CN116867784A - Pyridine derivative and application thereof in medicine - Google Patents

Pyridine derivative and application thereof in medicine Download PDF

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Publication number
CN116867784A
CN116867784A CN202280015678.XA CN202280015678A CN116867784A CN 116867784 A CN116867784 A CN 116867784A CN 202280015678 A CN202280015678 A CN 202280015678A CN 116867784 A CN116867784 A CN 116867784A
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membered
compound
alkyl
heterocycloalkyl
pharmaceutically acceptable
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张靖
魏用刚
周锡兵
高成
孙毅
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Chengdu Baiyu Pharmaceutical Co Ltd
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/499—Spiro-condensed pyrazines or piperazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

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  • Pyridine Compounds (AREA)

Abstract

The compound of the formula (I) and the application thereof in medicine, and the compound can be used for treating tumors

Description

Pyridine derivative and application thereof in medicine Technical Field
The present application relates to pyridine derivatives and their use in medicine.
Background
PARP (ploy (ADP-ribose) polymers are a class of Poly ADP-ribose polymerase that catalyzes the ribosylation of multiple proteins Poly-ADP-ribosylation (Poly-ADP-ribosylation), a process that plays an important role in many cellular processes such as DNA damage repair, transcriptional regulation, chromatin recombination, and remodeling. At present, although a plurality of PARP1/PARP2 inhibitors are successfully marketed, no matter the PARP1/PARP2 inhibitors are used singly or in combination, side effects such as blood, gastrointestinal tract and the like still commonly exist clinically, so that the clinical application is limited. Therefore, the development of safer and more effective PARP inhibitors remains a problem to be solved clinically. A series of researches show that compared with the PARP1/PARP2 inhibitor, the high-selectivity PARP1 inhibitor has better curative effect and lower toxicity, is expected to reduce the potential risk of the PARP medicament clinically at present, widens the clinical application range and improves the life quality of patients.
Disclosure of Invention
It is an object of the present application to provide pyridine derivatives or pharmaceutically acceptable salts or stereoisomers thereof, as well as pharmaceutical compositions comprising the same, and their use in medicine.
One or more embodiments of the present application provide a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof:
wherein:
R 1 is C 3-8 Cycloalkyl or C 3-8 Heterocycloalkyl, said C 3-8 Heterocycloalkyl comprises 1 to 4 heteroatoms selected from N, O and S;
l is-NH-, -CO-, or- (CR) L1 R L2 ) n -；
R L1 、R L2 Each independently is H or C 1-6 Alkyl, said C 1-6 Alkyl is optionally substituted with 1 or more substituents selected from halogen, hydroxy and cyano;
a is a 4 to 12 membered heterocycle which is a 4 to 12 membered monocyclic ring, a 5 to 12 membered spiro ring, a 4 to 12 membered fused ring or a 4 to 12 membered bridged ring, said 4 to 12 membered heterocycle comprising 1 to 4 heteroatoms selected from N, O and S;
R 2 h, C of a shape of H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or C 3-8 Heterocycloalkyl, said C 3-8 Heterocycloalkyl comprises 1 to 4 heteroatoms selected from N, O and S; the C is 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or C 3- 8 Heterocycloalkyl is optionally substituted with 1 or more groups selected from halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and C 3-8 Substituents of heterocycloalkyl groups;
n is 1 or 2.
In one or more embodiments, the compound of formula (I) is substituted with 1 or more (e.g., 1,2,3,4, 5,6, 7, 8, 9, or 10) deuterium.
In one or more embodiments, the C 3-8 The heterocycloalkyl or 4-to 12-membered heterocycle comprises 1,2,3 or 4 heteroatoms selected from N, O and S.
In one or more embodiments, the R 1 Is that
In one or more embodiments, L is-CH 2 -、-CH(CH 3 ) -or-CD 2 -。
In one or more embodiments, a is
In one or more embodiments, R 2 Is an oxetanyl, azetidinyl, methyl, ethyl or propyl group; the oxetanyl, azetidinyl, methyl, ethyl or propyl groups are optionally substituted with one or more substituents selected from methyl, methoxy and hydroxy.
