1-trifluoro-2-yl) oxy) ethyl) -1,4,5, 6-tetrahydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one
Figure BDA0003664464850000871
First step of
Preparation of 3-methyl-4-nitro-1H-pyrazole-5-carboxylic acid
3-methyl-1H-pyrazole-5-carboxylic acid ethyl ester Cpd-049A (3g, 19.5 mmol) was dissolved in a sulfuric acid/nitric acid (3/1) mixed solution (20 mL), and the reaction was stirred at 60 ℃ for 3 hours. After the reaction, the reaction mixture was extracted with dichloromethane (3X 10 mL), the organic phase was washed with supersaturated brine, and the solvent was dried by spin-drying to obtain a crude product. The crude product was isolated and purified by column chromatography (PE/EA) to give 3-methyl-4-nitro-1H-pyrazole-5-carboxylic acid Cpd-049B (3 g, white solid) in yield: 81 percent.
MS m/z(ESI):172.1[M+1] + .
Second step of
Preparation of 3-methyl-4-nitro-1H-pyrazole-5-carboxylic acid ethyl ester
3-methyl-4-nitro-1H-pyrazole-5-carboxylic acid Cpd-049B (3 g, 17.5mmol) was dissolved in ethanol (20 mL), thionyl chloride (420mg, 3.5mmol) was added and the reaction stirred at 70 ℃ for 1 hour. After the reaction, the reaction mixture was extracted with dichloromethane (10 mL. Times.3), and the organic phase was washed with supersaturated brine, and then the solvent was removed by swirling to obtain a crude product. The crude product was purified by column chromatography to give 3-methyl-4-nitro-1H-pyrazole-5-carboxylic acid ethyl ester Cpd-049C (2.5 g, white solid) in yield: 65 percent.
MS m/z(ESI):200.2[M+1] + .
The third step
Preparation of 1- (4-methoxybenzyl) -3-methyl-4-nitro-1H-pyrazole-5-carboxylic acid ethyl ester and 1- (4-methoxybenzyl) -5-methyl-4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester
Ethyl 3-methyl-4-nitro-1H-pyrazole-5-carboxylate Cpd-049C (2g, 10.04mmol) was dissolved in acetonitrile (10 mL), potassium iodide (1.67g, 10.04mmol) and potassium carbonate (1.39g, 10.04mmol) were added, followed by p-methoxybenzyl chloride (3.15g, 20.08mmol). The reaction was stirred at 85 ℃ for 2 hours. After the reaction, the reaction solution was extracted with dichloromethane (3X 10 mL), and the organic phase was washed with supersaturated brine, and then the solvent was spin-dried to obtain a crude product. The crude product was purified by column chromatography to give a mixture of 1- (4-methoxybenzyl) -3-methyl-4-nitro-1H-pyrazole-5-carboxylic acid ethyl ester Cpd-049D-1 and 1- (4-methoxybenzyl) -5-methyl-4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester Cpd-049D-2 (3 g, orange oily liquid), yield: 84 percent.
MS m/z(ESI):342.1[M+1] + .
The fourth step
Preparation of 1- (4-methoxybenzyl) -3-methyl-4-amino-1H-pyrazole-5-carboxylic acid ethyl ester and 1- (4-methoxybenzyl) -5-methyl-4-amino-1H-pyrazole-3-carboxylic acid ethyl ester
A mixture of ethyl 1- (4-methoxybenzyl) -3-methyl-4-nitro-1H-pyrazole-5-carboxylate Cpd-049D-1 and ethyl 1- (4-methoxybenzyl) -5-methyl-4-nitro-1H-pyrazole-3-carboxylate Cpd-049D-2 (2g, 6.3 mmol) was dissolved in methanol (10 mL) and palladium on charcoal catalyst (340mg, 3.1mmol) was added. The reaction was stirred at room temperature for 2 hours under an atmosphere of hydrogen. After the reaction, the reaction solution was extracted with dichloromethane (10 mL. Times.3), the organic phase was washed with supersaturated brine, and the solvent was spin-dried to obtain a crude product. The crude product was purified by column chromatography to give a mixture of ethyl 1- (4-methoxybenzyl) -3-methyl-4-amino-1H-pyrazole-5-carboxylate Cpd-049E-1 and ethyl 1- (4-methoxybenzyl) -5-methyl-4-amino-1H-pyrazole-3-carboxylate Cpd-049E-2 (1.6 g, white solid), yield: 79 percent.
MS m/z(ESI):290.2[M+1] + .
The fifth step
Preparation of ethyl 1- (4-methoxybenzyl) -3-methyl-4- ((2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrazole-5-carboxylate and ethyl 1- (4-methoxybenzyl) -5-methyl-4- ((2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrazole-3-carboxylate
A mixture of ethyl 1- (4-methoxybenzyl) -3-methyl-4-amino-1H-pyrazole-5-carboxylate Cpd-049E-1 and ethyl 1- (4-methoxybenzyl) -5-methyl-4-amino-1H-pyrazole-3-carboxylate Cpd-049E-2 (500mg, 1.73mmol) was dissolved in methanol (5 mL), acetic acid (0.1 mL) was added, 2- ((1, 1-trifluoropropan-2-yl) oxy) acetaldehyde (217mg, 1.38mmol) was added and the reaction stirred at room temperature for 30 min. Sodium cyanoborohydride (325mg, 5.18mmol) was then added and the reaction was allowed to stir at room temperature for an additional 2 hours. After the reaction, the reaction solution was extracted with dichloromethane (10 mL × 3), and the organic phase was washed with supersaturated brine, and then the solvent was spin-dried to obtain a crude product. The crude product was purified by column chromatography to give a mixture of ethyl 1- (4-methoxybenzyl) -3-methyl-4- ((2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrazole-5-carboxylate Cpd-049F-1 and ethyl 1- (4-methoxybenzyl) -5-methyl-4- ((2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrazole-3-carboxylate Cpd-049F-2 (582 mg, colorless liquid), yield: 71 percent.
MS m/z(ESI):430.2[M+1] + .
The sixth step
Preparation of ethyl 4- (3- (ethoxycarbonyl) -1- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) thioureido) -1- (4-methoxybenzyl) -3-methyl-1H-pyrazole-5-carboxylate and ethyl 4- (3- (ethoxycarbonyl) -1- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) thioureido) -1- (4-methoxybenzyl) -5-methyl-1H-pyrazole-3-carboxylate
A mixture of 1- (4-methoxybenzyl) -3-methyl-4- ((2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrazole-5-carboxylic acid ethyl ester Cpd-049F-1 and 1- (4-methoxybenzyl) -5-methyl-4- ((2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrazole-3-carboxylic acid ethyl ester Cpd-049F-2 (260mg, 0.60mmol) was dissolved in dichloromethane (5 mL) and ethyl N-thiocarbamate (158mg, 1.2mmol) was added at 0 ℃. The reaction was stirred at room temperature for 2 hours. After the reaction, the reaction mixture was extracted with dichloromethane (10 mL. Times.3), the organic phase was washed with supersaturated brine, and the solvent was dried by spin-drying to obtain a crude product. The crude product was purified by column chromatography to give a mixture of 4- (3- (ethoxycarbonyl) -1- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) thioureido) -1- (4-methoxybenzyl) -3-methyl-1H-pyrazole-5-carboxylic acid ethyl ester Cpd-049G-1 and 4- (3- (ethoxycarbonyl) -1- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) thioureido) -1- (4-methoxybenzyl) -5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester Cpd-049G-2 (200 mg, colorless liquid), yield: 53 percent.
MS m/z(ESI):561.2[M+1] + .
Seventh step
Preparation of 1- (4-methoxybenzyl) -3-methyl-5-thioxo-4- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) -1,4,5, 6-tetrahydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one and 2- (4-methoxybenzyl) -3-methyl-5-thioxo-4- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) -2,4,5, 6-tetrahydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one
A mixture of 4- (3- (ethoxycarbonyl) -1- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) thioureido) -1- (4-methoxybenzyl) -3-methyl-1H-pyrazole-5-carboxylic acid ethyl ester Cpd-049G-1 and 4- (3- (ethoxycarbonyl) -1- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) thioureido) -1- (4-methoxybenzyl) -5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester Cpd-049G-2 (100mg, 0.18mmol) was dissolved in ethanol (3 mL) and sodium ethoxide (24mg, 0.36mmol) was added. The reaction was stirred at 100 ℃ for 2 hours under microwave conditions. After the reaction is finished, the solvent is dried by spinning to obtain a crude product. The crude product was purified by column chromatography to give a mixture of 1- (4-methoxybenzyl) -3-methyl-5-thioxo-4- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) -1,4,5, 6-tetrahydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one Cpd-049H-1 and 2- (4-methoxybenzyl) -3-methyl-5-thioxo-4- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) -2,4,5, 6-tetrahydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one Cpd-049H-2 (60 mg, colorless oily liquid), yield: 68 percent.
MS m/z(ESI):456.1(M+23).
Eighth step
Preparation of 3-methyl-5-thioxo-4- (2- ((1, 1-trifluoro-2-yl) oxy) ethyl) -1,4,5, 6-tetrahydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one
Reacting 1- (4-methoxybenzyl) -3-methyl-5-thioxo-4- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) -1,4,5, 6-tetrahydro-7H-pyrazolo [4,3-d ]Pyrimidin-7-one Cpd-049H-1 and 2- (4-methoxybenzyl) -3-methyl-5-thioxo-4- (2- ((1, 1-trifluoropropan-2-yl) oxy) ethyl) -2,4,5, 6-tetrahydro-7H-pyrazolo [4,3-d ] s]A mixture of pyrimidin-7-one Cpd-049H-2 (60mg, 0.14mmol) was dissolved in trifluoroacetic acid (5 mL) and the reaction was run at 90 ℃ for 2 hours. After the reaction is finished, the solvent is dried by spinning to obtain a crude product. The crude product was purified by Prep-HPLC (CAN/H) 2 O (formic acid 1 thousandth)), concentrating, washing with sodium bicarbonate water solution, extracting with ethyl acetate, concentrating, and drying to obtain 3-methyl-5-sulfo-4- (2- ((1, 1-trifluoro-2-yl) oxy) ethyl) -1,4,5, 6-tetrahydro-7H-pyrazole [4,3-d ]]Pyrimidin-7-one Cpd-049 (2 mg, white solid), yield: 7 percent.
MS m/z(ESI):323.0[M+1] + .
Example 50
1- (2- (1, 1-Trifluoroisopropoxy) ethyl) -2-thioxo-7-methyl-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000891
First step of
Preparation of 3-amino-4-bromo-1H-pyrrole-2-carboxylic acid ethyl ester
Ethyl 3-amino-1H-pyrrole-2-carboxylate Cpd-050A (1500 mg, 9.74mmol) was dissolved in tetrahydrofuran (20 mL). The temperature was lowered to 0 ℃ and NBS (1730 mg, 9.74mmol) was added in portions and after the addition was complete, stirred at 0 ℃ for 1 hour. After the reaction, the reaction mixture was washed with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated. The obtained residue was subjected to column purification, separation and purification to give ethyl 3-amino-4-bromo-1H-pyrrole-2-carboxylate Cpd-050B (1200 mg, brown oil), yield: 52.9 percent.
Second step of
Preparation of ethyl 1-tert-butoxycarbonyl-3-bis (tert-butoxycarbonyl) amino-4-bromo-1H-pyrrole-2-carboxylate
Ethyl 3-amino-4-bromo-1H-pyrrole-2-carboxylate Cpd-050B (1.20g, 5.15mmol) was dissolved in tetrahydrofuran (20 mL), to which was added (Boc) 2 O (5.61g, 25.75mmol), DIPEA (3.32g, 25.75mmol) and DMAP (628mg, 5.15mmol) were reacted at 75 ℃ for 16 hours. After the reaction was complete, concentration was performed and the residue was purified by column to give ethyl 1-tert-butoxycarbonyl-3-bis (tert-butoxycarbonyl) amino-4-bromo-1H-pyrrole-2-carboxylate Cpd-050C (1.5 g, light yellow solid), yield: 55.5 percent.
MS m/z(ESI):433,435(M-100+1).
The third step
Preparation of ethyl 1-tert-butoxycarbonyl-3-bis (tert-butoxycarbonyl) amino-4-methyl-1H-pyrrole-2-carboxylate
Ethyl 1-tert-butoxycarbonyl-3-bis (tert-butoxycarbonyl) amino-4-bromo-1H-pyrrole-2-carboxylate Cpd-050C (500mg, 1.15mmol) was dissolved in dioxane (10 mL), and methylboronic acid (208mg, 3.46mmol) and Pd (amphos) Cl were added in that order 2 (82mg, 0.11mmol) and potassium carbonate (800mg, 5.77mmol), with nitrogen, and heated to 90 ℃ for 2 hours. After the reaction is finished, adding 2mL of water for quenching, extracting with ethyl acetate, washing an organic phase with saturated sodium chloride, drying with anhydrous sodium sulfate, performing rotary evaporation to obtain a crude product, and performing column purification to obtain 1-tert-butoxycarbonyl-3-bis (tert-butoxycarbonyl) amino-4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-050D (300 mg, light yellow liquid), wherein the yield is as follows: 68.3 percent.
MS m/z(ESI):369(M-100+1).
The fourth step
Preparation of ethyl 3-amino-4-methyl-1H-pyrrole-2-carboxylate
Ethyl 1-tert-butoxycarbonyl-3-bis (tert-butoxycarbonyl) amino-4-methyl-1H-pyrrole-2-carboxylate Cpd-050D (300mg, 0.64mmol) was dissolved in HCl-EtOH (10mL, 2M), followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction solution was neutralized with saturated sodium bicarbonate, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated. Ethyl 3-amino-4-methyl-1H-pyrrole-2-carboxylate Cpd-050E (100 mg, light yellow solid) was obtained, yield: 93 percent.
MS m/z(ESI):169[M+1] + .
The fifth step
Preparation of ethyl 4-methyl-3- (((2- (((1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate
Ethyl 3-amino-4-methyl-1H-pyrrole-2-carboxylate Cpd-050E (100mg, 0.59mmol) was dissolved in methanol (5 mL), and acetic acid (36mg, 0.59mmol) and 2- ((1, 1-trifluoropropan-2-yl) oxy) acetaldehyde (102mg, 0.59mmol) were added in this order and stirred at room temperature for 1 hour. Sodium cyanoborohydride (37mg, 0.59mmol) was then added and stirred at room temperature for 16 hours. After the reaction is finished, 5mL of water is added for quenching, ethyl acetate is used for extraction, an organic phase is washed by saturated sodium chloride, dried by anhydrous sodium sulfate and evaporated in a rotary mode to obtain a crude product, and the crude product is purified by a column to obtain the 4-methyl-3- (((2- (((1, 1-trifluoropropane-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-ethyl formate Cpd-050F (80 mg, colorless oily matter), wherein the yield is 43.7%.
MS m/z(ESI):309[M+1] + .
The sixth step
Preparation of ethyl 3- (3- (ethoxycarbonyl) -1- (2- (((1, 1-trifluoropropan-2-yl) oxy) ethyl) thioureido) -4-methyl-1H-pyrrole-2-carboxylate
Ethyl 4-methyl-3- (((2- (((1, 1-trifluoropropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-050F (80mg, 0.26mmol) was dissolved in dichloromethane (5 mL), cooled to 0 ℃, and ethyl isothiocyanate (41mg, 0.31mmol) was added thereto, followed by stirring at 0 ℃ for 1 hour after completion of the reaction, the reaction solution was washed once with water (5 mL), the organic layer was dried over anhydrous sodium sulfate and concentrated, and the obtained residue was separated and purified with a silica gel column (petroleum ether/ethyl acetate = 3/1) to obtain 3- (3- (ethoxycarbonyl) -1- (2- (((1, 1-trifluoropropan-2-yl) oxy) ethyl) thioureido) -4-methyl-1H-pyrrole-2-carboxylate Cpd-050G (80 mg, light brown oil) in yield: 70.2%.
MS m/z(ESI):440[M+1] + .
Step seven
Preparation of 1- (2- (1, 1-trifluoroisopropoxy) ethyl) -2-thioxo-7-methyl-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Ethyl 3- (3- (ethoxycarbonyl) -1- (2- (((1, 1-trifluoropropan-2-yl) oxy) ethyl) thioureido) -4-methyl-1H-pyrrole-2-carboxylate Cpd-050G (80mg, 0.18mmol) was dissolved in methanol (3 mL) and cesium carbonate (178mg, 0.55mmol) was added thereto, the reaction solution was heated to 65 ℃ for 6 hours, after the completion of the reaction, the reaction solution was cooled to room temperature and quenched with ammonium chloride, ethyl acetate was extracted, the organic layer was dried over anhydrous sodium sulfate and concentrated, and the obtained residue was isolated by plate preparation to give 1- (2- (1, 1-trifluoroisopropoxy) ethyl) -2-thio-7-methyl-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-050 (30 mg, white solid) with a yield of 52%.
MS m/z(ESI):322[M+1] + .
1 H NMR(400MHz,CDCl 3 )δ12.24(s,1H),12.13(s,1H),7.17(s,1H),4.70(s,2H),4.18-4.12(m,1H),4.05-3.93(m,2H),2.30(s,3H),1.15(d,J＝6.4Hz,3H).
Example 51
1- (2- (2-aminoethoxy) ethyl) -7-methyl-2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000911
First step of
Preparation of tert-butyl (2- (2-hydroxyethoxy) ethyl) carbamate
2- (2-Aminoethoxy) ethanol Cpd-051A (1.0 g,9.5 mmol) was dissolved in anhydrous dichloromethane (10 mL), cooled to 0 ℃ in an ice bath, di-tert-butyl dicarbonate (3.1g, 14.2 mmol) and triethylamine (1.4 g,14.2 mmol) were added, and the mixture was stirred for 2 hours. After the reaction was complete, 1M dilute hydrochloric acid (30 mL) was added followed by three washes, the organic phase was dried over anhydrous sodium sulfate and the solvent was removed by rotary evaporation to give (tert-butyl 2- (2-hydroxyethoxy) ethyl) carbamate Cpd-051B (1.5 g, colorless liquid), yield: and 76 percent.
1 H NMR(400MHz,CDCl 3 )δ3.78-3.70(m,2H),3.61-3.51(m,4H),3.33(t,J＝5.1Hz,2H),1.55-1.41(m,9H).
Second step of
Preparation of tert-butyl (2- (2-oxoethoxy) ethyl) carbamate
Tert-butyl (2- (2-hydroxyethoxy) ethyl) carbamate, cpd-051B (400mg, 1.8mmol), was dissolved in dry dichloromethane (2 mL) and Des-Martin oxidant (1.0 g, 2.2mmol) was slowly added. The reaction solution was stirred at room temperature for 1 hour. After completion of the reaction, a saturated sodium thiosulfate solution (30 mL) was added to quench, and the organic phase was washed with a saturated sodium carbonate solution (30 mL. Times.3), dried over anhydrous sodium sulfate, and filtered through celite. Purification by column chromatography (EA/PE = 1/1) yielded (2- (2-oxoethoxy) ethyl) carbamic acid tert-butyl ester Cpd-051C (200mg, 51%).
The third step
Preparation of ethyl 3- ((2- (2- ((tert-butoxycarbonyl) amino) ethoxy) ethyl) amino) -4-methyl-1H-pyrrole 2-carboxylate
Tert-butyl (2- (2-oxoethoxy) ethyl) carbamate, cpd-051C (50mg, 0.2mmol), ethyl 3-amino-4-methyl-1H-pyrrole-2-carboxylate (41mg, 0.2mmol), acetic acid (15mg, 0.2mmol) and methanol (2 mL) were added to the flask, and stirred at room temperature for 1 hour under nitrogen atmosphere, followed by addition of sodium cyanoborohydride (15mg, 0.2mmol) to the flask and reaction continued for 1 hour. After the reaction, the reaction solution was quenched with a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate (10 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. Purification by column chromatography (EA/PE = 1/1) gave ethyl 3- ((2- (2- ((tert-butoxycarbonyl) amino) ethoxy) ethyl) amino) -4-methyl-1H-pyrrole 2-carboxylate Cpd-051D (25mg, 30%).
The fourth step
Preparation of ethyl 3- (1- (2- (2- (2- ((tert-butoxycarbonyl) amino) ethoxy) ethyl) -3- (ethoxycarbonyl) thioureido) -4-methyl-1H-pyrrole-2-carboxylate
Ethyl 3- ((2- (2- ((tert-butoxycarbonyl) amino) ethoxy) ethyl) amino) -4-methyl-1H-pyrrole 2-carboxylate Cpd-051D (25mg, 0.07mmol), ethyl isothiocyanatecarboxylate (10mg, 0.07mmol) were dissolved in dichloromethane (20 mL), and the reaction mixture was reacted at room temperature for 1 hour under a nitrogen atmosphere. After the reaction, the reaction solution was quenched with water, extracted with ethyl acetate (10 mL × 3), the organic phases were combined and dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was isolated and purified by Flash column (petroleum ether/ethyl acetate = 85/15) to give ethyl 3- (1- (2- (2- (2- ((tert-butoxycarbonyl) amino) ethoxy) ethyl) -3- (ethoxycarbonyl) thioureido) -4-methyl-1H-pyrrole-2-carboxylate Cpd-051E (20mg, 60%).
MS m/z(ESI):509(M+23).
The fifth step
Preparation of tert-butyl (2- (2- (7-methyl-4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) ethyl) carbamate
Ethyl 3- (1- (2- (2- (2- ((tert-butoxycarbonyl) amino) ethoxy) ethyl) -3- (ethoxycarbonyl) thioureido) -4-methyl-1H-pyrrole-2-carboxylate, cpd-051E (20mg, 0.04mmol), cesium carbonate (20mg, 0.05mmol) were dissolved in methanol (3 mL), and the reaction mixture was reacted at 60 ℃ overnight after completion of the reaction, silica gel preparation plates were separated to give tert-butyl (2- (2- (7-methyl-4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) ethyl) carbamate, cpd-051F (21mg, 80%).
MS m/z(ESI):369[M+1] + .
The sixth step
Preparation of 1- (2- (2-aminoethoxy) ethyl) -7-methyl-2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Tert-butyl (2- (2- (7-methyl-4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) ethyl) carbamate, cpd-051F (12mg, 0.03mmol), was dissolved in methanol (1 mL), and a solution of hydrogen chloride in 1, 4-dioxane (1 mL) was added dropwise to the solution and allowed to react for 1 hour. After the reaction, the mixture was slurried with ethyl acetate, filtered, the filter cake was washed with an aqueous solution of sodium hydrogencarbonate, extracted with ethyl acetate, concentrated and dried to give 1- (2- (2-aminoethoxy) ethyl) -7-methyl-2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-051 (5 mg, 58%).
MS m/z(ESI):269[M+1] + .
Example 52
7-methyl-1- ((4-methyl-1, 4-oxazepin-7-yl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000921
First step of
Preparation of 2-hydroxy-4- ((4-methoxybenzyl) amino) butyric acid
Sodium hydroxide (0.7g, 18.0mmol) was added to water (20 mL), and after dissolution, 4-amino-2-hydroxybutyric acid Cpd-052A (2.0g, 16.8mmol) was added in portions, followed by p-methoxybenzaldehyde (2.4g, 18.0mmol), and stirred at room temperature for half an hour, followed by addition of sodium borohydride (0.6g, 16.8mmol) in portions in ice bath, and after completion of addition, stirred overnight, and the temperature was naturally raised to room temperature. After the reaction, water (20 mL) was used for dilution, ethyl acetate (20 mL) was used for extraction, the aqueous phase was adjusted to pH 3 with concentrated hydrochloric acid, no precipitate was precipitated from the reaction solution, and the aqueous phase was passed through a C18 reverse column (methanol/water (1 ‰ formic acid) = 1/4) to obtain 2-hydroxy-4- ((4-methoxybenzyl) amino) butyric acid Cpd-052B (2.0 g, white solid), yield: 50 percent.
MS m/z(ESI):240[M+1] + .
Second step of
Preparation of ethyl 2-hydroxy-4- ((4-methoxybenzyl) amino) butyrate
Thionyl chloride (2.0 g,16.8 mmol) was added dropwise to ice-cooled absolute ethanol (20 mL), followed by ethyl 2-hydroxy-4- ((4-methoxybenzyl) amino) butyrate Cpd-052B (2.0 g,8.4 mmol), the ice bath was removed, and the mixture was stirred at room temperature for one hour under nitrogen. After the reaction was completed, it was concentrated at room temperature, quenched with ice-water sodium bicarbonate (100 mL), extracted with ethyl acetate (50 mL × 2), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated at room temperature to give ethyl 2-hydroxy-4- ((4-methoxybenzyl) amino) butyrate Cpd-052C (2.2 g, colorless oil), yield: 98 percent.
MS m/z(ESI):268[M+1] + .
The third step
Preparation of ethyl 4- (2-chloro-N- (4-methoxybenzyl) acetamide) -2-hydroxybutyrate
Ethyl 2-hydroxy-4- ((4-methoxybenzyl) amino) butyrate Cpd-052C (2.2g, 8.2mmol) and N, N-diisopropylethylamine (2.1g, 16.4mmol) were dissolved in dichloromethane (30 mL), chloroacetyl chloride (1.1g, 9.8mmol) was added dropwise under nitrogen protection in an ice bath and stirred for half an hour. After the reaction was completed, the reaction solution was quenched by pouring it into ice water (100 mL), dichloromethane (50 mL × 2) was extracted, the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 1/1) to obtain ethyl 4- (2-chloro-N- (4-methoxybenzyl) acetamide) -2-hydroxybutyrate Cpd-052D (2.0 g, white solid) in yield: and 69 percent.
MS m/z(ESI):344[M+1] + .
The fourth step
Preparation of ethyl 4- (4-methoxybenzyl) -3-oxo-1, 4-oxazacyclopentane-7-carboxylate
4- (2-chloro-N- (4-methoxybenzyl) acetamide) -2-hydroxybutyric acid ethyl ester Cpd-052D (2.0 g, 5.8mmol) was dissolved in anhydrous N, N-dimethylformamide (25 mL), sodium hydride (0.3 g,12.5 mmol) was added under ice-cooling, and the ice-cooling was removed under nitrogen protection and stirred for 1 hour. After completion of the reaction, the reaction mixture was poured into an ice-saturated aqueous ammonium chloride solution (200 mL), extracted with ethyl acetate (100 mL × 2), and the combined organic phases were washed with a saturated common salt solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was separated and purified with a silica gel column (petroleum ether/ethyl acetate = 1/1) to obtain 4- (4-methoxybenzyl) -3-oxo-1, 4-oxaziclopentane-7-carboxylic acid ethyl ester Cpd-052E (1.0 g, white solid), yield: 58 percent.
MS m/z(ESI):308[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ7.18(d,J＝8.6Hz,2H),6.89(d,J＝8.6Hz,2H),4.44(s,2H),4.36-4.27(m,3H),4.11(q,J＝7.1Hz,2H),3.73(s,3H),3.50(dd,J＝14.2,9.8Hz,1H),3.36(d,J＝7.5Hz,1H),2.16-2.06(m,1H),1.85(dt,J＝13.4,9.9Hz,1H),1.22-1.16(m,3H).
The fifth step
Preparation of (4- (4-methoxybenzyl) -1, 4-oxazol-7-yl) methanol
Ethyl 4- (4-methoxybenzyl) -3-oxo-1, 4-oxazacyclopentane-7-carboxylate Cpd-052E (1.0 g,3.3 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and a tetrahydrofuran suspension of lithium aluminum hydride (5.0 mL,5.0mmol, 1M) was added dropwise under nitrogen protection in ice, followed by heating to 60 ℃ for 1.5 hours. After completion of the reaction, tetrahydrofuran (100 mL) was added to dilute the reaction solution, and the reaction was quenched by dropping an aqueous sodium hydroxide solution (0.6 mL, 2M) in ice bath, followed by drying over anhydrous sodium sulfate, filtration through celite, and concentration of the filtrate to give crude (4- (4-methoxybenzyl) -1, 4-oxazol-7-yl) methanol Cpd-052F (0.6 g, colorless oil), yield: 70 percent. The crude product was used directly in the next reaction without further purification.
MS m/z(ESI):252[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ7.21(d,J＝8.6Hz,2H),6.92-6.82(m,2H),4.55(t,J＝5.7Hz,1H),3.78-3.70(m,4H),3.69-3.58(m,1H),3.55-3.45(m,3H),3.39-3.33(m,1H),3.25-3.17(m,1H),2.64-2.51(m,4H),1.826-1.78(m,1H),1.67-1.55(m,1H).
The sixth step
Preparation of 7- (hydroxymethyl) -1, 4-oxazepine-4-carboxylic acid tert-butyl ester
(4- (4-methoxybenzyl) -1, 4-oxazol-7-yl) methanol Cpd-052F (300mg, 1.2mmol) and palladium hydroxide (84mg, 0.6 mmol) were dissolved in ethanol (10 mL), reacted at 60 ℃ for 1 hour after three gas replacements by a hydrogen balloon, and after completion of the reaction, the reaction solution was cooled to room temperature, followed by addition of di-tert-butyl dicarbonate (521mg, 2.4 mmol) and stirring at room temperature for one hour. After the reaction, the reaction mixture was filtered through celite, the residue was washed with methanol, and the combined organic phases were concentrated to give a crude product, which was separated and purified by silica gel column (petroleum ether/ethyl acetate = 1/1) to give t-butyl 7- (hydroxymethyl) -1, 4-oxazepin-4-carboxylate Cpd-052G (191 mg, colorless oil), yield: and 69 percent.
MS m/z(ESI):132[M-100+1] + .
Seventh step
Preparation of 7-formyl-1, 4-oxazetidine-4-carboxylic acid tert-butyl ester
7- (hydroxymethyl) -1, 4-oxazepine-4-carboxylic acid tert-butyl ester Cpd-052G (191mg, 0.83mmol) was dissolved in dichloromethane (5 mL), dessimidine oxidant (420mg, 0.99mmol) was added portionwise under ice bath, and then stirred for half an hour with the ice bath nitrogen blanketed. After the reaction is finished, the reaction turbid liquid is filtered by diatomite, filter residues are washed by dichloromethane, combined organic phases are concentrated, and the obtained crude product is separated and purified by a silica gel column (petroleum ether/ethyl acetate = 2/1) to obtain 7-formyl-1, 4-oxazetidine-4-carboxylic acid tert-butyl ester Cpd-052H (170 mg, colorless oily matter), yield: 90 percent.
