CN118164988A - Pyridazinone derivatives and their use in medicine - Google Patents

Pyridazinone derivatives and their use in medicine Download PDF

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Publication number
CN118164988A
CN118164988A CN202311641452.3A CN202311641452A CN118164988A CN 118164988 A CN118164988 A CN 118164988A CN 202311641452 A CN202311641452 A CN 202311641452A CN 118164988 A CN118164988 A CN 118164988A
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membered
alkyl
compound
pharmaceutically acceptable
independently
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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 application relates to a pyridazinone compound or pharmaceutically acceptable salt, stereoisomer or deuterated compound thereof, a composition thereof and application thereof in preparing antitumor drugs.

Description

Pyridazinone derivatives and their use in medicine
Technical Field
The present invention relates generally to the field of pharmaceutical chemistry, and in particular to pyridazinone derivatives or pharmaceutically acceptable salts, stereoisomers or deuterides thereof, and their use 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 selective PARP7 inhibitors or pharmaceutically acceptable salts, stereoisomers or deuterides thereof, and their use in medicine, for example in anticancer therapy.
One or more embodiments of the present application provide a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, or deuterate thereof:
wherein:
Each L 1、L2、L3、L4 is independently NH, O, S, a bond, OR a 4 to 10 membered heterocyclic ring, said 4 to 10 membered heterocyclic ring optionally being further substituted with a substituent selected from OR L; the 4-to 10-membered heterocyclic ring comprises 1 to 3 heteroatoms selected from N, O or S;
R L is C 3-10 cycloalkyl, 3 to 10 membered heterocycloalkyl, C 6-10 aryl, 5 to 10 membered heteroaryl; the 3-to 10-membered heterocycloalkyl, 5-to 10-membered heteroaryl contains 1 to 3 heteroatoms selected from N, O and S;
Each R 1、R2、R3、R4、R5、R6、R7、R8 is independently H, D or C 1-6 alkyl;
Or R 1 and R 2、R3 and R 4、R5 and R 6、R7 and R 8 each independently form a 3-to 5-membered cycloalkyl group with the carbon atom to which they are attached;
Each R 9 is independently C 1-6 alkyl, C 1-6 alkoxy, C (O) NR d3Rd4、S(O)2Rd2、SRd1, halogen, cyano or 3 to 5 membered cycloalkyl, said C 1-6 alkyl, C 1-6 alkoxy optionally substituted with 1 to 3 halogens;
Each R d1、Rd2、Rd3、Rd4 is independently H, D or C 1-6 alkyl;
A is
R a1, which may be the same or different, R a1 is selected from C 1-6 alkyl, C 3-5 cycloalkyl, halogen or cyano, said C 1-6 alkyl optionally being substituted with 1 to 3 halogens;
B is
Each X 1、X2、X3 is independently C or N;
D is a 5-to 6-membered heterocyclic ring comprising 1 to 3 heteroatoms selected from N, O, S;
R x1, which may be the same or different, R x1 is selected from H, D, C 1-6 alkyl, halogen or cyano, said C 1-6 alkyl optionally being substituted with 1 to 3 halogens;
R x2, which may be the same or different, R x2 is selected from H, D or C 1-6 alkyl; or two R x2 form with the attached carbon atom = O; or two R x1 are linked to form a 3-to 8-membered cycloalkyl group;
C is a 5-to 10-membered carbocyclic or heterocyclic ring containing 1 to 3 heteroatoms selected from N, O and S;
m is 0,1, 2,3 or 4;
n is 0, 1,2, 3 or 4;
o is 0,1, 2,3 or 4;
p is 0,1, 2,3 or 4;
q is 0,1, 2,3 or 4;
r is 0,1, 2,3 or 4;
s is 0,1, 2,3 or 4;
t is 0,1, 2,3 or 4;
v is 0,1, 2, 3 or 4
W 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 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 preparation of an antitumor drug.
One or more embodiments of the present application provide a compound of the present application or a pharmaceutically acceptable salt, stereoisomer or deuteride thereof or a composition of the present application for use as a medicament.
One or more embodiments of the present application provide a compound of the present application or a pharmaceutically acceptable salt, stereoisomer, or deuteride thereof or a composition of the present application for use in a method of treating/preventing cancer.
One or more embodiments of the present application provide methods of treating/preventing cancer comprising administering a compound of the present application, or a pharmaceutically acceptable salt, stereoisomer, or deuteride thereof, or a composition of the present application to a subject in need thereof.