In one or more embodiments, the compound is:
in one or more embodiments, the above compounds are substituted with 1 or more (e.g., 1,2,3,4, 5,6, 7, 8, 9, or 10) deuterium.
In one or more embodiments, the halogen is F, cl or Br.
One or more embodiments of the present application provide a pharmaceutical composition comprising:
(1) The above-mentioned compounds of the present application or pharmaceutically acceptable salts or stereoisomers 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 a compound represented by the general formula (I'):
wherein:
R 1 selected from C 3-8 Cycloalkyl or C 3-8 Heterocycloalkyl, said C 3-8 Heterocycloalkyl may contain 1 to 4 heteroatoms selected from N, O or S;
l is selected from-NH-, -CO-, or- (CR) L1 R L2 ) n -；
R L1 、R L2 Each independently selected from H or C 1-6 Alkyl, said C 1-6 The alkyl group is optionally further substituted with 1 or more substituents selected from halogen, hydroxy or cyano;
a is a 4 to 12 membered heterocycle selected from a 4 to 12 membered monocyclic ring, a 5 to 12 membered spiro ring, a 4 to 12 membered fused ring or a 4 to 12 membered bridged ring, said 4 to 12 membered heterocycle may contain 1 to 4 heteroatoms selected from N, O or S;
R 2 selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or C 3-8 Heterocycloalkyl, said C 3-8 Heterocycloalkyl may contain 1 to 4 heteroatoms selected from N, O or S; the C is 1-6 Alkyl, C 1-6 Alkoxy, C 3- 8 Cycloalkyl or C 3-8 The heterocycloalkyl group optionally being further substituted by 1 or more groups selected from halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or C 3-8 Substituents of heterocycloalkyl groups;
n is 1 or 2.
One or more embodiments of the present application provide a compound represented by the general formula (I') or a stereoisomer thereof:
wherein:
R 1 selected from H, halogen, C 2-6 Alkenyl or C 2-6 Alkynyl, said C 2-6 Alkenyl or C 2-6 Alkynyl is optionally further substituted with 1 or more groups selected from halogen or C 1-6 Substituent substitution of alkyl;
l is selected from-NH-, -CO-, or- (CR) L1 R L2 ) n -；
R L1 、R L2 Each independently selected from H or C 1-6 Alkyl, said C 1-6 The alkyl group is optionally further substituted with 1 or more substituents selected from halogen, hydroxy or cyano;
a is a 4 to 12 membered heterocycle selected from a 4 to 12 membered monocyclic ring, a 5 to 12 membered spiro ring, a 4 to 12 membered fused ring or a 4 to 12 membered bridged ring, said 4 to 12 membered heterocycle may contain 1 to 4 heteroatoms selected from N, O or S;
R 2 selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or C 3-8 Heterocycloalkyl, said C 3-8 Heterocyclylalkyl may contain 1 to 4 heteroatoms selected from N, O or S, said C 1-6 Alkyl, C 1-6 Alkoxy, C 3- 8 Cycloalkyl or C 3-8 The heterocycloalkyl group optionally being further substituted by 1 or more groups selected from halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or C 3-8 Substituents of heterocycloalkyl groups;
n is 1 or 2.
One or more embodiments of the present application provide a compound represented by the general formula (I' "):
wherein:
R 1 selected from C 1-6 An alkyl group;
l is selected from-NH-, -CO-, or- (CR) L1 R L2 ) n -；
R L1 、R L2 Each independently selected from H or C 1-6 Alkyl, said C 1-6 The alkyl group is optionally further substituted with 1 or more substituents selected from halogen, hydroxy or cyano;
a is a 7 to 12 membered heterocycle selected from a 7 to 12 membered monocyclic ring, a 7 to 12 membered spiro ring, a 7 to 12 membered fused ring or a 7 to 12 membered bridged ring, said 7 to 12 membered heterocycle may contain 1 to 4 heteroatoms selected from N, O or S;
R 2 selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or C 3-8 Heterocycloalkyl, said C 3-8 Heterocyclylalkyl may contain 1 to 4 heteroatoms selected from N, O or S, said C 1-6 Alkyl, C 1-6 Alkoxy, C 3- 8 Cycloalkyl or C 3-8 The heterocycloalkyl group optionally being further substituted by 1 or more groups selected from halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or C 3-8 Substituents of heterocycloalkyl groups;
n is 1 or 2.