Eighth step
Preparation of tert-butyl 7- (((2- (ethoxycarbonyl) -4-methyl-1H-pyrrol-3-yl) amino) methyl) -1, 4-oxaazacyclo-4-carboxylate
7-formyl-1, 4-Oxetane-4-carboxylic acid tert-butyl ester Cpd-052H (136mg, 0.59mmol) and 3-amino-4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (100mg, 0.59mmol) were dissolved in methanol (5 mL), a drop of acetic acid was added dropwise, stirring was continued at room temperature for half an hour, followed by the addition of sodium cyanoborohydride (150mg, 2.38mmol), stirring at room temperature for half an hour. After the reaction was completed, the reaction solution was diluted with water (100 mL), extracted with ethyl acetate (50 mL × 2), dried over anhydrous sodium sulfate of the combined organic phases, filtered, and the crude product obtained by concentration was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 4/1) to give t-butyl 7- (((2- (ethoxycarbonyl) -4-methyl-1H-pyrrol-3-yl) amino) methyl) -1, 4-oxa-azetidine-4-carboxylate Cpd-052I (120 mg, colorless oil), yield: 53 percent.
MS m/z(ESI):382[M+1] + .
The ninth step
Preparation of tert-butyl 7- ((3- (ethoxycarbonyl) -1- (2- (ethoxycarbonyl) -4-methyl-1H-pyrrol-3-yl) thioureido) methyl) -1, 4-oxaza-4-carboxylate
Tert-butyl 7- (((2- (ethoxycarbonyl) -4-methyl-1H-pyrrol-3-yl) amino) methyl) -1, 4-oxa-azetidine-4-carboxylate Cpd-052I (120mg, 0.31mmol) was dissolved in dichloromethane (3 mL) and ethoxycarbonyl isothiocyanate (62mg, 0.47mmol) was added at room temperature and stirred for one hour. After the reaction was completed, the reaction solution was concentrated to give crude 7- ((3- (ethoxycarbonyl) -1- (2- (ethoxycarbonyl) -4-methyl-1H-pyrrol-3-yl) thioureido) methyl) -1, 4-oxaza-4-carboxylic acid tert-butyl ester Cpd-052J (170 mg, colorless oil), yield: 105 percent. The crude product was used directly in the next reaction without further purification.
MS m/z(ESI):513[M+1] + .
The tenth step
Preparation of tert-butyl 7- ((7-methyl-4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) methyl) -1, 4-oxazepine-4-carboxylate
7- ((3- (ethoxycarbonyl) -1- (2- (ethoxycarbonyl) -4-methyl-1H-pyrrol-3-yl) thioureido) methyl) -1, 4-oxaza-4-carboxylic acid tert-butyl ester Cpd-052J (160mg, 0.31mmol) and cesium carbonate (508mg, 1.56mmol) were dissolved in methanol (5 mL) and then heated to 60 ℃ with stirring for 6 hours. After completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL. Times.2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and the crude product obtained by concentration was separated and purified by silica gel column (petroleum ether/ethyl acetate = 1/1) to give t-butyl 7- ((7-methyl-4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) methyl) -1, 4-oxazepin-4-carboxylate Cpd-052K (70 mg, white solid) yield: 57 percent.
MS m/z(ESI):395[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.18(s,1H),12.07(s,1H),7.13(s,1H),4.71(s,1H),4.14(s,2H),3.73(d,J＝8.7Hz,1H),3.57-3.38(m,3H),3.23(d,J＝32.4Hz,2H),2.29(s,3H),1.93(s,1H),1.63(s,1H),1.39(d,J＝9.6Hz,9H).
The eleventh step
Preparation of 7-methyl-1- ((1, 4-oxazepin-7-yl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
7- ((7-methyl-4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) methyl) -1, 4-oxazepin-4-carboxylic acid tert-butyl ester Cpd-052K (60mg, 0.15mmol) was dissolved in methanol hydrochloride (5mL, 3M) and heated to 30 ℃ for half an hour with stirring. After the reaction was completed, the reaction solution was concentrated to obtain crude 7-methyl-1- ((1, 4-oxazepin-7-yl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-052L (50 mg, white solid) in yield: 111%. The crude product was used directly in the next reaction without further purification.
MS m/z(ESI):295[M+1] + .
The twelfth step
Preparation of 7-methyl-1- ((4-methyl-1, 4-oxazepin-7-yl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
7-methyl-1- ((1, 4-Oxazepin-7-yl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-052L (50mg, 0.15mmol), paraformaldehyde (14mg, 0.45mmol) were dissolved in methanol (3 mL) and a saturated aqueous solution of sodium bicarbonate (2 mL), followed by addition of sodium cyanoborohydride (47mg, 0.75mmol) and stirring at room temperature for half an hour. After the reaction was completed, the reaction solution was poured into a water (100 mL) solution, ethyl acetate (50 mL. Times.2) was extracted, and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was sent to pre-HPLC to give formate salt Cpd-052 (3 mg, white solid) of 7-methyl-1- ((4-methyl-1, 4-oxazepin-7-yl) methyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one: 6.4 percent.
MS m/z(ESI):309[M+1] + .
1 H NMR(400MHz,MeOD)δ8.48(s,1H),7.11(s,1H),4.48(s,2H),3.98(d,J＝14.1Hz,1H),3.70(d,J＝14.1Hz,1H),3.47-3.39(m,1H),3.25(d,J＝10.5Hz,3H),2.84(s,3H),2.39(s,3H),2.33-2.01(m,3H).
Example 53
7-methyl-1- ((4-methyl-1, 4-oxazepin-2-yl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000951
First step of
Preparation of 1, 4-oxaheptane-4-carboxylic acid tert-butyl ester-2-carbaldehyde
Oxalyl chloride (90mg, 0.7 mmol) was dissolved in dry dichloromethane (5 mL). The temperature is reduced to-65 ℃, then a solution of dimethyl sulfoxide (110mg, 1.4 mmol) in dichloromethane (1 mL) is slowly added, the temperature is controlled to be lower than-60 ℃, after the addition is finished, the mixture is stirred for 30 minutes at-65 ℃, then a solution of 1, 4-oxaheptane-4-tert-butyl formate-2-hydroxymethyl Cpd-053A (150mg, 0.6 mmol) in dichloromethane (1 mL) is dropwise added, and the temperature is kept for 2 hours after the addition is finished. Then, triethylamine (195mg, 1.9 mmol) was added dropwise, the temperature was gradually raised to 0 ℃ naturally, water (10 mL) was added thereto, the mixture was separated, the organic phase was washed with saturated brine, and dried over anhydrous sodium sulfate to obtain a dichloromethane solution (7 mL) containing 1, 4-oxaheptane-4-carboxylic acid tert-butyl ester-2-formaldehyde Cpd-053B, which was used in the next step without further treatment.
Second step of
Preparation of ethyl 2- (1, 4-oxaheptane-4-carboxylate-methylamino) -1H-pyrrole-2-carboxylate
Ethyl 3-amino-4-methyl-1H-pyrrole-2-carboxylate (100mg, 0.6 mmol) was dissolved in methanol (10 mL), and acetic acid (36mg, 0.6 mmol) and a solution of 1, 4-oxaheptane-4-carboxylic acid tert-butyl ester-2-carbaldehyde Cpd-053B in dichloromethane (7 mL) were added in this order and stirred at room temperature for 0.5 hour. Then, sodium cyanoborohydride (41mg, 0.6 mmol) was added in portions, and stirred at room temperature for 16 hours. After the reaction, water (5 mL) was added for quenching, ethyl acetate was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated to give a crude product, which was purified by column chromatography to give 2- (1, 4-oxaheptane-4-carboxylic acid tert-butyl ester-methylamino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-053C (100 mg, light brown oil), yield: 40 percent.
The third step
Preparation of tert-butyl 2- ((3- (ethoxycarbonyl) -1- (2- (ethoxycarbonyl) -4-methyl-1H-pyrrol-3-yl) thioureido) methyl) -1, 4-oxaza-4-carboxylate
2- (1, 4-Oxoheptane-4-carboxylic acid tert-butyl ester-methylamino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-053C (100mg, 0.2mmol) was dissolved in dichloromethane (10 mL), cooled to 0 deg.C, and to it was added isothiocyanatoethyl ester (39mg, 0.3mmol), followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction mixture was washed once with water (5 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated. The resulting residue was separated and purified by a silica gel column (ethyl acetate/petroleum ether = 1/3) to give 2- ((3- (ethoxycarbonyl) -1- (2- (ethoxycarbonyl) -4-methyl-1H-pyrrol-3-yl) thioureido) methyl) -1, 4-oxaza-4-carboxylic acid tert-butyl ester Cpd-053D (100 mg, light brown oil), yield: 74 percent.
MS m/z(ESI):513[M+1] + .
The fourth step
Preparation of tert-butyl 2- ((7-methyl-4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) methyl) -1, 4-oxazepin-4-carboxylate
2- ((3- (ethoxycarbonyl) -1- (2- (ethoxycarbonyl) -4-methyl-1H-pyrrol-3-yl) thioureido) methyl) -1, 4-oxaza-4-carboxylic acid tert-butyl ester Cpd-053D (100mg, 0.2mmol) was dissolved in methanol (2 mL), cesium carbonate (195mg, 0.6 mmol) was added thereto, and the reaction solution was heated to 65 ℃ for 3 hours. The reaction solution was cooled to room temperature, saturated aqueous ammonium chloride solution (5 mL) was added, extraction was performed with ethyl acetate (10 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was isolated on preparative silica gel plates to give 2- ((7-methyl-4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) methyl) -1, 4-oxazepin-4-carboxylic acid tert-butyl ester Cpd-053E (50 mg, white solid), yield: 77 percent.
The fifth step
Preparation of 1- ((1, 4-Oxazacyclo-2-yl) methyl) -7-methyl-2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
2- ((7-methyl-4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) methyl) -1, 4-oxazepin-4-carboxylic acid tert-butyl ester Cpd-053E (50mg, 0.1mmol) was dissolved in methanol hydrochloride (2 mL) and stirred at room temperature for 2 hours, after completion of the reaction, neutralized with aqueous sodium bicarbonate, extracted with ethyl acetate and concentrated to give 1- ((1, 4-oxazepin-2-yl) methyl) -7-methyl-2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-053F (20 mg, white solid) in yield: 54 percent.
MS m/z(ESI):295[M+1] + .
The sixth step
Preparation of 7-methyl-1- ((4-methyl-1, 4-oxazepin-2-yl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
1- ((1, 4-Oxazacyclo-2-yl) methyl) -7-methyl-2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-053F (20mg, 0.07mmol) was dissolved in methanol (2 mL), paraformaldehyde (9mg, 0.1mmol) and sodium cyanoborohydride (7mg, 0.1mmol) were added, the reaction mixture was stirred at room temperature for 3 hours, after completion of the reaction, concentration was carried out, and the residue was isolated by preparative isolation to give 7-methyl-1- ((4-methyl-1, 4-oxazepin-2-yl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-053 (6 mg, white solid), yield: 28 percent.
MS m/z(ESI):309[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.16(s,1H),12.07(s,1H),7.13(d,J＝2.8Hz,1H),4.70(s,1H),4.35-4.25(m,2H),3.70-3.65(m,1H),3.50-3.45(m,1H),2.85-2.75(m,1H),2.66-2.61(m,1H),2.34-2.26(m,8H),1.85-1.65(m,2H).
Example 54
2-thioxo-1- (2- ((1, 1-trifluoro-2-methyl-3- (methylamino) propan-2-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000971
First step of
Preparation of 1, 1-trifluoro-2-methyl-3-nitropropan-2-ol
Hexadecyltrimethylammonium chloride (1.7g, 5.8mmol), lithium hydroxide (0.1g, 4.5mmol), anhydrous magnesium sulfate (1.1g, 8.9mmol) were dissolved in water (15 mL), nitromethane Cpd-054A (2.7g, 44.6mmol) and 1, 1-trifluoroacetone (5.0g, 44.6mmol) were added, the reaction solution was stirred at room temperature for 16 hours, after the reaction was completed, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether/ethyl acetate = 4/1) to obtain 1, 1-trifluoro-2-methyl-3-nitropropane-2-ol Cpd-054B (7.0 g, colorless liquid), yield: 91 percent.
1 H NMR(400MHz,DMSO-d6)δ6.96(s,1H),4.85-4.73(m,2H),1.48(s,3H).
Second step of
Preparation of 3-amino-1, 1-trifluoro-2-methylpropan-2-ol
1, 1-trifluoro-2-methyl-3-nitropropane-2-ol Cpd-054B (7.0g, 49mmol) was dissolved in methanol (100 mL), and Pd (OH) was added 2 C (500 mg), stirred at room temperature for 1 hour under a hydrogen atmosphere. After the reaction was completed, the pad was filtered with celite, and the filtrate was spin-dried to give 3-amino-1, 1-trifluoro-2-methylpropan-2-ol Cpd-054C (5.0 g, colorless liquid) in yield: 88 percent. The crude product was used directly in the next reaction without further purification.
1 H NMR(400MHz,DMSO-d6)δ3.17(s,1H),2.71-2.49(m,2H),1.21(s,3H).
The third step
Preparation of 1, 1-trifluoro-3- ((4-methoxybenzyl) methylamino) -2-methylpropan-2-ol
3-amino-1, 1-trifluoro-2-methylpropan-2-ol Cpd-054C (2.2g, 15.5 mmol) and 4-methoxybenzaldehyde (2.1g, 15.5 mmol) were dissolved in methanol (50 mL), and a catalytic amount of acetic acid was added, followed by stirring at room temperature for 0.5 hour, sodium cyanoborohydride (2.9g, 46.5 mmol) was then added, stirring at room temperature for 0.5 hour, paraformaldehyde (0.9g, 31.0 mmol) was added, and stirring at room temperature for 0.5 hour. After the reaction is finished, water is added for quenching, ethyl acetate is used for extraction, an organic phase is dried by anhydrous sodium sulfate, concentrated and purified by column chromatography to obtain 1, 1-trifluoro-3- ((4-methoxybenzyl) methylamino) -2-methylpropane-2-ol Cpd-054D (2.9 g, colorless liquid), and the yield: 67%.
1 H NMR(400MHz,MeOD)δ7.25(d,J＝8.6Hz,2H),6.88(d,J＝8.6Hz,2H),3.79(s,3H),3.57(dd,J＝106.0,12.9Hz,2H),2.62(s,2H),2.32(s,3H),1.33(s,3H).
The fourth step
Preparation of ethyl 2- ((1, 1-trifluoro-3- ((4-methoxybenzyl) methylamino) -2-methylpropan-2-yl) oxy) acetate
1, 1-trifluoro-3- ((4-methoxybenzyl) methylamino) -2-methylpropan-2-ol Cpd-054D (1000mg, 3.6mmol) was dissolved in N, N-dimethylformamide (10 mL), cooled to 0 deg.C, sodium hydride (173mg, 4.3mmol) was added in portions, and after the addition was complete, stirring was performed at room temperature for 1 hour, then ethyl 2-bromoacetate (663mg, 4.0 mmol) was slowly added, and the reaction solution was stirred at room temperature for 16 hours. After the reaction is finished, water is added for quenching, ethyl acetate is used for extraction, an organic phase is dried by anhydrous sodium sulfate, concentrated and purified by column chromatography to obtain 2- ((1, 1-trifluoro-3- ((4-methoxybenzyl) methylamino) -2-methylpropane-2-yl) oxy) ethyl acetate Cpd-054E (800 mg, colorless liquid), and the yield: 61 percent.
MS m/z(ESI):364[M+1] + .
The fifth step
Preparation of 2- ((1, 1-trifluoro-3- ((4-methoxybenzyl) methylamino) -2-methylpropan-2-yl) oxy) ethan-1-ol
Ethyl 2- ((1, 1-trifluoro-3- ((4-methoxybenzyl) methylamino) -2-methylpropan-2-yl) oxy) acetate Cpd-054E (100mg, 0.3mmol) was dissolved in tetrahydrofuran (5 mL), cooled to 0 ℃, lithium tetrahydroaluminium (0.3ml, 0.3mmol,1.0m in THF) was slowly added, and then reacted at 0 ℃ for 1 hour, after completion of the reaction, quenched with water, filtered, the filtrate was dried over anhydrous sodium sulfate, and concentrated to give 2- ((1, 1-trifluoro-3- ((4-methoxybenzyl) methylamino) -2-methylpropan-2-yl) oxy) ethan-1-ol Cpd-054F (60 mg, colorless liquid), yield: 68 percent.
MS m/z(ESI):322[M+1] + .
The sixth step
Preparation of 2- ((1, 1-trifluoro-3- ((4-methoxybenzyl) methylamino) -2-methylpropan-2-yl) oxy) acetaldehyde
Oxalyl chloride (44mg, 0.34mmol) was dissolved in dichloromethane (5 mL), cooled to-65 deg.C, dimethylsulfoxide (53mg, 0.68mmol) was slowly added, the reaction was incubated for 0.5 h, a solution of 2- ((1, 1-trifluoro-3- ((4-methoxybenzyl) methylamino) -2-methylpropan-2-yl) oxy) ethan-1-ol Cpd-054F (100mg, 0.31mmol) in dichloromethane (0.5 mL) was added, the reaction was incubated for 1 h, triethylamine (94mg, 0.93mmol) was then added, and the temperature was naturally raised to 0 deg.C. After the reaction is finished, water is added for quenching, dichloromethane is used for extraction, and an organic phase is dried by anhydrous sodium sulfate to obtain a dichloromethane solution of 2- ((1, 1-trifluoro-3- ((4-methoxybenzyl) methylamino) -2-methylpropane-2-yl) oxy) acetaldehyde Cpd-054G. The solution was used directly in the next reaction without further purification.
Seventh step
Preparation of ethyl 3- ((2- ((1, 1-trifluoro-3- ((4-methoxybenzyl) methylamino) -2-methylpropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate
A dichloromethane solution of 2- ((1, 1-trifluoro-3- ((4-methoxybenzyl) methylamino) -2-methylpropan-2-yl) oxy) acetaldehyde Cpd-054G (0.31 mmol) was dissolved in methanol (5 mL), ethyl 3-amino-1H-pyrrole-2-carboxylate (48mg, 0.31mmol) and acetic acid (18.6 mg, 0.31mmol) were added successively, and the reaction was stirred at room temperature for 1 hour, followed by addition of sodium cyanoborohydride (21mg, 0.31mmol) and stirring at room temperature for 16 hours. After the reaction, water was added for quenching, ethyl acetate was extracted, the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether/ethyl acetate = 3/1) to give ethyl 3- ((2- ((1, 1-trifluoro-3- ((4-methoxybenzyl) methylamino) -2-methylpropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-054H (100 mg, colorless liquid), yield: 70 percent.
MS m/z(ESI):458[M+1] + .
The eighth step
Preparation of ethyl 3- ((2- ((1, 1-trifluoro-2-methyl-3- (methylamino) propan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate
Ethyl 3- ((2- ((1, 1-trifluoro-3- ((4-methoxybenzyl) methylamino) -2-methylpropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-054H (100mg, 0.22mmol) was dissolved in isopropanol (5 mL), palladium hydroxide on carbon (10 mg) was added, and stirring was carried out at 50 ℃ for 16 hours under a hydrogen atmosphere. After the reaction was completed, celite was filtered, and the filtrate was spin-dried to obtain ethyl 3- ((2- ((1, 1-trifluoro-2-methyl-3- (methylamino) propan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-054I (70 mg, colorless liquid), yield: 95 percent.
MS m/z(ESI):338[M+1] + .
The ninth step
Preparation of ethyl 3- ((2- ((3- ((tert-butoxycarbonyl) methylamino) -1, 1-trifluoro-2-methylpropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate
Ethyl 3- ((2- ((1, 1-trifluoro-2-methyl-3- (methylamino) propan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-054I (70mg, 0.2mmol) was dissolved in dichloromethane (10 mL), di-tert-butyl dicarbonate (44mg, 0.2mmol) was added, stirring was carried out at room temperature for 1 hour, and after completion of the reaction, concentration was carried out to obtain ethyl 3- ((2- ((3- ((tert-butoxycarbonyl) methylamino) -1, 1-trifluoro-2-methylpropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-054J (80 mg, colorless liquid), yield: 88 percent.
MS m/z(ESI):438[M+1] + .
The tenth step
Preparation of ethyl 3- (1- (2- ((3- ((tert-butoxycarbonyl) methylamino) -1, 1-trifluoro-2-methylpropan-2-yl) oxy) ethyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate
Ethyl 3- ((2- ((3- ((tert-butoxycarbonyl) methylamino) -1, 1-trifluoro-2-methylpropan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-054J (80mg, 0.18mmol) was dissolved in dichloromethane (5 mL), ethyl isothiocyanatecarboxylate (29mg, 0.22mmol) was added, and after completion of the reaction, the mixture was concentrated to give ethyl 3- (1- (2- ((3- ((tert-butoxycarbonyl) methylamino) -1, 1-trifluoro-2-methylpropan-2-yl) oxy) ethyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-054K (80 mg, pale brown liquid), yield: 77 percent.
MS m/z(ESI):569[M+1] + .
Preparation of eleventh step (3, 3-trifluoro-2-methyl-2- (2- (4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) propyl) t-butyl methylcarbamate
3- (1- (2- ((3- ((tert-butoxycarbonyl) methylamino) -1, 1-trifluoro-2-methylpropan-2-yl) oxy) ethyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-054K (80mg, 0.14mmol) was dissolved in methanol (5 mL), cesium carbonate (137mg, 0.42mmol) was added, the reaction solution was stirred at 60 ℃ for 3 hours, after completion of the reaction, washed with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and column chromatography (dichloromethane/methanol = 10/1) was purified to give (3, 3-trifluoro-2-methyl-2- (2- (4-oxo-2-thio-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) propyl) carbamic acid tert-butyl ester Cpd-054L (30 mg, white solid) in yield: and 63 percent.
MS m/z(ESI):451[M+1] + .
The twelfth step
Preparation of 1- (2- (((1, 1-trifluoro-2-methyl-3- (methylamino) propan-2-yl) oxy) ethyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
(3, 3-trifluoro-2-methyl-2- (2- (4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) propyl) t-butyl methylcarbamate Cpd-054L (30mg, 0.07mmol) was dissolved in methanol hydrochloride solution (2mL, 4M) and stirred at room temperature for 2 hours. After the reaction was completed, it was neutralized with aqueous sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the prepared plate (dichloromethane/methanol = 10/1) was separated to give 1- (2- ((1, 1-trifluoro-2-methyl-3- (methylamino) propan-2-yl) oxy) ethyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-054 (10 mg, white solid) in yield: and 43 percent.
MS m/z(ESI):351[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.37(s,1H),7.36(d,J＝2.8Hz,1H),6.30(d,J＝2.8Hz,1H),4.55-4.51(m,2H),3.99-3.90(m,2H),2.69-2.54(m,2H),2.19(s,3H),1.23(s,3H).
Example 55
1- (2- ((3- (dimethylamino) -1, 1-trifluoro-2-methylpropan-2-yl) oxy) ethyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850000991
2-thio-1- (2- ((1, 1-trifluoro-2-methyl-3- (methylamino) propan-2-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-054 (40mg, 0.1mmol) was dissolved in methanol (5 mL), paraformaldehyde (18mg, 0.2mmol) and sodium cyanoborohydride (12mg, 0.2mmol) were added, the reaction was stirred warmly for 16 hours, after the reaction was complete, concentration was performed, plate separation was made (dichloromethane/methanol = 10/1) to give 1- (2- ((3- (dimethylamino) -1, 1-trifluoro-2-methylpropan-2-yl) oxy) ethyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-055 (2 mg, white solid), yield: 5 percent.
MS m/z(ESI):365[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.32(s,1H),12.19(s,1H),7.35(d,J＝2.8Hz,1H),6.23(t,J＝2.8Hz,1H),4.54-4.50(m,2H),4.00-3.91(m,2H),2.41-2.31(m,2H),2.10(s,6H),1.29(s,3H).
Example 56
2-thio-1- (2- (1- (1- (trifluoromethyl) cyclobutoxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850001001
First step of
Preparation of 1- (trifluoromethyl) cyclobutan-1-ol
Cyclobutanone Cpd-056A (4 g, 57.1mmol) was dissolved in tetrahydrofuran (50 mL), then trimethyl (trifluoromethyl) silane (9.74g, 68.5 mmol) was added, then the temperature was cooled to 0 ℃, and tetrahydrofuran solution of tetrabutylammonium fluoride (0.5ml, 1m) was slowly added dropwise, after the addition was completed, stirring was performed at room temperature for 2 hours, after completion of the reaction, ethyl acetate was added for dilution, washing was performed twice with saturated aqueous sodium chloride solution, the organic phase was dried with anhydrous sodium sulfate, filtration and concentration were performed to obtain the product 1- (trifluoromethyl) cyclobutan-1-ol Cpd-056B (1.7 g, brown liquid), yield: 21 percent.
Second step of
Preparation of ethyl 2- (1- (trifluoromethyl) cyclobutoxy) acetate
1- (trifluoromethyl) cyclobutan-1-ol Cpd-056B (1.2g, 8.6 mmol) was dissolved in tetrahydrofuran (20 mL), then sodium hydrogen (0.3g, 12.9 mmol) was added portionwise at zero temperature, the reaction was warmed to room temperature and stirred for 30 minutes, then ethyl bromoacetate (2.15g, 12.9 mmol) was slowly added dropwise, and the solution was stirred at room temperature for 2 hours. After the reaction, water was added to quench, extraction was performed with ethyl acetate, the organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain a crude product, which was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 2/1) to obtain ethyl 2- (1- (trifluoromethyl) cyclobutoxy) acetate Cpd-056C (500 mg, colorless oily substance) as a product, in yield: 26 percent.
MS m/z(ESI):227[M+1] + .
The third step
Preparation of 2- (1- (trifluoromethyl) cyclobutoxy) ethan-1-ol
Dissolving 2- (1- (trifluoromethyl) cyclobutoxy) ethyl acetate Cpd-056C (500mg, 2.21mmol) in tetrahydrofuran (10 mL), slowly adding lithium borohydride tetrahydrofuran solution (1m, 0.5ml) dropwise at zero, heating the reaction to room temperature, stirring for 16 hours, quenching with methanol after the reaction is finished, adding water for dilution, extracting with ethyl acetate, washing an organic phase twice with saturated saline, drying with anhydrous sodium sulfate, spin-drying to obtain a crude product, separating and purifying with a silica gel column (petroleum ether/ethyl acetate = 1/1) to obtain a product, namely, 2- (1- (trifluoromethyl) cyclobutoxy) ethane-1-ol, cpd-056D (200 mg, colorless oily liquid), wherein the yield is as follows: 53 percent.
The fourth step
Preparation of 2- (1- (trifluoromethyl) cyclobutoxy) acetaldehyde
Oxalyl chloride (75.81mg, 0.59mmol) is dissolved in dry dichloromethane (2 mL), the temperature of the solution is cooled to-70 ℃ under the protection of nitrogen, then dimethyl sulfoxide (93mg, 1.2mmol) is dissolved in dichloromethane (1 mL) and slowly added dropwise, the solution is kept at-70 ℃ and stirred for 30 minutes, then 2- (1- (trifluoromethyl) cyclobutoxy) ethane-1-ol Cpd-056D (100mg, 0.54mmol) is slowly added dropwise, the mixed solution is stirred at-70 ℃ for 2 hours, then triethylamine (164.84mg, 1.63mmol) is added and stirred for 30 minutes, the temperature is slowly and naturally raised to room temperature, the reaction solution is diluted by dichloromethane (20 mL), water (10 mL) is added thereto, the solution is separated, the organic phase is washed by saturated sodium chloride, and after drying anhydrous sodium sulfate, 20mL dichloromethane Cpd-056E solution containing 2- (1- (trifluoromethyl) cyclobutoxy) acetaldehyde is obtained, and the next step is carried out without treatment.
The fifth step
Preparation of ethyl 3- ((2- (1- (trifluoromethyl) cyclobutoxy) ethyl) amino) -1H-pyrrole-2-carboxylate
Ethyl 3-amino-1H-pyrrole-2-carboxylate (100mg, 0.55mmol) was dissolved in methanol (5 mL), and acetic acid (10mg, 0.16mmol) and a solution of 2- (1- (trifluoromethyl) cyclobutoxy) acetaldehyde Cpd-056E in methylene chloride (20 mL) were sequentially added and stirred at room temperature for 0.5 hour. Then, sodium cyanoborohydride (103.50mg, 1.65mmol) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, 20mL of water was added for quenching, ethyl acetate was used for extraction, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate and rotary evaporated to obtain a crude product, which was purified by column to obtain 3- ((2- (1- (trifluoromethyl) cyclobutoxy) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-056F (40 mg, light brown oil) in yield: 23 percent.
MS m/z(ESI):227[M+1] + .
The sixth step
Preparation of ethyl 3- (3- (ethoxycarbonyl) -1- (2- (1- (trifluoromethyl) cyclobutoxy) ethyl) thioureido) -1H-pyrrole-2-carboxylate
Ethyl 3- ((2- (1- (trifluoromethyl) cyclobutoxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-056F (40mg, 0.125mmol) was dissolved in dichloromethane (3 mL), cooled to 0 ℃ and to this was added ethyl isothiocyanatocarboxylate (19.66mg, 0.15mmol), followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction mixture was washed once with water (20 mL), and the organic layer was dried over anhydrous sodium sulfate and concentrated. The obtained residue was isolated and purified by a silica gel column (petroleum ether/ethyl acetate = 1/1) to give ethyl 3- (3- (ethoxycarbonyl) -1- (2- (1- (trifluoromethyl) cyclobutoxy) ethyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-056G (88 mg, light brown oil), yield: 88 percent.
MS m/z(ESI):452[M+1] + .
Seventh step
Preparation of 2-thioxo-1- (2- (1- (1- (trifluoromethyl) cyclobutoxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Ethyl 3- (3- (ethoxycarbonyl) -1- (2- (1- (trifluoromethyl) cyclobutoxy) ethyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-056G (50mg, 0.11mmol) was dissolved in methanol (3 mL), sodium methoxide (12mg, 0.22mmol) was added thereto, and the reaction mixture was heated to 90 ℃ for 2 hours. The reaction was cooled to room temperature and adjusted to pH =4-5 with dilute hydrochloric acid (1M), the solution was spun dry to give the crude product, which was purified by Prep-HPLC (acetonitrile/water (formic acid 1 ‰)) to give 2-thio-1- (2- (1- (1- (trifluoromethyl) cyclobutoxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-056 (10 mg, white solid) in 27% yield.
MS m/z(ESI):334[M+1] + .
1 H NMR(400MHz,CDCl 3 )δ10.12(s,1H),9.47(s,1H),7.23(s,1H),6.29(s,1H),4.66-4.53(m,2H),4.08-3.94(m,,2H),2.35-2.19(m,2H),2.12-1.99(m,2H),1.80-1.69(m,2H).
