CN118126063A - Pyridazinone derivatives and their use in medicine - Google Patents

Pyridazinone derivatives and their use in medicine Download PDF

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Publication number
CN118126063A
CN118126063A CN202311641385.5A CN202311641385A CN118126063A CN 118126063 A CN118126063 A CN 118126063A CN 202311641385 A CN202311641385 A CN 202311641385A CN 118126063 A CN118126063 A CN 118126063A
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trifluoromethyl
compound
reaction
pyrimidin
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朱钰沁
魏用刚
楚洪柱
孙毅
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Chengdu Baiyu Pharmaceutical Co Ltd
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Chengdu Baiyu Pharmaceutical Co Ltd
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Abstract

The invention relates to a pyridazinone derivative or pharmaceutically acceptable salt, stereoisomer or deuterated compound thereof and application thereof in medicine.

Description

Pyridazinone derivatives and their use in medicine
Technical Field
The invention relates to a pyridazinone derivative or pharmaceutically acceptable salt, stereoisomer or deuteride thereof and application thereof in medicine.
Background
Adenosine diphosphate ribosylation (ADP-ribosylation) is a post-transcriptional modification of proteins by inserting single or multiple adenosine diphosphate ribose (ADP-ribose) groups into amino acid residues of the protein. ADP-ribosylation is a reversible process involving physiological regulation of cell signaling, DNA damage repair, transcription, gene expression regulation, apoptosis, etc. ADP-ribose is derived from a redox cofactor: nicotinamide adenine dinucleotide (Nicotinamide adenine dinucleotide, NAD+), the enzyme mediating the ADP-ribose intercalating modification is ADP-ribosylase. In this regulation of the physiological response, the N-glycosidic bond of NAD+ linking the ADP-ribose molecule and the nicotinamide group is cleaved and subsequently captured to the corresponding amino acid residue of the target protein. ADP-ribosyl enzymes can undergo two types of modifications: mono-ADP ribosylation and poly-ADP ribosylation. When DNA damage or cells are stressed by pressure, PARP is activated, resulting in an increase in poly ADP-ribose and a decrease in nad+. PARP1 has been considered for over a decade to be the only poly ADP-ribose polymerase in mammalian cells and therefore the enzyme has been the most studied. To date, scientists have identified 17 different PARPs. MonoPARP occupy a large part of the PARP family and mediate important biological functions and various stress responses, such as: unfolded protein response, NF- κb signaling, antiviral response, and cytokine signaling. 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD) induced poly (ADP-ribose) polymerase (PARP-7) is one of the MonoPARP family members whose expression is regulated by TCDD activating Aromatic Hydrocarbon Receptors (AHR), a ligand activated transcription factor, that mediates the toxic activity of many environmental heterologous organisms. AHR up-regulates the expression of PARP-7, which causes inhibition of TBK1 activity and down-regulation of IFN-I (type I interferon) response by interaction with and ADP-ribosylation of kinase TBK1, thereby resulting in inhibition of antiviral and tumor immune responses in the body.
Disclosure of Invention
One or more embodiments of the present application provide a pyridazinone derivative or a pharmaceutically acceptable salt, stereoisomer or deuterate thereof, and a use thereof in medicine, for example, in anticancer.
One or more embodiments of the present application provide a compound represented by formula (I) or a pharmaceutically acceptable salt, stereoisomer, or deuterate thereof:
Wherein:
X 1 is NH, O, or a 4 to 10 membered heterocyclic ring, said 4 to 10 membered heterocyclic ring comprising 1 to 3 heteroatoms selected from N and O;
x 2 is O or a bond;
x 3 is CH or N;
X 4 is S or O;
Each X 5、X6 is independently CH or N;
r 1 is C 1-6 alkyl, C 3-5 cycloalkyl, halogen or cyano, said C 1-6 alkyl optionally substituted with 1 to 3 halogens;
Each R 2、R3、R4、R5 is independently H, D or C 1-6 alkyl;
R 6, which may be the same or different, are each independently C 1-6 alkyl, C 1-6 alkoxy, halogen, cyano or C 3-5 cycloalkyl, the C 1-6 alkyl, C 1-6 alkoxy being optionally substituted with 1 to 3 halogens;
a is 1, 2 or 3;
b is 1, 2 or 3;
m is 1, 2 or 3;
n is 0,1, 2 or 3;
t is 0,1, 2 or 3.
In one or more embodiments of the application, the compounds of the application are selected from the following structures:
one or more embodiments of the present application provide a compound, or a pharmaceutically acceptable salt, stereoisomer, or deuterate thereof, wherein the compound is selected from the following structures:
one or more embodiments of the present application provide a pharmaceutical composition comprising:
(1) A compound of the application or a pharmaceutically acceptable salt, stereoisomer or deuterate thereof;
(2) Optionally one or more other active ingredients; and
(3) Pharmaceutically acceptable carriers and/or excipients.
One or more embodiments of the present application provide the use of a compound of the present application or a pharmaceutically acceptable salt, stereoisomer or deuteride thereof or a pharmaceutical composition of the present application for the manufacture of a medicament for the treatment and/or prevention of cancer.
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
The carbon, hydrogen, oxygen, sulfur, nitrogen or F, cl, br, I referred to in the groups and compounds of the present application each include their isotopic condition, and the carbon, hydrogen, oxygen, sulfur or nitrogen referred to in the groups and compounds of the present application are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12C, 13C and 14C, the isotopes of hydrogen include protium (H), deuterium (D, also known as heavy hydrogen), tritium (T, also known as heavy hydrogen), the isotopes of oxygen include 16O, 17O and 18O, the isotopes of sulfur include 32S, 33S, 34S and 36S, the isotopes of nitrogen include 14N and 15N, the isotopes of fluorine include 17F and 19F, the isotopes of chlorine include 35Cl and 37Cl, and the isotopes of bromine include 79Br and 81Br.
"Alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 (e.g., 1, 2, 3, 4, 5, 6, 7, 8) carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, still more preferably an alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and various branched isomers thereof; when the alkyl group is substituted, it may optionally be further substituted with 1 or more substituents.