One or more embodiments of the present application provide a compound represented by the general formula (II'):
wherein:
R 1 selected from C 1-6 An alkyl group;
l is selected from-NH-, -CO-, or- (CR) L1 R L2 ) n -；
R L1 、R L2 Each independently selected from H or C 1-6 Alkyl, said C 1-6 The alkyl group is optionally further substituted with 1 or more substituents selected from halogen, hydroxy or cyano;
X 1 、X 2 each independently selected from CR X Or N;
R X selected from H, hydroxy, cyano or C 1-6 An alkyl group;
when X is 1 、X 2 When both are N, R a Selected from hydroxy, cyano, =o or C 1-6 Alkyl, said C 1-6 The alkyl group is optionally further substituted with 1 or more substituents selected from hydroxy, halogen, or cyano;
when X is 1 、X 2 One is CR X When R is a Selected from H, hydroxy, cyano, =o or C 1-6 Alkyl, said C 1-6 The alkyl group is optionally further substituted with 1 or more substituents selected from hydroxy, halogen, or cyano;
R 2 selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or C 3-8 Heterocycloalkyl, said C 3-8 Heterocyclylalkyl may contain 1 to 4 heteroatoms selected from N, O or S, said C 1-6 Alkyl, C 1-6 Alkoxy, C 3- 8 Cycloalkyl or C 3-8 The heterocycloalkyl group optionally being further substituted by 1 or more groups selected from halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or C 3-8 Substituents of heterocycloalkyl groups;
m is 1,2 or 3;
n is 1 or 2.
One or more embodiments of the present application provide a compound represented by the general formula (III'):
wherein:
R 1 selected from C 1-6 An alkyl group;
l is selected from-NH-, -CO-, or- (CR) L1 R L2 ) n -；
R L1 、R L2 Each independently selected from H or C 1-6 Alkyl, said C 1-6 The alkyl group is optionally further substituted with 1 or more substituents selected from halogen, hydroxy or cyano;
R 3 selected from H, halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or C 3-8 A heterocycloalkyl group; the C is 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or C 3-8 The heterocycloalkyl group optionally being further substituted with 1 or more groups selected from H, halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or C 3-8 Substituents of heterocycloalkyl groups;
R 2 selected from C 5-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or C 3-8 Heterocycloalkyl, said C 3-8 Heterocycloalkyl may contain 1 to 4 heteroatoms selected from N, O or S; the C is 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or C 3-8 The heterocycloalkyl group optionally being further substituted by 1 or more groups selected from halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or C 3-8 Substituents of heterocycloalkyl groups;
n is 1 or 2.
m is 0, 1,2 or 3
One or more embodiments of the present application provide a compound represented by the general formula (III') or a stereoisomer thereof:
wherein:
R 1 selected from C 1-6 An alkyl group;
l is selected from-NH-, -CO-, or- (CR) L1 R L2 ) n -；
R L1 、R L2 Each independently selected from H or C 1-6 Alkyl, said C 1-6 The alkyl group is optionally further substituted with 1 or more substituents selected from halogen, hydroxy or cyano;
R 2 selected from C 5-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or C 3-8 Heterocycloalkyl, said C 3-8 Heterocycloalkyl may contain 1 to 4 heteroatoms selected from N, O or S; the C is 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or C 3-8 The heterocycloalkyl group optionally being further substituted by 1 or more groups selected from halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or C 3-8 Substituents of heterocycloalkyl groups;
n is 1 or 2.
One or more embodiments of the present application provide the use of the above-described compound of the present application or a pharmaceutically acceptable salt or stereoisomer thereof or the above-described pharmaceutical composition for the preparation of an antitumor or anticancer drug.
One or more embodiments of the present application provide the above-described compound of the present application or a pharmaceutically acceptable salt or stereoisomer thereof or the above-described pharmaceutical composition for use as a medicament.