Example 57
2-thioxo-1- (2- ((3- (trifluoromethyl) azetidin-3-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850001011
First step of
Preparation of 3-hydroxy-3- (trifluoromethyl) azetidine-1-carboxylic acid tert-butyl ester
3-Oxoazaphenylamine-1-carboxylic acid tert-butyl ester Cpd-057A (2.0g, 11.7mmol), trifluoromethyltrimethylsilane (3.3g, 23.4mmol) and tetrabutylammonium fluoride (3.0g, 11.7mmol) were dissolved in dry tetrahydrofuran (50 mL). The reaction mixture was reacted at room temperature overnight. To the reaction mixture was added saturated brine (50 mL), followed by extraction with ethyl acetate (50 mL. Times.3). The organic phases were combined and dried over anhydrous sodium sulfate, concentrated and then isolated and purified (petroleum ether/ethyl acetate = 5/1) to give 3-hydroxy-3- (trifluoromethyl) azetidine-1-carboxylic acid tert-butyl ester Cpd-057B (1.8 g, yellow liquid), yield: and 64 percent.
1 H NMR(400MHz,DMSO-d6)δ7.37(s,1H),4.08-3.97(m,2H),3.85(d,J＝9.6Hz,2H),1.39(s,9H).
Second step of
Preparation of 3- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) -3- (trifluoromethyl) azetidine-1-carboxylic acid tert-butyl ester
3-hydroxy-3- (trifluoromethyl) azetidine-1-carboxylic acid tert-butyl ester Cpd-057B (1.8g, 7.5 mmol) was dissolved in N, N-dimethylformamide (5 mL), cooled to 0 ℃ in an ice bath, sodium hydride (269mg, 11.2mmol) was added thereto, and after stirring for 30 minutes, (2-bromoethoxy) (tert-butyl) dimethylsilane (2.7g, 11.2mmol) was added. The reaction mixture was reacted at 25 ℃ for 12 hours. The reaction was washed with saturated brine (50 mL × 3) and the organic phase was dried over anhydrous sodium sulfate to give 3- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) -3- (trifluoromethyl) azetidine-1-carboxylic acid tert-butyl ester Cpd-057C (1.5 g, yellow liquid), yield: 50 percent. The crude product was used in the next step without further purification.
MS m/z(ESI):344[M-56+1] + .
The third step
Preparation of 3- (2-hydroxyethoxy) -3- (trifluoromethyl) azetidine-1-carboxylic acid tert-butyl ester
3- (2- ((tert-butyldimethylsilyl) oxy) ethoxy) -3- (trifluoromethyl) azetidine-1-carboxylic acid tert-butyl ester, cpd-057C (1.5g, 3.8mmol), was dissolved in tetrahydrofuran (5 mL) and tetrabutylammonium fluoride (3.8mL, 3.8mmol, 1M) was added thereto. The reaction mixture was reacted at 25 ℃ for two hours. After completion of the reaction, tetrahydrofuran was removed by rotary evaporation, and the mixture was dissolved in ethyl acetate (5 mL), washed with saturated brine (10 mL. Times.3), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated. The obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 1/2) to obtain 3- (2-hydroxyethoxy) -3- (trifluoromethyl) azetidine-1-carboxylic acid tert-butyl ester Cpd-057D (500 mg, yellow liquid), yield: 46 percent.
The fourth step
Preparation of 3- (2-oxyethoxy) -3- (trifluoromethyl) azetidine-1-carboxylic acid tert-butyl ester
Oxalyl chloride (333mg, 2.6 mmol) was dissolved in dry dichloromethane (3 mL) and dimethyl sulfoxide (409mg, 5.2 mmol) was added and cooled to-60 ℃ under nitrogen. 3- (2-hydroxyethoxy) -3- (trifluoromethyl) azetidine-1-carboxylic acid tert-butyl ester Cpd-057D (500mg, 1.8mmol) dissolved in dry dichloromethane (2 mL) was added to the reaction and allowed to react for 30 minutes. Triethylamine (795mg, 7.9mmol) was added thereto, and the mixture was stirred for 10 minutes. The reaction mixture was washed with saturated brine (10 mL. Times.3). The organic phase was dried over anhydrous sodium sulfate and rotary evaporated to give 3- (2-oxoethoxy) -3- (trifluoromethyl) azetidine-1-carboxylic acid tert-butyl ester Cpd-057E (200 mg, yellow liquid), yield: 40 percent. The crude product was used directly in the next step without further purification.
The fifth step
Preparation of ethyl 3- ((2- ((1- (tert-butoxycarbonyl) -3- (trifluoromethyl) azetidin-3-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate
3- (2-Oxoethoxy) -3- (trifluoromethyl) azetidine-1-carboxylic acid tert-butyl ester Cpd-057E (200mg, 0.7 mmol) was dissolved in methanol (5 mL) and ethyl 3-amino-1H-pyrrole-2-carboxylate (109mg, 0.7 mmol) and acetic acid (0.5 mL) were added successively. After the reaction mixture was stirred for 1 hour, sodium cyanoborohydride (88mg, 1.4mmol) was added, and stirring was continued for 4 hours. After the reaction was completed, methanol was removed by rotary evaporation, and the reaction solution was dissolved in ethyl acetate (5 mL), washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate and concentrated, and the resulting crude product was isolated and purified by a silica gel column (petroleum ether/ethyl acetate = 1/2) to give ethyl 3- ((2- ((1- (tert-butoxycarbonyl) -3- (trifluoromethyl) azetidin-3-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-057F (150 mg, yellow liquid) in yield: 50 percent.
MS m/z(ESI):422[M+1] + .
The sixth step
3- (1- (2- ((1- (tert-butoxycarbonyl) -3- (trifluoromethyl) azetidin-3-yl) oxy) ethyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylic acid ethyl ester
Preparation of esters
Ethyl 3- ((2- ((1- (tert-butoxycarbonyl) -3- (trifluoromethyl) azetidin-3-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-057F (150mg, 0.35mmol) was dissolved in dichloromethane (2 mL), ethoxycarbonyl isothiocyanate (46mg, 0.35mmol) was added and the reaction mixture was reacted at room temperature for 30 minutes. After the reaction was finished, rotary evaporation was performed to give crude 3- (1- (2- ((1- (tert-butoxycarbonyl) -3- (trifluoromethyl) azetidin-3-yl) oxy) ethyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-057G (120 mg, yellow oil), yield: 62 percent. The crude product was used directly in the next reaction without further purification.
MS m/z(ESI):553[M+1] + .
Seventh step
Preparation of 3- (2- (4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) -3- (trifluoromethyl) azetidine-1-carboxylic acid tert-butyl ester
Ethyl 3- (1- (2- ((1- (tert-butoxycarbonyl) -3- (trifluoromethyl) azetidin-3-yl) oxy) ethyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-057G (120mg, 0.21mmol) was dissolved in anhydrous methanol (5 mL), cesium carbonate (136mg, 0.42mmol) was added and the reaction was warmed to 65 ℃ and stirred for 12 hours. After the reaction was complete, the reaction was cooled to room temperature, spun dry, and run on a plate (petroleum ether/ethyl acetate = 1/2) to give 3- (2- (4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) -3- (trifluoromethyl) azetidine-1-carboxylic acid tert-butyl ester Cpd-057H (60 mg, yellow solid) in yield: 66 percent.
MS m/z(ESI):379[M-56+1] + .
Eighth step
Preparation of 2-thioxo-1- (2- ((3- (trifluoromethyl) azetidin-3-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
The resulting 3- (2- (4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) -3- (trifluoromethyl) azetidine-1-carboxylic acid tert-butyl ester Cpd-057H (60mg, 0.14mmol) was dissolved in methanol (2 mL) and then methanolic hydrochloric acid (1 mL) was added. The reaction solution was stirred at room temperature for 2 hours, followed by rotary evaporation to remove methanol, slurrying the residue with ethyl acetate, filtration, washing the filter cake with aqueous sodium bicarbonate solution, extraction with ethyl acetate, concentration and drying to give 2-thio-1- (2- ((3- (trifluoromethyl) azetidin-3-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-057 (30 mg, white solid) in yield: and 64 percent.
MS m/z(ESI):335[M+1] + .
Example 58
1- (2- ((1-methyl-3- (trifluoromethyl) azetidin-3-yl) oxy) ethyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850001031
First step of
Preparation of 1- (2- ((1-methyl-3- (trifluoromethyl) azetidin-3-yl) oxy) ethyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
2-thioxo-1- (2- ((3- (trifluoromethyl) azetidin-3-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-057 (15mg, 0.04mmol) was dissolved in methanol (2 mL) and paraformaldehyde (2 mg) and two drops of acetic acid were added. The reaction was stirred at room temperature for 1 h, followed by addition of sodium cyanoborohydride (20mg, 0.32mmol), and stirring was continued for 2 h. After the reaction was completed, the methanol was removed by rotary evaporation, and the residue was isolated and purified by column chromatography (dichloromethane/methanol = 10/1) to give 1- (2- ((1-methyl-3- (trifluoromethyl) azetidin-3-yl) oxy) ethyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-058 (10 mg, white solid) in yield: 71 percent.
MS m/z(ESI):349[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.30(br,2H),7.37(d,J＝2.8Hz,1H),6.34(d,J＝2.8Hz,1H),4.57(t,J＝5.2Hz,2H),4.00(t,J＝5.1Hz,2H),3.41(d,J＝9.6Hz,2H),2.86(d,J＝9.1Hz,2H),2.06(s,3H).
Example 59
1- (2- ((1-methylpyrrolidin-3-yl) oxy) ethyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850001041
First step of
Preparation of 3-hydroxy-3-methylpyrrolidine-1-carboxylic acid tert-butyl ester
3-Oxopyrrolidine-1-carboxylic acid tert-butyl ester Cpd-059A (5.0 g,27.0 mmol) was dissolved in dry ether (100 mL), cooled to 0 deg.C, and magnesium methyl bromide (6.4 g,5.4 mmol) was added dropwise and reacted at room temperature for 1 hour. After the reaction was completed, the reaction mixture was quenched by adding saturated aqueous ammonium chloride (50 mL), extracted with ethyl acetate (3X 50 mL), and the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and rotary evaporated to give 3-hydroxy-3-methylpyrrolidine-1-carboxylic acid tert-butyl ester Cpd-059B (5.0 g, light brown oil) in yield: 83 percent.
1 H NMR(400MHz,DMSO-d6)δ4.71(s,1H),3.32-3.26(m,2H),3.16(d,J＝10.9Hz,1H),3.04(t,J＝11.4Hz,1H),1.72(t,J＝9.4Hz,2H),1.39(s,9H),1.24(d,J＝2.5Hz,3H).
Second step of
Preparation of 3- (2- (tert-butyldimethylsilyloxy) ethoxy) -3-methylpyrrolidine-1-carboxylic acid tert-butyl ester
3-hydroxy-3-methylpyrrolidine-1-carboxylic acid tert-butyl ester Cpd-059B (5.0 g, 24.8mmol) was dissolved in anhydrous N, N-dimethylformamide (50 mL), cooled to 0 ℃, sodium hydrogen (1.2 g, 3.8mmol) was carefully added, reacted at room temperature for 10 minutes, (2-bromoethoxy) (tert-butyl) dimethylsilane (8.9 g,37.2 mmol) was added, and then the reaction was continued at room temperature for 2 hours, after completion of the reaction, quenched with a saturated aqueous ammonium chloride solution, extracted with ethyl acetate (100 mL × 3), and concentrated by organic phase drying, and the resulting residue was separated and purified with a silica gel column (petroleum ether/ethyl acetate = 10/1) to give 3- (2- (tert-butyldimethylsiloxy) ethoxy) -3-methylpyrrolidine-1-carboxylic acid tert-butyl ester Cpd-059C (700 mg, colorless oil) yield: 7 percent.
1 H NMR(400MHz,CDCl3)δ3.70(t,J＝5.6Hz,2H),3.50-3.36(m,5H),3.12(d,J＝11.5Hz,1H),2.08-2.03(m,1H),1.73-1.68(m,1H),1.45(s,9H),1.29(s,2H),0.89(s,9H),0.06(s,6H).
The third step
Preparation of 3- (2-hydroxyethoxy) -3-methylpyrrolidine-1-carboxylic acid tert-butyl ester
3- (2- (tert-butyldimethylsiloxy) ethoxy) -3-methylpyrrolidine-1-carboxylic acid tert-butyl ester Cpd-059C (700mg, 1.9 mmol) was dissolved in tetrahydrofuran (10 mL), then tetrahydrofuran solution (1m, 6ml,6 mmol) of tetrabutylammonium fluoride was added, reaction was carried out at room temperature for 2 hours, after the reaction was completed, quenching reaction was carried out with saturated ammonium chloride aqueous solution, extraction was carried out with ethyl acetate (50 mL × 3), organic phase drying and concentration were carried out, and the obtained residue was separated and purified with a silica gel column (petroleum ether/ethyl acetate = 4/1) to obtain 3- (2-hydroxyethoxy) -3-methylpyrrolidine-1-carboxylic acid tert-butyl ester Cpd-059D (300 mg, yellow oil) with a yield: 60 percent.
1 H NMR(400MHz,DMSO-d6)δ4.52(s,1H),3.43(s,2H),3.37-3.24(m,5H),3.05(t,J＝10.6Hz,1H),2.01-1.98(m,1H),1.68(tt,J＝13.2,9.1Hz,1H),1.39(s,9H),1.25(s,3H).
The fourth step
Preparation of 3-methyl-3- (2-carbonylethoxy) pyrrolidine-1-carboxylic acid tert-butyl ester
Oxalyl chloride (414mg, 3.3mmol) was dissolved in dry dichloromethane (10 mL), to which was added dry dimethyl sulfoxide (510mg, 6.5 mmol) dissolved in dichloromethane at-55 ℃ under nitrogen. After stirring for 10 minutes, 3- (2-hydroxyethoxy) -3-methylpyrrolidine-1-carboxylic acid tert-butyl ester Cpd-059D (200mg, 0.8mmol) dissolved in methylene chloride was added thereto. After the reaction mixture was stirred at-55 ℃ for 30 minutes, triethylamine (660mg, 6.5mmol) was added thereto. The reaction solution was stirred and returned to room temperature. After the reaction was completed, the reaction mixture was washed with water, dried over sodium sulfate for the organic phase, and concentrated to give crude tert-butyl 3-methyl-3- (2-carbonylethoxy) pyrrolidine-1-carboxylate Cpd-059E (200 mg, yellow oil). The crude product was used in the next reaction without further treatment.
The fifth step
Preparation of ethyl 3- ((2- ((1- (tert-butoxycarbonyl) -3-methylpyrrolidin-3-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate
3-methyl-3- (2-carbonylethoxy) pyrrolidine-1-carboxylic acid tert-butyl ester Cpd-059E (200mg, 0.8mmol) was dissolved in methanol (4 mL) and 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester (139mg, 0.9mmol) and glacial acetic acid (1 drop) were added thereto. The reaction mixture was reacted at 25 ℃ for 1 hour. To the reaction solution was added sodium cyanoborohydride (210mg, 3.3 mmol) and the reaction was continued for 16 hours. After the reaction was completed, methanol was removed by rotary evaporation, and the obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 1/1) to obtain ethyl 3- ((2- ((1- (tert-butoxycarbonyl) -3-methylpyrrolidin-3-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-059F (65 mg, yellow oil) in yield: 9 percent.
MS m/z(ESI):382[M+1] + .
The sixth step
Preparation of ethyl 3- (1- (2- ((1- (tert-butoxycarbonyl) -3-methylpyrrolidin-3-yl) oxy) ethyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate
Ethyl 3- ((2- ((1- (tert-butoxycarbonyl) -3-methylpyrrolidin-3-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate 108F (65mg, 0.2mmol) was dissolved in dichloromethane (2 mL), and ethyl isothiocyanatecarboxylate (46mg, 0.4 mmol) was added thereto and reacted at 25 ℃ for 2 hours. After the reaction was completed, methylene chloride was removed by rotary evaporation. The resulting residue was extracted with ethyl acetate (15 mL × 3), the organic phases combined, dried over anhydrous sodium sulfate and concentrated to give crude preparation of crude ethyl 3- (1- (2- ((1- (tert-butoxycarbonyl) -3-methylpyrrolidin-3-yl) oxy) ethyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-059G (80 mg, yellow oil) yield: 73 percent.
MS m/z(ESI):513[M+1] + .
Seventh step
Preparation of 3-methyl-3- (2- (4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) pyrrolidine-1-carboxylic acid tert-butyl ester
Preparation of ethyl 3- (1- (2- ((1- (tert-butoxycarbonyl) -3-methylpyrrolidin-3-yl) oxy) ethyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-059G (80mg, 0.2mmol) was dissolved in methanol (2 mL), and cesium carbonate (102mg, 0.3mmol) was added thereto. The reaction mixture was heated to 65 ℃ and reacted for 6 hours. After the reaction was completed, methylene chloride (10 mL) was added, and the mixture was washed with water (5 mL) and saturated brine (5 mL), dried over anhydrous sodium sulfate, and concentrated to give tert-butyl 3-methyl-3- (2- (4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) pyrrolidine-1-carboxylate Cpd-059H (70 mg, yellow oil), yield: 90 percent.
MS m/z(ESI):395[M+1] + .
Eighth step
Preparation of 1- (2- ((3-methylpyrrolidin-3-yl) oxy) ethyl) -2-thioxo-1, 2,3, 5-tetrahydroxy-4H-pyrrolo [3,2-d ] pyrimidin-4-one
3-methyl-3- (2- (4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) ethoxy) pyrrolidine-1-carboxylic acid tert-butyl ester Cpd-059H (70mg, 0.2mmol) was dissolved in methanol (1 mL), and 4N methanol hydrochloride solution (1 mL) was added thereto and reacted at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated, neutralized with an aqueous sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was concentrated, and the residue was purified by reverse phase preparative column to give 1- (2- ((3-methylpyrrolidin-3-yl) oxy) ethyl) -2-thioxo-1, 2,3, 5-tetrahydroxy-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-059 (32 mg, white solid) in yield: 40 percent.
MS m/z(ESI):295[M+1] + 。
1 H NMR(400MHz,MeOD)δ8.53(s,1H),7.31(s,1H),6.32(s,1H),4.69-4.59(m,2H),3.90(d,J＝4.4Hz,2H),3.39-3.34(m,1H),2.99(d,J＝12.2Hz,1H),2.20(dd,J＝13.3,6.8Hz,1H),1.83(dd,J＝23.6,10.1Hz,1H),1.32(s,3H).
Example 60
1- (2- ((1, 3-dimethylpyrrolidin-3-yl) oxy) ethyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850001061
1- (2- ((3-Methylpyrrolidin-3-yl) oxy) ethyl) -2-thioxo-1, 2,3, 5-tetrahydroxy-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-059 (30mg, 0.09mmol) was dissolved in methanol (2 mL) and saturated sodium bicarbonate (0.5 mL), paraformaldehyde (6 mg, 0.18mmol) was added, and the reaction was carried out at room temperature for 1 hour. Sodium cyanoborohydride (6 mg, 0.18mmol) was added and the reaction was carried out at room temperature for 16 hours. The reaction was purified by reverse phase preparative column to give 1- (2- ((1, 3-dimethylpyrrolidin-3-yl) oxy) ethyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-060 (2.17 mg, white solid) in yield: 7 percent.
MS m/z(ESI):309[M+1] + .
1 H NMR(400MHz,MeOD)δ7.32(d,J＝2.4Hz,1H),6.33(d,J＝2.5Hz,1H),4.65(dd,J＝9.4,4.9Hz,2H),3.92(dd,J＝10.1,5.1Hz,2H),3.13(s,2H),2.82(s,3H),2.23(s,1H),1.97(s,1H),1.33(s,3H).
Example 61
2-thioxo-1- (2- ((1- (trifluoromethyl) cyclopentyl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850001062
First step of
Preparation of 1- (trifluoromethyl) cyclopentan-1-ol
Cyclopentanone Cpd-061A (2.0g, 23.8mmol), trifluoromethyl trimethylsilane (5.1g, 35.7mmol) and tetrabutylammonium fluoride (6.2g, 23.8mmol) were dissolved in dry tetrahydrofuran (50 mL). The reaction mixture was reacted at room temperature overnight. To the reaction mixture was added saturated brine (50 mL), followed by extraction with ethyl acetate (50 mL. Times.2). The organic phases were combined and dried over anhydrous sodium sulfate, concentrated and isolated and purified (petroleum ether/ethyl acetate = 5/1) to give 1- (trifluoromethyl) cyclopentan-1-ol Cpd-061B (1.5 g, white solid) in yield: 42 percent.
Second step of
Preparation of ethyl 2- ((1- (trifluoromethyl) cyclopentyl) oxy) acetate
1- (trifluoromethyl) cyclopentan-1-ol Cpd-061B (1.5g, 9.7 mmol) was dissolved in N, N-dimethylformamide (5 mL), the reaction was cooled to 0 ℃ in an ice bath, sodium hydride (350mg, 14.6 mmol) was added thereto, and stirring was carried out for 30 minutes, followed by ethyl bromoacetate (1.8g, 10.7 mmol). The reaction mixture was reacted at 25 ℃ for 12 hours. After completion of the reaction, the reaction mixture was washed with saturated brine (50 mL. Times.5). The organic phase was dried over anhydrous sodium sulfate, concentrated and then separated and purified by a silica gel column (petroleum ether/ethyl acetate = 8/1) to give 2- ((1- (trifluoromethyl) cyclopentyl) oxy) ethyl acetate Cpd-061C (1.1 g, yellow liquid), yield: and 47 percent. The crude product was used directly in the next step without further purification.
The third step
Preparation of 2- ((1- (trifluoromethyl) cyclopentyl) oxy) ethan-1-ol
Ethyl 2- ((1- (trifluoromethyl) cyclopentyl) oxy) acetate Cpd-061C (500mg, 2.1mmol) was dissolved in tetrahydrofuran (5 mL) and a suspension of lithium aluminum hydride in tetrahydrofuran (4.2 mL,4.2mmol, 1M) was added and the reaction stirred at 25 ℃ for 30 min. After the reaction is finished, 15% sodium hydroxide aqueous solution (2 mL) is added and stirred for 10 minutes, a white solid is separated out, the pH value is adjusted to 7 by dilute hydrochloric acid, a small amount of anhydrous sodium sulfate is added and stirred for 10 minutes, suction filtration is carried out, and the filtrate is dried in a spinning mode to obtain crude product 2- ((1- (trifluoromethyl) cyclopentyl) oxy) ethane-1-alcohol Cpd-061D (200 mg, colorless liquid), yield: 49 percent. The crude product was used in the next step without further purification.
The fourth step
Preparation of 2- ((1- (trifluoromethyl) cyclopentyl) oxy) acetaldehyde
Oxalyl chloride (192mg, 1.5 mmol) was dissolved in dry dichloromethane (4 mL), cooled to-60 ℃ under a nitrogen atmosphere, and dimethyl sulfoxide (236mg, 3.0 mmol) was added and stirred for 15 minutes. 2- ((1- (trifluoromethyl) cyclopentyl) oxy) ethane-1-ol Cpd-061D (200mg, 1.0 mmol) was dissolved in dry dichloromethane (1 mL) and added dropwise to the reaction system, the temperature was controlled to not exceed-55 ℃ throughout the reaction, and the reaction was carried out for 30 minutes. To this was added triethylamine (459mg, 4.5mmol), and the mixture was stirred for 10 minutes. After the reaction was completed, it was washed with saturated brine (10 mL × 3), and the organic phase was dried over anhydrous sodium sulfate and then rotoevaporated to give 2- ((1- (trifluoromethyl) cyclopentyl) oxy) acetaldehyde Cpd-061E (150 mg, colorless liquid), yield: 75 percent. The crude product was used in the next step without further purification.
The fifth step
Preparation of ethyl 3- ((2- ((1- (trifluoromethyl) cyclopentyl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate
2- ((1- (trifluoromethyl) cyclopentyl) oxy) acetaldehyde Cpd-061E (150mg, 0.76mmol) was dissolved in methanol (2 mL) and then ethyl 3-amino-1H-pyrrole-2-carboxylate (117mg, 0.76mmol) and acetic acid (0.5 mL) were added in that order. The reaction was stirred at room temperature for 4 h, followed by addition of sodium cyanoborohydride (94mg, 1.52mmol) and stirring continued for 1 h. After the reaction was completed, methanol was removed by rotary evaporation, the residue was dissolved with ethyl acetate (5 mL), washed with saturated brine (10 mL × 3), the organic phase was dried over anhydrous sodium sulfate and rotary dried, and the crude product was separated and purified with a silica gel column (petroleum ether/ethyl acetate = 2/1) to give ethyl 3- ((2- ((1- (trifluoromethyl) cyclopentyl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-061F (90 mg, yellow liquid), yield: 35 percent.
The sixth step
Preparation of ethyl 3- (3- (ethoxycarbonyl) -1- (2- ((1- (trifluoromethyl) cyclopentyl) oxy) ethyl) thioureido) -1H-pyrrole-2-carboxylate
Ethyl 3- ((2- ((1- (trifluoromethyl) cyclopentyl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-061F (90mg, 0.27mmol) was dissolved in dichloromethane (4 mL), ethoxycarbonyl isothiocyanate (42mg, 0.32mmol) was added, and the reaction mixture was reacted at room temperature for 30 minutes. After the reaction was completed, crude 3- (3- (ethoxycarbonyl) -1- (2- ((1- (trifluoromethyl) cyclopentyl) oxy) ethyl) thioureido) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-061G (80 mg, yellow liquid) was obtained by rotary evaporation, yield: and 64 percent. The crude product was used directly in the next step without further treatment.
MS m/z(ESI):466[M+1] + .
Seventh step
Preparation of 2-thioxo-1- (2- ((1- (trifluoromethyl) cyclopentyl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
3- (3- (ethoxycarbonyl) -1- (2- ((1- (trifluoromethyl) cyclopentyl) oxy) ethyl) thioureido) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-061G (80mg, 0.17mmol) was dissolved in anhydrous methanol (4 mL) and cesium carbonate (112mg, 0.34mmol) was added. The reaction was warmed to 65 ℃ and stirred for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature and spin-dried, and the crude product was purified by climbing up a plate (petroleum ether/ethyl acetate = 1/2) to give 2-thio-1- (2- ((1- (trifluoromethyl) cyclopentyl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-061 (50 mg, yellow oil), yield: 84 percent.
MS m/z(ESI):348[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.31(s,1H),12.24(s,1H),7.35(d,J＝2.9Hz,1H),6.28(d,J＝2.9Hz,1H),4.51(t,J＝5.5Hz,2H),3.93(t,J＝5.3Hz,2H),1.72(t,J＝6.3Hz,4H),1.59-1.46(m,2H),1.40-1.30(m,2H).
Example 62
2-thio-1- (2- ((1- (trifluoromethyl) cyclohexyl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850001081
First step of
Preparation of 1- (trifluoromethyl) cyclohexanol
Cyclohexanone Cpd-062A (2.0 g, 20mmol) was dissolved in tetrahydrofuran (20 mL) and (trifluoromethyl) trimethylsilane (5.8g, 40mmol) and tetrabutylammonium fluoride (2.6 g, 10mmol) were added at 0 ℃. The reaction was stirred at room temperature for 2 hours. Point plate monitoring reaction is finished, water is added for quenching, ethyl acetate is used for extraction, an organic phase is washed by water, saturated salt solution is washed by water, anhydrous sodium sulfate is dried and then is dried in a spinning way, and a crude product is purified by column chromatography (petroleum ether/ethyl acetate = 4/1) to obtain 1- (trifluoromethyl) cyclohexanol Cpd-062B (675 mg, colorless oily matter), wherein the yield: 18 percent.
1 H NMR(400MHz,DMSO-d6)δ5.58(s,1H),1.66-1.27(m,10H).
Second step of
Preparation of ethyl 2- ((1- (trifluoromethyl) cyclohexyl) oxy) acetate
1- (trifluoromethyl) cyclohexanol Cpd-062B (500mg, 2.9 mmol) was dissolved in dry N, N-dimethylformamide (10 mL), sodium hydrogen (143mg, 3.5 mmol) was added portionwise at 0 ℃ and allowed to react at room temperature for 1 hour, then ethyl bromoacetate (520mg, 3.1mmol) was added slowly at 0 ℃ and stirred at room temperature for 4 hours. Plate counting is carried out to monitor the end of the reaction, water is added for quenching the reaction, ethyl acetate is used for extraction, an organic phase is washed with water, saturated salt water is used for washing, anhydrous sodium sulfate is dried and then is dried in a spinning way, and a crude product is purified by column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain 2- ((1- (trifluoromethyl) cyclohexyl) oxy) ethyl acetate Cpd-062C (370 mg, colorless oily matter), and the yield: 49 percent.
1 H NMR(400MHz,CDCl 3 )δ4.23(q,J＝7.2Hz,2H),4.18(s,2H),2.04-1.98(m,2H),1.75-1.48(m,8H),1.31(t,J＝7.2Hz,3H).
The third step
Preparation of 2- ((1- (trifluoromethyl) cyclohexyl) oxy) ethan-1-ol
Ethyl 2- ((1- (trifluoromethyl) cyclohexyl) oxy) acetate Cpd-062C (370mg, 1.4mmol) was dissolved in tetrahydrofuran (10 mL), cooled to 0 ℃ and a tetrahydrofuran suspension of lithium tetrahydroaluminium (1.4mL, 1.4mmol, 1M) was slowly added dropwise and stirred at room temperature for 1 hour. After the reaction was complete, water (0.5 mL) and aqueous sodium hydroxide (0.5 mL) were added and quenched, stirred at room temperature for 15 minutes, dried over anhydrous magnesium sulfate, filtered, and the filtrate was spin-dried to give crude 2- ((1- (trifluoromethyl) cyclohexyl) oxy) ethan-1-ol Cpd-062D (250 mg, colorless oil), yield: 81 percent. The product was used directly in the next step without further treatment.
The fourth step
Preparation of 2- ((1- (trifluoromethyl) cyclohexyl) oxy) acetaldehyde
Oxalyl chloride (76mg, 0.6 mmol) was dissolved in dry dichloromethane (5 mL). The temperature was reduced to-65 ℃ and a solution of dimethylsulfoxide (78mg, 1.0 mmol) in dichloromethane (0.5 mL) was slowly added thereto, the temperature was controlled at a level below-60 ℃ and the mixture was stirred at-65 ℃ for 30 minutes after the addition. A solution of 2- ((1- (trifluoromethyl) cyclohexyl) oxy) ethan-1-ol Cpd-062D (100mg, 0.5 mmol) in dichloromethane (0.5 mL) was added and stirred at-65 ℃ for 2 h. Triethylamine (151mg, 1.5 mmol) was added thereto, the temperature was gradually raised to 0 ℃ and water (10 mL) was added thereto, the mixture was separated, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate to obtain 6mL of a dichloromethane solution containing 2- ((1- (trifluoromethyl) cyclohexyl) oxy) acetaldehyde Cpd-062E. The solution was used directly in the next step without further purification.