"Alkoxy" refers to a group formed by substitution of at least 1 carbon atom in an alkyl group with an oxygen atom. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy and cyclobutoxy. The alkyl group is as defined above for the "alkyl" group.
"Heterocyclyl" or "heterocycle" refers to a saturated or unsaturated aromatic or non-aromatic heterocycle, which, when aromatic, is as defined above for "heteroaryl"; when a non-aromatic heterocycle, it may be a 3 to 10 membered (e.g., 3,4, 5, 6, 7, 8, 9, 10 membered) monocyclic, 4 to 12 membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic or 10 to 15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system and contains 1 to 4 (e.g., 1,2,3, 4) heteroatoms selected from N, O or S, preferably 3 to 8 membered heterocyclyl. 1 to 4 (e.g., 1,2,3, 4) N, S of the "heterocyclyl" or "heterocyclic" rings that are optionally substituted may be oxidized to various oxidation states; "heterocyclyl" or "heterocycle" may be attached to a heteroatom or carbon atom; "heterocyclyl" or "heterocycle" may be bridged or spiro. Non-limiting examples of "heterocyclyl" or "heterocycle" include epoxy ethyl, epoxy propyl, aziridinyl, oxetanyl, azetidinyl, thietanyl, 1, 3-dioxolanyl, 1, 4-dioxolanyl, 1, 3-dioxanyl, azepanyl, oxepinyl, thiepanyl, oxazepinyl, diazapanyl, thiazepinyl, pyridyl, homopiperidinyl, and combinations thereof furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, thiaxalkyl, 1, 3-dithianyl, dihydrofuryl, dithianyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyridinyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, thiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridinyl, pyrazolopyrimidinyl, imidazopyrazinyl, benzodihydrofuranyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1, 3-dioxapentyl, pyrazolinyl, dithianyl, dithiadienyl, dihydrothienyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 1,2,3, 4-tetrahydroisoquinolyl, 3-azabicyclo [3.1.0] hexyl, 3-azabicyclo [4.1.0] heptyl, azabicyclo [2.2.2] hexyl, 3H-indolylquinolizinyl, N-pyridyl urea, 1-dioxothiomorpholinyl, azabicyclo [3.2.1] octanyl, azabicyclo [5.2.0] nonanyl, oxatricyclo [5.3.1.1] dodecyl, azaadamantyl and oxaspiro [3.3] heptyl. The "heterocyclyl" or "heterocycle" may be optionally further substituted with 1 or more substituents.
"Cycloalkyl" refers to a saturated cyclic hydrocarbon group, the ring of which may be a 3 to 10 membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10 membered) monocyclic, 4 to 12 membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic, or 10 to 20 membered (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 membered) polycyclic ring system, the ring carbon atoms preferably being 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms. Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1, 5-cyclooctadienyl, 1, 4-cyclohexanedienyl, cycloheptatrienyl, and the like. When cycloalkyl is substituted, it may optionally be further substituted with 1 or more substituents.
When the above-described "alkyl", "alkoxy", "heterocyclyl", "heterocycle", "cycloalkyl" is substituted, it may be optionally further substituted with 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 groups selected from F, cl, br, I, hydroxy, mercapto, nitro, cyano, amino, C 1-6 alkylamino, = O, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, -NR q4Rq5、＝NRq6、-C(＝O)OC1-6 alkyl, -OC (=o) C 1-6 alkyl, -C (=o) NR q4Rq5、C3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-10 aryl, C 5-10 heteroaryl, -C (=o) OC 6-10 aryl, -OC (=o) C 6-10 aryl, -OC (=o) C 5-10 heteroaryl, -C (=o) OC 5-10 heteroaryl, -OC (=o) C 3-8 heterocycloalkyl, -C (=o) OC 3-8 heterocycloalkyl, -OC (=o) C 3-8 cycloalkyl, -C (=o) OC 3-8 cycloalkyl, -NHC (=o) C 3-8 heterocycloalkyl, -NHC (=o) C 6-10 aryl, -NHC (=o) C 5-10 heteroaryl, -NHC (=o) C 3-8 cycloalkyl, -NHC (=o) C 3-8 heterocycloalkyl, -NHC (=o) C 2-6 alkenyl, or-NHC (=o) C 2-6 alkynyl, and wherein said substituents C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-10 aryl, C 5-10 heteroaryl, -NHC (=O) C 6-10 aryl, -NHC (=O) C 5-10 heteroaryl, -NHC (=O) C 3-8 heterocycloalkyl, or-NHC (=O) C 3-8 cycloalkyl optionally further substituted with 1 to 3 groups selected from OH, F, cl, br, I, C 1-6 alkyl, C 1-6 alkoxy, -NR q4Rq5, or = O; r q1 is selected from C 1-6 alkyl, C 1-6 alkoxy or C 6-10 aryl; r q2、Rq3 is selected from H or C 1-6 alkyl; wherein R q4、Rq5 is selected from H, C 1-6 alkyl, -NH (c=nr q1)NRq2Rq3、-S(＝O)2NRq2Rq3、-C(＝O)Rq1 or-C (=o) NR q2Rq3, wherein said C 1-6 alkyl is optionally further substituted with 1 or more substituents selected from OH, F, cl, br, I, C 1-6 alkyl, C 1-6 alkoxy, C 6-10 aryl, C 5-10 heteroaryl, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl; or R q4 forms a 3 to 8 membered heterocyclic ring with R q5 and the N atom, which may contain 1 or more heteroatoms selected from N, O or S.
Halogen includes F, cl, br and I.
By "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" is meant a salt of a compound of the application that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reaction with a non-toxic inorganic or organic base.
"Pharmaceutical composition" refers to a mixture of one or more compounds of the present application, pharmaceutically acceptable salts or prodrugs thereof, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and/or one or more other therapeutic agents.
By "carrier" is meant a material that does not cause significant irritation to the organism and does not abrogate the biological activity and properties of the administered compound.
"Excipient" refers to an inert substance that is added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrating agents.
"Stereoisomers" refers to isomers arising from the spatial arrangement of atoms in a molecule, and include cis-trans isomers, enantiomers and conformational isomers.
"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may be, but is not necessarily, present, and the description includes cases where the heterocyclic group is substituted with an alkyl group, and cases where the heterocyclic group is not substituted with an alkyl group.