One or more embodiments of the present application provide the above-described compound of the present application or a pharmaceutically acceptable salt or stereoisomer thereof or the above-described pharmaceutical composition for use in a method of treating/preventing cancer.
One or more embodiments of the present application provide a method for treating/preventing a tumor or cancer, comprising administering the above-described compound of the present application or a pharmaceutically acceptable salt or stereoisomer thereof or the above-described pharmaceutical composition to a subject in need thereof.
One or more embodiments of the present application provide a method of inhibiting PARP1 and/or PARP2 comprising administering to a subject in need thereof the above-described compound of the present application or a pharmaceutically acceptable salt or stereoisomer thereof or the above-described pharmaceutical composition.
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 application each include their isotopic condition, and the carbon, hydrogen, oxygen, sulfur or nitrogen referred to in the groups and compounds of the application are optionally further replaced by one or more of their corresponding isotopes, where the isotopes of carbon include 12 C、 13 C and C 14 Isotopes of C, hydrogen include protium (H), deuterium (D, also known as heavy hydrogen), tritium (T, also known as super heavy hydrogen), isotopes of oxygen include 16 O、 17 O and 18 isotopes of O, sulfur include 32 S、 33 S、 34 S and 36 isotopes of S, nitrogen include 14 N and 15 isotopes of N, fluorine include 17 F and F 19 Isotopes of F, chlorine include 35 Cl and Cl 37 Isotopes of Cl, bromine include 79 Br and 81 Br。
"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.
"alkenyl" means an alkenyl group containing 1 to 10 (e.g., 1,2,3,4, 5,6, 7, 8, 9, 10) carbon-carbon double bonds, a straight or branched chain unsaturated aliphatic hydrocarbon group consisting of 2 to 20 carbon atoms, preferably 2 to 12 (e.g., 2,3,4, 5,6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably 2 to 8 carbon atoms, even more preferably 2 to 6 carbon atoms. Non-limiting examples include vinyl, propen-2-yl, buten-2-yl, penten-4-yl, hexen-2-yl, hexen-3-yl, hepten-2-yl, hepten-3-yl, hepten-4-yl, octen-3-yl, nonen-3-yl, decen-4-yl and undecen-3-yl. The alkenyl group may optionally be further substituted with 1 or more substituents.
"alkynyl" refers to alkynyl groups containing 1 to 10 (e.g., 1,2,3,4, 5,6, 7, 8, 9, or 10) carbon-carbon triple bonds, straight or branched chain unsaturated aliphatic hydrocarbon groups consisting of 2 to 20 carbon atoms, preferably 2 to 12 (e.g., 2,3,4, 5,6, 7, 8, 9, 10, 11, or 12) carbon atoms, more preferably alkynyl groups of 2 to 8 carbon atoms, even more preferably alkynyl groups of 2 to 6 carbon atoms. Non-limiting examples include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3-dimethylbutyyn-2-yl, pentyn-1-yl, pentyn-2-yl, hexyn-1-yl, 1-heptyn-1-yl, heptyn-3-yl, heptyn-4-yl, octyn-3-yl, nonyn-3-yl, decyn-4-yl, undecyn-3-yl, dodyn-4-yl. The alkynyl group may be optionally further substituted with one or more substituents.