The fifth step
Preparation of ethyl 3- ((2- ((1- (trifluoromethyl) cyclohexyl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate
Ethyl 3-amino-1H-pyrrole-2-carboxylate (77mg, 0.5 mmol) was dissolved in methanol (10 mL), and acetic acid (30mg, 0.5 mmol) and a solution of 2- ((1- (trifluoromethyl) cyclohexyl) oxy) acetaldehyde Cpd-062E in methylene chloride (6 mL,0.5 mmol) were added in this order and stirred at room temperature for 0.5 hour. Sodium cyanoborohydride (31mg, 0.5 mmol) was added portionwise and stirred at room temperature for 16 hours. After the reaction was completed, water (5 mL) was added for quenching, ethyl acetate was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and rotary evaporated to give a crude product, which was purified by column chromatography (petroleum ether/ethyl acetate = 3/1) to give ethyl 3- ((2- ((1- (trifluoromethyl) cyclohexyl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-062F (80 mg, light brown oil), yield: 46 percent.
MS m/z(ESI):349[M+1] + .
The sixth step
Preparation of ethyl 3- (3- (ethoxycarbonyl) -1- (2- ((1- (trifluoromethyl) cyclohexyl) oxy) ethyl) thioureido) -1H-pyrrole-2-carboxylate
Ethyl 3- ((2- ((1- (trifluoromethyl) cyclohexyl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-062F (80mg, 0.2mmol) was dissolved in dichloromethane (10 mL), cooled to 0 ℃ and ethyl isothiocyanatecarboxylate (39mg, 0.3mmol) was added thereto and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was washed once with water (5 mL), the organic phase was dried over anhydrous sodium sulfate and concentrated, and the residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 3/1) to give ethyl 3- (3- (ethoxycarbonyl) -1- (2- ((1- (trifluoromethyl) cyclohexyl) oxy) ethyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-062G (85 mg, pale brown oil), yield: 77 percent.
Seventh step
Preparation of 2-thioxo-1- (2- ((1- (trifluoromethyl) cyclohexyl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Ethyl 3- (3- (ethoxycarbonyl) -1- (2- ((1- (trifluoromethyl) cyclohexyl) oxy) ethyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-062G (50mg, 0.1mmol) was dissolved in methanol (2 mL), cesium carbonate (98mg, 0.3mmol) was added thereto, and the reaction was heated to 65 ℃ for 3 hours. The reaction solution was cooled to room temperature, saturated aqueous ammonium chloride solution (5 mL) was added, extraction was performed with ethyl acetate (10 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was isolated on preparative silica gel plates to give 2-thio-1- (2- ((1- (trifluoromethyl) cyclohexyl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-062 (10 mg, white solid), yield: 26 percent.
MS m/z(ESI):362[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.32(s,1H),12.22(s,1H),7.35(d,J＝2.8Hz,1H),6.29(t,J＝2.8Hz,1H),4.57(t,J＝5.2Hz,2H),3.95(t,J＝5.2Hz,2H),1.76(d,J＝12.8Hz,2H),1.45-1.30(m,5H),1.15-1.00(m,3H).
Example 63
2-thio-1- (2- ((3- (trifluoromethyl) tetrahydrofuran-3-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850001101
First step of
Preparation of 3- (trifluoromethyl) tetrahydrofuran-3-ol
Dihydro-3 (2H) -furanone Cpd-063A (2.0 g, 23.2mmol), trifluoromethyl trimethylsilane (6.6 g,46.5 mmol) and tetrabutylammonium fluoride (12.1g, 46.5 mmol) were dissolved in dry tetrahydrofuran (20 mL). The reaction solution was reacted at room temperature overnight. To the reaction mixture was added saturated brine (50 mL), followed by extraction with ethyl acetate (50 mL × 2), the organic phases were combined and dried over anhydrous sodium sulfate, and after concentration, separation and purification with (petroleum ether/ethyl acetate = 5/1), 3- (trifluoromethyl) tetrahydrofuran-3-ol Cpd-063 (800 mg, white solid) was obtained in yield: 20 percent.
1 H NMR(400MHz,DMSO-d6)δ6.41(s,1H),3.94-3.81(m,3H),3.63(d,J＝9.9Hz,1H),2.05-1.90(m,2H).
Second step of
Preparation of ethyl 2- ((3- (trifluoromethyl) tetrahydrofuran-3-yl) oxy) acetate
3- (trifluoromethyl) tetrahydrofuran-3-ol Cpd-063B (800mg, 5.1mmol) was dissolved in N, N-dimethylformamide (5 mL), cooled to 0 deg.C, and sodium hydride (185mg, 7.7 mmol) was added thereto and stirred for 30 minutes. Ethylbromoacetate (1.1g, 5.6 mmol) was added to the reaction, and the reaction solution was stirred at 25 ℃ for 12 hours. After the reaction was completed, the reaction solution was washed with saturated brine (50 mL × 5), the organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 8/1) to obtain ethyl 2- ((3- (trifluoromethyl) tetrahydrofuran-3-yl) oxy) acetate Cpd-063C (600 mg, yellow liquid), yield: 48 percent.
The third step
Preparation of 2- ((3- (trifluoromethyl) tetrahydrofuran-3-yl) oxy) ethan-1-ol
Ethyl 2- ((3- (trifluoromethyl) tetrahydrofuran-3-yl) oxy) acetate Cpd-063C (600mg, 2.5 mmol) was dissolved in tetrahydrofuran (5 mL) and a tetrahydrofuran suspension of lithium aluminum hydride (5.0 mL,5.0mmol, 1M) was added thereto. The reaction mixture was reacted at 25 ℃ for 30 minutes. After the reaction, 15% aqueous sodium hydroxide (2 mL) was added and stirred for 10 minutes, the pH was adjusted to 7 with dilute hydrochloric acid, a small amount of anhydrous sodium sulfate was added, and stirring and suction filtration were carried out for 10 minutes. The filtrate was spin dried to give crude 2- ((3- (trifluoromethyl) tetrahydrofuran-3-yl) oxy) ethane-1-ol Cpd-063D (180 mg, yellow liquid), yield: 36 percent. The crude product was used in the next step without further purification.
The fourth step
Preparation of 2- ((3- (trifluoromethyl) tetrahydrofuran-3-yl) oxy) acetaldehyde
Oxalyl chloride (170mg, 1.4mmol) was dissolved in dry dichloromethane (4 mL), cooled to-60 ℃ under nitrogen, dimethyl sulfoxide (210mg, 2.7mmol) was added and stirred for 15 minutes. 2- ((3- (trifluoromethyl) tetrahydrofuran-3-yl) oxy) ethane-1-ol Cpd-063D (180mg, 0.9mmol) was dissolved in dry dichloromethane (1 mL) and added dropwise to the reaction system, with the temperature being controlled throughout no more than-55 ℃. After 30 minutes of reaction, triethylamine (409mg, 4.1mmol) was added to the reaction solution, and stirring was continued for 10 minutes. After the reaction was completed, the reaction solution was washed with saturated brine (10 mL × 3), and the organic phase was dried over anhydrous sodium sulfate and then spin-dried to obtain 2- ((3- (trifluoromethyl) tetrahydrofuran-3-yl) oxy) acetaldehyde Cpd-063E (150 mg, white liquid), yield: 84 percent. The crude product was used directly in the next step without further purification.
The fifth step
Preparation of ethyl 3- ((2- ((3- (trifluoromethyl) tetrahydrofuran-3-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate
2- ((3- (trifluoromethyl) tetrahydrofuran-3-yl) oxy) acetaldehyde Cpd-063E (150mg, 0.75mmol) was dissolved in methanol (2 mL) and then ethyl 3-amino-1H-pyrrole-2-carboxylate (115mg, 0.76mmol) and acetic acid (0.5 mL) were added sequentially. After the reaction mixture was reacted for 4 hours, sodium cyanoborohydride (93mg, 1.47mmol) was added and the reaction was continued for 1 hour. After the reaction was completed, methanol was removed by rotary evaporation, the residue was dissolved in ethyl acetate (5 mL), washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate of the organic phase, and the resulting crude product was separated and purified with a silica gel column (petroleum ether/ethyl acetate = 2/1) to obtain ethyl 3- ((2- ((3- (trifluoromethyl) tetrahydrofuran-3-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-063F (60 mg, yellow liquid), yield: 24 percent.
The sixth step
Preparation of ethyl 3- (3- (ethoxycarbonyl) -1- (2- ((3- (trifluoromethyl) tetrahydrofuran-3-yl) oxy) ethyl) thioureido) -1H-pyrrole-2-carboxylate
Ethyl 3- ((2- ((3- (trifluoromethyl) tetrahydrofuran-3-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-063F (60mg, 0.17mmol) was dissolved in dichloromethane (3 mL), ethoxycarbonyl isothiocyanate (30mg, 0.21mmol) was added, and the reaction solution was reacted at room temperature for 30 minutes. After the reaction was complete crude 3- (3- (ethoxycarbonyl) -1- (2- ((3- (trifluoromethyl) tetrahydrofuran-3-yl) oxy) ethyl) thioureido) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-063G (60 mg, yellow liquid) was obtained by rotary evaporation, yield: 75 percent. The crude product was used directly in the next step without further purification.
MS m/z(ESI):468[M+1] + .
Seventh step
Preparation of 2-thioxo-1- (2- ((3- (trifluoromethyl) tetrahydrofuran-3-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Ethyl 3- (3- (ethoxycarbonyl) -1- (2- ((3- (trifluoromethyl) tetrahydrofuran-3-yl) oxy) ethyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-063G (60mg, 0.13mmol) was dissolved in anhydrous methanol (2 mL). Cesium carbonate (85mg, 0.26mmol) was added. The reaction was warmed up to 65 ℃ for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature and spin dried, and the crude product was purified by climbing up a plate (petroleum ether/ethyl acetate = 1/2) to give 2-thio-1- (2- ((3- (trifluoromethyl) tetrahydrofuran-3-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-063 (40 mg, white solid), yield: 88 percent.
MS m/z(ESI):350[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.35(s,1H),12.24(s,1H),7.35(d,J＝2.7Hz,1H),6.30(d,J＝2.8Hz,1H),4.54(t,J＝5.6Hz,2H),4.05-3.93(m,2H),3.79(d,J＝10.6Hz,1H),3.77-3.68(m,2H),3.61(q,J＝7.6Hz,1H),2.11-2.04(m,2H).
Example 64
1- (2, 2-Difluorocyclopropyloxy) ethyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850001111
First step of
Preparation of 2- (vinyloxy) ethyl benzoate
2- (ethyleneoxy) ethan-1-ol Cpd-064A (5g, 57mmol) was dissolved in dichloromethane (250 mL) and triethylamine (20mL, 142mmol) was added. Benzoyl chloride (10mL, 85mmol) was added dropwise at room temperature. The reaction solution was reacted at room temperature for 6 hours. The reaction solution was cooled to 0 ℃, and 1M hydrochloric acid (50 mL) was added, followed by extraction with dichloromethane (200 mL × 3). The organic phases were combined and washed with saturated sodium bicarbonate (75 mL) and saturated brine (75 mL), dried over anhydrous sodium sulfate and concentrated. The obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 10/1) to obtain 2- (ethyleneoxy) ethyl benzoate Cpd-064B (7.0 g, colorless oil), yield: and 64 percent.
1 H NMR(400MHz,CDCl 3 )δ8.07(d,J＝7.2Hz,2H),7.56(t,J＝7.4Hz,1H),7.44(t,J＝7.7Hz,2H),6.52(dd,J＝14.3,6.8Hz,1H),4.57-4.55(m,2H),4.24(dd,J＝14.3,2.2Hz,1H),4.07(dd,J＝6.8,2.3Hz,1H),4.04-4.01(m,2H).
Second step of
Preparation of 2- (2, 2-difluorocyclopropoxy) ethyl) benzoate
(2- (ethyleneoxy) ethyl) benzoate Cpd-064B (1.0g, 5.2mmol) tetrahydrofuran (10 mL) was added to the reaction solution, and (trifluoromethyl) trimethylsilane (1.5g, 10.4mmol) and sodium iodide (1.6g, 10.4mmol) were stirred at 65 ℃ for 4 hours under a nitrogen atmosphere. Then, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL. Times.3), dried over anhydrous sodium sulfate and concentrated. The obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 10/1) to obtain Cpd-064C (1.2 g, colorless oil) which is benzoic acid (2- (2, 2-difluorocyclopropoxy) ethyl) ester, yield: 94 percent.
1 H NMR(400MHz,DMSO-d6)δ8.06(d,J＝7.1Hz,2H),7.57(t,J＝7.4Hz,1H),7.45(t,J＝7.7Hz,2H),4.51-4.49(m,2H),3.94(t,J＝4.6Hz,2H),3.76-3.70(m,1H),1.59-1.42(m,2H).
The third step
Preparation of 2- (2, 2-difluorocyclopropoxy) ethan-1-ol
Benzoic acid (2- (2, 2-difluorocyclopropoxy) ethyl) ester, cpd-064C (1.0 g, 4.1mmol), was dissolved in methanol (10 mL), 2N sodium hydroxide solution (10 mL) was added and the reaction was stirred at room temperature for 2 h. Dilution with water (10 mL), extraction with ethyl acetate (20 mL. Times.3), drying over anhydrous sodium sulfate and concentration gave 2- (2, 2-difluorocyclopropoxy) ethane-1-ol Cpd-064D (380 mg, colorless oil), yield: 61 percent.
1 H NMR(400MHz,DMSO-d6)δ4.72(s,1H),3.92-3.79(m,1H),3.60-3.46(m,4H),1.66(dtd,J＝15.6,9.0,6.7Hz,1H),1.49(ddt,J＝17.1,9.4,4.9Hz,1H).
The fourth step
Preparation of 2- (2, 2-difluorocyclopropoxy) acetaldehyde
Oxalyl chloride (1.40g, 11.0 mmol) was dissolved in dry dichloromethane (10 mL), to which was added dry dimethyl sulfoxide (1.72g, 22.0 mmol) dissolved in dichloromethane at-55 ℃ under nitrogen protection. After stirring for 10 minutes, cpd-064D (380mg, 2.8mmol) 2- (2, 2-difluorocyclopropoxy) ethane-1-ol, dissolved in methylene chloride, was added thereto. After the reaction mixture was stirred at-55 ℃ for 30 minutes, triethylamine (2.23g, 22.0 mmol) was added thereto. The reaction mixture was stirred back to room temperature, washed with water, dried over sodium sulfate in the organic phase and concentrated to give crude 2- (2, 2-difluorocyclopropoxy) acetaldehyde Cpd-064E (380 mg, yellow oil). The crude product was used in the next reaction without further treatment.
The fifth step
Preparation of ethyl 3- ((2- (2, 2-difluorocyclopropoxy) ethyl) amino) -1H-pyrrole-2-carboxylate
2- (2, 2-Difluorocyclopropoxy) acetaldehyde Cpd-064E (380mg, 2.80mmol) was dissolved in methanol (4 mL) and 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester (473mg, 3.07mmol) and glacial acetic acid (2 drops) were added thereto. The reaction mixture was reacted at 25 ℃ for 1 hour. To the reaction solution was added sodium cyanoborohydride (210mg, 3.35mmol) and the reaction was continued for 16 hours. After the completion of the reaction, methanol was removed by rotary evaporation, and the obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 1/1) to obtain ethyl 3- ((2- (2, 2-difluorocyclopropoxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-064F (80 mg, yellow oil), yield: 9 percent.
MS m/z(ESI):275[M+1] + .
The sixth step
Preparation of ethyl 3- (1- (2, 2-difluorocyclopropoxy) ethyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate
Ethyl 3- ((2- (2, 2-difluorocyclopropoxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-064F (80mg, 0.29mmol) was dissolved in dichloromethane (2 mL), and to this was added ethyl isothiocyanatocarboxylate (46mg, 0.35mmol) and reacted at 25 ℃ for 2 hours. After the reaction was completed, dichloromethane was removed by rotary evaporation. The resulting residue was extracted with ethyl acetate (15 mL × 3), the organic phases combined, dried over anhydrous sodium sulfate and concentrated to give crude ethyl 3- (1- (2, 2-difluorocyclopropoxy) ethyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-064G (60 mg, yellow oil) in yield: 100 percent.
MS m/z(ESI):406[M+1] + .
Seventh step
Preparation of 1- (2, 2-difluorocyclopropoxy) ethyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Ethyl 3- (1- (2, 2-difluorocyclopropoxy) ethyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-064G (60mg, 0.15mmol) was dissolved in methanol (2 mL) and cesium carbonate (96mg, 0.30mmol) was added thereto. The reaction mixture was heated to 65 ℃ and reacted for 6 hours. After the reaction was completed, the reaction solution was cooled to room temperature to remove methanol by rotary evaporation, and the obtained residue was subjected to preparative purification in reverse phase to give 1- (2, 2-difluorocyclopropoxy) ethyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-064 (6 mg, white solid), yield: 14 percent.
MS m/z(ESI):288[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.34(br,2H),8.48(s,1H),7.36(d,J＝2.4Hz,1H),6.29(d,J＝2.3Hz,1H),4.58(d,J＝5.4Hz,2H),3.93(t,J＝5.8Hz,3H),1.67(td,J＝15.8,8.6Hz,1H),1.53-1.36(m,1H).
Example 65
1- (4-chloro-3- (difluoromethoxy) benzyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850001131
First step of
Preparation of 4-bromo-1-chloro-2- (difluoromethoxy) benzene
5-bromo-2-chlorophenol Cpd-065A (500mg, 2.41mmol), sodium 2-chloro-2, 2-difluoroacetate (735mg, 4.82mmol), cesium carbonate (1178mg, 3.61mmol) and water (87mg, 4.82mmol) were dissolved in N, N-dimethylformamide (5 mL) and heated at 100 ℃ for 12 hours. After the completion of the reaction, the reaction mixture was diluted with 100mL of water, extracted twice with ethyl acetate (50 mL), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 10/1) to obtain 4-bromo-1-chloro-2- (difluoromethoxy) benzene Cpd-065B (500 mg, colorless oil), yield: 80 percent.
1 H NMR(400MHz,DMSO-d6)δ7.64(d,J＝1.7Hz,1H),7.58(d,J＝8.6Hz,1H),7.50(dd,J＝8.6,2.1Hz,1H),7.37(t,J＝72.9Hz,1H).
Second step of
Preparation of 4-chloro-3- (difluoromethoxy) benzaldehyde
4-bromo-1-chloro-2- (difluoromethoxy) benzene Cpd-065B (250mg, 0.97mmol), dichlorodi-tert-butyl- (4-dimethylaminophenyl) palladium (II) phosphate (137mg, 0.19mmol), triethoxysilane (395mg, 3.40mmol), N, N-diisopropylethylamine (188mg, 1.46mmol) were dissolved in dimethyl sulfoxide (5 mL) and subsequently heated at 90 ℃ for 2 hours after three gasations over carbon monoxide. After completion of the reaction, the reaction mixture was diluted with 100mL of water and 100mL of ethyl acetate, filtered through celite, extracted, mixed and separated, the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 10/1) to obtain 4-chloro-3- (difluoromethoxy) benzaldehyde Cpd-065C (170 mg, colorless oil) in yield: 84 percent.
1 H NMR(400MHz,DMSO-d6)δ10.01(s,1H),7.98-7.75(m,3H),7.44(t,J＝72.8Hz,1H).
The third step
Preparation of ethyl 3- ((4-chloro-3- (difluoromethoxy) benzyl) amino) -1H-pyrrole-2-carboxylate
4-chloro-3- (difluoromethoxy) benzaldehyde, cpd-065C (170mg, 0.82mmol), ethyl 3-amino-1H-pyrrole-2-carboxylate (127mg, 0.82mmol) and two drops of acetic acid were dissolved in methanol (5 mL), stirred at room temperature for half an hour, followed by addition of sodium cyanoborohydride (259mg, 4.11mmol) and stirring continued for half an hour. After the reaction was completed, the reaction solution was diluted with 100mL of water, extracted with 100mL of ethyl acetate, and the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was separated and purified with a silica gel column (petroleum ether/ethyl acetate = 4/1) to obtain ethyl 3- ((4-chloro-3- (difluoromethoxy) benzyl) amino) -1H-pyrrole-2-carboxylate Cpd-065D (100 mg, colorless oil), yield: 35 percent.
1 H NMR(400MHz,DMSO-d6)δ10.78(s,1H),7.52(d,J＝8.2Hz,1H),7.34(s,1H),7.24(t,J＝73.2Hz,1H),7.23(s,1H),6.69(t,J＝3.0Hz,1H),5.90(s,1H),5.54(t,J＝2.4Hz,1H),4.31(d,J＝6.4Hz,2H),4.20(q,J＝7.1Hz,2H),1.27(t,J＝7.1Hz,3H).
The fourth step
Preparation of ethyl 3- ((4-chloro-3- (difluoromethoxy) benzyl) (((((ethoxycarbonyl) amino) methionyl)) amino) -1H-pyrrole-2-carboxylate
Ethyl 3- ((4-chloro-3- (difluoromethoxy) benzyl) amino) -1H-pyrrole-2-carboxylate Cpd-065D (100mg, 0.29mmol) was dissolved in dichloromethane (3 mL) and ethyl isothiocyanatecarboxylate (76mg, 0.58mmol) was added and stirred at room temperature for half an hour. After the reaction was complete, concentration gave crude ethyl 3- ((4-chloro-3- (difluoromethoxy) benzyl) (((((ethoxycarbonyl) amino) methionyl)) amino) -1H-pyrrole-2-carboxylate Cpd-065E (150 mg, colorless oil) which was used directly in the next step.
MS m/z(ESI):476[M+1] + .
The fifth step
Preparation of 1- (4-chloro-3- (difluoromethoxy) benzyl) -2-thioxo-3H, 5H-pyrrolo [3,2-d ] pyrimidin-4-one
Ethyl 3- ((4-chloro-3- (difluoromethoxy) benzyl) ((((ethoxycarbonyl) amino) methionyl)) amino) -1H-pyrrole-2-carboxylate Cpd-065E (150mg, 0.31mmol) was dissolved in methanol (5 mL) and cesium carbonate (513mg, 1.58mmol) was added and heated at 60 ℃ for 8H. After the reaction was completed, the reaction solution was concentrated, quenched with saturated aqueous ammonium chloride (100 mL), extracted twice with ethyl acetate (50 mL), and the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the concentrated crude product was slurried with methanol to give 1- (4-chloro-3- (difluoromethoxy) benzyl) -2-thioxo-3 h, 5h-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-065 (40 mg, white solid), yield: 34 percent.
MS m/z(ESI):358[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.47(s,1H),12.37(s,1H),7.54(d,J＝8.3Hz,1H),7.45(s,1H),7.32(d,J＝2.3Hz,1H),7.24(t,J＝73.2Hz,1H),7.17(d,J＝8.3Hz,1H),6.19(d,J＝2.7Hz,1H),5.71(s,2H).
Example 66
1- (4-chloro-3- ((methylamino) methyl) benzyl) -7-methyl-2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850001141
First step of
Preparation of tert-butyl (5-bromo-2-chlorobenzyl) carbamate
To a solution of (5-bromo-2-chlorophenyl) methylamine Cpd-066A (500mg, 2.27mmol) in dichloromethane (10 mL) was added di-tert-butyl dicarbonate (594mg, 2.72mmol) and triethylamine (459mg, 4.54mmol). The reaction solution was stirred at 25 ℃ for 3 hours. The reaction solution is cooled to room temperature, and the solvent is removed by rotary evaporation. Crude flash column chromatography (petroleum ether/ethyl acetate = 10/1) gave after isolation and purification (5-bromo-2-chlorobenzyl) carbamic acid tert-butyl ester Cpd-066B (640 mg, white solid) in yield: 88 percent.
MS m/z(ESI):264(M-56+1).
Second step of
Preparation of tert-butyl (5-bromo-2-chlorobenzyl) methylcarbamate
To a solution of tert-butyl (5-bromo-2-chlorobenzyl) carbamate, cpd-066B (50mg, 0.16mmol), in DMF (1 mL), was added sodium hydride (7mg, 0.19mmol, 60%) and the reaction solution was stirred at 25 ℃ for 1 h. Methyl iodide (27mg, 0.19mmol) was then added to the solution, and the reaction solution was stirred at 25 ℃ overnight. Then, water (10 mL) was added to quench, and the residue was extracted with ethyl acetate (15 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give tert-butyl (5-bromo-2-chlorobenzyl) carbamate Cpd-066C (27 mg, white solid) in yield: and 52 percent.
MS m/z(ESI):278(M-56+1).
The third step
Preparation of tert-butyl (2-chloro-5-formylbenzyl) methylcarbamate
(5-bromo-2-chlorobenzyl) carbamic acid tert-butyl ester Cpd-066C (800mg, 2.34mmol), pd (Amphos) Cl in an atmosphere of carbon monoxide 2 (338mg, 0.48mmol), triethylsilane (973mg, 8.37mmol), DIPEA (463mg, 3.58mmol) in DMSO (8 mL) were reacted at 90 ℃. Then, water (10 mL) was added to quench, and the residue was extracted with ethyl acetate (15 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated. Separating and purifying a crude product by using a flash column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain (2-chloro-5-formylbenzyl) methylamineTert-butyl carbamate Cpd-066D (72 mg, white solid), yield: 52 percent.
MS m/z(ESI):228[M-56+1].
The fourth step
Preparation of ethyl 3- (3- (((tert-butoxycarbonyl) methylamino) methyl) -4-chlorobenzyl) amino) -4-methyl-1H-pyrrole-2-carboxylate
To a solution of tert-butyl (2-chloro-5-formylbenzyl) carbamate, cpd-066D (80mg, 0.28mmol), and ethyl 3-amino-4-methyl-1H-pyrrole-2-carboxylate (47mg, 0.28mmol) in methanol (3 mL) was added acetic acid (17mg, 0.28mmol), the mixture was stirred for 1 hour, then sodium cyanoborohydride (18mg, 0.28mmol) was added, and the mixture was stirred overnight. After the reaction was completed, rotary evaporation was performed to obtain a crude product, which was isolated and purified by preparative TLC method (petroleum ether/ethyl acetate = 5/1) to obtain 3- ((3- (((tert-butoxycarbonyl) methylamino) methyl) -4-chlorobenzyl) amino) -4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-066E (100 mg, colorless oil), yield: 82 percent.
MS m/z(ESI):436[M+1] + .
The fifth step
Preparation of ethyl 3- (1- (3- (((tert-butoxycarbonyl) methylamino) methyl) -4-chlorobenzyl) -3- (ethoxycarbonyl) thioureido) -4-methyl-1H-pyrrole-2-carboxylate
Ethyl 3- ((3- (((tert-butoxycarbonyl) methylamino) methyl) -4-chlorobenzyl) amino) -4-methyl-1H-pyrrole-2-carboxylate Cpd-066E (40mg, 0.09mmol) was dissolved in dichloromethane (2 mL), cooled on ice and ethyl isothiocyanatecarboxylate (14mg, 0.11mmol) was added thereto, followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction mixture was washed once with water (2 mL), and the organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was isolated and purified by preparative TLC method (petroleum ether/ethyl acetate = 3/1) to give ethyl 3- (1- (3- (((tert-butoxycarbonyl) methylamino) methyl) -4-chlorobenzyl) -3- (ethoxycarbonyl) thioureido) -4-methyl-1H-pyrrole-2-carboxylate Cpd-066F (50 mg, colorless oil) yield: 96 percent.
MS m/z(ESI):567[M+1] + .
The sixth step
Preparation of tert-butyl (2-chloro-5- ((7-methyl-4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) methyl) benzyl) methylcarbamate
Cesium carbonate (172mg, 0.53mmol) was added to a solution of ethyl 3- (1- (3- (((tert-butoxycarbonyl) methylamino) methyl) -4-chlorobenzyl) -3- (ethoxycarbonyl) thioureido) -4-methyl-1H-pyrrole-2-carboxylate Cpd-066F (100mg, 0.18mmol) in methanol (5 mL) and the mixture was stirred at 60 ℃ for 5 hours. After the reaction was completed, the reaction solution was cooled to room temperature and quenched with water (5 mL), extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was subjected to preparative TLC method (dichloromethane/methanol = 20/1) to give (2-chloro-5- ((7-methyl-4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) methyl) benzyl) carbamic acid tert-butyl ester Cpd-066G (70 mg, white solid), yield: 88 percent.
MS m/z(ESI):449[M+1] + .
Step seven
Preparation of 1- (4-chloro-3- ((methylamino) methyl) benzyl) -7-methyl-2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
A solution of tert-butyl (2-chloro-5- ((7-methyl-4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) methyl) benzyl) carbamate, cpd-066G (55mg, 0.12mmol) in HCl in MeOH (4M, 2mL) was stirred at 25 ℃ for 12 hours. After completion of the reaction, the reaction mixture was neutralized by adding saturated sodium bicarbonate, extracted with a mixed solution (10/1) of methylene chloride and methanol, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was subjected to preparative TLC method (dichloromethane/methanol = 10/1) to give 1- (4-chloro-3- ((methylamino) methyl) benzyl) -7-methyl-2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-066 (12 mg, white solid) in yield: 25 percent.
MS m/z(ESI):294[M+1] + .
HNMR： 1 H NMR(400MHz,DMSO-d6)δ12.21(br,1H),7.36(d,J＝8.2Hz,1H),7.30(s,1H),7.12(s,1H),6.92(d,J＝7.6Hz,1H),3.68(s,2H),2.23(s,3H),1.95(s,3H).
Example 67
1- (4-chloro-3- (methylamino) benzyl) -7-methyl-2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850001161
First step of
Preparation of tert-butyl (5-bromo-2-chlorophenyl) carbamate
5-bromo-2-chloroaniline Cpd-067A (2.0g, 9.7 mmol), di-tert-butyl dicarbonate (2.5g, 11.6 mmol), triethylamine (2.9g, 29.1mmol) and 4-dimethylaminopyridine (1.2g, 9.7 mmol) were dissolved in dichloromethane (20 mL) and stirred at room temperature for two days. After completion of the reaction, the reaction mixture was diluted with water (100 mL), extracted with dichloromethane (50 mL × 2), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 10/1) to obtain tert-butyl (5-bromo-2-chlorophenyl) carbamate Cpd-067B (2.9 g, white solid) in yield: 98 percent.
1 H NMR(400MHz,CDCl 3 )δ8.41(d,J＝1.8Hz,1H),7.18(d,J＝8.5Hz,1H),7.08(dd,J＝8.5,2.3Hz,1H),6.99(s,1H),1.54(s,9H).
Second step of
Preparation of N- (5-bromo-2-chlorophenyl) -N-methylcarbamic acid tert-butyl ester
Tert-butyl (5-bromo-2-chlorophenyl) carbamate Cpd-067B (2.9 g,9.5 mmol) was dissolved in N, N-dimethylformamide (30 mL), and sodium hydrogen (0.46g, 11.3 mmol) was added under ice bath and stirred under nitrogen for half an hour. Methyl iodide (1.75g, 12.3mmol) was then added and stirring continued for ten minutes on ice after addition was complete. After the reaction was completed, the reaction solution was quenched by pouring it into an aqueous solution of ice ammonium chloride (200 mL), extracted with ethyl acetate (100 mL × 2), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was separated and purified with a silica gel column (petroleum ether/ethyl acetate = 10/1) to obtain N- (5-bromo-2-chlorophenyl) -N-methylcarbamic acid tert-butyl ester Cpd-067C (3.0 g, white solid), yield: 99 percent.