Detailed Description
The following examples illustrate the technical aspects of the present invention in detail, but the scope of the present invention is not limited thereto.
The examples are not particularly described, and the reaction temperature is room temperature, and the optimum reaction temperature at room temperature is 20-30 ℃.
Intermediate 1
5-Chloro-2- (4-methoxybenzyl) -4- (trifluoromethyl) pyridazin-3 (2H) -one (intermediate 1)
5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one
The first step:
4, 5-dibromo-2- (4-methoxybenzyl) pyridazin-3 (2H) -one (1 b)
4,5-dibromo-2-(4-methoxybenzyl)pyridazin-3(2H)-one
To a solution of 4, 5-dibromo-2, 3-dihydropyridazin-3-one (1 a,50g,196.94mmol,1.0 equiv.) in N, N-dimethylformamide (500 mL) at 0-10℃was added sodium hydrogen (11.82 g,295.41mmol,1.5 equiv., 60%) in portions and 1- (chloromethyl) -4-methoxybenzene (46.06 g,294.11mmol,1.49 equiv.) at 0 ℃. After the addition, the reaction mixture was stirred at room temperature for 3h. After the reaction was complete, the reaction solution was slowly poured into 1.0L of ice-water mixture to quench and extracted with 2×500mL of dichloromethane. The organic layers were combined and concentrated. The solid was washed with methanol (500 mL. Times.2) to give compound 1b as a yellow solid (48.4 g, 66% yield).
LC-MS m/z(ESI)＝375.0[M+1]。
And a second step of:
4-bromo-5-methoxy-2- (4-methoxybenzyl) pyridazin-3 (2H) -one (1 c)
4-bromo-5-methoxy-2-(4-methoxybenzyl)pyridazin-3(2H)-one
Compound 1b (48.4 g,129.40mmol,1.0 equiv) was dissolved in methanol (417 mL) and the reaction stirred at room temperature for 2.0h. The resulting reaction mixture was concentrated to 80mL and filtered to give crude product. The resulting filter cake was slurried in water (160 mL) for 1.0h and filtered to give compound 1c as a white solid (38.72 g, 92% yield).
LC-MS m/z(ESI)＝326.30[M+1]。
And a third step of:
5-methoxy-2- (4-methoxybenzyl) -4- (trifluoromethyl) pyridazin-3 (2H) -one (1 d)
5-methoxy-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one
Compound 1c (14 g,43.04mmol,1.0 equiv) and copper iodide (4.10 g,21.52mmol,0.50 equiv) were weighed into a 250mL reaction flask and dissolved in nitrogen methyl pyrrolidone (72 mL), followed by slow addition of methyl 2, 2-difluoro-2- (fluorosulfonyl) acetate (16.4 mL,129.11mmol,3.0 equiv). After the addition, the reaction was stirred in an oil bath at 100℃for 3.0h. After the reaction was completed, 90mL of water was added to the reaction solution for quenching. The resulting solution was extracted with 3X 60mL of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo, and the residue was purified by column chromatography (petroleum ether: ethyl acetate=1:1) to give compound 1d as a white solid (12.1 g, yield 89%).
LC-MS m/z(ESI)＝315.10[M+1]。
Fourth step:
5-hydroxy-2- (4-methoxybenzyl) -4- (trifluoromethyl) pyridazin-3 (2H) -one (1 e)
5-hydroxy-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one
To a solution of compound 1d (12.1 g,38.52mmol,1.0 equiv.) in DMF (60 mL) was added dropwise trimethyliodosilane (9.97 g,50.07mmol,1.3 equiv.) at room temperature. The resulting reaction solution was stirred at 0℃for 20h. After the reaction was completed, 60mL of water was added to the reaction mixture to quench the reaction, followed by extraction of the resulting solution with 3×60mL of dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo, and the residue was purified by column chromatography (petroleum ether: ethyl acetate=1:1) to give compound 1e as a white solid (10.4 g, yield 90%).
LC-MS m/z(ESI)＝301.07[M+1]。
Fifth step:
5-chloro-2- (4-methoxybenzyl) -4- (trifluoromethyl) pyridazin-3 (2H) -one (intermediate 1)
5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one
Oxalyl dichloride (8.79 g,69.32mmol,2.0 equiv.) was slowly added dropwise to a solution of compound 1e (10.4 g,34.66mmol,1.0 equiv.) in N, N-dimethylformamide (52 mL) at 0deg.C. After the addition, the reaction mixture was stirred at room temperature for 8 hours. After the reaction was completed, 550mL of water was added to the reaction mixture to quench. The mixture was filtered to give intermediate 1 as a white solid (11.04 g, 99%).
LC-MS m/z(ESI)＝319.68[M+1]。
Intermediate 2
2- (Bromomethyl) -5- (5- (trifluoromethyl) pyrimidin-2-yl) -4,5,6, 7-tetrahydrooxazol [5,4-c ] pyridine (intermediate 2)
2-(bromomethyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridine
The first step:
2- (hydroxymethyl) -6, 7-dihydro-oxazol [5,4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester (2 b)
tert-butyl 2-(hydroxymethyl)-6,7-dihydrooxazolo[5,4-c]pyridine-5(4H)-carboxylate
2A (2.82 g,10.0mmol,1.0 equiv) was weighed into a 100mL three-necked flask, dissolved in anhydrous tetrahydrofuran (28 mL), and added slowly over a portion of ice bath to lithium aluminum hydride (417 mg,11.0mmol,1.1 equiv) and reacted for 1h over Bi Bing baths. After completion of the reaction, 5.00g of sodium sulfate decahydrate and 3.00g of anhydrous magnesium sulfate were slowly added to the reaction mixture under ice bath and stirred for 10min, filtered, the cake was washed with ethyl acetate, and the combined filtrates were concentrated in vacuo to give 2b as pale yellow solid (2.30 g, yield 90%).