"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, 5 to 12 membered (e.g., 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 which may be a bridged or spiro ring, non-limiting examples including 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, 5 to 12 membered (e.g., 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 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 bridged or spiro rings, non-limiting examples include cyclic pyridyl, furyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl benzimidazolyl, benzopyridyl, 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, or 10 to 15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, which may be bridged or spiro, 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, cyclohexadienyl, 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 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 optionally substituted by "heterocyclyl" or a ring of "heterocycle" can 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, oxazepine, diazanyl, thiazepine, pyridinyl, piperidinyl, homopiperidinyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, thiaalkyl, 1, 3-dithianyl, dihydrofuranyl, dithianyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyranyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridinyl, 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 [ 2.2.2.2 ] hexyl, 3H-indolylquinolizinyl, N-pyridyl urea, 1-dioxothiomorpholinyl, azabicyclo [3.2.1] octyl, azabicyclo [5.2.0] nonyl, oxatricyclic [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 1,2,3, or 4 heteroatoms selected from N, O or S, preferably 3 to 8 membered heterocyclyl. Optionally substituted 1,2 or 3N, S of the "heterocycloalkyl" rings 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", "alkenyl", "alkynyl", "aryl", "heteroaryl", "carbocyclyl", "heterocyclyl", "heterocycle", "cycloalkyl", "heterocycloalkyl" or "heterocyclyl" described above is substituted, it may optionally be further substituted with 0, 1,2,3,4, 5,6, 7,8. 9 or 10 are 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 q4 R q5 、＝NR q6 、-C(＝O)OC 1-6 Alkyl, -OC (=o) C 1-6 Alkyl, -C (=o) NR q4 R q5 、C 3-8 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 Substituted by alkynyl groups, 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 is optionally further substituted with 1 to 3 substituents selected from OH, F, cl, br, I, C 1-6 Alkyl, C 1-6 Alkoxy, -NR q4 R q5 Or = O; r is R q1 Selected from C 1-6 Alkyl, C 1-6 Alkoxy or C 6-10 An aryl group; r is R q2 、R q3 Selected from H or C 1-6 An alkyl group; wherein R is q4 、R q5 Selected from H, C 1-6 Alkyl, -NH (c=nr q1 )NR q2 R q3 、-S(＝O) 2 NR q2 R q3 、-C(＝O)R q1 or-C (=O) NR q2 R q3 Wherein said C 1-6 The alkyl group optionally being further substituted by 1 or more groups 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 Substituted by a substituent of heterocycloalkyl; or R is q4 And R is R q5 And the N atom forms a 3 to 8 membered heterocyclic ring which may contain 1 or more heteroatoms selected from N, O or S.
Halogen includes F, cl, br and I.
"pharmaceutically acceptable salts" or "pharmaceutically acceptable salts thereof" refer to salts of the compounds of the present application which retain the biological effectiveness and properties of the free acid or free base 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, a pharmaceutically acceptable salt or prodrug thereof, and other chemical components, wherein "other chemical components" refers to a pharmaceutically acceptable carrier, excipient, 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 application in detail, but the scope of the present application is not limited thereto.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (sum) Mass Spectrometry (MS). NMR shift (. Delta.) of 10 - 6 Units of (ppm) are given. NMR was performed using a Bruker Avance III and Bruker Avance 300 magnetonucleate, with deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated chloroform (CDCl) 3 ) Deuterated methanol (CD) 3 OD), internal standard Tetramethylsilane (TMS);
agilent 6120B (ESI) and Agilent 6120B (APCI) for MS measurement;
the thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15mm-0.20mm, and the specification of the thin layer chromatography separation and purification product is 0.4mm-0.5mm;
column chromatography generally uses tobacco stage yellow sea silica gel 200-300 mesh silica gel as carrier.
Example 1
5- (4- ((7-cyclopropyl-6-oxo-5, 6-dihydro-1, 5-naphthyridin-3-yl) methyl) piperazin-1-yl) -N-methylpyridine amide compound 1
5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylpicolinamide
First step
6-formyl-5-nitronicotinic acid ethyl ester 1b
ethyl 6-formyl-5-nitronicotinate
Ethyl 6-methyl-5-nitronicotinate 1a (available from Jiangsu ai Kang Shengwu pharmaceutical development Co., ltd., 10g,45.6 mmol) and selenium dioxide (7.6 g,68.4 mmol) were dissolved in dioxane (100 mL), refluxed at 110℃for 4 hours, filtered thermally after the reaction was completed, and the filtrate was concentrated under reduced pressure and subjected to column chromatography to give compound 1b (yellow solid, 9.7g, yield 90%).