MS m/z(ESI):266[M-56+1] + .
The third step
Preparation of N- (2-chloro-5-formylphenyl) -N-methylcarbamic acid tert-butyl ester
N- (5-bromo-2-chlorophenyl) -N-methylcarbamic acid tert-butyl ester Cpd-067C (1.0g, 3.1mmol), dichlorodi-tert-butyl- (4-dimethylaminophenyl) palladium (II) (0.2g, 0.31mmol), triethylsilane (1.1g, 9.3mmol) and N, N-diisopropylethylamine (0.6g, 4.6mmol) were dissolved in anhydrous dimethylsulfoxide (40 mL), and after replacing the gas with a balloon of carbon monoxide four times, the mixture was heated to 90 ℃ and stirred for 12 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate (200 mL) and water (300 mL), filtered through celite, the aqueous phase was extracted with ethyl acetate (100 mL × 2) after separation of the filtrate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was separated and purified with a silica gel column (petroleum ether/ethyl acetate = 10/1) to obtain N- (2-chloro-5-formylphenyl) -N-methylcarbamic acid tert-butyl ester Cpd-067D (0.5 g, colorless oil), yield: 61 percent.
1 H NMR(400MHz,DMSO-d6)δ9.99(s,1H),7.95(d,J＝1.6Hz,1H),7.86(d,J＝8.3Hz,1H),7.79(d,J＝8.2Hz,1H),3.11(s,3H),1.52-1.25(m,9H).
The fourth step
Preparation of ethyl 3- ((3- ((tert-butoxycarbonyl) methylamino) -4-chlorobenzyl) amino) -4-methyl-1H-pyrrole-2-carboxylate
N- (2-chloro-5-formylphenyl) -N-methylcarbamic acid tert-butyl ester Cpd-067D (150mg, 0.56mmol), 3-amino-4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (93mg, 0.56mmol) and two drops of acetic acid were dissolved in methanol (3 mL) and stirred at room temperature for half an hour, followed by addition of sodium cyanoborohydride (175mg, 2.78mmol) and stirring at room temperature for an additional 1 hour. After the reaction was completed, the reaction solution was diluted with water (100 mL), extracted with ethyl acetate (50 mL × 2), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product, which was separated and purified with a silica gel column (petroleum ether/ethyl acetate = 4/1) to obtain ethyl 3- ((3- ((t-butoxycarbonyl) methylamino) -4-chlorobenzyl) amino) -4-methyl-1H-pyrrole-2-carboxylate Cpd-067E (110 mg, colorless oil) in yield: and 47 percent.
MS m/z(ESI):422[M+1] + .
The fifth step
Preparation of ethyl 3- (1- (3- ((tert-butoxycarbonyl) methylamino) -4-chlorobenzyl) -3- (ethoxycarbonyl) thioureido) -4-methyl-1H-pyrrole-2-carboxylate
Ethyl 3- ((3- ((tert-butoxycarbonyl) methylamino) -4-chlorobenzyl) amino) -4-methyl-1H-pyrrole-2-carboxylate Cpd-067E (116mg, 0.27mmol) and ethoxycarbonyl isothiocyanate (54mg, 0.41mmol) were dissolved in dichloromethane (3 mL) and stirred at room temperature for half an hour. After the reaction was completed, the reaction solution was concentrated, and the obtained crude product was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 1/1) to obtain ethyl 3- (1- (3- ((tert-butoxycarbonyl) methylamino) -4-chlorobenzyl) -3- (ethoxycarbonyl) thioureido) -4-methyl-1H-pyrrole-2-carboxylate Cpd-067F (133 mg, colorless oil), yield: 87 percent.
MS m/z(ESI):553[M+1] + .
Sixth step preparation of tert-butyl (2-chloro-5- ((7-methyl-4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) methyl) phenyl) methylcarbamate
Ethyl 3- (1- (3- ((tert-butoxycarbonyl) methylamino) -4-chlorobenzyl) -3- (ethoxycarbonyl) thioureido) -4-methyl-1H-pyrrole-2-carboxylate, cpd-067F (130mg, 0.23mmol), and cesium carbonate (383mg, 1.18mmol) were dissolved in methanol (5 mL) and then heated to 65 ℃ under nitrogen and stirred for 5 hours. After completion of the reaction, the reaction mixture was concentrated, a saturated aqueous ammonium chloride solution (50 mL) was dispersed, ethyl acetate (30 mL × 2) was extracted, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was separated and purified with a silica gel column (petroleum ether/ethyl acetate = 1/1) to obtain (tert-butyl 2-chloro-5- ((7-methyl-4-oxo-2-thio-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) methyl) phenyl) methylcarbamate Cpd-067G (55 mg, white solid) in yield: 54 percent.
MS m/z(ESI):379[M-56+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.38(s,1H),12.23(s,1H),7.48(d,J＝8.3Hz,1H),7.40-6.78(m,3H),3.02(s,3H),1.94(s,3H),1.45(s,2H),1.28-1.04(m,9H).
Seventh step
Preparation of 1- (4-chloro-3- (methylamino) benzyl) -7-methyl-2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Tert-butyl (2-chloro-5- ((7-methyl-4-oxo-2-thioxo-2, 3,4, 5-tetrahydro-1H-pyrrolo [3,2-d ] pyrimidin-1-yl) methyl) phenyl) methylcarbamate Cpd-067G (25mg, 0.057 mmol) was dissolved in methanol hydrochloride (5 mL) and heated to 30 ℃ for half an hour with stirring. After the reaction was completed, the reaction solution was concentrated, washed with an aqueous sodium bicarbonate solution, extracted with ethyl acetate, concentrated and dried to obtain 1- (4-chloro-3- (methylamino) benzyl) -7-methyl-2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-067 (18 mg, white solid), yield: and 69 percent.
MS m/z(ESI):335[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.31(s,1H),12.20(s,1H),7.13(s,2H),6.44(s,1H),6.15(s,1H),5.26(br,2H),2.68(s,3H),1.99(s,3H).
Example 68
7-methyl-2-thioxo-1- (2- ((1, 1-trifluorobutan-2-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850001181
First step of
Preparation of ethyl 2- ((1, 1-trifluorobutan-2-yl) oxy) acetate
1, 1-trifluorobutan-2-ol Cpd-068A (400mg, 3.1mmol) was dissolved in N, N-dimethylformamide (10 mL), stirred for half an hour under ice bath with sodium hydrogen (186mg, 4.6 mmol) added under nitrogen, followed by dropwise ethyl bromoacetate (776mg, 4.6 mmol) under ice bath and stirring for half an hour. After the reaction was completed, the reaction solution was quenched by pouring into an aqueous solution of ammonium chloride ice (100 mL), extracted with ethyl acetate (50 mL × 2), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated at room temperature to obtain a crude product, which was then subjected to silica gel column (petroleum ether/ethyl acetate = 10/1) to obtain ethyl 2- ((1, 1-trifluorobutan-2-yl) oxy) acetate Cpd-068B (500 mg, colorless oil), yield: 75 percent.
1 H NMR(400MHz,DMSO-d6)δ4.39-4.27(m,2H),4.13(q,J＝7.1Hz,2H),4.09-4.01(m,1H),1.75-1.56(m,2H),1.20(dd,J＝9.5,4.7Hz,3H),1.00(t,J＝7.4Hz,3H).
Second step of
Preparation of 2- ((1, 1-trifluorobutan-2-yl) oxy) ethan-1-ol
Ethyl 2- ((1, 1-trifluorobutan-2-yl) oxy) acetate Cpd-068B (500mg, 2.3mmol) was dissolved in tetrahydrofuran (5 mL), a tetrahydrofuran suspension of lithium aluminum (3.0 mL,3.0mmol, 1M) was added dropwise under ice-cooling, and stirring was continued for half an hour after completion of the addition. After the reaction was completed, the reaction solution was diluted with tetrahydrofuran (50 mL), and an aqueous sodium hydroxide solution (0.3 mL, 2m) was dropped under ice bath, stirred for ten minutes, followed by addition of anhydrous sodium sulfate for drying, filtration through celite, and concentration of the filtrate to obtain 2- ((1, 1-trifluorobutan-2-yl) oxy) ethane-1-ol Cpd-068C (360 mg, colorless oil), yield: 89 percent.
1 H NMR(400MHz,DMSO-d6)δ4.67(t,J＝5.3Hz,1H),3.95-3.84(m,1H),3.75-3.65(m,1H),3.65-3.55(m,1H),3.51(q,J＝5.2Hz,2H),1.69-1.58(m,1H),1.57-1.46(m,1H),0.98(t,J＝7.4Hz,3H).
The third step
Preparation of 2- ((1, 1-trifluorobutan-2-yl) oxy) acetaldehyde
Oxalyl chloride (220mg, 1.7 mmol) was dissolved in dichloromethane (7 mL) with anhydrous sodium sulfate (50 mg) under nitrogen, and a solution of anhydrous dimethyl sulfoxide (203mg, 2.6 mmol) diluted with dichloromethane (1 mL) was added dropwise at-60 ℃. After 5 minutes, a solution of 2- ((1, 1-trifluorobutan-2-yl) oxy) ethan-1-ol Cpd-068C (150mg, 0.9mmol) in dichloromethane (2 mL) was added dropwise, maintaining the temperature no higher than-55 ℃. Stirring was carried out for half an hour while maintaining the same temperature, and then triethylamine (526 mg, 5.2mmol) was added dropwise while maintaining the temperature at not higher than-55 ℃ and after completion of the addition, the temperature was naturally raised to room temperature and stirring was carried out for 10 minutes. After the reaction was completed, the reaction solution was poured into water (100 mL), dichloromethane (50 mL × 2) was extracted, the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude 2- ((1, 1-trifluorobutan-2-yl) oxy) acetaldehyde Cpd-068D (180 mg, colorless oil), yield: 121 percent. The crude product was used directly in the next reaction without further purification.
The fourth step
Preparation of ethyl 4-methyl-3- ((2- ((1, 1-trifluorobutan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate
Ethyl 3-amino-4-methyl-1H-pyrrole-2-carboxylate (100mg, 0.59mmol) and 2- ((1, 1-trifluorobutan-2-yl) oxy) acetaldehyde Cpd-068D (132mg, 0.77mmol) were dissolved in methanol (10 mL), stirred under nitrogen with two drops of glacial acetic acid added dropwise for half an hour at room temperature, followed by sodium cyanoborohydride (112mg, 1.78mmol) for half an hour at room temperature. After the reaction was completed, the reaction solution was poured into water (100 mL), ethyl acetate (50 mL × 2) was extracted, the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product, which was separated and purified with a silica gel column (petroleum ether/ethyl acetate = 4/1) to give 4-methyl-3- ((2- ((1, 1-trifluorobutan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-068E (100 mg, colorless oil), yield: 52 percent.
MS m/z(ESI):323[M+1] + .
The fifth step
Preparation of ethyl 3- (3- (ethoxycarbonyl) -1- (2- ((1, 1-trifluorobutan-2-yl) oxy) ethyl) thioureido) -4-methyl-1H-pyrrole-2-carboxylate
Ethyl 4-methyl-3- ((2- ((1, 1-trifluorobutan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-068E (80mg, 0.25mmol) was dissolved in dichloromethane (3 mL) and ethoxycarbonyl isothiocyanate (65mg, 0.50mmol) was added dropwise at room temperature and stirred at room temperature for half an hour. After the reaction was complete, concentration gave crude ethyl 3- (3- (ethoxycarbonyl) -1- (2- ((1, 1-trifluorobutan-2-yl) oxy) ethyl) thioureido) -4-methyl-1H-pyrrole-2-carboxylate Cpd-068F (160 mg, colorless oil) in yield: 142 percent. The crude product was used directly in the next step without further purification.
MS m/z(ESI):454[M+1] + .
The sixth step
Preparation of 7-methyl-2-thioxo-1- (2- ((1, 1-trifluorobutan-2-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
3- (3- (ethoxycarbonyl) -1- (2- ((1, 1-trifluorobutan-2-yl) oxy) ethyl) thioureido) -4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-068F (160mg, 0.35mmol) was dissolved in methanol (7 mL), cesium carbonate (344mg, 1.06mmol) was added, and heated to 65 ℃ under nitrogen and stirred for 4 hours. After the reaction was completed, the reaction solution was poured into dilute aqueous hydrochloric acid (100mL, 1M), ethyl acetate (50 mL. Times.2) was extracted, the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product which was subjected to HPLC to preparative to give 7-methyl-2-thio-1- (2- ((1, 1-trifluorobutan-2-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-068 (23 mg, white solid) in yield: 19 percent.
MS m/z(ESI):336[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.22(s,1H),12.11(s,1H),7.17(s,1H),4.73(s,2H),4.11-3.99(m,2H),3.98-3.83(m,1H),2.31(s,3H),1.64-1.51(m,1H),1.47-1.33(m,1H),0.81(t,J＝7.4Hz,3H).
Example 69
7-methyl-2-thioxo-1- (2- ((1, 1-trifluoropentan-2-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850001201
First step of
Preparation of 1, 1-trifluoropentan-2-ol
Cpd-069A butyraldehyde (1.0 g,13.9 mmol) and trifluoromethyl trimethylsilane (3.9 g,27.8 mmol) were dissolved in dry tetrahydrofuran (10 mL), followed by dropwise addition of tetrabutylammonium fluoride tetrahydrofuran solution (20.9 mL,20.9mmol, 1M) under ice-cooling with nitrogen protection, and after completion of the dropwise addition, stirring was resumed at room temperature for two hours. After the reaction was completed, the reaction solution was diluted with water (100 mL), extracted with ethyl acetate (50 mL. Times.2), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated at room temperature to give crude 1, 1-trifluoropentan-2-ol Cpd-069B (1.6 g, colorless oil), yield: 81 percent. The crude product was used directly in the next step without further purification.
1 H NMR(400MHz,DMSO-d6)δ6.03(d,J＝6.8Hz,1H),3.93-3.81(m,1H),1.52-1.30(m,4H),0.93-0.85(m,3H).
Second step of
Preparation of ethyl 2- ((1, 1-trifluoropentan-2-yl) oxy) acetate
1, 1-Trifluoropentane-2-ol Cpd-069B (1.6 g,11.2 mmol) was dissolved in N, N-dimethylformamide (30 mL), sodium hydrogen (0.9g, 22.4mol) was added in ice bath, and stirred for half an hour under nitrogen protection, followed by ethyl bromoacetate (1.9g, 11.2mmol) added dropwise in ice bath, and then allowed to return to room temperature and stirred for two hours. After the reaction was completed, the reaction solution was quenched by pouring into an aqueous solution of ammonium chloride ice (300 mL), extracted with ethyl acetate (100 mL × 2), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated at room temperature with a filtrate, and the resulting crude product was purified with a silica gel column (petroleum ether/ethyl acetate = 10/1) to give ethyl 2- ((1, 1-trifluoropentan-2-yl) oxy) acetate Cpd-069C (1.3 g, colorless oil), yield: 51 percent.
1 H NMR(400MHz,DMSO-d6)δ4.39-4.27(m,2H),4.21-4.05(m,3H),1.64-1.36(m,4H),1.20(dd,J＝9.0,5.2Hz,3H),0.94-0.86(m,3H).
The third step
Preparation of 2- ((1, 1-trifluoropentan-2-yl) oxy) ethan-1-ol
Ethyl 2- ((1, 1-trifluoropentan-2-yl) oxy) acetate Cpd-069C (1.3g, 5.7 mmol) was dissolved in tetrahydrofuran (20 mL), a suspension of lithium aluminum tetrahydridofuran (8.6 mL,8.6mmol, 1M) was added dropwise under ice-bath, and stirring was continued for half an hour after completion of the dropwise addition. After the reaction was completed, the reaction solution was diluted with tetrahydrofuran (50 mL), an aqueous sodium hydroxide solution (0.6 mL, 2m) was dropped under ice bath, stirred for ten minutes, followed by addition of anhydrous sodium sulfate for drying, celite was filtered, and the filtrate was concentrated to give a crude product obtained by silica gel column (petroleum ether/ethyl acetate = 4/1) to give 2- ((1, 1-trifluoropentan-2-yl) oxy) ethan-1-ol Cpd-069D (0.7 g, colorless oil) in yield: 65 percent.
1 H NMR(400MHz,DMSO-d6)δ4.66(t,J＝5.4Hz,1H),3.99-3.92(m,1H),3.77-3.66(m,1H),3.62-3.54(m,1H),3.50(q,J＝5.2Hz,2H),1.55-1.37(m,4H),0.91(t,J＝6.9Hz,3H).
The fourth step
Preparation of 2- ((1, 1-trifluoropentan-2-yl) oxy) acetaldehyde
Oxalyl chloride (203mg, 1.6 mmol) was dissolved in dichloromethane (10 mL) with anhydrous sodium sulfate (50 mg) under nitrogen protection, and a diluted solution of anhydrous dimethyl sulfoxide (167mg, 2.1 mmol) in dichloromethane (1 mL) was added dropwise at-60 ℃. After 5 minutes, a solution of 2- ((1, 1-trifluoropentan-2-yl) oxy) ethan-1-ol Cpd-069D (200mg, 1.1mmol) in dichloromethane (3 mL) was added dropwise, maintaining the temperature no higher than-55 ℃. Stirring was carried out for half an hour while maintaining the same temperature, and then triethylamine (432mg, 4.3mmol) was added dropwise while maintaining the temperature at not higher than-55 ℃ and, after completion of the addition, the temperature was naturally raised to room temperature and stirring was carried out for 10 minutes. After the reaction was completed, the reaction solution was poured into a water (100 mL) solution, extracted with dichloromethane (50 mL × 2), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude 2- ((1, 1-trifluoropentan-2-yl) oxy) acetaldehyde Cpd-069E (220 mg, colorless oil) in yield: 111%. The crude product was used in the next reaction without further purification.
The fifth step
Preparation of ethyl 4-methyl-3- ((2- ((1, 1-trifluoropentan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate
Ethyl 3-amino-4-methyl-1H-pyrrole-2-carboxylate (100mg, 0.59mmol) and 2- ((1, 1-trifluoropentan-2-yl) oxy) acetaldehyde Cpd-069E (220mg, 1.10mmol) were dissolved in methanol (5 mL), stirred under nitrogen two drops of glacial acetic acid dropwise at room temperature for half an hour, followed by addition of sodium cyanoborohydride (187mg, 2.97mmol) at room temperature for half an hour. After the reaction was completed, the reaction solution was poured into a water (100 mL) solution, ethyl acetate (50 mL × 2) was extracted, the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 4/1) to obtain 4-methyl-3- ((2- ((1, 1-trifluoropentan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-069F (130 mg, colorless oil), yield: 65 percent.
MS m/z(ESI):337[M+1] + .
The sixth step
Preparation of ethyl 3- (3- (ethoxycarbonyl) -1- (2- ((1, 1-trifluoropentan-2-yl) oxy) ethyl) thioureido) -4-methyl-1H-pyrrole-2-carboxylate
Ethyl 4-methyl-3- ((2- ((1, 1-trifluoropentan-2-yl) oxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-069F (130mg, 0.39mmol) was dissolved in dichloromethane (5 mL), followed by dropwise addition of ethoxycarbonyl isothiocyanate (76mg, 0.58mmol) at room temperature and stirring at room temperature for half an hour. After the reaction was complete, concentration gave crude ethyl 3- (3- (ethoxycarbonyl) -1- (2- ((1, 1-trifluoropentan-2-yl) oxy) ethyl) thioureido) -4-methyl-1H-pyrrole-2-carboxylate Cpd-069G (180 mg, colorless oil) in yield: 99 percent. The crude product was used directly in the next step without further purification.
MS m/z(ESI):468[M+1] + .
Seventh step
Preparation of 7-methyl-2-thioxo-1- (2- ((1, 1-trifluoropentan-2-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
3- (3- (ethoxycarbonyl) -1- (2- ((1, 1-trifluoropentan-2-yl) oxy) ethyl) thioureido) -4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-069G (180mg, 0.38mmol) was dissolved in methanol (10 mL), cesium carbonate (375mg, 1.15mmol) was added, and the mixture was heated to 65 ℃ under nitrogen and stirred for 4 hours. After the reaction was completed, the reaction solution was poured into an aqueous ammonium chloride solution (100 mL), ethyl acetate (50 mL × 2) was extracted, and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product which was subjected to HPLC preparation to give 7-methyl-2-thio-1- (2- ((1, 1-trifluoropentan-2-yl) oxy) ethyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-069 (6 mg, white solid) with a yield: 4 percent.
MS m/z(ESI):350[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.15(s,2H),7.17(s,1H),4.72(s,2H),4.12-3.92(m,3H),2.30(s,3H),1.48-1.32(m,2H),1.26-1.16(m,2H),0.77(t,J＝7.3Hz,3H).
Example 70
1- (4-chloro-3- (fluoromethoxy) benzyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850001221
First step of
Preparation of 4-chloro-3- (fluoromethoxy) benzaldehyde
4-chloro-3-hydroxybenzaldehyde Cpd-070A (500mg, 3.19mmol) is dissolved in acetonitrile (10 mL), then potassium carbonate (1.324g, 9.58mmol) and iodofluoromethane (612.88mg, 3.83mmol) are added in sequence, after the addition is finished, stirring is carried out at room temperature for 4 hours, after the reaction is finished, water (20 mL) is added for quenching, extraction is carried out by ethyl acetate, an organic phase is washed twice by saturated aqueous sodium chloride solution, drying is carried out by anhydrous sodium sulfate, spin-drying is carried out to obtain a crude product, and a product, namely 4-chloro-3- (fluoromethoxy) benzaldehyde Cpd-070B (0.5 g, white solid) is obtained after separation and purification by a silica gel column (petroleum ether/ethyl acetate = 2/1), and the yield: 83 percent.
1 H NMR(400MHz,CDCl 3 )δ9.97(s,1H),7.70(s,1H),7.63–7.54(m,2H),5.89(s,1H),5.76(s,1H).
Second step of
Preparation of ethyl 3- ((4-chloro-3- (fluoromethoxy) benzyl) amino) -1H-pyrrole-2-carboxylate
4-chloro-3- (fluoromethoxy) benzaldehyde Cpd-070B (200mg, 1.06mmol) was dissolved in methanol (10 mL), followed by the addition of ethyl 3-amino-1H-pyrrole-2-carboxylate (179.84mg, 1.1665 mmol) and acetic acid (6.37mg, 0.1060 mmol) in that order, the reaction was stirred at room temperature for 30 minutes, followed by the addition of sodium cyanoborohydride (133.28mg, 2.12mmol), and the solution was stirred at room temperature for 16 hours. After the reaction is finished, water is added for quenching, dichloromethane is used for extraction, an organic phase is washed twice by saturated saline solution, anhydrous sodium sulfate is dried, a crude product is obtained by spin drying, and a product of ethyl 3- ((4-chloro-3- (fluoromethoxy) benzyl) amino) -1H-pyrrole-2-carboxylate Cpd-070C (250 mg, yellow oily substance) is obtained after separation and purification by a silica gel column (petroleum ether/ethyl acetate = 2/1), wherein the yield is 72%.
MS m/z(ESI)：327(M+1).
The third step
Preparation of ethyl 3- (1- (4-chloro-3- (fluoromethoxy) benzyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate
Ethyl 3- ((4-chloro-3- (fluoromethoxy) benzyl) amino) -1H-pyrrole-2-carboxylate Cpd-070C (250mg, 0.765mmol) was dissolved in dichloromethane (20 mL), cooled to 0 deg.C, and ethyl isothiocyanatocarboxylate (120.41mg, 0.9181mmol) was added thereto, followed by stirring at 0 deg.C for 3 hours. After completion of the reaction, the reaction mixture was washed once with water (20 mL), and the organic layer was dried over anhydrous sodium sulfate and concentrated. The obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 1/1) to obtain ethyl 3- (1- (4-chloro-3- (fluoromethoxy) benzyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-070D (300 mg, yellow oil) in 86% yield.
MS m/z(ESI)：458(M+1).
The fourth step
Preparation of 1- (4-chloro-3- (fluoromethoxy) benzyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Ethyl 3- (1- (4-chloro-3- (fluoromethoxy) benzyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-070D (200mg, 0.44mmol) was dissolved in methanol (10 mL), cesium carbonate (426.95mg, 1.31mmol) was added thereto, and the reaction solution was heated to 90 ℃ for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and then the solution was spun dry to give a crude product, which was isolated and purified by Prep-HPLC (acetonitrile/water (0.1% formic acid)) to give 1- (4-chloro-3- (fluoromethoxy) benzyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-070 (133.69 mg, white solid) with a yield of 86%.
MS m/z(ESI)：340(M+1).
1 H NMR(400MHz,CDCl 3 )δ12.41(s,2H),7.44(d,J＝8.4Hz,2H),7.32(d,J＝2.8Hz,1H),7.01(d,J＝8.2Hz,1H),6.18(d,J＝2.8Hz,1H),5.96(s,1H),5.82(s,1H),5.71(s,2H).
Example 71
1- (4-chloro-3- (trifluoromethoxy) benzyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850001231
First step of
Preparation of ethyl 3- ((4-chloro-3- (trifluoromethoxy) benzyl) amino) -1H-pyrrole-2-carboxylate
4-chloro-3- (trifluoromethoxy) benzaldehyde Cpd-071A (300mg, 1.34mmol) was dissolved in methanol (20 mL), 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester (247mg, 1.60mmol) and acetic acid (1 drop) were added and the reaction stirred at room temperature for 1H. Sodium cyanoborohydride (252mg, 4.01mmol) was added to the solution, and the reaction was stirred at room temperature for an additional 1 hour. After the reaction, the reaction solution was extracted with dichloromethane (3x 10mL), and the organic phase was washed with supersaturated brine, and then the solvent was spin-dried to obtain a crude product. The crude product was isolated and purified by column chromatography (petroleum ether/ethyl acetate) to give ethyl 3- ((4-chloro-3- (trifluoromethoxy) benzyl) amino) -1H-pyrrole-2-carboxylate Cpd-071B (450 mg, white solid) in yield: 93 percent.
MS m/z(ESI)363.1(M+1).
Second step of
Preparation of ethyl 3- (1- (4-chloro-3- (trifluoromethoxy) benzyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate
Ethyl 3- ((4-chloro-3- (trifluoromethoxy) benzyl) amino) -1H-pyrrole-2-carboxylate Cpd-071B (450mg, 1.24mmol) was dissolved in dichloromethane (5 mL), ethoxycarbonyl isothiocyanate (179mg, 1.36mmol) was added and the reaction stirred at room temperature for 2H. After the reaction, the reaction solution was extracted with dichloromethane (10x3ml), and the organic phase was washed with supersaturated brine, and then the solvent was spin-dried to obtain a crude product. The crude product was isolated and purified by column chromatography (petroleum ether/ethyl acetate) to give ethyl 3- (1- (4-chloro-3- (trifluoromethoxy) benzyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-071C (359 mg, white solid) in yield: 53 percent.
MS m/z(ESI)494.0(M+1).
The third step
Preparation of 1- (4-chloro-3- (trifluoromethoxy) benzyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Ethyl 3- (1- (4-chloro-3- (trifluoromethoxy) benzyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-071C (330mg, 0.69mmol) was dissolved in methanol (5 mL), cesium carbonate (653mg, 2.00mmol) was added and the reaction stirred at 80 ℃ for 4H. After the reaction, the reaction mixture was purified by methylene chloride (3 ×) 10 mL), washing an organic phase by supersaturated salt solution, and spin-drying the solvent to obtain a crude product. The crude product was purified by Prep-HPLC (CAN/H) 2 O (0.1% FA)) to obtain 1- (4-chloro-3- (trifluoromethoxy) benzyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ]]Pyrimidin-4-one Cpd-071 (9.63 mg, white solid), yield: 4 percent.
MS m/z(ESI):376.0(M+1).
1 H NMR(400MHz,DMSO-d6)δ12.10(br,1H),7.62(d,J＝8.4Hz,2H),7.35(d,J＝8.4Hz,1H),7.15(s,1H),6.05(s,1H),5.75(s,2H).
19 F NMR(376MHz,DMSO-d6)δ-56.92.
Example 72
1- (4-chloro-3- (1-hydroxyethyl) benzyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850001241
First step of
Preparation of 2-bromo-1-chloro-4- (dimethoxymethyl) benzene
3-bromo-4-chlorobenzaldehyde Cpd-072A (4 g, 18.2mmol), trimethyl orthoformate (9.66g, 91mmol) and p-toluenesulfonic acid (0.63g, 0.4 mmol) were dissolved in methanol (50 mL) and reacted at 70 ℃ for 16h. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (ethyl acetate/petroleum ether = 12/88) to give 2-bromo-1-chloro-4- (dimethoxymethyl) benzene Cpd-072B (3.1 g, colorless oily liquid), yield: and 64 percent.
1 H NMR(400MHz,CDCl 3 )δ7.73(d,J＝2.0Hz,1H),7.44(d,J＝8.4Hz,1H),7.32(dd,J＝8.4,2.0Hz,1H),5.35(s,1H),3.31(s,6H).
Second step of
Preparation of 2-chloro-5- (dimethoxymethyl) benzaldehyde
2-bromo-1-chloro-4- (dimethoxymethyl) benzene Cpd-072B (500mg, 1.9 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), n-butyllithium (0.92mL, 2.3mmol,2.5M in hexane) was slowly added dropwise at-70 ℃ and reacted at-70 ℃ for 1 hour after the addition was completed. Anhydrous N, N-dimethylformamide (165mg, 2.3 mmol) was slowly added dropwise at-70 ℃ and after completion of the addition, the temperature was slowly raised to room temperature. Quenching the reaction solution by using a saturated ammonium chloride solution, extracting by using ethyl acetate, washing by using saturated sodium chloride water, and drying by using anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure, and purification of the resulting residue by column chromatography (ethyl acetate/petroleum ether = 13/87) gave 2-chloro-5- (dimethoxymethyl) benzaldehyde Cpd-072C (250 mg, colorless oily liquid), yield: 62 percent.