LC-MS m/z(ESI)＝255.1[M+1]。
And a second step of:
(4, 5,6, 7-tetrahydrooxazol [5,4-c ] pyridin-2-yl) methanol (2 c)
(4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)methanol
To a 100mL reaction flask, compound 2b (2.00 g,7.87mmol,1.0 equiv) was added and dissolved in dioxane hydrochloride solution (4N, 20 mL) under an ice bath. Stirring for 1h. The reaction was complete and concentrated in vacuo to give compound 2c as a white solid (1.21 g, 99% yield).
LC-MS m/z(ESI)＝155.0[M+1]。
And a third step of:
(5- (5- (trifluoromethyl) pyrimidin-2-yl) -4,5,6, 7-tetrahydrooxazol [5,4-c ] pyridin-2-yl) methanol (2 e)
(5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)methanol
2C (1.00 g,6.49mmol,1.0 equiv) was weighed into a 100mL three-necked flask, anhydrous N, N-dimethylformamide (10.0 mL) was added to dissolve, N-diisopropylethylamine (3.35 g,26.0mmol,4.0 equiv) was slowly added, and 2d (1.41 g,7.78mmol,1.2 equiv) was added and reacted at room temperature for 3 hours. The reaction was complete, poured into 100mL of water, the solid was filtered, washed and dried to give 2e as a white solid (1.49 g, 76% yield).
LC-MS m/z(ESI)＝301.0[M+1]。
Fourth step:
2- (bromomethyl) -5- (5- (trifluoromethyl) pyrimidin-2-yl) -4,5,6, 7-tetrahydrooxazol [5,4-c ] pyridine (intermediate 2)
2-(bromomethyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridine
Synthesis of intermediate 2, reference is made to patent CN106496110a, example 2 preparation of compound c. .
LC-MS m/z(ESI)＝363.0[M+1]。
Intermediate 3
(S) -2- (4-methoxybenzyl) -4- (trifluoromethyl) -5- ((1- (2- (7- (5- (trifluoromethyl) pyrimidin-2-yl) -5,6,7, 8-tetrahydroimidazo [1,5-a ] pyrazin-3-yl) ethoxy) propan-2-yl) amino) pyridazin-3 (2H) -one (intermediate 3)
(S)-2-(4-methoxybenzyl)-4-(trifluoromethyl)-5-((1-(2-(7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)ethoxy)propan-2-yl)amino)pyridazin-3(2H)-one
The first step:
((tert-Butyldiphenylsilyl) oxy) propanoic acid ethyl ester (3 b)
ethyl 3-((tert-butyldiphenylsilyl)oxy)propanoate
Imidazole (20.4 g,300mmol,3.0 equiv) was weighed into a 500mL reaction flask and dissolved in dichloromethane (40 mL). Ethyl 3-hydroxypropionate (3 a,11.8g,100mmol,1.0 equiv) was added to the reaction system, followed by slow dropwise addition of t-butyldiphenylchlorosilane (32.98 g,120mmol,1.2 equiv) at 0 ℃; after the addition, the reaction was stirred at room temperature overnight. After the reaction was complete, the reaction solution was slowly poured into 300mL of water, separated, and extracted with 2×500mL of dichloromethane. The organic phases were combined, concentrated in vacuo and the residue was purified by column chromatography (petroleum ether: ethyl acetate=100:1) to give 3b as a colourless liquid (21.8 g, 61% yield).
LC-MS m/z(ESI)＝357.54[M+1]。
And a second step of:
3- ((tert-butyldiphenylsilyl) oxy) propanoic acid (3 c)
3-((tert-butyldiphenylsilyl)oxy)propanoic acid
Compound 3b (21.8 g,61.14mmol,1.0 equiv) was dissolved in a mixed solution of tetrahydrofuran (11 mL) and methanol (11 mL), and lithium hydroxide monohydrate (3.8 g,61.14mmol,1.5 equiv) was slowly added with stirring at room temperature; after the addition, the reaction mixture was stirred at room temperature for 2.0h. After the reaction was completed, the ph=3 of the reaction system was adjusted with hydrochloric acid (2N). The reaction was slowly poured into 60mL of water and extracted with 3X 60mL of ethyl acetate. The organic phases were combined and concentrated in vacuo to give crude compound 3c as a colourless liquid (12.4 g, 62% yield).
LC-MS m/z(ESI)＝329.48[M+1]。
And a third step of:
4- (3- ((tert-Butyldiphenylsilyl) oxy) propionyl tert-butyl) -3- (hydroxymethyl) piperazine-1-carboxylic acid tert-butyl ester (3 d)
tert-butyl 4-(3-((tert-butyldiphenylsilyl)oxy)propanoyl)-3-(hydroxymethyl)piperazine-1-carboxylate
3C (12.4 g,37.75mmol,1.0 equiv.) t-butyl 3- (hydroxymethyl) piperazine-1-carboxylate (8.16 g,37.75mmol,1.0 equiv.) urea hexafluorophosphate (14.35 g,37.75mmol,1.0 equiv.) is weighed out separately into a 250mL reaction flask and dissolved in DMF (120 mL). N, N diisopropylethylamine (25 mL,151mmol,4 equiv) was added to the mixture and the reaction was stirred at 25℃for 1.0h. After the reaction was complete, the reaction mixture was concentrated in vacuo. The residue was purified by C18 reverse phase chromatography (water: acetonitrile=1:5) to give compound 3d as a white solid (14.4 g, yield 72%).
LC-MS m/z(ESI)＝527.74[M+1]。
Fourth step:
tert-butyl 4- (3- (((tert-butyldiphenylsilyl) oxy) propionyl) tert-butylpiperazine-1-carboxylate (3 e)
tert-butyl 4-(3-((tert-butyldiphenylsilyl)oxy)propanoyl)-3-formylpiperazine-1-carboxylate
Compound 3d (7.5 g,14.2mmol,1.0 equiv) was weighed into a 250mL reaction flask and dissolved by adding dichloromethane (75 mL). Dess-Martin periodate (7.83 g) was added to the mixture under ice-cooling; after the addition, the reaction was stirred at room temperature for 40min. A saturated aqueous sodium thiosulfate solution was added to the reaction mixture under ice-cooling. The reaction mixture was concentrated under reduced pressure, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride in this order. The organic layer was dried over sodium sulfate. Sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate=10:1) to give compound 3e as an oily liquid (6.84 g, yield 92%).