LC-MS m/z(ESI)＝225.10[M+1]。
Second step
6- (2-bromo-3-ethoxy-3-oxypropane-1-en-1-yl) -5-nitronicotinic acid ethyl ester 1c
ethyl 6-(2-bromo-3-ethoxy-3-oxoprop-1-en-1-yl)-5-nitronicotinate
Ethyl 2-bromo-2- (diethoxyphosphoryl) acetate (20 g,66.6mmol, available from Shanghai Michael chemical Co., ltd.) was dissolved in tetrahydrofuran (100 mL), -sodium hydrogen (1.6 g,66.6 mmol) was slowly added at 78℃and allowed to react for 10min at 40℃and then cooled to-78℃and quenched by slowly dropping 1b (9.7 g,44.4 mmol) of tetrahydrofuran solution, after 15min of reaction saturated aqueous ammonium chloride solution (100 mL) was added, extracted with ethyl acetate (100 mL. Times.3), the combined organic phases were concentrated under reduced pressure, and column chromatography afforded 1c (yellow solid, 13g, 81% yield, E/Z=10:3).
1 H NMR(400MHz,DMSO-d 6 )δ9.42(d,1H),9.23(d,0.3H),8.86(d,1H),8.80(d,0.3H),8.61(s,1H),7.89(s,0.3H),4.46-4.38(m,2.6H),4.34(q,2H),4.16(q,0.6H),1.39-1.34(m,3.9H),1.32(t,3H),1.08(t,0.9H)。
LC-MS m/z(ESI)＝373.00[M+1]。
Third step
5-amino-6- (2-bromo-3-ethoxy-3-oxoprop-1-en-1-yl) nicotinic acid ethyl ester 1d
ethyl 5-amino-6-(2-bromo-3-ethoxy-3-oxoprop-1-en-1-yl)nicotinate
Compound 1c (13 g,34.8 mmol) was dissolved in acetic acid (130 mL), iron powder (5.8 g,104.5 mmol) was added, the reaction was quenched by the addition of distilled water (100 mL) after 2h at room temperature, extracted with ethyl acetate (100 mL. Times.3), and the combined organic phases were concentrated under reduced pressure to give compound 1d (yellow solid, 10g, 83% yield).
LC-MS m/z(ESI)＝343.00[M+1]。
Fourth step
7-bromo-6-oxo-5, 6-dihydro-1, 5-naphthyridine-3-carboxylic acid ethyl ester 1e
ethyl 7-bromo-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylate
Compound 1d (10 g,29.1 mmol) was placed in a reaction flask, hydrogen bromide in acetic acid (100 mL) was added under nitrogen protection, the reaction was concentrated under reduced pressure after 4h at 50℃and quenched with saturated aqueous sodium bicarbonate (100 mL), extracted with ethyl acetate (50 mL. Times.3), concentrated under reduced pressure, and column chromatography gave compound 1e (yellow solid, 2g, 23% yield).
1 H NMR(400MHz,DMSO-d 6 )δ12.54(s,1H),8.88(d,1H),8.51(s,1H),8.14(d,1H),4.37(q,2H),1.35(t,3H)。
LC-MS m/z(ESI)＝297.00[M+1]。
Fifth step
7-cyclopropyl-6-oxo-5, 6-dihydro-1, 5-naphthyridine-3-carboxylic acid ethyl ester 1f
ethyl 7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylate
Compound 1e (400 mg,1.3 mmol), [1,1' -bis (diphenylphosphine) ferrocene ] dichloropalladium dichloromethane complex (available from Chengdu Ding-Dang-Chemie medical science, inc., 328mg,0.40 mmol), potassium carbonate (745 mg,5.4 mmol), cyclopropylboronic acid (231mg, 2.7 mmol) were dissolved in dioxane (4 mL), refluxed at 110℃for 8h, quenched with water (5 mL), extracted with ethyl acetate (5 mL. Times.3), and purified by column chromatography under reduced pressure to give compound 1f (yellow solid, 270mg, 77% yield).