1 H NMR(400MHz,CDCl 3 )δ10.49(s,1H),8.02(d,J＝2.2Hz,1H),7.64(dd,J＝8.2,2.2Hz,1H),7.47(d,J＝8.2Hz,1H),5.41(s,1H),3.32(s,6H).
The third step
Preparation of 1- (2-chloro-5- (dimethoxymethyl) phenyl) ethan-1-ol
2-chloro-5- (dimethoxymethyl) benzaldehyde Cpd-072C (250mg, 1.2mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) and methyl magnesium bromide (208mg, 1.7mmol,3M in Et was slowly added dropwise at 0 ℃ 2 O), reacting at room temperature for 2 hours after the dropwise addition is finished. The reaction solution was poured into a precooled saturated ammonium chloride solution, extracted with ethyl acetate, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate under reduced pressure and column chromatography (ethyl acetate/petroleum ether = 3/7) of the resulting residue afforded 1- (2-chloro-5- (dimethoxymethyl) phenyl) ethan-1-ol Cpd-072D (170 mg, colorless oily liquid), yield: and 63 percent.
1 H NMR(400MHz,DMSO-d 6 )δ7.66(d,J＝2.2Hz,1H),7.37(d,J＝8.2Hz,1H),7.24(dd,J＝8.2,2.2Hz,1H),5.41(d,J＝4.4Hz,1H),5.40(s,1H),5.02(dd,J＝6.4,4.4Hz,1H),3.25(s,6H),1.30(d,J＝6.4Hz,3H).
The fourth step
Preparation of 4-chloro-3- (1-hydroxyethyl) benzaldehyde
1- (2-chloro-5- (dimethoxymethyl) phenyl) ethan-1-ol Cpd-072D (150mg, 0.7 mmol) was dissolved in the mixed solution of tetrahydrofuran/concentrated HCl =2/1 (6 mL) and reacted at room temperature for 1h. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with saturated sodium bicarbonate solution and sodium chloride solution, respectively, and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure gave 4-chloro-3- (1-hydroxyethyl) benzaldehyde Cpd-072E (110 mg, orange-red liquid), yield: 92 percent.
MS m/z(ESI)：185.0(M+1).
The fifth step
Preparation of ethyl 3- ((4-chloro-3- (1-hydroxyethyl) benzyl) amino) -1H-pyrrole-2-carboxylate
4-chloro-3- (1-hydroxyethyl) benzaldehyde Cpd-072E (100mg, 0.5mmol), ethyl 3-amino-1H-pyrrole-2-carboxylate (100mg, 0.7 mmol), catalytic amount of acetic acid and molecular sieves were dissolved in 1, 2-dichloroethane (10 mL) and reacted at room temperature for 1H. Then, sodium triacetoxyborohydride (345mg, 1.6mmol) was added and reacted at room temperature for 16 hours. The reaction was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (ethyl acetate/petroleum ether = 3/7) to give ethyl 3- ((4-chloro-3- (1-hydroxyethyl) benzyl) amino) -1H-pyrrole-2-carboxylate Cpd-072F (130 mg, pale yellow oily liquid), yield: 74 percent.
MS m/z(ESI)：323.2(M+1).
The sixth step
Preparation of ethyl 3- (1- (4-chloro-3- (1-hydroxyethyl) benzyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylate
Compound Cpd-072F (100mg, 0.3 mmol) was dissolved in dichloromethane (5 mL), ethyl isothiocyanatecarboxylate (122mg, 0.9 mmol) was added and the reaction was allowed to proceed at room temperature for 1h. The reaction was concentrated under reduced pressure and the resulting residue was purified by column chromatography (ethyl acetate/petroleum ether =3/7 followed by methanol/dichloromethane = 2.5/97.5) to give ethyl 3- (1- (4-chloro-3- (1-hydroxyethyl) benzyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylate Cpd-072G (130 mg, light yellow oily liquid), yield: 92 percent.
MS m/z(ESI)：454.1(M+1).
Seventh step
Preparation of 1- (4-chloro-3- (1-hydroxyethyl) benzyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Ethyl 3- (1- (4-chloro-3- (1-hydroxyethyl) benzyl) -3- (ethoxycarbonyl) thiourea) -1H-pyrrole-2-carboxylate Cpd-072G (100mg, 0.2mmol) was dissolved in methanol (5 mL), sodium methoxide (36mg, 0.7 mmol) was added and the reaction was carried out at 70 ℃ for 4H. The reaction was concentrated under reduced pressure and the resulting residue was purified by prep-HPLC (acetonitrile/water (0.1% formic acid) = 44/56) to give 1- (4-chloro-3- (1-hydroxyethyl) benzyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-072 (42.83 mg, white solid) in yield: 58 percent.
MS m/z(ESI)：336.0(M+1).
1 H NMR(400MHz,DMSO-d 6 )δ12.46(s,1H),12.34(s,1H),7.63(d,J＝2.2Hz,1H),7.34–7.29(m,2H),7.14(dd,J＝8.2,2.2Hz,1H),6.13(d,J＝2.8Hz,1H),5.77-5.64(m,2H),5.36(d,J＝4.0Hz,1H),5.01–4.93(m,1H),1.26(d,J＝6.4Hz,3H).
Example 73
1- (4-chloro-3- (2, 2-trifluoroethoxy) benzyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850001251
First step of
Preparation of 4-chloro-3- (2, 2-trifluoroethoxy) benzaldehyde
4-chloro-3-hydroxybenzaldehyde Cpd-073A (300mg, 1.92mmol) was dissolved in DMF (10 mL) and 2, 2-trifluoroethyl trifluoromethanesulfonate (447mg, 1.91mmol) and cesium carbonate (936mg, 2.87mmol) were added. The reaction was stirred at 60 ℃ for 16 hours. After the reaction is finished, extracting the reaction liquid by using dichloromethane (3x 10mL), washing an organic phase by using supersaturated salt solution, drying the solvent by spinning to obtain a crude product, and separating and purifying by using column chromatography (petroleum ether/ethyl acetate) to obtain 4-chloro-3- (2, 2-trifluoroethoxy) benzaldehyde Cpd-073B (450 mg, light yellow oily liquid), wherein the yield is as follows: 99 percent.
1 H NMR(400MHz,DMSO-d6)δ9.95(s,1H),7.75–7.70(m,2H),7.61(d,J＝8.0Hz,1H),4.98(q,J＝8.8Hz,2H).
Second step of
Preparation of ethyl 3- ((4-chloro-3- (2, 2-trifluoroethoxy) benzyl) amino) -1H-pyrrole-2-carboxylate
4-chloro-3- (2, 2-trifluoroethoxy) benzaldehyde Cpd-073B (300mg, 1.25mmol) was dissolved in methanol (20 mL), ethyl 3-amino-1H-pyrrole-2-carboxylate (290mg, 1.88mmol) and acetic acid (1 drop) were added and the reaction was stirred at room temperature for 1 hour. To the solution was added sodium cyanoborohydride (236 mg, 3.76mmol), and the reaction was stirred at room temperature for additional 1 hour. After the reaction is finished, extracting the reaction solution by using dichloromethane (3x 10mL), washing an organic phase by using supersaturated salt solution, carrying out spin-drying on the solvent to obtain a crude product, and separating and purifying by using column chromatography (petroleum ether/ethyl acetate) to obtain 3- ((4-chloro-3- (2, 2-trifluoroethoxy) benzyl) amino) -1H-pyrrole-2-ethyl formate Cpd-073C (276 mg, white solid), wherein the yield is as follows: 59 percent.
1 H NMR(400MHz,DMSO-d6)δ10.77(s,1H),7.40(d,J＝8.0Hz,1H),7.29(d,J＝1.2Hz,1H),7.03(dd,J＝8.0,1.2Hz,1H),6.70(t,J＝3.2Hz,1H),5.84(s,1H),5.57(t,J＝2.4Hz,1H),4.83(q,J＝8.8Hz,2H),4.27(d,J＝6.4Hz,2H),4.20(q,J＝7.2Hz,2H),1.17(t,J＝7.2Hz,3H).
The third step
Preparation of ethyl 3- (1- (4-chloro-3- (2, 2-trifluoroethoxy) benzyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate
Ethyl 3- ((4-chloro-3- (2, 2-trifluoroethoxy) benzyl) amino) -1H-pyrrole-2-carboxylate Cpd-073C (250mg, 0.66mmol) was dissolved in dichloromethane (5 mL), ethoxycarbonyl isothiocyanate (87mg, 0.66mmol) was added and the reaction stirred at room temperature for 2 hours. After the reaction, the reaction solution was extracted with dichloromethane (10mL × 3), the organic phase was washed with supersaturated saline solution, and the solvent was dried by spin drying to obtain a crude product, which was separated and purified by column chromatography (petroleum ether/ethyl acetate) to obtain 3- (1- (4-chloro-3- (2, 2-trifluoroethoxy) benzyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-073D (232 mg, white solid), yield: and 69 percent.
1 H NMR(400MHz,DMSO-d6)δ11.97(s,1H),9.50(s,1H),7.39(d,J＝8.0Hz,1H),7.24(s,1H),7.06(d,J＝8.0Hz,1H),6.90(t,J＝3.2Hz,1H),6.02(t,J＝2.4Hz,1H),5.74(d,J＝15.6Hz,1H),5.04(d,J＝14.8Hz,1H),4.75(dt,J＝13.2,6.8Hz,2H),4.29–4.11(m,2H),3.94(d,J＝7.2Hz,2H),1.27(t,J＝7.2Hz,3H),1.08(t,J＝7.2Hz,3H).
The fourth step
Preparation of 1- (4-chloro-3- (2, 2-trifluoroethoxy) benzyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Ethyl 3- (1- (4-chloro-3- (2, 2-trifluoroethoxy) benzyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-073D (200mg, 0.39mmol) was dissolved in methanol (5 mL), cesium carbonate (256 mg, 0.78mmol) was added and the reaction stirred at 80 ℃ for 4 hours. After the reaction, the reaction solution was extracted with dichloromethane (3x 10mL), the organic phase was washed with supersaturated brine, and the solvent was spin-dried to obtain a crude product, which was then subjected to Prep-HPLC (CAN/H) 2 O (0.1% FA)) to obtain 1- (4-chloro-3- (2, 2-trifluoroethoxy) benzyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ]]Pyrimidin-4-one Cpd-073 (13.39 mg, white solid), yield: 9 percent.
MS m/z(ESI):390.1(M+1).
1 H NMR(400MHz,DMSO-d6)δ11.81(br,1H),7.42(s,1H),7.36(d,J＝8.0Hz,1H),7.05(s,1H),6.93(d,J＝1.6Hz,1H),5.95(s,1H),5.71(s,2H),4.84(q,J＝8.0Hz,2H).
19 F NMR(376MHz,DMSO-d6)δ-72.70.
Example 74
1- (4-chloro-3- (difluoromethoxy) benzyl) -2-thioxo-6-phenyl-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850001271
First step of
Preparation of 3- (4-toluenesulfonyloxy) -3-phenylprop-2-enenitrile
3-oxo-3-phenylpropionitrile Cpd-074A (5.0 g, 34mmol) and p-methylbenzenesulfonyl chloride (7.9 g, 41mmol) were dissolved in dichloromethane (100 mL) and triethylamine (5.2 g, 52mmol) was added dropwise at 0 ℃ under nitrogen. After completion of the dropwise addition, the reaction solution was allowed to return to room temperature and stirred for 1 hour. After the reaction was completed, the reaction solution was diluted with water (200 mL), dichloromethane (100 mL × 2) was extracted, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated at room temperature to obtain a crude product, which was purified by a silica gel column (petroleum ether/ethyl acetate = 4/1), and the purified crude product was recrystallized from a mixed solvent (petroleum ether/ethyl acetate = 4/1) to obtain 3- (4-tosyloxy) -3-phenylprop-2-enenitrile Cpd-074B (3.0 g, yellow solid), yield: 29 percent.
1 H NMR(400MHz,DMSO-d6)δ7.80(d,J＝8.4Hz,2H),7.56-7.36(m,7H),6.61(s,1H),2.41(s,3H).
Second step of
Preparation of 3-amino-5-phenyl-1H-pyrrole-2-carboxylic acid ethyl ester
3- (4-Toluenesulfonyloxy) -3-phenylprop-2-enenitrile Cpd-074B (3.0g, 10mmol) and diethyl 2-aminomalonate hydrochloride (2.54g, 12mmol) were dissolved in a mixed solvent of absolute ethanol (40 mL) and absolute tetrahydrofuran (20 mL), and the mixed solution was added dropwise to an ethanol solution of sodium ethoxide (23.5mL, 47mmol, 2M) at 0 ℃ under nitrogen protection. After the dropwise addition, the ice bath was removed and the mixture was returned to room temperature and stirred for 2 hours. After the reaction was completed, the reaction solution was quenched by pouring into an aqueous solution of ammonium chloride ice (200 mL), extracted with ethyl acetate (100 mL × 2), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated at room temperature in the filtrate, and the resulting crude product was purified with a silica gel column (petroleum ether/ethyl acetate = 4/1), and the resulting solid was recrystallized with a mixed solvent of petroleum ether and ethyl acetate to give ethyl 3-amino-5-phenyl-1H-pyrrole-2-carboxylate Cpd-074C (1.0 g, tan solid), yield: 32 percent.
MS m/z(ESI):231[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ10.74(s,1H),7.80-7.69(m,2H),7.36(t,J＝7.6Hz,2H),7.26(t,J＝7.3Hz,1H),6.00(d,J＝2.8Hz,1H),5.10(s,2H),4.23(q,J＝7.1Hz,2H),1.30(t,J＝7.1Hz,3H).
The third step
Preparation of ethyl 3- ((4-chloro-3- (difluoromethoxy) benzyl) amino) -5-phenyl-1H-pyrrole-2-carboxylate
Ethyl 3-amino-5-phenyl-1H-pyrrole-2-carboxylate Cpd-074C (120mg, 0.52mmol), 4-chloro-3- (difluoromethoxy) benzaldehyde (129mg, 0.62mmol) was dissolved in a mixed solvent of methanol (5 mL) and tetrahydrofuran (5 mL), and two drops of glacial acetic acid were added dropwise under nitrogen and stirred at room temperature for half an hour. Sodium cyanoborohydride (164mg, 2.61mmol) was added and stirring continued at room temperature for half an hour. After the reaction was completed, the reaction solution was poured into water (100 mL), ethyl acetate (50 mL × 2) was extracted, the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the crude product was separated and purified with a silica gel column (petroleum ether/ethyl acetate = 4/1) to obtain ethyl 3- ((4-chloro-3- (difluoromethoxy) benzyl) amino) -5-phenyl-1H-pyrrole-2-carboxylate Cpd-074D (130 mg, white solid), yield: 59 percent.
MS m/z(ESI):421[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ10.97(s,1H),7.79-7.69(m,2H),7.54(d,J＝8.2Hz,1H),7.44-7.20(m,6H),6.12(dd,J＝7.1,2.7Hz,1H),6.01(s,1H),4.38(d,J＝6.5Hz,2H),4.26(q,J＝7.1Hz,2H),1.31(t,J＝7.1Hz,3H).
The fourth step
Preparation of ethyl 3- (1- (4-chloro-3- (difluoromethoxy) benzyl) -3- (ethoxycarbonyl) thioureido) -5-phenyl-1H-pyrrole-2-carboxylate
Ethyl 3- ((4-chloro-3- (difluoromethoxy) benzyl) amino) -5-phenyl-1H-pyrrole-2-carboxylate Cpd-074D (110mg, 0.26mmol) was dissolved in dichloromethane (5 mL) followed by the dropwise addition of ethoxycarbonyl isothiocyanate (51mg, 0.39mmol) and stirred at room temperature for half an hour. After the reaction was complete, concentration gave crude 3- (1- (4-chloro-3- (difluoromethoxy) benzyl) -3- (ethoxycarbonyl) thioureido) -5-phenyl-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-074E (150 mg, colorless oil) in yield: 103 percent. The crude product was used directly in the next step without further purification.
MS m/z(ESI):552[M+1] + .
The fifth step
Preparation of 1- (4-chloro-3- (difluoromethoxy) benzyl) -2-thio-6-phenyl-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Ethyl 3- (1- (4-chloro-3- (difluoromethoxy) benzyl) -3- (ethoxycarbonyl) thioureido) -5-phenyl-1H-pyrrole-2-carboxylate Cpd-074E (150mg, 0.27mmol) was dissolved in methanol (5 mL), cesium carbonate (266mg, 0.81mmol) was added, and the mixture was heated to 65 ℃ under nitrogen and stirred for 8 hours. After the reaction was completed, the reaction solution was poured into dilute aqueous hydrochloric acid (100mL, 1M), ethyl acetate (50 mL. Times.2) was extracted, the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the crude product was sent to HPLC for preparative 1- (4-chloro-3- (difluoromethoxy) benzyl) -2-thio-6-phenyl-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-074 (3 mg, white solid) in yield: 3 percent.
MS m/z(ESI):434[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.80(s,1H),12.42(s,1H),7.86(d,J＝7.4Hz,2H),7.61-7.49(m,2H),7.48-6.72(m,6H),5.73(s,2H).
Example 75
1- (2- (1- (trifluoromethyl) -3-oxetanyloxy) ethyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850001281
First step of
Preparation of 3- (trifluoromethyl) -1-oxetan-3-ol
3-Oxetanone Cpd-086A (10.0 g, 0.14mol) and trifluoromethyltrimethylsilane (20.7g, 0.15mmol) were dissolved in anhydrous tetrahydrofuran (200 mL), followed by dropwise addition of tetrabutylammonium fluoride tetrahydrofuran solution (150mL, 0.15mol, 1M) under ice bath with nitrogen protection, and after completion of the dropwise addition, stirring was resumed at room temperature for two hours. After the reaction was completed, the reaction solution was diluted with water (400 mL), extracted with ethyl acetate (100 mL × 2), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated at room temperature to give crude 3- (trifluoromethyl) -1-oxetan-3-ol Cpd-086B (19.0 g, colorless oil), yield: 96 percent. The crude product was used directly in the next step without further purification.
Second step of
Preparation of ethyl 2- (1- (trifluoromethyl) -3-oxetanyloxy) acetate
3- (trifluoromethyl) -1-oxetan-3-ol Cpd-086B (19.7 g, 0.14mol) was dissolved in N, N-dimethylformamide (200 mL), sodium hydrogen (6.6 g, 0.17mol) was added under ice bath, stirred for half an hour under nitrogen blanket, ethyl bromoacetate (25.3g, 0.15mol) was added dropwise under ice bath, and stirred for two hours returning to room temperature. After the reaction was completed, the reaction solution was quenched by pouring into an aqueous solution of ice ammonium chloride (500 mL), extracted with ethyl acetate (200 mL × 2), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated at room temperature to give a crude product, which was purified with a silica gel column (petroleum ether/ethyl acetate = 4/1) to give ethyl 2- (1- (trifluoromethyl) -3-oxetanyloxy) acetate Cpd-086C (11.4 g, colorless oil), yield: 36 percent.
1 H NMR(400MHz,DMSO-d6)δ4.80(dd,J＝9.5,1.5Hz,2H),4.63(d,J＝9.3Hz,2H),4.47(s,2H),4.16(q,J＝7.1Hz,2H),1.21(t,J＝7.1Hz,2H).
The third step
Preparation of 2- (1- (trifluoromethyl) -3-oxocyclobutoxy) ethan-1-ol
Ethyl 2- (1- (trifluoromethyl) -3-oxetanyloxy) acetate, cpd-086C (6.0 g, 26.2mmol), was dissolved in ethanol (70 mL) and sodium borohydride (3.0 g,78.6 mmol) was added slowly. The reaction solution was heated to 40 ℃ and stirred for one hour. After the reaction was completed, the reaction solution was quenched by pouring into an aqueous solution of ice ammonium chloride (300 mL), extracted with ethyl acetate (100 mL × 2), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated at room temperature to give a crude product, which was then purified by silica gel column (petroleum ether/ethyl acetate = 2/1) to give 2- (1- (trifluoromethyl) -3-oxocyclobutoxy) ethane-1-ol Cpd-086D (4.0 g, colorless oil), yield: 82 percent.
1 H NMR(400MHz,DMSO-d6)δ4.82(t,J＝5.5Hz,1H),4.78(d,J＝7.6Hz,2H),4.64(d,J＝8.6Hz,2H),3.67(t,J＝4.9Hz,2H),3.55(dd,J＝10.2,5.1Hz,2H).
The fourth step
Preparation of 2- (1- (trifluoromethyl) -3-oxacyclobutoxy) acetaldehyde
Oxalyl chloride (4.2 g,32.9 mmol) was dissolved in dichloromethane (100 mL) with anhydrous sodium sulfate (1000 mg) under nitrogen, and a solution of anhydrous dimethyl sulfoxide (5.1 g,65.7 mmol) in dichloromethane (20 mL) was added dropwise at-60 ℃. After 5 minutes, a solution of 2- (1- (trifluoromethyl) -3-oxocyclobutoxy) ethane-1-ol Cpd-086D (5.6 g,29.9 mmol) in dichloromethane (10 mL) was added dropwise, maintaining the temperature no higher than-60 ℃. Stirring is carried out for half an hour while maintaining the same temperature, then triethylamine (12.1g, 119.6 mmol) is added dropwise while maintaining the temperature at not higher than 60 ℃, stirring is carried out for half an hour while maintaining the same temperature after completion of the addition, and then stirring is carried out for 10 minutes while naturally rising to room temperature. After completion of the reaction, the reaction mixture was poured into water (300 mL), extracted with dichloromethane (100 mL × 2), and the combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude 2- (1- (trifluoromethyl) -3-oxetanyloxy) acetaldehyde Cpd-086E (5.0 g, colorless oil) in yield: 90 percent. The crude product was used directly in the next reaction without further purification.
The fifth step
Preparation of ethyl 3- ((2- (1- (trifluoromethyl) -3-oxocyclobutoxy) ethyl) amino) -1H-pyrrole-2-carboxylate
3-amino-4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (4.2g, 27.0 mmol) and 2- (1- (trifluoromethyl) -3-oxocyclobutoxy) acetaldehyde Cpd-086E (5.0 g,27.0 mmol) were dissolved in methanol (70 mL), tetraisopropyl titanate (10.0 g, 35.10 mmol) was added, heated to 40 ℃ under nitrogen blanket and stirred for half an hour, followed by addition of sodium cyanoborohydride (11.4g, 54.0 mmol) and stirring at room temperature for half an hour. After the reaction was completed, the reaction solution was diluted with dichloromethane (300 mL), water (20 mL) was added dropwise with stirring until no solid separated, the solid-liquid mixture was filtered through celite, the residue was washed with a mixed solvent (DCM/MeOH =10/1, 200 mL), the combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was separated and purified with a silica gel column (petroleum ether/ethyl acetate = 2/1) to give 3- ((2- (trifluoromethyl) -3-oxacyclobutoxy) ethyl) amino) -1H-pyrrole-2-carboxylic acid ethyl ester Cpd-086F (5.0 g, colorless oil), yield: 57 percent.
MS m/z(ESI):323[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ10.79(s,1H),6.77(t,J＝3.0Hz,1H),5.71(t,J＝2.6Hz,1H),5.44(s,1H),4.67(dd,J＝30.6,8.2Hz,4H),4.18(q,J＝7.1Hz,2H),3.79(t,J＝5.3Hz,2H),3.30(d,J＝6.2Hz,2H),1.25(dd,J＝8.5,5.7Hz,3H).
The sixth step
Preparation of ethyl 3- (1- (2- (1- (trifluoromethyl) oxocyclobutoxy) ethyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate
Ethyl 3- ((2- (1- (trifluoromethyl) -3-oxetanyloxy) ethyl) amino) -1H-pyrrole-2-carboxylate Cpd-086F (5.0g, 15.5mmol) was dissolved in acetonitrile (70 mL), followed by dropwise addition of ethoxycarbonyl isothiocyanate (4.1g, 31mmol) at room temperature and stirring at room temperature for half an hour. After the reaction was completed, concentration was performed, and the crude product was isolated and purified by a silica gel column (petroleum ether/ethyl acetate = 2/1) to obtain ethyl 3- (1- (2- (1- (trifluoromethyl) oxocyclobutoxy) ethyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-086G (6.7G, colorless oil), yield: 95 percent.
MS m/z(ESI):454[M+1] + .
1 H NMR(400MHz,DMSO-d 6 )δ11.99(s,1H),9.32(s,1H),6.99(t,J＝3.1Hz,1H),6.15(t,J＝2.6Hz,1H),4.72-4.58(m,4H),4.42(s,1H),4.27-4.05(m,4H),3.98-3.81(m,3H),1.25(t,J＝7.1Hz,3H),1.07(t,J＝7.1Hz,3H).
Seventh step
Preparation of 1- (2- (1- (trifluoromethyl) -3-oxetanyloxy) ethyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Ethyl 3- (1- (2- (1- (trifluoromethyl) oxocyclobutoxy) ethyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-086G (6.7g, 14.8mmol) was dissolved in methanol (100 mL), cesium carbonate (14.5g, 44.4mmol) was added, and the mixture was heated to 65 ℃ under nitrogen and stirred for 8 hours. After the reaction was completed, the reaction solution was poured into dilute aqueous hydrochloric acid (1 mol/L,200 mL), ethyl acetate (100 mL × 2) was extracted, the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was slurried with a mixed solvent (dichloromethane/methanol =10/1, 100 mL) to give 1- (2- (1- (trifluoromethyl) -3-oxetanyloxy) ethyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-086 (3.1 g, white solid), yield: 62 percent.
MS m/z(ESI):336[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.38(s,1H),12.27(s,1H),7.36(t,J＝3.0Hz,1H),6.40-6.31(m,1H),4.63(t,J＝5.7Hz,2H),4.60(s,4H),4.09(t,J＝5.6Hz,2H).
Example 76
1- (3- (difluoromethoxy) -4-fluorobenzyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850001301
First step of
Preparation of 3- (difluoromethoxy) -4-fluorobenzaldehyde
4-bromo-1-fluoro-2- (difluoromethoxy) benzene Cpd-087A (1.0g, 4.1mmol), dichlorodi-tert-butyl- (4-dimethylaminophenyl) phosphorus Palladium (II) (290mg, 0.4 mmol), triethylsilane (1.2g, 10.3mmol), and N, N-diisopropylethylamine (1.3g, 10.3mmol) were dissolved in dimethyl sulfoxide (40 mL), followed by heating at 90 ℃ for 1 hour under a carbon monoxide atmosphere. After completion of the reaction, the reaction mixture was diluted with water (100 mL) and ethyl acetate (200 mL), filtered through celite, and the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 4/1) to obtain 3- (difluoromethoxy) -4-fluorobenzaldehyde Cpd-087B (300 mg, yellow oil) in 34% yield.
1 H NMR(400MHz,CDCl 3 )δ9.95(s,1H),7.79-7.76(m,2H),7.35(dd,J＝9.4,8.5Hz,1H),6.62(t,J＝72.5Hz,1H).
Second step of
Preparation of ethyl 3- ((3- (difluoromethoxy) -4-fluorobenzyl) amino) -1H-pyrrole-2-carboxylate
3- (Difluoromethoxy) -4-fluorobenzaldehyde Cpd-087B (280mg, 1.5 mmol), ethyl 3-amino-1H-pyrrole-2-carboxylate (227mg, 1.5 mmol) and two drops of acetic acid were dissolved in methanol (5 mL) and stirred at room temperature for half an hour, followed by addition of sodium cyanoborohydride (185mg, 3.0 mmol) and stirring continued for half an hour. After completion of the reaction, the reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (100 mL), and the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude product, which was separated and purified with a silica gel column (petroleum ether/ethyl acetate = 4/1) to obtain ethyl 3- ((3- (difluoromethoxy) -4-fluorobenzyl) amino) -1H-pyrrole-2-carboxylate Cpd-087C (300 mg, colorless oil), yield: 60 percent.
MS m/z(ESI):329[M+1] + .
The third step
Preparation of ethyl 3- (1- (3- (difluoromethoxy) -4-fluorobenzyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate
Ethyl 3- ((3- (difluoromethoxy) -4-fluorobenzyl) amino) -1H-pyrrole-2-carboxylate Cpd-087C (290mg, 0.88mmol) was dissolved in acetonitrile (3 mL) and ethoxycarbonyl isothiocyanate (139mg, 1.06mmol) was added and stirred at room temperature for half an hour. After the reaction was completed, the reaction mixture was concentrated to give a crude product, which was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 2/1) to give ethyl 3- (1- (3- (difluoromethoxy) -4-fluorobenzyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-087D (300 mg, colorless oil), yield: 74 percent
MS m/z(ESI):460[M+1] + .
The fourth step
Preparation of 1- (3- (difluoromethoxy) -4-fluorobenzyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Ethyl 3- (1- (3- (difluoromethoxy) -4-fluorobenzyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-087D (160mg, 0.35mmol) was dissolved in methanol (5 mL), cesium carbonate (227mg, 0.70mmol) was added, and the mixture was heated at 65 ℃ for 8 hours. After the reaction was completed, the reaction solution was cooled to room temperature, water (10 mL) was added, and the mixture was stirred for half an hour, filtered, and the filter cake was lyophilized to give 1- (3- (difluoromethoxy) -4-fluorobenzyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-087 (105 mg, white solid) in 87% yield.
MS m/z(ESI):342[M+1] + .
1 H NMR(400MHz,DMSO-d6)δ12.39(s,2H),7.46(d,J＝7.6Hz,1H),7.39-7.21(m,4H),6.19(d,J＝2.8Hz,1H),5.69(s,2H).
Example 77
1- ((1- (2, 2-difluoroethyl) -1H-pyrazol-3-yl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850001311
First step of
Preparation of 1- (2, 2-difluoroethyl) -1H-pyrazole-3-carboxylic acid ethyl ester
1H-pyrazole-3-carboxylic acid ethyl ester Cpd-088A (2g, 14mmol) is dissolved in DMF (20 mL), 1-difluoro-2-iodoethane (5.5g, 28mmol), potassium carbonate (2.1g, 15.4mmol) and potassium iodide (4.6g, 28mmol) are sequentially added, the reaction is heated to 100 ℃ in a sealed tank for 18 hours, after the reaction is finished, water (50 mL) is added, ethyl acetate is extracted (2x 100mL), organic phases are combined, washed by saturated sodium chloride, dried by sodium sulfate and concentrated. The obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 3/1) to obtain ethyl 1- (2, 2-difluoroethyl) -1H-pyrazole-3-carboxylate Cpd-088B (1.2 g, colorless oil), yield: and 47 percent.
1 H NMR(400MHz,DMSO)δ7.91(d,J＝2.4Hz,1H),6.80(d,J＝2.4Hz,1H),6.42-6.26(m,1H),4.78-4.70(m,2H),4.27(q,J＝7.2Hz,2H),1.28(t,J＝7.2Hz,3H).
Second step of
Preparation of (1- (2, 2-difluoroethyl) -1H-pyrazol-3-yl) methanol
1- (2, 2-Difluoroethyl) -1H-pyrazole-3-carboxylic acid ethyl ester Cpd-088B (500mg, 2.45mmol) was dissolved in tetrahydrofuran (10 mL), lithium aluminum hydride (2.4 mL,2.45mmol, 1M) was added at 0 ℃ and the reaction was stirred at 0 ℃ for 1 hour. After the reaction was completed, water was added to quench, the mixture was filtered, and the filtrate was dried and concentrated to give (1- (2, 2-difluoroethyl) -1H-pyrazol-3-yl) methanol Cpd-088C (350 mg, colorless liquid), yield: 88 percent.