LC-MS m/z(ESI)＝525.60[M+1]。
Fifth step:
3- (2- (((tert-butyldiphenylsilyl) oxy) ethyl) tert-butyl-5, 6-dihydroimidazo [1,5-a ] pyrazine-7 (8H) -carboxylate (3 f)
tert-butyl 3-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate
Compound 3d (6.84 g,13mmol,1.0 equiv), acetic acid (46 mL) and ammonium acetate (3.5 g,45.6mmol,3.5 equiv) were weighed and mixed. The reaction mixture was stirred at 90℃for 1.0h. After the reaction was complete, the reaction mixture was concentrated in vacuo. The residue was purified by C18 reverse phase chromatography (water: acetonitrile=1:10) to give compound 3f as an oil (3.12 g, yield 48%).
LC-MS m/z(ESI)＝506.20[M+1]。
Sixth step:
2- (5, 6,7, 8-tetrahydroimidazo [1,5-a ] pyrazin-3-yl) ethan-1-ol (3 g)
2-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)ethan-1-ol
Compound 3f (3.12 g,6.18mmol,1.0 equiv) was weighed and dissolved in hydrochloric acid/dioxane (9 mL, 4M/L). The reaction was stirred at room temperature for 4.0h. When the reaction was complete, the suspension was filtered, the filter cake was washed with dioxane, and dried to give 3g of the compound as a white solid (347.7 mg, yield 33%).
LC-MS m/z(ESI)＝168.20[M+1]。
Seventh step:
2- (7- (5- (trifluoromethyl) pyrimidin-2-yl) -5,6,7, 8-tetrahydroimidazo [1,5-a ] pyrazin-3-yl) ethan-1-ol (3 h)
2-(7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)ethan-1-ol
3G (347.7 mg,2.08mmol,1.0 equiv) of the compound, 2-chloro-5-trifluoromethylpyrimidine (381.7 mg,2.08mmol,1.0 equiv) was weighed out separately in a 25mL reaction flask and dissolved in N, N-dimethylformamide (8.0 mL). N, N-diisopropylethylamine (1.38 mL,8.32mmol,4 equiv) was added to the mixture and the reaction stirred at 90℃for 4.0h. After the reaction was complete, the reaction mixture was concentrated in vacuo. The residue was purified by C18 reverse phase chromatography (water: acetonitrile=1:4) to give 3h as a white solid (150 mg, yield 23%).
LC-MS m/z(ESI)＝313.30[M+1]。
Eighth step:
(S) -1- (2- (7- (5- (trifluoromethyl) pyrimidin-2-yl) -5,6,7, 8-tetrahydroimidazo [1,5-a ] pyrazin-3-yl) ethoxy) propan-2-amine (3 i)
(S)-1-(2-(7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)ethoxy)propan-2-amine
To a 25mL reaction flask, the weighed compound (150 mg,0.479mmol,1.0 equiv) was added and dissolved in anhydrous N, N-dimethylformamide (3.0 mL). N 2 protection, sodium hydride (48 mg,1.2mmol,2.5 eq) was added in portions at 0deg.C; after the addition, the reaction was stirred for a further 30min at this temperature. Subsequently, an N, N-dimethylformamide solution (3.0 mL) of (S) -4-methyl-1, 2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2, 2-dioxide was slowly dropped into the reaction system, the dropping process temperature was maintained at 0℃and stirring was continued for 2.0 hours. After the reaction was completed, the reaction system ph=3 was adjusted and stirred at room temperature for 0.5h. The reaction mixture was extracted with 3X 120mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give crude, column chromatographed (dichloromethane: methanol=30:1) to give 3i as a white solid (224 mg, 50% yield).
LC-MS m/z(ESI)＝371.40[M+1]。
Ninth step:
(S) -2- (4-methoxybenzyl) -4- (trifluoromethyl) -5- ((1- (2- (7- (5- (trifluoromethyl) pyrimidin-2-yl) -5,6,7, 8-tetrahydroimidazo [1,5-a ] pyrazin-3-yl) ethoxy) propan-2-yl) amino) pyridazin-3 (2H) -one (intermediate 3)
(S)-2-(4-methoxybenzyl)-4-(trifluoromethyl)-5-((1-(2-(7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)ethoxy)propan-2-yl)amino)pyridazin-3(2H)-one
3I (224 mg,0.604mmol,1.0 eq) was weighed into a 10mL reaction flask with intermediate 1 (192.4 mg,0.604mmol,1.0 eq) and dissolved in N, N-dimethyl-formamide (4.0 mL). Subsequently, N-diisopropylethylamine (0.399 mL,2.41mmol,4.0 equiv) was added sequentially. The mixture was stirred at 100℃for 2.0h. After completion of the reaction, concentrated in vacuo and the residue purified by column chromatography (dichloromethane: methanol=40:1) to give intermediate 3 as a white solid (110.2 mg, yield 28%).
LC-MS m/z(ESI)＝653.45[M+1]。
Intermediate 4
(S) -5- (5- (5- (trifluoromethyl) pyrimidin-2-yl) -4,5,6, 7-tetrahydro-2H-pyrazolo [4,3-c ] pyridin-2-yl) pentan-2-amine (intermediate 4)
(S)-5-(5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-2-yl)pentan-2-amine
The first step:
4,5,6, 7-tetrahydro-2H-pyrazolo [4,3-c ] pyridine (4 b)
4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine
Weigh 4a (1.1 g,5mmol,1.0 equiv) in a 50mL reaction flask; under ice bath, dioxane hydrochloride (4N, 10 mL) is added into the system, and the reaction is stirred for 1h after the addition. After the reaction was complete, it was concentrated in vacuo to give crude 4b as a white solid (1 g, 99% yield).
LC-MS m/z(ESI)＝124.08[M+1]。
And a second step of:
5- (5- (trifluoromethyl) pyrimidin-2-yl) -4,5,6, 7-tetrahydro-2H-pyrazolo [4,3-c ] pyridine (4 c)
5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine
The intermediate 13, described in patent WO2022242750, was prepared purified at medium pressure to give 4c as a white solid (800 mg, 75% yield).