1 H NMR(400MHz,DMSO-d 6 )δ12.07(s,1H),8.85(d,1H),8.12(d,1H),7.46(s,1H),4.36(q,2H),2.25-2.12(m,1H),1.34(t,3H),1.02(dt,2H),0.90(dt,2H)。
LC-MS m/z(ESI)＝259.10[M+1]。
Sixth step
1g of 3-cyclopropyl-7- (hydroxymethyl) -1, 5-naphthyridin-2 (1H) -one
3-cyclopropyl-7-(hydroxymethyl)-1,5-naphthyridin-2(1H)-one
Compound 1f (270 mg,1 mmol) was dissolved in tetrahydrofuran (2 mL), a solution of lithium aluminum hydride in tetrahydrofuran (available from Anaglycone, 2mL,2 mmol) was slowly added dropwise under ice water bath, stirring was completed for 10min, ethyl acetate (1 mL) was added, and column chromatography was concentrated under reduced pressure to give compound 1g (yellow solid, 100mg, yield 44%).
1 H NMR(400MHz,DMSO-d 6 )δ11.92(s,1H),8.35(d,1H),7.59(d,1H),7.41(s,1H), 5.45(t,1H),4.60(d,2H),2.16-2.09(m,1H),0.96(dt,2H),0.82(dt,2H)。
LC-MS m/z(ESI)＝217.10[M+1]。
Seventh step
7- (bromomethyl) -3-cyclopropyl-1, 5-naphthyridin-2 (1H) -one for 1H
7-(bromomethyl)-3-cyclopropyl-1,5-naphthyridin-2(1H)-one
Compound 1g (100 mg,0.46 mmol) and triphenylphosphine (available from Shanghai Aldamus reagent Co., ltd., 242mg,0.92 mmol) were dissolved in dichloromethane (1 mL), a solution of carbon tetrabromide (available from Anemargi Chemie, 306mg,0.92 mmol) in dichloromethane (0.5 mL) was added under ice-water bath, reacted for 0.5h, and the reaction solution was concentrated under reduced pressure and then subjected to column chromatography to give compound 1h (yellow solid, 100mg, yield 78%).
LC-MS m/z(ESI)＝279.00[M+1]。
Eighth step
5- (4- ((7-cyclopropyl-6-oxo-5, 6-dihydro-1, 5-naphthyridin-3-yl) methyl) piperazin-1-yl) -N-methylpyridine amide compound 1
5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylpicolinamide
Compound 1h (100 mg,0.36 mmol), N-methyl-5- (piperazin-1-yl) pyridine carboxamide 1i (Jiangsu medical science, inc., 86mg,0.39 mmol), N-diisopropylethylamine (230 mg,1.8 mmol) were dissolved in acetonitrile (4 mL), reacted at 80℃for 4h, and the reaction solution was concentrated under reduced pressure to give compound 1 (white solid, 40mg, yield 27%) by preparative chromatography.
1 H NMR(400MHz,DMSO-d 6 )δ11.89(s,1H),8.40(d,1H),8.38(d,1H),8.26(d,1H),7.82(d,1H),7.60(d,1H),7.42(s,1H),7.38(dd,1H),3.63(s,2H),2.34-3.31(s,4H),2.77(d,3H),2.56-2.53(d,4H),2.19-2.09(m,1H),0.99-0.91(m,2H),0.84-0.76(m,2H)。
LC-MS m/z(ESI)＝419.20[M+1]。
Example 2
(R) -5- (4- ((7-cyclopropyl-6-oxo-5, 6-dihydro-1, 5-naphthyridin-3-yl) methyl) piperazin-1-yl) -N- (tetrahydrofuran-3-yl) picolinamide Compound 2
(R)-5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide
Compound 2a (22.08 mg,0.08 mmol) and compound 1h (22.32 mg,0.08 mmol) were dissolved in acetonitrile (5 mL), N-diisopropylethylamine (from Shanghai Mecanlin Biochemical technologies Co., ltd., 51.7mg,0.4 mmol) was added and reacted at 70℃for 3h, the reaction mixture was dried by spin-drying, and the crude product was isolated by column chromatography (MeOH: DCM=1:60 to 1:15) to give compound 2 (white solid, 26mg, 71% yield).