One or more embodiments of the present application provide the use of a compound of the present application, all stereoisomers, pharmaceutically acceptable salts or deuterides thereof, or a pharmaceutical composition of the present application for the manufacture of a medicament for the treatment and 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.
"Aryl" refers to a substituted or unsubstituted aromatic ring which may be a 5 to 8 membered (e.g., 5,6, 7, 8 membered) monocyclic ring, a 5 to 12 membered (e.g., 5,6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring, a 10 to 15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, or a 13 to 20 membered (e.g., 13, 14, 15, 16, 17, 18, 19, 20 membered) tetracyclic ring system, which may be fused, bridged or spiro rings, non-limiting examples include phenyl, naphthyl. The aryl group may optionally be further substituted with 1 or more substituents.
"Heteroaryl" refers to a substituted or unsubstituted aromatic ring which may be a 3 to 8 membered (e.g., 3, 4,5, 6, 7, 8 membered) monocyclic ring, a 5 to 12 membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring, a 10 to 15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, or a 13 to 20 membered (e.g., 13, 14, 15, 16, 17, 18, 19, 20 membered) tetracyclic ring system and which contains 1 to 6 (e.g., 1, 2, 3, 4,5, 6) heteroatoms selected from N, O or S, preferably 5 to 8 membered heteroaryl, with 1 to 4 (e.g., 1, 2, 3, 4) N, S optionally substituted in the heteroaryl ring being oxidizable to various oxidation states. Heteroaryl groups may be attached to a heteroatom or carbon atom, and heteroaryl groups may be fused rings, bridged rings, or spiro rings, non-limiting examples of which include cyclic pyridyl, furyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl benzimidazolyl, benzopyridyl, benzopyrimidinyl, pyrrolopyridinyl. Heteroaryl is optionally further substituted with 1 or more substituents.
"Carbocyclyl" or "carbocycle" refers to a saturated or unsaturated aromatic or non-aromatic ring. When aromatic, the definition is the same as for "aryl" above; when non-aromatic, 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, 10 to 15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system or 13 to 20 membered (e.g., 13, 14, 15, 16, 17, 18, 19, 20 membered) tetracyclic ring system, which may be a fused ring, bridged ring or spiro ring, non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, The "carbocyclyl" or "carbocycle" is optionally further substituted with 1 or more substituents.
"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 a3 to 10 membered (e.g. 3,4, 5,6, 7, 8, 9, 10 membered) monocyclic ring, a 4 to 12 membered (e.g. 4,5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring, a10 to 15 membered (e.g. 10, 11, 12, 13, 14, 15 membered) tricyclic ring system or a 13 to 20 membered (e.g. 13, 14, 15, 16, 17, 18, 19, 20 membered) tetracyclic ring system and comprises 1 to 4 (e.g. 1,2,3, 4) heteroatoms selected from N, O or S, preferably a3 to 8 membered heterocyclyl group. 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 a fused ring, bridged ring, or spiro ring. 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.
"Heterocycloalkyl" refers to a substituted or unsubstituted saturated non-aromatic ring radical which may be a 3 to 8 membered (e.g., 3, 4, 5, 6, 7, 8 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 1,2, or 3 heteroatoms selected from N, O or S, preferably 3 to 8 membered heterocyclyl. Optionally substituted 1,2 or 3N, S of the rings of the "heterocycloalkyl" can be oxidized to various oxidation states; "heterocycloalkyl" may be attached to a heteroatom or carbon atom; "heterocycloalkyl" may be a bridged or spiro ring. Non-limiting examples of "heterocycloalkyl" include epoxy, aziridinyl, oxetanyl, azetidinyl, 1, 3-dioxolanyl, 1, 4-dioxolanyl, 1, 3-dioxanyl, azepanyl, piperidinyl, piperdinyl, morpholinyl, thiomorpholinyl, 1, 3-dithianyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, azabicyclo [3.2.1] octanyl, azabicyclo [5.2.0] nonanyl, oxatricyclo [5.3.1.1] dodecyl, azaadamantyl and oxaspiro [3.3] heptanyl.
When "alkyl", "alkoxy", "aryl", "heteroaryl", "carbocyclyl", "heterocyclyl", "heterocycle", "cycloalkyl" or "heterocycloalkyl" described above is substituted, it is 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 substituent 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 is optionally further substituted with 1 to 3 substituents selected from OH, 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.