MS m/z(ESI)：163(M+1)
The third step
Preparation of 1- (2, 2-difluoroethyl) -1H-pyrazole-3-carbaldehyde
(1- (2, 2-difluoroethyl) -1H-pyrazol-3-yl) methanol Cpd-088C (350mg, 2.16mmol) was dissolved in dichloromethane (5 mL), dess-martin oxidant (1.1g, 2.60mmol) was added, and the reaction was carried out at room temperature for 1 hour, followed by filtration and washing of the filtrate with an aqueous solution of sodium hydrogencarbonate. The organic phase was dried over anhydrous sodium sulfate and concentrated. The obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 10/1) to give 1- (2, 2-difluoroethyl) -1H-pyrazole-3-carbaldehyde Cpd-088D (300 mg, colorless liquid), yield: 87 percent.
MS m/z(ESI)：161(M+1)
The fourth step
Preparation of ethyl 3- ((1- (2, 2-difluoroethyl) -1H-pyrazol-3-yl) methyl) amino) -1H-pyrrole-2-carboxylate
1- (2, 2-Difluoroethyl) -1H-pyrazole-3-carbaldehyde Cpd-088D (300mg, 1.87mmol) was dissolved in methanol (5 mL), and ethyl 3-amino-1H-pyrrole-2-carboxylate (289mg, 1.87mmol) and acetic acid (112mg, 1.87mmol) were added. The reaction mixture was stirred at 25 ℃ for 30 minutes, sodium cyanoborohydride (117mg, 1.87mmol) was added, and stirring was continued at 25 ℃ for 16 hours. After completion of the reaction, the reaction was quenched with water (10 mL), and then extracted with ethyl acetate (2X 30 mL). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 3/1) to give ethyl 3- ((1- (2, 2-difluoroethyl) -1H-pyrazol-3-yl) methyl) amino) -1H-pyrrole-2-carboxylate Cpd-088E (500 mg, pale yellow solid), yield: 90 percent.
MS m/z(ESI)：299(M+1)。
The fifth step
Preparation of ethyl 3- (1- ((1- (2, 2-difluoroethyl) -1H-pyrazol-3-yl) methyl) -3- (ethoxycarbonyl) thiourea-1H-pyrrole-2-carboxylate
Ethyl 3- ((1- (2, 2-difluoroethyl) -1H-pyrazol-3-yl) methyl) amino) -1H-pyrrole-2-carboxylate Cpd-088E (500mg, 1.67mmol) was dissolved in dichloromethane (10 mL). Ethylisothiocyanatecarboxylate (220mg, 1.67mmol) was added. The reaction mixture was reacted at 25 ℃ for 2 hours. After the reaction was completed, the reaction mixture was evaporated to dryness, and the obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 1/1) to obtain ethyl 3- (1- ((1- (2, 2-difluoroethyl) -1H-pyrazol-3-yl) methyl) -3- (ethoxycarbonyl) thiourea-1H-pyrrole-2-carboxylate Cpd-088F (500 mg, yellow solid) in a yield of 69%.
MS m/z(ESI)：430(M+1)。
The sixth step
Preparation of 1- ((1- (2, 2-difluoroethyl) -1H-pyrazol-3-yl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
3- (1- ((1- (2, 2-difluoroethyl) -1H-pyrazol-3-yl) methyl) -3- (ethoxycarbonyl) thiourea-1H-pyrrole-2-carboxylic acid ethyl ester Cpd-088F (500mg, 1.16mmol) and cesium carbonate (1140mg, 3.5mmol) were dissolved in methanol (10 mL) and reacted at 60 ℃ for 6 hours, after completion of the reaction, 1/3 methanol was concentrated and removed, the concentrate was slowly added to an aqueous ammonium chloride solution (20 mL), a solid was precipitated, filtered, washed with water, the filter cake was slurried and purified by dichloromethane/methanol =20/1 (10 mL), and dried to give 1- ((1- (2, 2-difluoroethyl) -1H-pyrazol-3-yl) methyl) -2-sulfoxy-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-088 (200 mg, white solid) in a yield of 55%.
MS m/z(ESI)：312(M+1)
1 H NMR(400MHz,DMSO)δ12.27(s,2H),7.68(d,J＝2.4Hz,1H),7.31(d,J＝2.8Hz,1H),6.30-6.15(m,3H),5.63(s,2H),4.61-4.53(m,2H).
Example 78
1- ((1- (2, 2-difluoroethyl) -1H-pyrazol-5-yl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850001331
First step of
Preparation of 1- (2, 2-difluoroethyl) -1H-pyrazole-5-carboxylic acid ethyl ester
Dissolving 1H-pyrazole-3-carboxylic acid ethyl ester Cpd-089A (2g, 14mmol) in DMF (20 mL), sequentially adding 1, 1-difluoro-2-iodoethane (5.5g, 28mmol), potassium carbonate (2.1g, 15.4mmol) and potassium iodide (4.6g, 28mmol), heating to 100 ℃ in a sealed tank for reaction for 18 hours, adding water (50 mL) after the reaction is finished, extracting with ethyl acetate (2x 100mL), combining organic phases, washing with saturated sodium chloride, drying with anhydrous sodium sulfate, and concentrating. The obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 10/1) to obtain ethyl 1- (2, 2-difluoroethyl) -1H-pyrazole-5-carboxylate Cpd-089B (1.1 g, colorless oil) in yield: and 43 percent.
1 H NMR(400MHz,DMSO)δ7.67(d,J＝2.0Hz,1H),6.96(d,J＝2.0Hz,1H),6.53-6.23(m,1H),5.02-4.94(m,2H),4.31(q,J＝7.2Hz,2H),1.31(t,J＝7.2Hz,3H).
Second step of
Preparation of (1- (2, 2-difluoroethyl) -1H-pyrazol-5-yl) methanol
1- (2, 2-Difluoroethyl) -1H-pyrazole-5-carboxylic acid ethyl ester Cpd-089B (500mg, 2.45mmol) was dissolved in tetrahydrofuran (10 mL), lithium aluminum hydride (2.4 mL,2.45mmol, 1M) was added at 0 ℃ and the reaction was stirred at 0 ℃ for 1 hour. After the reaction was completed, water was added to the reaction mixture to quench, the mixture was filtered, and the filtrate was dried and concentrated to give (1- (2, 2-difluoroethyl) -1H-pyrazol-5-yl) methanol Cpd-089C (380 mg, colorless liquid) in yield: 96 percent.
MS m/z(ESI)：163(M+1)
The third step
Preparation of 1- (2, 2-difluoroethyl) -1H-pyrazole-5-carbaldehyde
(1- (2, 2-difluoroethyl) -1H-pyrazol-5-yl) methanol Cpd-089C (380mg, 2.34mmol) was dissolved in methylene chloride (5 mL), dess-martin oxidant (1.2g, 2.81mmol) was added thereto, the reaction was carried out at room temperature for 1 hour, and after the completion of the reaction, the mixture was filtered, and the filtrate was washed with an aqueous sodium hydrogencarbonate solution. The organic phase was dried over anhydrous sodium sulfate and concentrated. The obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 10/1) to give 1- (2, 2-difluoroethyl) -1H-pyrazole-5-carbaldehyde Cpd-089D (350 mg, colorless liquid), yield: 92 percent.
1 H NMR(400MHz,DMSO)δ9.92(s,1H),7.75(d,J＝2.0Hz,1H),7.18(d,J＝2.4Hz,1H),6.50-6.23(m,1H),5.03-4.95(m,2H).
The fourth step
Preparation of ethyl 3- ((1- (2, 2-difluoroethyl) -1H-pyrazol-5-yl) methyl) amino) -1H-pyrrole-2-carboxylate
1- (2, 2-Difluoroethyl) -1H-pyrazole-5-carbaldehyde Cpd-089D (350mg, 2.2mmol) was dissolved in methanol (5 mL), and ethyl 3-amino-1H-pyrrole-2-carboxylate (337 mg, 2.2mmol) and acetic acid (132mg, 2.2mmol) were added. The reaction mixture was stirred at 25 ℃ for 30 minutes, sodium cyanoborohydride (138mg, 2.2mmol) was added, and stirring was continued at 25 ℃ for 16 hours. After completion of the reaction, the reaction was quenched with water (10 mL) and extracted with ethyl acetate (2X 30mL). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 3/1) to obtain ethyl 3- ((1- (2, 2-difluoroethyl) -1H-pyrazol-5-yl) methyl) amino) -1H-pyrrole-2-carboxylate Cpd-089E (500 mg, pale yellow solid), yield: 77 percent.
MS m/z(ESI)：299(M+1)。
The fifth step
Preparation of ethyl 3- (1- ((1- (2, 2-difluoroethyl) -1H-pyrazol-5-yl) methyl) -3- (ethoxycarbonyl) thiourea-1H-pyrrole-2-carboxylate
Ethyl 3- ((1- (2, 2-difluoroethyl) -1H-pyrazol-5-yl) methyl) amino) -1H-pyrrole-2-carboxylate Cpd-089E (500mg, 1.67mmol) was dissolved in dichloromethane (10 mL). Ethylisothiocyanatecarboxylate (220mg, 1.67mmol) was added. The reaction mixture was reacted at 25 ℃ for 2 hours. After the reaction was completed, the reaction mixture was evaporated to dryness, and the obtained residue was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 1/1) to obtain ethyl 3- (1- ((1- (2, 2-difluoroethyl) -1H-pyrazol-5-yl) methyl) -3- (ethoxycarbonyl) thiourea-1H-pyrrole-2-carboxylate Cpd-089F (500 mg, yellow solid) in a yield of 69%.
MS m/z(ESI)：430(M+1)
The sixth step
Preparation of 1- ((1- (2, 2-difluoroethyl) -1H-pyrazol-5-yl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Ethyl 3- (1- ((1- (2, 2-difluoroethyl) -1H-pyrazol-5-yl) methyl) -3- (ethoxycarbonyl) thiourea-1H-pyrrole-2-carboxylate Cpd-089F (500mg, 1.16mmol) and cesium carbonate (1140mg, 3.5mmol) were dissolved in methanol (10 mL) and reacted at 60 ℃ for 6 hours after completion of the reaction, 1/3 methanol was concentrated to remove 1/3 of the methanol, the concentrate was slowly added to an aqueous ammonium chloride solution (20 mL), and a solid was precipitated, filtered, washed with water, and the filter cake was slurried with dichloromethane/methanol =20/1 (10 mL) to remove impurities, and dried to give 1- ((1- (2, 2-difluoroethyl) -1H-pyrazol-5-yl) methyl) -2-sulfoxy-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-089 (250 mg, white solid) in a yield of 69%.
MS m/z(ESI)：312(M+1)。
1 H NMR(400MHz,DMSO)δ12.42(s,2H),7.40(d,J＝1.6Hz,1H),7.35(d,J＝2.8Hz,1H),6.54-6.26(m,1H),6.18(d,J＝2.8Hz,1H),5.93(d,J＝2.0Hz,1H),5.75(s,2H),4.88-4.79(m,2H).
Example 79
1- ((1- (2, 2-difluoroethyl) -1H-imidazol-5-yl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850001341
First step of
Preparation of 1- (2, 2-difluoroethyl) -1H-imidazole-5-carbaldehyde
1H-imidazole-5-Formaldehyde Cpd-093A (1.0g, 10.4mmol) was dissolved in N, N-dimethylformamide (10 mL), and sodium-hydrogen (1.7g, 12.5mmol) was added in ice bath, followed by stirring for half an hour under nitrogen protection, followed by dropwise addition of 1, 1-difluoro-2-iodoethane (2.6g, 12.5mmol), and stirring for 6 hours at 40 ℃. The reaction solution was quenched with ammonium chloride (100 mL), extracted with ethyl acetate (50 mL × 2), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was separated and purified by silica gel column (petroleum ether/ethyl acetate = 2/1) to give 1- (2, 2-difluoroethyl) -1H-imidazole-5-carbaldehyde Cpd-093B (360 mg, colorless oil), yield: 21 percent.
MS m/z(ESI):161(M+1)。
1 H NMR(400MHz,DMSO-d6)δ9.76(d,J＝0.8Hz,1H),8.10(s,1H),7.96(d,J＝0.7Hz,1H),6.33(tt,J＝55.0,3.5Hz,1H),4.84(td,J＝15.3,3.5Hz,2H).
Second step of
Preparation of ethyl 3- (((1- (2, 2-difluoroethyl) -1H-imidazol-5-yl) methyl) amino) -1H-pyrrole-2-carboxylate
1- (2, 2-Difluoroethyl) -1H-imidazole-5-carbaldehyde Cpd-093B (300mg, 1.87mmol) and ethyl 3-amino-1H-pyrrole-2-carboxylate (289mg, 1.87mmol) were dissolved in 1, 2-dichloroethane (3 mL), glacial acetic acid (56mg, 0.93mmol) was added dropwise, stirred at room temperature for half an hour under nitrogen protection, followed by addition of sodium borohydride acetate (1.19g, 5.62mmol) and stirring at room temperature for 2 hours. The reaction was quenched with water (100 mL), extracted with dichloromethane (50 mL × 2), the combined organic phases washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was isolated and purified by silica gel column (petroleum ether/ethyl acetate = 2/1) to give preparation of ethyl 3- (((1- (2, 2-difluoroethyl) -1H-imidazol-5-yl) methyl) amino) -1H-pyrrole-2-carboxylate Cpd-093C (360 mg, colorless oil) in yield: 66 percent.
MS m/z(ESI):299(M+1)。
1 H NMR(400MHz,DMSO-d6)δ10.82(s,1H),7.61(s,1H),6.87(s,1H),6.75(t,J＝3.0Hz,1H),6.29(tt,J＝55.2,3.5Hz,1H),5.54(s,1H),4.54(td,J＝15.7,3.4Hz,2H),4.29(d,J＝5.9Hz,2H),4.18(q,J＝7.1Hz,2H),1.25(t,J＝7.1Hz,3H).
The third step
Preparation of ethyl 3- (1- ((1- (2, 2-difluoroethyl) -1H-imidazol-5-yl) methyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate
Ethyl 3- (((1- (2, 2-difluoroethyl) -1H-imidazol-5-yl) methyl) amino) -1H-pyrrole-2-carboxylate Cpd-093C (350mg, 1.17mmol) was dissolved in dichloromethane (8 mL), followed by dropwise addition of ethoxycarbonyl isothiocyanate (308mg, 2.34mmol) at room temperature, stirring for half an hour under nitrogen, and after completion of the reaction, concentration at room temperature gave crude 3- (1- ((1- (2, 2-difluoroethyl) -1H-imidazol-5-yl) methyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-093D (430 mg, black oil) yield: 128 percent.
MS m/z(ESI):430(M+1)。
The fourth step
Preparation of 1- ((1- (2, 2-difluoroethyl) -1H-imidazol-5-yl) methyl) -2-thioxo-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Ethyl 3- (1- ((1- (2, 2-difluoroethyl) -1H-imidazol-5-yl) methyl) -3- (ethoxycarbonyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-093D (500mg, 1.16mmol) and cesium carbonate (1.13g, 3.49mmol) were dissolved in methanol (7 mL), followed by heating to 65 ℃ under nitrogen protection and stirring for 6 hours, the reaction was concentrated, the crude product was quenched with ammonium chloride (100 mL), the precipitated solid was filtered, the crude product was prepared with C18 reverse phase (acetonitrile/water =0% -10%,0.1% fa) to give 1- ((1- (2, 2-difluoroethyl) -1H-imidazol-5-yl) methyl) -2-thio-1, 2,3, 5-tetrahydro-4H-pyrrolo [3,2-D ] pyrimidin-4-one Cpd-093 (40 mg, white solid) yield: 11 percent.
MS m/z(ESI):312(M+1)。
1 H NMR(400MHz,DMSO-d6)δ12.46(s,1H),12.32(s,1H),7.64(s,1H),7.35(d,J＝2.8Hz,1H),6.70(s,1H),6.52-6.21(m,2H),5.68(s,2H),4.77(dd,J＝16.0,13.3Hz,2H).
Example 80
2-thioxo-1- ((1- (2, 2-trifluoroethyl) -1H-pyrazol-5-yl) methyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one
Figure BDA0003664464850001351
First step of
Preparation of 1- (2, 2-trifluoroethyl) -1H-pyrazole-5-carboxylic acid ethyl ester
1H-pyrazole-5-carboxylic acid ethyl ester Cpd-098A (2.0g, 14.3mmol) was dissolved in N, N-dimethylformamide (15 mL), and 1, 1-trifluoro-2-iodoethane (6.1g, 28.6 mmol) and potassium carbonate (3.9g, 28.6 mmol) were added thereto. The reaction solution was reacted at 100 ℃ for 16 hours with tube sealed. After the reaction was completed, water (50 mL) was added for dilution and then extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with water (30 mL × 5), dried over anhydrous sodium sulfate and concentrated, and the resulting crude product was isolated and purified by a silica gel column (petroleum ether/ethyl acetate = 9/1) to give ethyl 1- (2, 2-trifluoroethyl) -1H-pyrazole-5-carboxylate Cpd-098B (540 mg, colorless liquid), yield: 17 percent.
MS m/z(ESI):223(M+1)。
Second step of
Preparation of (1- (2, 2-trifluoroethyl) -1H-pyrazol-5-yl) methanol
1- (2, 2-trifluoroethyl) -1H-pyrazole-5-carboxylic acid ethyl ester Cpd-098B (500mg, 2.2mmol) was dissolved in tetrahydrofuran (8 mL), to which was slowly added an aluminum lithium hydrogen tetrahydrofuran solution (3.3 mL,3.3mmol, 1M). The reaction mixture was reacted at 0 ℃ for 1 hour. After the reaction was completed, sodium hydroxide solution (2ml, 1m) was added and then filtered, and the filtrate was concentrated to give crude (1- (2, 2-trifluoroethyl) -1H-pyrazol-5-yl) methanol Cpd-098C (300 mg, colorless liquid) in yield: 73 percent.
MS m/z(ESI):181(M+1)。
The third step
Preparation of 1- (2, 2-trifluoroethyl) -1H-pyrazole-5-carbaldehyde
(1- (2,2,2-trifluoroethyl) -1H-pyrazol-5-yl) methanol Cpd-098C (300mg, 1.6 mmol) was dissolved in dichloromethane (5 mL) and dess-martin oxidant (1.1g, 2.4 mmol) was added thereto. The reaction mixture was reacted at 0 ℃ for 1 hour. After completion of the reaction, filtration was performed, and the residue obtained by concentrating the filtrate was separated and purified by a silica gel column (petroleum ether/ethyl acetate = 9/1) to obtain 1- (2, 2-trifluoroethyl) -1H-pyrazole-5-carbaldehyde Cpd-098D (50 mg, pale yellow solid), yield: 17 percent.
MS m/z(ESI):179(M+1)。
The fourth step
Preparation of ethyl 3- (((1- (2, 2-trifluoroethyl) -1H-pyrazol-5-yl) methyl) amino) -1H-pyrrole-2-carboxylate
1- (2, 2-trifluoroethyl) -1H-pyrazole-5-carbaldehyde Cpd-098D (50mg, 0.31mmol) was dissolved in methanol (3 mL) and to this was added ethyl 3-amino-1H-pyrrole-2-carboxylate (47mg, 0.31mmol) and two drops of glacial acetic acid. The reaction mixture was reacted at 25 ℃ for 1 hour. To the reaction solution was added sodium cyanoborohydride (30mg, 0.46mmol) and the reaction was continued for 16 hours. After the reaction was completed, methanol was removed by rotary evaporation, and the obtained residue was extracted with ethyl acetate (15 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated to obtain crude product, which was isolated and purified by a silica gel column (petroleum ether/ethyl acetate = 9/1) to obtain ethyl 3- (((1- (2, 2-trifluoroethyl) -1H-pyrazol-5-yl) methyl) amino) -1H-pyrrole-2-carboxylate Cpd-098E (60 mg, pale yellow solid), yield: 48 percent.
MS m/z(ESI):317(M+1)。
The fifth step
Preparation of ethyl 3- (3- (ethoxycarbonyl) -1- ((1- (2, 2-trifluoroethyl) -1H-pyrazol-5-yl) methyl) thioureido) -1H-pyrrole-2-carboxylate
Ethyl 3- (((1- (2, 2-trifluoroethyl) -1H-pyrazol-5-yl) methyl) amino) -1H-pyrrole-2-carboxylate Cpd-098E (60mg, 0.19mmol) was dissolved in dichloromethane (3 mL), and the ethoxycarbonyl isothiocyanate (30mg, 0.23mmol) was added thereto and reacted at 25 ℃ for 2 hours. After the reaction was completed, methylene chloride was removed by rotary evaporation. The resulting crude product was isolated and purified by silica gel column (petroleum ether/ethyl acetate = 3/2) to give ethyl 3- (3- (ethoxycarbonyl) -1- ((1- (2, 2-trifluoroethyl) -1H-pyrazol-5-yl) methyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-098F (50 mg, white solid), yield: 58 percent.
MS m/z(ESI):448(M+1)。
The sixth step
Preparation of 2-thioxo-1- ((1- (2, 2-trifluoroethyl) -1H-pyrazol-5-yl) methyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Ethyl 3- (3- (ethoxycarbonyl) -1- ((1- (2, 2-trifluoroethyl) -1H-pyrazol-5-yl) methyl) thioureido) -1H-pyrrole-2-carboxylate Cpd-098F (48mg, 0.11mmol) was dissolved in methanol (3 mL), and cesium carbonate (69mg, 0.21mmol) was added thereto. The reaction mixture was heated to 65 ℃ and reacted for 6 hours. After the reaction was completed, the reaction solution was cooled to room temperature, methanol was removed by rotary evaporation, saturated ammonium chloride (10 mL) was added to the obtained residue, and after a solid was precipitated, the mixture was filtered, and a cake was collected and dried. Dichloromethane (3 mL) was then added and stirred for 30 minutes and filtered, the filter cake was collected and dried to give 2-thio-1- ((1- (2, 2-trifluoroethyl) -1H-pyrazol-5-yl) methyl) -1,2,3, 5-tetrahydro-4H-pyrrolo [3,2-d ] pyrimidin-4-one Cpd-098 (19 mg, white solid), yield: 51 percent.
MS m/z(ESI):330(M+1)。
1 H NMR(400MHz,DMSO-d6)δ12.41(br,2H),7.46(d,J＝1.8Hz,1H),7.35(d,J＝2.8Hz,1H),6.17(d,J＝2.8Hz,1H),5.99(d,J＝1.6Hz,1H),5.78(s,2H),5.34(d,J＝9.1Hz,2H).
Biological evaluation
Test example 1 determination of the Activity of the Compound of the present invention on human MPO
This method was used to determine the inhibitory activity of the compounds of the present invention against human MPO.
Experimental procedure
1. Compounds were dissolved in DMSO and diluted three-fold;
2. adding 8uLMPO enzyme into 384-well plate and diluting by 50 times;
3. adding 48uL of compound in DMSO to the enzyme, and incubating at 30 ℃ for 30 minutes;
4. adding Ample × Red and hydrogen peroxide, and incubating for 30 minutes at 30 ℃;
5. reading the plate with a microplate reader: e X530nm, em.
The IC of the compound of the invention, which is determined by the experiment of the human MPO inhibitor, is measured 50 The values are shown in Table 1.
TABLE 1 IC of the compounds of the invention for human MPO inhibitors 50 Value of
Figure BDA0003664464850001371
Figure BDA0003664464850001381
And (4) experimental conclusion: the data show that the compound has obvious inhibition effect on human MPO, and the activity of the compound is obviously superior to that of a positive control medicament BHV3241.
Test example 2 mouse pharmacokinetic experiment of candidate Compound
This method was used to determine the mouse pharmacokinetics of the compounds of the present invention.
The experimental steps are as follows:
1. animals: CD-1 mice
2. Sex and quantity: 3 Male/group, 2 group/Compound
3. Preparing a dosing preparation: the% DMSO +10% of Solutol +85% of Saline. The test compound is ground dry, then an appropriate amount of test compound (in terms of purity and salt system) is weighed, the prescribed amount of formulated 5% DMSO +10% by weight Solutol +85% Saline is added, and stirred to give a clear and homogeneous solution.
4. Mouse diet status: fasting was overnight before dosing and feeding was resumed 4 hours after dosing. The water is freely drunk.
5. Administration: iv.3mg/kg; po.15mg/kg
6. Sampling time points of 5min, 15min, 30min, 1h, 2h, 4h, 8h and 24h after administration. Approximately 30. Mu.L of blood samples were collected at each time point and placed in the EDTA-K containing chamber 2 And centrifuging the mixture in an anticoagulant tube within 30 minutes to obtain plasma. Whole blood samples were placed on wet ice prior to centrifugation. All collected plasma samples were kept on dry ice or notAbove-70 ℃ until assayed.
The mouse pharmacokinetics of the compounds of the present invention were determined by the above experiments, and the measured data are shown in table 2.
Table 2 mouse pharmacokinetics of some of the compounds of the invention
Figure BDA0003664464850001382
And (4) experimental conclusion: the data show that the pharmacokinetics of the compound of the invention is obviously superior to that of the positive compound BHV3241.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (14)

1. A compound of formula I, racemates, stereoisomers, tautomers, isotopic labels, solvates, polymorphs, pharmaceutically acceptable salts or prodrug compounds thereof:
Figure FDA0003664464840000011
Wherein:
a is present or absent;
when A is absent, the carbon-carbon double bond may be substituted by one or two R's selected from hydrogen, deuterium, halogen, hydroxy, mercapto, nitro, cyano, unsubstituted or optionally substituted by one, two or more R a Substituted of the following groups: amino group, C 1-40 Alkyl radical, C 1-40 Alkyloxy, C 1-40 Hydroxyalkyl radical, C 1-40 Haloalkyl, C 1-40 Alkylamino radical, (C) 1-8 Alkyl radical) 2 Amino, amino-C 1-40 Alkyl radical, C 2-40 Alkenyl radical, C 2-40 Alkynyl, C 3-40 Cycloalkyl, 3-20 membered heterocyclyl, C 3-40 Cycloalkylamino, 3-20 membered heterocyclylamino, C 6-20 Aryl, 5-20 membered heteroaryl, C 6-20 Arylamino, 5-20 membered heteroarylamino, C 3-40 Cycloalkyloxy, 3-20 membered heterocyclyloxy, C 6-20 Aryloxy or 5-20 membered heteroaryloxy;
when A is present, A is selected from unsubstituted or optionally substituted by one, two or more R a Substituted C 3-40 Cycloalkyl radical, C 3-40 Cycloalkenyl radical, C 3-40 Cycloalkynyl, 3-to 20-membered heterocyclic group, C 6-20 Aryl or 5-20 membered heteroaryl;
each R a Identical or different, independently of one another, from hydrogen, halogen, OH, CN, NO 2 Oxo (= O), thio (= S), unsubstituted or optionally substituted by one, two or more R a1 Substituted of the following groups: c 1-40 Alkyl radical, C 1-40 Haloalkyl, C 2-40 Alkenyl radical, C 2-40 Alkynyl, C 3-40 Cycloalkyl radical, C 3-40 Cycloalkenyl radical, C 3-40 Cycloalkynyl group, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, C 1-40 Alkyloxy, C 2-40 Alkenyloxy radical, C 2-40 Alkynyloxy, C 3-40 Cycloalkyloxy radical, C 3-40 Cycloalkenyloxy, C 3-40 Cycloalkynyloxy, C 6-20 Aryloxy, 5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, NH 2 ；
Each R a1 Identical or different, independently of one another, from hydrogen, halogen, OH, NH 2 、CN、NO 2 Oxo (= O), C 1-40 Alkyl radical, C 1-40 Haloalkyl, C 2-40 Alkenyl radical, C 2-40 Alkynyl, C 3-40 Cycloalkyl, C 3-40 Cycloalkenyl radical, C 3-40 Cycloalkynyl group, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, C 1-40 Alkylamino radical, (C) 1-40 Alkyl radical) 2 An amino group;
r is selected from unsubstituted or optionally substituted by one, two or more R b Substituted of the following groups: c 1-40 Alkyl radical, C 1-40 Haloalkyl, C 2-40 Alkenyl radical, C 2-40 Alkynyl, C 3-40 Cycloalkyl, C 3-40 Cycloalkenyl radical, C 3-40 Cycloalkynyl group, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, C 1-40 Alkyloxy, C 2-40 Alkenyloxy radical, C 2-40 Alkynyloxy, C 3-40 Cycloalkyloxy radical, C 3-40 Cycloalkenyloxy, C 3-40 Cycloalkynyloxy, C 6-20 Aryloxy, 5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, NH 2 ；
Each R b Identical or different, independently of one another, from hydrogen, halogen, OH, CN, NO 2 Oxo (= O), thio (= S), unsubstituted or optionally substituted by one, two or more R b1 Substituted of the following groups: c 1-40 Alkyl radical, C 1-40 Haloalkyl, C 2-40 Alkenyl radical, C 2-40 Alkynyl, C 3-40 Cycloalkyl, C 3-40 Cycloalkenyl radical, C 3-40 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, C 1-40 Alkyloxy, C 2-40 Alkenyloxy radical, C 2-40 Alkynyloxy, C 3-40 Cycloalkyl oxy, C 3-40 Cycloalkenyloxy, C 3-40 Cycloalkynyloxy, C 6-20 Aryloxy, 5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, NH 2 ；
Each R b1 Identical or different, independently of one another, from hydrogen, halogen, OH, CN, NO 2 Oxo (= O), thio (= S), unsubstituted or optionally substituted by one, two or more R b2 Substituted of the following groups: c 1-40 Alkyl radical, C 1-40 Haloalkyl, C 2-40 Alkenyl radical, C 2-40 Alkynyl, C 3-40 Cycloalkyl radical, C 3-40 Cycloalkenyl radical, C 3-40 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, C 1-40 Alkyloxy, C 2-40 Alkenyloxy radical, C 2-40 Alkynyloxy, C 3-40 Cycloalkyl oxy, C 3-40 Cycloalkenyloxy, C 3-40 Cycloalkynyloxy, C 6-20 Aryloxy, 5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, NH 2 ；
Each R b2 Identical or different, independently of one another, from hydrogen, halogen, OH, CN, NO 2 Oxo (= O), thio (= S), unsubstituted or optionally substituted by one, two or more R b3 Substituted of the following groups: c 1-40 Alkyl radical, C 1-40 Haloalkyl, C 2-40 Alkenyl radical, C 2-40 Alkynyl, C 3-40 Cycloalkyl radical, C 3-40 Cycloalkenyl radical, C 3-40 Cycloalkynyl group, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, C 1-40 Alkyloxy, C 2-40 Alkenyloxy radical, C 2-40 Alkynyloxy, C 3-40 Cycloalkyl oxy, C 3-40 Cycloalkenyloxy, C 3-40 Cycloalkynyloxy, C 6-20 Aryloxy, 5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, NH 2 ；
Each R b3 Identical or different, independently of one another, from hydrogen, halogen, OH, NH 2 、CN、NO 2 Oxo (= O), thio (= S), C 1-40 Alkyl radical, C 1-40 Haloalkyl, C 2-40 Alkenyl radical, C 2-40 Alkynyl, C 3-40 Cycloalkyl radical, C 3-40 Cycloalkenyl radical, C 3-40 Cycloalkynyl group, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl.