1H NMR(400MHz,DMSO-d6)δ12.55(s,1H),8.73(s,2H),7.58(s,1H),4.87(s,2H),4.15(t,2H),2.74(s,2H).
LC-MS m/z(ESI)＝269.09[M+1]。
And a third step of:
tert-butyl (S) - (5- (5- (5- (trifluoromethyl) pyrimidin-2-yl) -4,5,6, 7-tetrahydro-2H-pyrazolo [4,3-c ] pyridin-2-yl) pent-2-yl) carbamate (4 e)
tert-butyl(S)-(5-(5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)pentan-2-yl)carbamate
4C (124 mg,0.46mmol,1.5 equiv) was weighed into a 50mL reaction flask and dissolved in anhydrous N, N-dimethylacetamide (3 mL), followed by the sequential addition of 4d (110 mg,0.31mmol,1.0 equiv) and cesium carbonate (293 mg,0.93mmol,3.0 equiv). After the addition, the reaction was stirred at 80℃for 1h. After the reaction was complete, the reaction solution was purified by medium pressure preparation (water: acetonitrile=75:25) to give 4e as a white solid (58 mg, yield 75%).
LC-MS m/z(ESI)＝455.23[M+1]。
Fourth step
(S) -5- (5- (5- (trifluoromethyl) pyrimidin-2-yl) -4,5,6, 7-tetrahydro-2H-pyrazolo [4,3-c ] pyridin-2-yl) pentan-2-amine (intermediate 4)
(S)-5-(5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)pentan-2-amine
The tenth step of the synthesis of intermediate 13, described in patent WO2022242750, gives intermediate 4 as a white solid (48 mg, 99% yield).
LC-MS m/z(ESI)＝355.23[M+1]。
Intermediate 5
(S) -5- (5- (5- (trifluoromethyl) pyrimidin-2-yl) -5, 6-dihydropyrrolo [3,4-c ] pyrazol-2 (4H) -yl) pent-2-amine (intermediate 5)
(S)-5-(5-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)pentan-2-amine
The first step:
2,4,5, 6-tetrahydropyrrolo [3,4-c ] pyrazole (5 b)
2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole
A similar synthetic procedure was followed to give compound 5b as a white solid (1.2 g, 99% yield).
LC-MS m/z(ESI)＝110.06[M+1]。
And a second step of:
5- (5- (trifluoromethyl) pyrimidin-2-yl) -2,4,5, 6-tetrahydropyrrolo [3,4-c ] pyrazole (5 c)
5-(5-(trifluoromethyl)pyrimidin-2-yl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole
The intermediate 13, described in patent WO2022242750, was purified in a ninth step to give 5c as a white solid (2.3 g, 75% yield).
1HNMR(400MHz,DMSO-d6)δ12.79(s,1H),8.78(s,2H),7.63(d,1H),4.65(s,4H)。
LC-MS m/z(ESI)＝256.07[M+1]。
And a third step of:
Tert-butyl (S) - (5- (5- (5- (trifluoromethyl) pyrimidin-2-yl) -5, 6-dihydropyrrolo [3,4-c ] pyrazol-2 (4H) -yl) pentan-2-yl) carbamate (5 d)
tert-butyl(S)-(5-(5-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)pentan-2-yl)carbamate
The third step of the synthesis of intermediate 20, described in patent WO2022242750, gives 5d as a white solid (174 mg, 55% yield).
1H NMR(400MHz,DMSO-d6)δ8.78(s,2H),6.70(d,1H),4.77(d,1H),4.61(d,4H),4.08-4.04(m,2H),3.45(d,1H),1.74(d,2H),1.36(d,9H),0.98(d,3H).
LC-MS m/z(ESI)＝441.21[M+1]。
Fourth step
(S) -5- (5- (5- (trifluoromethyl) pyrimidin-2-yl) -5, 6-dihydropyrrolo [3,4-c ] pyrazol-2 (4H) -yl) pent-2-amine (intermediate 5)
(S)-5-(5-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)pentan-2-amine
The tenth step of the synthesis of intermediate 13 described in reference to WO2022242750 gave intermediate 5 as a white solid (148 mg, 99% yield).
LC-MS m/z(ESI)＝341.23[M+1]。
Example 1
(S) -4- (trifluoromethyl) -5- ((1- ((5- (5- (trifluoro) methyl) pyrimidin-2-yl) -4,5,6, 7-tetrahydrooxazol [5,4-c ] pyridin-2-yl) methoxy) propan-2-yl) amino) pyridazin-3 (2H) -one (compound 1)
(S)-4-(trifluoromethyl)-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one
The first step:
Tert-butyl (S) - (1- ((5- (trifluoromethyl) pyrimidin-2-yl) -4,5,6, 7-tetrahydrooxazolo [5,4-c ] pyridin-2-yl) methoxy) propan-2-yl) carbamate (1A)
tert-butyl(S)-(1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydroxazolo[5,4-c]pyridin-2-yl)methoxy)propan-2-yl)carbamate
Synthesis of Compound 1A reference patent CN107033052A example 1 Synthesis of Compound 3.
LC-MS m/z(ESI)＝458.2[M+1]。
And a second step of:
(S) -1- ((5- (5- (trifluoromethyl) pyridin-2-yl) -4,5,6, 7-tetrahydrooxazolo [5,4-c ] pyridin-2-yl ] methoxy) propan-2-amine (1B)
(S)-1-((5-(5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)methoxy)propan-2-amine
To a 100mL reaction flask, compound 1A (457 mg,1mmol,1.0 equiv) was added and dissolved in dioxane hydrochloride solution (4N, 15 mL) under ice bath. Stirring for 1h. The reaction was complete and concentrated in vacuo to give compound 1B as a white solid (330 mg, 92% yield).