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.
Intermediate 1
6-Chloro-2- (4-methoxybenzyl) -4- (trifluoromethyl) pyridazin-3 (2H) -one (intermediate 1)
6-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one
The preparation of intermediate 1 is described in reference to the process for the preparation of intermediate E described in WO 2022253101.
Example 1
4- (Trifluoromethyl) -6- (2- (5- (5- (trifluoromethyl) pyrimidin-2-yl) -4,5,6, 7-tetrahydropyrazol [1,5-a ] pyrazin-2-yl) ethyl) pyrrolidin-1-yl) pyridazin-3 (2H) -one (compound 1)
4-(trifluoromethyl)-6-(2-(2-(5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7tetrahydropyrazolo[1,5-a]pyrazin-2-yl)ethyl)pyrrolidin-1-yl)pyridazin-3(2H)-one
The first step:
(E) -tert-butyl 2- (2- (1-benzyl-pyrrolidin-2-yl) vinyl) -6, 7-dihydropyrazolo [1,5-a ] pyrazine-5 (4H) -carboxylate (1 c)
tert-butyl(E)-2-(2-(1-benzylpyrrolidin-2-yl)vinyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate
To the sealed tube was added, in order, 1-benzyl-2-vinylpyrrolidine (1 b,936.5mg,5mmol,3.0 eq), tert-butyl 2-bromo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-5 (4H) -carboxylate (1 a,503.6mg,1.67mmol,1.0 eq), tris (o-methylphenyl) phosphorus (50 mg, 0.67 mmol,0.1 eq), palladium (II) acetate (0.374 g, 0.67 mmol,0.1 eq). After the addition, the mixture was dissolved in acetonitrile (10 mL) and nitrogen blanketed. The reaction mixture was heated to 80 ℃ and stirred for 14 hours. The reaction mixture was cooled, filtered through a pad of celite, and washed with dichloromethane (3×5 mL). The reaction mixture was concentrated in vacuo and the residue was chromatographed (petroleum ether: ethyl acetate=20:1) to give 1c as a colourless liquid (422.1 mg, 62%).
LC-MS m/z(ESI)＝409.5[M+1]。
And a second step of:
2- (2- (pyrrolidin-2-yl) ethyl) -6, 7-dihydropyrazolo [1,5-a ] pyrazine-5 (4H) -carboxylic acid tert-butyl ester (1 d)
tert-butyl 2-(2-(pyrrolidin-2-yl)ethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate
Compound 1c (400 mg,0.979mmol,1.0 eq) was weighed into a 50mL three-necked flask and methanol (12 mL) was added. Then, a weighed amount of palladium on carbon (40 mg, 10%) was added to the reaction system, and the mixture was purged with hydrogen. The reaction was stirred for 30 minutes at 25℃under hydrogen (15 psi). After the reaction was complete, the mixture was filtered and the filtrate was concentrated under reduced pressure to give crude 1d (288 mg). The crude 1d was used directly in the next reaction without further purification.
LC-MS m/z(ESI)＝321.4[M+1]。
And a third step of:
2- (2- (1- (4-methoxybenzyl) -6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-3-yl) pyrrolidin-2-yl) ethyl) -6, 7-dihydropyrazol [1,5-a ] pyrazine-5 (4H) -carboxylic acid tert-butyl ester (1 e)
tert-butyl 2-(2-(1-(1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-3-yl)pyrrolidin-2-yl)ethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate
To a mixture of compound 1d (280 mg,0.875mmol,1.0 eq), intermediate 1 (418.3 mg,1.31mmol,1.5 eq), cesium carbonate (285.1, 0.875mmol,1.0 eq), tris (dibenzylideneacetone) dipalladium (80.1 mg,0.0875mmol,0.1 eq) and 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine (108.9 mg,0.175mmol,0.2 eq) was added toluene (6 mL), and stirred at 80℃for 16 hours under nitrogen. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column (petroleum ether: ethyl acetate=2:1) to give 1e as a white solid (210.9 mg, 40%).
LC-MS m/z(ESI)＝603.7[M+1]。
Fourth step:
6- (2- (2- (4, 5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazin-2-yl) ethyl) pyrrolidin-1-yl) -4- (trifluoromethyl) pyridazin-3 (2H) -one (1 f)
6-(2-(2-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)ethyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one
The preparation of compound 1f is described in WO2022242750 as intermediate 3 in the second step.
LC-MS m/z(ESI)＝383.4[M+1]。
Fifth step
4- (Trifluoromethyl) -6- (2- (5- (5- (trifluoromethyl) pyrimidin-2-yl) -4,5,6, 7-tetrahydropyrazol [1,5-a ] pyrazin-2-yl) ethyl) pyrrolidin-1-yl) pyridazin-3 (2H) -one (compound 1)
4-(trifluoromethyl)-6-(2-(2-(5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7tetrahydropyrazolo[1,5-a]pyrazin-2-yl)ethyl)pyrrolidin-1-yl)pyridazin-3(2H)-one
The preparation of compound 1 is described in patent WO2022242750, with reference to the ninth step of the preparation of intermediate 13.
LC-MS m/z(ESI)＝529.5[M+1]。
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 (4)