2. The compound of formula I, its racemate, stereoisomer, tautomer, isotopic label, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound according to claim 1, characterized in that, when a is absent, formula I has the structure shown in formula I-1:
Figure FDA0003664464840000021
wherein R' is selected from 3-10 member heterocyclic radical, C 6-14 Aryl, 5-14 membered heteroaryl, 3-10 membered heterocyclylamino, C 6-14 Arylamino, 5-14 membered heteroarylamino, 3-10 membered heterocyclyloxy, C 6-14 Aryloxy or 5-14 membered heteroaryloxy;
When A is present, formula I has a structure represented by formula I-2, formula I-2', or formula I-3:
Figure FDA0003664464840000022
wherein:
Figure FDA0003664464840000023
represents a single bond or a double bond;
m is an integer from 0 to 4;
when formula I has a structure as shown in formula I-2, D is selected from O, C (O), CH 2 Or NH; e is selected from C (O), CH or N;
when formula I has a structure represented by formula I-2', D is selected from O, C (O), CH 2 Or NH;
Figure FDA0003664464840000024
is selected from C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, 3-8 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl;
each R a Identical or different, independently of one another, from hydrogen, halogen, OH, CN, NO 2 Oxo (= O), thio (= S), unsubstituted or optionally substituted by one, two or more R a1 Substituted of the following groups: c 1-8 Alkyl radical, C 1-8 Haloalkyl, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkenyl radical, C 3-8 Cycloalkynyl group, C 6-14 Aryl, 5-14 membered heteroaryl, 3-8 membered heterocyclyl, C 1-8 Alkyloxy, C 2-8 Alkenyloxy radical, C 2-8 Alkynyloxy, C 3-8 Cycloalkyloxy radical, C 3-8 Cycloalkenyloxy, C 3-8 Cycloalkynyloxy, C 6-14 Aryloxy, 5-14 membered heteroaryloxy, 3-8 membered heterocyclyloxy, NH 2 ；
Each R a1 Same or different, independently of each otherIs selected from hydrogen, halogen, OH, NH 2 、CN、NO 2 Oxo (= O), thio (= S), C 1-8 Alkyl radical, C 1-8 Hydroxyalkyl radical, C 1-8 Haloalkyl, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkenyl radical, C 3-8 Cycloalkynyl, C 6-14 Aryl, 5-14 membered heteroaryl, 3-8 membered heterocyclyl, C 1-8 Alkylamino radical, (C) 1-8 Alkyl radical) 2 An amino group;
r is selected from unsubstituted or optionally substituted by one, two or more R b Substituted of the following groups: c 1-8 Alkyl radical, C 1-8 Haloalkyl, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl radical, C 3-8 Cycloalkynyl group, C 6-14 Aryl, 5-14 membered heteroaryl, 3-8 membered heterocyclyl, C 1-8 Alkyloxy, C 2-8 Alkenyloxy radical, C 2-8 Alkynyloxy, C 3-8 Cycloalkyl oxy, C 3-8 Cycloalkenyloxy, C 3-8 Cycloalkynyloxy, C 6-14 Aryloxy, 5-14 membered heteroaryloxy, 3-8 membered heterocyclyloxy, NH 2 ；
Each R b Identical or different, independently of one another, from hydrogen, halogen, OH, CN, NO 2 Oxo (= O), thio (= S), unsubstituted or optionally substituted by one, two or more R b1 Substituted of the following groups: c 1-8 Alkyl radical, C 1-8 Haloalkyl, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkenyl radical, C 3-8 Cycloalkynyl, C 6-14 Aryl, 5-14 membered heteroaryl, 3-8 membered heterocyclyl, C 1-8 Alkyloxy, C 2-8 Alkenyloxy radical, C 2-8 Alkynyloxy, C 3-8 Cycloalkyloxy radical, C 3-8 Cycloalkenyloxy, C 3-8 Cycloalkynyloxy, C 6-14 Aryloxy, 5-14 membered heteroaryloxy, 3-8 membered heterocyclyloxy, NH 2 ；
Each R b1 Identical or different, independently of one another, from hydrogen, halogen, OH, CN, NO 2 Oxo (= O), thio (= S), noneSubstituted or optionally substituted by one, two or more R b2 Substituted of the following groups: c 1-8 Alkyl radical, C 1-8 Haloalkyl, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl radical, C 3-8 Cycloalkynyl, C 6-14 Aryl, 5-14 membered heteroaryl, 3-8 membered heterocyclyl, C 1-8 Alkyloxy, C 2-8 Alkenyloxy radical, C 2-8 Alkynyloxy, C 3-8 Cycloalkyl oxy, C 3-8 Cycloalkenyloxy, C 3-8 Cycloalkynyloxy, C 6-14 Aryloxy, 5-14 membered heteroaryloxy, 3-8 membered heterocyclyloxy, NH 2 ；
Each R b2 Identical or different, independently of one another, from hydrogen, halogen, OH, CN, NO 2 Oxo (= O), thio (= S), unsubstituted or optionally substituted by one, two or more R b3 Substituted of the following groups: c 1-8 Alkyl radical, C 1-8 Haloalkyl, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl radical, C 3-8 Cycloalkynyl, C 6-14 Aryl, 5-14 membered heteroaryl, 3-8 membered heterocyclyl, C 1-8 Alkyloxy, C 2-8 Alkenyloxy radical, C 2-8 Alkynyloxy, C 3-8 Cycloalkyl oxy, C 3-8 Cycloalkenyloxy, C 3-8 Cycloalkynyloxy, C 6-14 Aryloxy, 5-14 membered heteroaryloxy, 3-8 membered heterocyclyloxy, NH 2 ；
Each R b3 Identical or different, independently of one another, from hydrogen, halogen, OH, NH 2 、CN、NO 2 Oxo (= O), thio (= S), C 1-8 Alkyl radical, C 1-8 Hydroxyalkyl radical, C 1-8 Haloalkyl, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl radical, C 3-8 Cycloalkynyl, C 6-14 Aryl, 5-14 membered heteroaryl, 3-8 membered heterocyclyl;
preferably, when A is absent, formula I has the structure shown in formula I-1:
Figure FDA0003664464840000031
wherein R' is selected from 3-10 member heterocyclic radical, C 6-14 Aryl, 5-14 membered heteroaryl, 3-10 membered heterocyclylamino, C 6-14 Arylamino, 5-14 membered heteroarylamino, 3-10 membered heterocyclyloxy, C 6-14 Aryloxy or 5-14 membered heteroaryloxy;
when A is present, formula I has a structure represented by formula I-2 or formula I-3:
Figure FDA0003664464840000032
wherein:
Figure FDA0003664464840000033
represents a single bond or a double bond;
m is an integer from 0 to 4;
d is selected from O, C (O) and CH 2 Or NH;
e is selected from C (O), CH or N;
each R a Identical or different, independently of one another, from hydrogen, halogen, OH, CN, NO 2 Oxo (= O), thio (= S), unsubstituted or optionally substituted by one, two or more R a1 Substituted of the following groups: c 1-8 Alkyl radical, C 1-8 Haloalkyl, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl radical, C 3-8 Cycloalkynyl, C 6-14 Aryl, 5-14 membered heteroaryl, 3-8 membered heterocyclyl, C 1-8 Alkyloxy, C 2-8 Alkenyloxy radical, C 2-8 Alkynyloxy, C 3-8 Cycloalkyloxy radical, C 3-8 Cycloalkenyloxy, C 3-8 Cycloalkynyloxy, C 6-14 Aryloxy, 5-14 membered heteroaryloxy, 3-8 membered heterocyclyloxy, NH 2 ；
Each R a1 Identical or different, independently of one another, from hydrogen, halogen, OH, NH 2 、CN、NO 2 Oxo (= O), thio (= S), C 1-8 Alkyl radical, C 1-8 Hydroxyalkyl radical, C 1-8 Haloalkyl, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl radical, C 3-8 Cycloalkynyl, C 6-14 Aryl, 5-14 membered heteroaryl, 3-8 membered heterocyclyl, C 1-8 Alkylamino radical, (C) 1-8 Alkyl radical) 2 An amino group;
r is selected from unsubstituted or optionally substituted by one, two or more R b Substituted of the following groups: c 1-8 Alkyl radical, C 1-8 Haloalkyl, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl radical, C 3-8 Cycloalkynyl, C 6-14 Aryl, 5-14 membered heteroaryl, 3-8 membered heterocyclyl, C 1-8 Alkyloxy, C 2-8 Alkenyloxy radical, C 2-8 Alkynyloxy, C 3-8 Cycloalkyl oxy, C 3-8 Cycloalkenyloxy, C 3-8 Cycloalkynyloxy, C 6-14 Aryloxy, 5-14 membered heteroaryloxy, 3-8 membered heterocyclyloxy, NH 2 ；
Each R b Identical or different, independently of one another, from hydrogen, halogen, OH, CN, NO 2 Oxo (= O), thio (= S), unsubstituted or optionally substituted by one, two or more R b1 Substituted of the following groups: c 1-8 Alkyl radical, C 1-8 Haloalkyl, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkenyl radical, C 3-8 Cycloalkynyl group, C 6-14 Aryl, 5-14 membered heteroaryl, 3-8 membered heterocyclyl, C 1-8 Alkyloxy, C 2-8 Alkenyloxy radical, C 2-8 Alkynyloxy, C 3-8 Cycloalkyloxy radical, C 3-8 Cycloalkenyloxy, C 3-8 Cycloalkynyloxy, C 6-14 Aryloxy, 5-14 membered heteroaryloxy, 3-8 membered heterocyclyloxy, NH 2 ；
Each R b1 Identical or different, independently of one another, from hydrogen, halogen, OH, CN, NO 2 Oxo (= O), thio (= S), unsubstituted or optionally substituted by one, two or more R b2 Substituted of the following groups: c 1-8 Alkyl radical, C 1-8 Haloalkyl, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl radical, C 3-8 Cycloalkenyl radical, C 3-8 Cycloalkynyl group, C 6-14 Aryl, 5-14 membered heteroaryl, 3-8 membered heterocyclyl, C 1-8 Alkyloxy, C 2-8 Alkenyloxy radical, C 2-8 Alkynyloxy, C 3-8 Cycloalkyl oxy, C 3-8 Cycloalkenyloxy, C 3-8 Cycloalkynyloxy, C 6-14 Aryloxy, 5-14 membered heteroaryloxy, 3-8 membered heterocyclyloxy, NH 2 ；
Each R b2 Identical or different, independently of one another, from hydrogen, halogen, OH, CN, NO 2 Oxo (= O), thio (= S), unsubstituted or optionally substituted by one, two or more R b3 Substituted of the following groups: c 1-8 Alkyl radical, C 1-8 Haloalkyl, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl radical, C 3-8 Cycloalkynyl group, C 6-14 Aryl, 5-14 membered heteroaryl, 3-8 membered heterocyclyl, C 1-8 Alkyloxy, C 2-8 Alkenyloxy radical, C 2-8 Alkynyloxy, C 3-8 Cycloalkyloxy radical, C 3-8 Cycloalkenyloxy, C 3-8 Cycloalkynyloxy, C 6-14 Aryloxy, 5-14 membered heteroaryloxy, 3-8 membered heterocyclyloxy, NH 2 ；
Each R b3 Identical or different, independently of one another, from hydrogen, halogen, OH, NH 2 、CN、NO 2 Oxo (= O), thio (= S), C 1-8 Alkyl radical, C 1-8 Hydroxyalkyl radical, C 1-8 Haloalkyl, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl radical, C 3-8 Cycloalkynyl group, C 6-14 Aryl, 5-14 membered heteroaryl, 3-8 membered heterocyclyl.
3. The compound of formula I, its racemate, stereoisomer, tautomer, isotopic label, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof according to claim 1 or 2, characterized in that, when a is absent, R' is selected from the group consisting of phenyl, pyridyl, imidazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, thiazolyl, pyrrolyl, pyrazolyl, phenylamino, pyridylamino, imidazolylamino, 1,2, 3-triazolylamino, 1,2, 4-triazolylamino, thiazolylamino, pyrazolyl amino, phenyloxy, pyridyloxy, imidazolyloxy, 1,2, 3-triazolyloxy, 1,2, 4-triazolyloxy, thiazolyloxy or pyrazolyl oxy;
When A is present, A is selected from optionally substituted by one, two or more R a Substituted by
Figure FDA0003664464840000041
Figure FDA0003664464840000051
Each R a Identical or different, independently of one another, from hydrogen, halogen, OH, unsubstituted or optionally substituted by one, two or more R a1 Substituted of the following groups: c 1-8 Alkyl radical, C 1-8 Hydroxyalkyl radical, C 1-8 Haloalkyl, C 1-8 Alkyloxy, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl radical, C 3-8 Cycloalkynyl group, C 6-14 Aryl, 5-14 membered heteroaryl, 3-8 membered heterocyclyl, NH 2 ；
Each R a1 Identical or different, independently of one another, from the group consisting of halogen, OH, NH 2 、C 1-8 Alkyl radical, C 1-8 Hydroxyalkyl radical, C 1-8 Haloalkyl, C 3-8 Cycloalkyl, C 1-8 Alkylamino radical, (C) 1-8 Alkyl radical) 2 An amino group;
r is selected from unsubstituted or optionally substituted by one, two or more R b Substituted of the following groups: c 1-8 An alkyl group;
each R b Identical or different, independently of one another, from halogen, OH, unsubstituted or optionally substituted by one, two or more R b1 Substituted the following groupsAnd (3) clustering: c 1-8 Alkyl radical, C 1-8 Haloalkyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl radical, C 6-14 Aryl, 5-14 membered heteroaryl, 3-8 membered heterocyclyl, C 1-8 Alkyloxy, C 3-8 Cycloalkyloxy, 3-8 membered heterocyclyloxy, NH 2 ；
Each R b1 Identical or different, independently of one another, from halogen, OH, oxo (= O), unsubstituted or optionally substituted by one, two or more R b2 Substituted of the following groups: c 1-8 Alkyl radical, C 1-8 Haloalkyl, C 1-8 Alkyloxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, CN, NH 2 ；
Each R b2 Identical or different, independently of one another, from halogen, OH, unsubstituted or optionally substituted by one, two or more R b3 Substituted of the following groups: c 1-8 Alkyl radical, C 1-8 Haloalkyl, C 1-8 Alkyloxy, C 3-8 Cycloalkyl, CN, NH 2 ；
Each R b3 Identical or different, independently of one another, from the group consisting of halogen, OH, NH 2 、C 1-8 Alkyl radical, C 1-8 Haloalkyl, C 1-8 Alkyloxy, C 3-8 A cycloalkyl group;
preferably, when A is absent, R' is selected from phenyl, pyridyl, imidazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, thiazolyl, pyrrolyl, pyrazolyl, phenylamino, pyridylamino, imidazolylamino, 1,2, 3-triazolylamino, 1,2, 4-triazolylamino, thiazolylamino, pyrazolyl-amino, phenyloxy, pyridyloxy, imidazolyloxy, 1,2, 3-triazolyloxy, 1,2, 4-triazolyloxy, thiazolyloxy or pyrazolyl-oxy;
when A is present, A is selected from optionally substituted by one, two or more R a Substituted by
Figure FDA0003664464840000052
Figure FDA0003664464840000053
Each R a Identical or different, independently of one another, from hydrogen, halogen, OH, unsubstituted or optionally substituted by one, two or more R a1 Substituted of the following groups: c 1-8 Alkyl radical, C 1-8 Hydroxyalkyl radical, C 1-8 Haloalkyl, C 1-8 Alkyloxy, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl radical, C 3-8 Cycloalkynyl, C 6-14 Aryl, 5-14 membered heteroaryl, 3-8 membered heterocyclyl, NH 2 ；
Each R a1 Identical or different, independently of one another, from halogen, OH, NH 2 、C 1-8 Alkyl radical, C 1-8 Hydroxyalkyl radical, C 1-8 Haloalkyl, C 3-8 Cycloalkyl, C 1-8 Alkylamino radical, (C) 1-8 Alkyl radical) 2 An amino group;
r is selected from unsubstituted or optionally substituted by one, two or more R b Substituted of the following groups: c 1-8 An alkyl group;
each R b Identical or different, independently of one another, from halogen, OH, unsubstituted or optionally substituted by one, two or more R b1 Substituted of the following groups: c 1-8 Alkyl radical, C 1-8 Haloalkyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, C 6-14 Aryl, 5-14 membered heteroaryl, 3-8 membered heterocyclyl, C 1-8 Alkyloxy, C 3-8 Cycloalkyloxy, 3-8 membered heterocyclyloxy, NH 2 ；
Each R b1 Identical or different, independently of one another, from halogen, OH, oxo (= O), unsubstituted or optionally substituted by one, two or more R b2 Substituted of the following groups: c 1-8 Alkyl radical, C 1-8 Haloalkyl, C 1-8 Alkyloxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, CN, NH 2 ；
Each R b2 Identical or different, independently of one another, from halogen, OH, unsubstituted or optionally substituted by one, two or more R b3 Substituted of the following groups: c 1-8 Alkyl radical, C 1-8 Haloalkyl, C 1-8 Alkyloxy, C 3-8 Cycloalkyl, CN, NH 2 ；
Each R b3 Identical or different, independently of one another, from the group consisting of halogen, OH, NH 2 、C 1-8 Alkyl radical, C 1-8 Haloalkyl, C 1-8 Alkyloxy, C 3-8 A cycloalkyl group.
4. The compound of formula I, its racemate, stereoisomer, tautomer, isotopic label, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound according to any one of claims 1 to 3, wherein the compound of formula I has the structure shown in formula I-4, formula I-5, formula I-6, formula I-7, formula I-8, formula I-9 or formula I-10:
Figure FDA0003664464840000061
wherein m, R a Having the definition as set forth in any one of claims 1 to 3.
5. The compound of formula I, its racemate, stereoisomer, tautomer, isotopic label, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound according to any one of claims 1 to 4, wherein the compound of formula I has the structure shown in formula II:
Figure FDA0003664464840000062
wherein:
Figure FDA0003664464840000063
represents a single bond or a double bond;
m is a bond, O, S, NR 5 C (O) or CR 5 R 6 ；
R 1 And R 2 Identical or different, independently of one another, from the group consisting of hydrogen, deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, C 1-8 Alkyl radical, C 1-8 Alkyloxy, C 1-8 Hydroxyalkyl radical, C 1-8 Haloalkyl, C 1-8 Alkylamino radical, (C) 1-8 Alkyl radical) 2 Amino, amino-C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 Aryl or 5-to 14-membered heteroaryl, said amino, C 1-8 Alkyl radical, C 1-8 Alkyloxy, C 1-8 Hydroxyalkyl, C 1-8 Haloalkyl, C 1-8 Alkylamino radical, (C) 1-8 Alkyl radical) 2 Amino, amino-C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted by deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, C 1-8 Alkyl radical, C 1-8 Alkyloxy, C 1-8 Hydroxyalkyl radical, C 1-8 Haloalkyl, C 1-8 Alkylamino radical, (C) 1-8 Alkyl radical) 2 Amino, amino-C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl;
R 3 and R 4 Identical or different, independently of one another, from the group consisting of hydrogen, deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, C 1-8 Alkyl radical, C 1-8 Alkyloxy, C 1-8 Hydroxyalkyl radical, C 1-8 Haloalkyl, C 1-8 Alkylamino radical, (C) 1-8 Alkyl radical) 2 Amino, amino-C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said amino, C 1-8 Alkyl radical, C 1-8 Alkyloxy, C 1-8 Hydroxyalkyl radical, C 1-8 Haloalkyl, C 1-8 Alkylamino radical, (C) 1-8 Alkyl radical) 2 Amino, amino-C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted by deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, C 1-8 Alkyl radical, C 1-8 Alkyloxy, C 1-8 Hydroxyalkyl, C 1-8 Haloalkyl, C 1-8 Alkylamino, amino-C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl;
or, R 3 And R 4 Connection formation C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, said C 3-8 Cycloalkyl and 3-8 membered heterocyclyl, optionally further substituted by deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, C 1-8 Alkyl radical, C 1-8 Alkyloxy, C 1-8 Hydroxyalkyl, C 1-8 Haloalkyl, C 1-8 Alkylamino radical, (C) 1-8 Alkyl radical) 2 Amino, amino-C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl;
R 5 and R 6 Identical or different, independently of one another, from hydrogen, deuterium, halogen, hydroxyl, mercapto, nitro, cyano, amino, C 1-8 Alkyl radical, C 1-8 Alkyloxy, C 1-8 Hydroxyalkyl radical, C 1-8 Haloalkyl, C 1-8 Alkylamino radical, (C) 1-8 Alkyl radical) 2 Amino, amino-C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 Aryl or 5-to 14-membered heteroaryl, said amino, C 1-8 Alkyl radical, C 1-8 Alkyloxy, C 1-8 Hydroxyalkyl radical, C 1-8 Haloalkyl, C 1-8 Alkylamino radical, (C) 1-8 Alkyl radical) 2 Amino, amino-C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, alkynyl,C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted by deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, C 1-8 Alkyl radical, C 1-8 Alkyloxy, C 1-8 Hydroxyalkyl radical, C 1-8 Haloalkyl, C 1-8 Alkylamino, amino-C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl;
or, R 5 And R 6 Connection formation C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, said C 3-8 Cycloalkyl and 3-8 membered heterocyclyl, optionally further substituted by deuterium, halogen, hydroxy, mercapto, nitro, cyano, amino, C 1-8 Alkyl radical, C 1-8 Alkyloxy, C 1-8 Hydroxyalkyl radical, C 1-8 Haloalkyl, C 1-8 Alkylamino radical, (C) 1-8 Alkyl radical) 2 Amino, amino-C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl;
E. m and R a Having the definition as set forth in any one of claims 1 to 4.
6. The compound of formula I, its racemate, stereoisomer, tautomer, isotopic label, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound according to any one of claims 1 to 5, wherein the compound of formula I has the structure shown in formula III:
Figure FDA0003664464840000071
wherein: m is N or CH;
n is 0, 1, 2, 3, 4 or 5;
m、R a and R b1 Has the rightEvaluating any one of the definitions set forth in any one of claims 1-5.
7. The compound of formula I, its racemate, stereoisomer, tautomer, isotopic label, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound according to any one of claims 1 to 6, wherein the compound of formula I has the structure shown in formula IV:
Figure FDA0003664464840000081
wherein G is selected from 3-8 membered heterocyclyl, e.g. G is selected from
Figure FDA0003664464840000082
X is the same or different and is independently selected from C, CH, N, NH, O, S; g may be selected in particular from the following groups:
Figure FDA0003664464840000083
Figure FDA0003664464840000084
said 3-8 membered heterocyclyl is unsubstituted or optionally substituted with one, two or more R b1 Substituted heterocyclyl radical, R a M and R b1 Having the definition as set forth in any of claims 1 to 6.
8. The compound of formula I, its racemate, stereoisomer, tautomer, isotopic label, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound according to any one of claims 1 to 7, wherein R is selected from the group consisting of:
Figure FDA0003664464840000085
Figure FDA0003664464840000091
preferably, said R is selected from the group consisting of:
Figure FDA0003664464840000101
Figure FDA0003664464840000111
9. a compound of formula I according to claim 5, wherein
Figure FDA0003664464840000112
Selected from the group consisting of:
Figure FDA0003664464840000113
Figure FDA0003664464840000121
10. the compound of formula I according to any one of claims 1-9, wherein the structure of the compound of formula I is as follows:
Figure FDA0003664464840000122
Figure FDA0003664464840000131
Figure FDA0003664464840000141
Figure FDA0003664464840000151
Figure FDA0003664464840000161
11. a process for the preparation of a compound of formula I according to any one of claims 1 to 10, comprising the steps of:
reacting the compound 1 under the action of alkali to obtain a compound shown in a formula I;
Figure FDA0003664464840000162
wherein A and R have the definitions of any one of claims 1-10; r 0 Identical or different, independently of one another, from C 1-6 Alkyl groups such as methyl, ethyl, propyl;
preferably, the base in scheme 1 is an inorganic base, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide.
12. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of any one of claims 1-10, racemates, stereoisomers, tautomers, isotopic labels, solvates, polymorphs, pharmaceutically acceptable salts thereof or prodrug compounds thereof.
13. Use of at least one compound of any one of claims 1 to 10, racemates, stereoisomers, tautomers, isotopic labels, solvates, polymorphs, pharmaceutically acceptable salts or prodrug compounds thereof, and a pharmaceutical composition of claim 12 for the manufacture of a medicament;
preferably, the use is in the manufacture of a medicament for the treatment of a myeloperoxidase-associated disease, such as in the manufacture of a medicament for an MPO inhibitor.
14. Use of a compound of any one of claims 1-10, racemates, stereoisomers, tautomers, isotopic labels, solvates, polymorphs, pharmaceutically acceptable salts or prodrug compounds thereof, and a pharmaceutical composition of claim 12 for the manufacture of a medicament for the treatment of neurodegenerative diseases (including but not limited to dementia, parkinson, multiple sclerosis, huntington's chorea, amyotrophic lateral sclerosis, multiple system atrophy, aphasia), stroke, epilepsy, depression, traumatic brain injury, cardiovascular diseases (including but not limited to heart failure, atrial fibrillation, atherosclerosis, thrombosis, acute coronary syndrome, pulmonary hypertension, diabetes), novel coronary related disorders;
Preferably in the preparation of a medicament for treating neurodegenerative or cardiovascular diseases.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024038131A1 (en) * 2022-08-18 2024-02-22 Astrazeneca Ab Inhibitors of myeloperoxidase

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006062465A1 (en) * 2004-12-06 2006-06-15 Astrazeneca Ab Novel pyrrolo [3, 2-d] pyrimidin-4-one derivatives and their use in therapy
WO2007142577A1 (en) * 2006-06-05 2007-12-13 Astrazeneca Ab Pyrrolo[3,2-d]pyrimidin-4-one derivative as myeloperoxidase inhibitor
WO2009025618A1 (en) * 2007-08-23 2009-02-26 Astrazeneca Ab Mipo inhibitors for the treatment of huntington's disease and multiple system atrophy
US20090149475A1 (en) * 2006-04-13 2009-06-11 Astrazeneca Ab Thioxanthine Derivatives and Their Use as Inhibitors of MPO
US20090286813A1 (en) * 2006-04-13 2009-11-19 Astrazeneca Ab Thioxanthine Derivatives and Their Use as Inhibitors of MPO
US20160152623A1 (en) * 2014-12-01 2016-06-02 Astrazeneca Ab 1-[2-(AMINOMETHYL)BENZYL]-2-THIOXO-1,2,3,5-TETRAHYDRO-4H-PYRROLO[3,2-d]PYRIMIDIN-4-ONES AS INHIBITORS OF MYELOPEROXIDASE
AR102863A1 (en) * 2014-12-01 2017-03-29 Astrazeneca Ab 1- [2- (AMINOMETIL) BENCIL] -2-THIOXO-1,2,3,5-TETRAHYDRO-4H-PIRROLO [3,2-D] PYRIMIDIN-4-WAVES AS INHIBITORS OF MYELOPEROXIDASE
WO2019016074A1 (en) * 2017-07-17 2019-01-24 Astrazeneca Ab Mpo inhibitors for use in medicine
WO2020021300A1 (en) * 2018-07-24 2020-01-30 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of myeloperoxidase (mpo) inhibitors for the treatment of chemoresistant acute myeloid leukemia (aml)
WO2021072140A1 (en) * 2019-10-10 2021-04-15 Biohaven Therapeutics Ltd. Prodrugs of myeloperoxidase inhibitors

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006062465A1 (en) * 2004-12-06 2006-06-15 Astrazeneca Ab Novel pyrrolo [3, 2-d] pyrimidin-4-one derivatives and their use in therapy
US20080221136A1 (en) * 2004-12-06 2008-09-11 Astrazeneca Ab Novel Pyrrolo [3,2-D]Pyrimidin-4-One Derivatives And Their Use In Therapy
US20090149475A1 (en) * 2006-04-13 2009-06-11 Astrazeneca Ab Thioxanthine Derivatives and Their Use as Inhibitors of MPO
CN101466712A (en) * 2006-04-13 2009-06-24 阿斯利康(瑞典)有限公司 Thioxanthine derivatives and their use as inhibitors of mpo
US20090286813A1 (en) * 2006-04-13 2009-11-19 Astrazeneca Ab Thioxanthine Derivatives and Their Use as Inhibitors of MPO
WO2007142577A1 (en) * 2006-06-05 2007-12-13 Astrazeneca Ab Pyrrolo[3,2-d]pyrimidin-4-one derivative as myeloperoxidase inhibitor
WO2009025618A1 (en) * 2007-08-23 2009-02-26 Astrazeneca Ab Mipo inhibitors for the treatment of huntington's disease and multiple system atrophy
US20160152623A1 (en) * 2014-12-01 2016-06-02 Astrazeneca Ab 1-[2-(AMINOMETHYL)BENZYL]-2-THIOXO-1,2,3,5-TETRAHYDRO-4H-PYRROLO[3,2-d]PYRIMIDIN-4-ONES AS INHIBITORS OF MYELOPEROXIDASE
AR102863A1 (en) * 2014-12-01 2017-03-29 Astrazeneca Ab 1- [2- (AMINOMETIL) BENCIL] -2-THIOXO-1,2,3,5-TETRAHYDRO-4H-PIRROLO [3,2-D] PYRIMIDIN-4-WAVES AS INHIBITORS OF MYELOPEROXIDASE
WO2019016074A1 (en) * 2017-07-17 2019-01-24 Astrazeneca Ab Mpo inhibitors for use in medicine
WO2020021300A1 (en) * 2018-07-24 2020-01-30 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of myeloperoxidase (mpo) inhibitors for the treatment of chemoresistant acute myeloid leukemia (aml)
WO2021072140A1 (en) * 2019-10-10 2021-04-15 Biohaven Therapeutics Ltd. Prodrugs of myeloperoxidase inhibitors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"CAS号：2616663-68-2 等", ACS REGISTRY数据库, pages 1 - 29 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024038131A1 (en) * 2022-08-18 2024-02-22 Astrazeneca Ab Inhibitors of myeloperoxidase

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