LC-MS m/z(ESI)＝357.1[M+1]。
And a third step of:
(S) -2- (4-methoxybenzyl) -4- (trifluoromethyl) -5- ((1- ((5- (5- (trifluoro) methyl) pyrimidin-2-yl) -4,5,6, 7-tetrahydrooxazolo [5,4-C ] pyridin-2-yl) methoxy) propan-2-yl) amino) pyridazin-3 (2H) -one (1C)
(S)-2-(4-methoxybenzyl)-4-(trifluoromethyl)-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one
Compound 1B (178 mg,0.5mmol,1.0 eq) and intermediate 1 (175.3 mg,0.55mmol,1.1 eq) were weighed into a 50mL reaction flask and dissolved by adding N, N-dimethylformamide (3.0 mL). Subsequently, N-diisopropylethylamine (0.33 mL,2.0mmol,4.0 equiv) was added sequentially. The mixture was stirred at 100deg.C for 4h. After completion of the reaction, it was concentrated in vacuo, and the residue was purified by column chromatography (petroleum ether: ethyl acetate=3:1) to give compound 1C as a white solid (220 mg, yield 68%).
LC-MS m/z(ESI)＝640.2[M+1]。
Fourth step:
(S) -4- (trifluoromethyl) -5- ((1- ((5- (5- (trifluoro) methyl) pyrimidin-2-yl) -4,5,6, 7-tetrahydrooxazol [5,4-c ] pyridin-2-yl) methoxy) propan-2-yl) amino) pyridazin-3 (2H) -one (compound 1)
(S)-4-(trifluoromethyl)-5-((1-((5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)methoxy)propan-2-yl)amino)pyridazin-3(2H)-one
To a 25mL reaction flask weighed compound 1C (191 mg,0.3mmol,1.0 equiv) was added trifluoroacetic acid (6.0 mL) and trifluoromethanesulfonic acid (1.0 mL,1.2mmol,4.0 equiv) in sequence. After the addition, the reaction was stirred at room temperature for 1h. After the completion of the reaction, 5mL of water was added to the reaction mixture to quench the reaction mixture. The resulting solution was extracted with ethyl acetate (3X 30 mL). The pH of the organic layer was adjusted to 8 to 9 by aqueous potassium carbonate. The combined organic layers were concentrated in vacuo and the residue purified by MPLC (water: acetonitrile=3:5) to give compound 1 as a white solid (90.0 mg, 58% yield).
1H NMR(400MHz,DMSO-d6):δ13.05(s,1H),8.78(s,2H),7.90(s,1H),6.15(s,1H),5.01(s,2H),4.41(d,2H),4.30(t,2H),4.15(t,3H),3.50–3.45(m,2H),1.15(d,3H).
LC-MS m/z(ESI)＝520.1[M+1]。
Example 2
(S) -4- (trifluoromethyl) -5- ((1- (2- (7- (5- (trifluoromethyl) pyrimidin-2-yl) -5,6,7, 8-tetrahydroimidazo [1,5-a ] pyrazin-3-yl) ethoxy) propan-2-yl) amino) pyridazin-3 (2H) -one (Compound 2)
(S)-4-(trifluoromethyl)-5-((1-(2-(7-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)ethoxy)propan-2-yl)amino)pyridazin-3(2H)-one
To a 10mL reaction flask weighed intermediate 3 (110.2 mg,0.169mmol,1.0 equiv) was added trifluoroacetic acid (1.0 mL) and trifluoromethanesulfonic acid (0.120 mL,1.35mmol,8.0 equiv) in sequence. After the addition, the reaction was stirred at 25℃for 1h. After the reaction was completed, 15mL of water was added to the reaction mixture to quench. The resulting solution was extracted with 3X 15mL ethyl acetate. The pH of the organic layer was adjusted to 8 to 9 by aqueous potassium carbonate. The combined organic layers were concentrated in vacuo and the residue purified by C18 reverse phase chromatography (water: acetonitrile=1:4) to give compound 2 as a white solid (45 mg, 50% yield).
1H NMR(400MHz,DMSO-d6)δ14.02(s,1H),12.45(s,1H),8.85(s,2H),7.85(s,1H),7.50(d,1H),6.23(dd,1H),5.17–5.00(m,2H),4.36–4.19(m,4H),4.12(d,1H),3.84–3.68(m,2H),3.57–3.45(m,2H),3.18(t,2H),1.09(d,3H).
LCMS m/z＝533.50[M+l]。
Example 3
(S) -4- (trifluoromethyl) -5- ((5- (5- (5- (trifluoromethyl) pyrimidin-2-yl) -4,5,6, 7-tetrahydro-2H-pyrazolo [4,3-c ] pyridin-2-yl) pentan-2-yl) amino) pyridazin-3 (2H) -one (compound 3)
(S)-4-(trifluoromethyl)-5-((5-(5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)pentan-2-yl)amino)pyridazin-3(2H)-one
The first step:
(S) -2- (4-methoxybenzyl) -4- (trifluoromethyl) -5- ((5- (5- (trifluoromethyl) pyrimidin-2-yl) -4,5,6, 7-tetrahydro-2H-pyrazolo [4,3-c ] pyridin-2-yl) pentan-2-yl) amino) pyridazin-3 (2H) -one (3A)
(S)-2-(4-methoxybenzyl)-4-(trifluoromethyl)-5-((5-(5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)pentan-2-yl)amino)pyridazin-3(2H)-one
The first step of synthesis of intermediate 3, described in patent WO2022242750, gives compound 3A as a pale yellow solid (41 mg, 59% yield).
LCMS m/z＝637.24[M+l]。
And a second step of:
(S) -4- (trifluoromethyl) -5- ((5- (5- (5- (trifluoromethyl) pyrimidin-2-yl) -4,5,6, 7-tetrahydro-2H-pyrazolo [4,3-c ] pyridin-2-yl) pentan-2-yl) amino) pyridazin-3 (2H) -one (compound 3)
(S)-4-(trifluoromethyl)-5-((5-(5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)pentan-2-yl)amino)pyridazin-3(2H)-one
The second step synthesis of compound 6 described in patent WO2022242750 gives compound 3 as a white solid (17 mg, 39% yield).
1HNMR(400MHz,DMSO-d6)δ12.45(s,1H),8.76(s,2H),7.76(s,1H),6.70(d,1H),4.74(d,1H),4.61(d,4H),4.12-4.06(m,2H),3.45-3.38(m,3H),1.79(d,2H),1.13(dd,3H).