1. A compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer or deuterate thereof:
wherein:
Each L 1、L2、L3、L4 is independently NH, O, S, a bond, OR a 4 to 10 membered heterocyclic ring, said 4 to 10 membered heterocyclic ring optionally being further substituted with a substituent selected from OR L; the 4-to 10-membered heterocyclic ring comprises 1 to 3 heteroatoms selected from N, O or S;
R L is C 3-10 cycloalkyl, 3 to 10 membered heterocycloalkyl, C 6-10 aryl, 5 to 10 membered heteroaryl; the 3-to 10-membered heterocycloalkyl, 5-to 10-membered heteroaryl contains 1 to 3 heteroatoms selected from N, O and S;
Each R 1、R2、R3、R4、R5、R6、R7、R8 is independently H, D or C 1-6 alkyl;
Or R 1 and R 2、R3 and R 4、R5 and R 6、R7 and R 8 each independently form a 3-to 5-membered cycloalkyl group with the carbon atom to which they are attached;
Each R 9 is independently C 1-6 alkyl, C 1-6 alkoxy, C (O) NR d3Rd4、S(O)2Rd2、SRd1, halogen, cyano or 3 to 5 membered cycloalkyl, said C 1-6 alkyl, C 1-6 alkoxy optionally substituted with 1 to 3 halogens;
Each R d1、Rd2、Rd3、Rd4 is independently H, D or C 1-6 alkyl;
A is
R a1, which may be the same or different, R a1 is selected from C 1-6 alkyl, C 3-5 cycloalkyl, halogen or cyano, said C 1-6 alkyl optionally being substituted with 1 to 3 halogens;
B is
Each X 1、X2、X3 is independently C or N;
D is a 5-to 6-membered heterocyclic ring comprising 1 to 3 heteroatoms selected from N, O, S;
R x1, which may be the same or different, R x1 is selected from H, D, C 1-6 alkyl, halogen or cyano, said C 1-6 alkyl optionally being substituted with 1 to 3 halogens;
R x2, which may be the same or different, R x2 is selected from H, D or C 1-6 alkyl; or two R x2 form with the attached carbon atom = O; or two R x1 are linked to form a 3-to 8-membered cycloalkyl group;
C is a 5-to 10-membered carbocyclic or heterocyclic ring containing 1 to 3 heteroatoms selected from N, O and S;
m is 0,1, 2,3 or 4;
n is 0, 1,2, 3 or 4;
o is 0,1, 2,3 or 4;
p is 0,1, 2,3 or 4;
q is 0,1, 2,3 or 4;
r is 0,1, 2,3 or 4;
s is 0,1, 2,3 or 4;
t is 0,1, 2,3 or 4;
v is 0,1, 2,3 or 4;
w 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 pharmaceutical composition, the pharmaceutical composition comprising:
(1) The compound of claim 1 or 2, all stereoisomers, pharmaceutically acceptable salts or deuterates thereof;
(2) Optionally one or more other active ingredients; and
(3) Pharmaceutically acceptable carriers and/or excipients.
4. Use of a compound according to claim 1 or 2, all stereoisomers, pharmaceutically acceptable salts or deuterated thereof, a pharmaceutical composition according to claim 3 for the manufacture of a medicament for the treatment and prophylaxis of cancer.
CN202311641452.3A 2022-12-09 2023-12-01 Pyridazinone derivatives and their use in medicine Pending CN118164988A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN2022115607399 2022-12-09

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CN118164988A true CN118164988A (en) 2024-06-11

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