LCMS m/z＝517.18[M+l]。
Example 4
(S) -4- (trifluoromethyl) -5- ((5- (5- (5- (trifluoromethyl) pyrimidin-2-yl) -5, 6-dihydropyrrol [3,4-c ] pyrazol-2 (4H) -yl) pentan-2-yl) amino) pyridazin-3 (2H) -one (compound 4)
(S)-4-(trifluoromethyl)-5-((5-(5-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)pentan-2-yl)amino)pyridazin-3(2H)-one
The first step:
(S) -2- (4-methoxybenzyl) -4- (trifluoromethyl) -5- ((5- (5- (trifluoromethyl) pyrimidin-2-yl) -5, 6-dihydropyrrol [3,4-c ] pyrazol-2 (4H) -yl) pentan-2-yl) amino) pyridazin-3 (2H) -one (4A)
(S)-2-(4-methoxybenzyl)-4-(trifluoromethyl)-5-((5-(5-(5-(trifluoromethyl)pyrimidin-2-yl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)pentan-2-yl)amino)pyridazin-3(2H)-one
The first step of synthesis of intermediate 3, described in patent WO2022242750, gives compound 4A as a pale yellow solid (148 mg, 63% yield).
LCMS m/z＝622.22[M+l]。
And a second step of:
(S) -4- (trifluoromethyl) -5- ((5- (5- (5- (trifluoromethyl) pyrimidin-2-yl) -4,5,6, 7-tetrahydro-2H-pyrazolo [4,3-c ] pyridin-2-yl) pentan-2-yl) amino) pyridazin-3 (2H) -one (compound 4)
(S)-4-(trifluoromethyl)-5-((5-(5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)pentan-2-yl)amino)pyridazin-3(2H)-one
The second step synthesis of compound 6 described in patent WO2022242750 gives compound 4 as a white solid (80 mg, 45% yield).
1HNMR(400MHz,DMSO-d6)δ12.47(s,1H),8.78(s,2H),7.88(s,1H),6.70(d,1H),4.77(d,1H),4.61(d,4H),4.08-4.04(m,2H),3.45(d,1H),1.74(d,2H),1.09(d,3H).
LCMS m/z＝503.17[M+l]。
Biological assay
PARP enzymatic Biochemical assay
The experiment uses PARP1, TNKS2, PARP7 and PARP14 chemiluminescence detection kit (BPS, cat No. 80551/80552/80573/80578/79729/80568) to carry out the enzymatic biochemical detection of PARP. The specific scheme is as follows: the 1 Xhistone mixture was added to a 96-well plate at 50. Mu.L per well and incubated overnight at 4 ℃. The next day, after washing with PBST, 200. Mu.L of blocking buffer was added to each well and incubated for 90min. After washing again with PBST, 5. Mu.L of inhibitor, 20. Mu.L of 1 XPNP buffer and 25. Mu.L of streptavidin-HRP were added per well and incubated for 30min at room temperature. After washing with PBST, 100 μ L ELISA ECL substrate a and B mix was added to each well, and immediately chemiluminescent values were read using an enzyme-labeled instrument and IC 50 values were calculated.
The results show that: the compounds of the present invention have significant biological inhibitory activity against PARP 7.
NCI-H1373 cell proliferation inhibition experiment
Human lung adenocarcinoma cells NCI-H1373 (ATCC, CRL-5866 TM) were cultured in a cell incubator at 37℃with 5% CO 2 using RPMI-1640 medium containing 10% FBS and 1% diabody. Cell digestions were counted in the logarithmic growth phase and inoculated into 96-well plates at 1500 NCI-H1373 per well and placed in an incubator for overnight culture. The following day, test compounds were formulated as 10mM stock solution using DMSO, starting at a maximum dose of 10. Mu.M, and 3-fold gradient dilutions were performed using RPMI-1640 medium, setting a total of 10 gradient concentrations, 2 parallel wells per well. After 6 days of incubation, 100 μ LCELL TITER Blue working solution was added to each well and chemiluminescent readings were performed on the microplate reader. IC 50 was calculated using GraphPad prism7.0 software.
The results show that: the compound has remarkable inhibition effect on NCI-H1373 cell proliferation.
While the specification describes in detail specific embodiments of the present invention, those skilled in the art will recognize that the foregoing embodiments are illustrative and not to be construed as limiting the invention, and that many variations and modifications of the invention may be made without departing from the spirit of the invention, which is intended to fall within the scope of the appended claims.

Claims (5)

1. A compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or deuterate thereof:
Wherein:
X 1 is NH, O, or a 4 to 10 membered heterocyclic ring, said 4 to 10 membered heterocyclic ring comprising 1 to 3 heteroatoms selected from N and O;
x 2 is O or a bond;
x 3 is CH or N;
X 4 is S or O;
Each X 5、X6 is independently CH or N;
r 1 is C 1-6 alkyl, C 3-5 cycloalkyl, halogen or cyano, said C 1-6 alkyl optionally substituted with 1 to 3 halogens;
Each R 2、R3、R4、R5 is independently H, D or C 1-6 alkyl;
R 6, which may be the same or different, are each independently C 1-6 alkyl, C 1-6 alkoxy, halogen, cyano or C 3-5 cycloalkyl, the C 1-6 alkyl, C 1-6 alkoxy being optionally substituted with 1 to 3 halogens;
a is 1, 2 or 3;
b is 1, 2 or 3;
m is 1, 2 or 3;
n is 0,1, 2 or 3;
t is 0,1, 2 or 3.
2. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or deuterate thereof, wherein the compound is selected from the following structures:
3. a compound, or a pharmaceutically acceptable salt, stereoisomer, or deuterate thereof, wherein the compound is selected from the following structures:
4. A pharmaceutical composition, the pharmaceutical composition comprising:
(1) A compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, or deuterate thereof;
(2) Optionally one or more other active ingredients; and
(3) Pharmaceutically acceptable carriers and/or excipients.
5. Use of a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt, stereoisomer or deuteride thereof or a pharmaceutical composition according to claim 4 for the manufacture of a medicament for the treatment and/or prophylaxis of cancer.
CN202311641385.5A 2022-12-02 2023-12-01 Pyridazinone derivatives and their use in medicine Pending CN118126063A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN2022115354516 2022-12-02

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Publication Number Publication Date
CN118126063A true CN118126063A (en) 2024-06-04

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