1 H NMR(400MHz,DMSO-d 6 )δ12.13(s,1H),8.38(d,2H),8.27(s,1H),7.83(d,1H), 7.60(s,1H),7.40(d,2H),4.47-4.42(m,1H),3.87-3.79(m,2H),3.73-3.68(m,1H),3.63(s,2H),3.59-3.55(m,1H),3.43-3.37(m,4H),2.56-2.54(m,4H),2.17-2.09(m,2H),1.97-1.91(m,1H),0.99-0.93(m,2H),0.82-0.80(m,2H)。
LC-MS m/z(ESI)＝475.24[M+1]。
Example 3
5- (4- ((7-cyclopropyl-6-oxo-5, 6-dihydro-1, 5-naphthyridin-3-yl) methyl) piperazin-1-yl) -N- (2-hydroxyethyl) picolinamide Compound 3
5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-hydroxyethyl)picolinamide
Referring to the synthetic method of compound 2, compound 3 (white solid, 31mg, 76% yield) was obtained.
1 H NMR(400MHz,DMSO-d 6 )δ11.90(s,1H),8.41-8.33(m,2H),8.28(d,1H),7.83(d,1H),7.60(d,1H),7.42(s,1H),7.41-7.38(m,1H),4.79(t,1H),3.63(s,2H),3.49(q,2H),3.37-3.35(m,2H),3.34-3.32(m,4H),2.56-2.53(m,4H),2.18-2.12(m,1H),1.01-0.93(m,2H),0.85-0.80(m,2H)。
LC-MS m/z(ESI)＝449.22[M+1]。
Example 4
5- (4- ((7-cyclopropyl-6-oxo-5, 6-dihydro-1, 5-naphthyridin-3-yl) methyl) piperazin-1-yl) -N- (2-methoxyethyl) picolinamide Compound 4
5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(2-methoxyethyl)picolinamide
Referring to the synthetic method for compound 2, compound 4 (white solid, 28mg, yield 74%) was obtained.
1 H NMR(400MHz,DMSO-d 6 )δ11.90(s,1H),8.36(d,2H),8.28(d,1H),7.83(d,1H),7.60(s,1H),7.45-7.37(m,2H),3.63(s,2H),3.46-3.42(m,4H),3.39-3.35(t,2H),3.33-3.10(m,2H),3.26(s,3H),2.56-2.53(m,4H),2.18-2.11(m,1H),0.99-0.94(m,2H),0.85-0.79(m, 2H)。
LC-MS m/z(ESI)＝463.24[M+1]。
Example 5
(R) -5- (4- ((7-cyclopropyl-6-oxo-5, 6-dihydro-1, 5-naphthyridin-3-yl) methyl) piperazin-1-yl) -6-methyl-N- (tetrahydrofuran-3-yl) picolinamide Compound 5
(R)-5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-methyl-N-(tetrahydrofuran-3-yl)picolinamide
Referring to the synthetic method for compound 2, compound 5 (white solid, 29mg, 76% yield) was obtained.
1 H NMR(400MHz,DMSO-d6)δ11.89(s,1H),8.41–8.34(m,2H),7.80(d,1H),7.60(s,1H),7.48(d,1H),7.42(s,1H),4.50-4.42(m,1H),3.92–3.77(m,2H),3.74-3.70(m,1H),3.66(s,2H),3.59(dd,1H),2.96-2.93(m,4H),2.60-2.56(m,4H),2.51(s,3H),2.22–2.10(m,2H),1.97-1.89(m,1H),0.99-0.94(m,2H),0.85–0.79(m,2H)。
LC-MS m/z(ESI)＝489.25[M+1]。
Example 6
(R) -5- (4- ((7-ethyl-6-oxo-5, 6-dihydro-1, 5-naphthyridin-3-yl) methyl-d 2 ) Piperazin-1-yl) -N- (tetrahydrofuran-3-yl) picolinamide Compound 6
(R)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl-d 2 )piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide
First step
3-cyclopropyl-7- (hydroxymethyl-d) 2 ) -1, 5-naphthyridin-2 (1H) -one 6a
3-cyclopropyl-7-(hydroxymethyl-d 2 )-1,5-naphthyridin-2(1H)-one
Referring to the synthesis of 1g, using tetradeuterated lithium aluminum instead of tetrahydrolithium aluminum, 6a (white solid, 700g, 58% yield) was obtained.
LC-MS m/z(ESI)＝219.1[M+1]。
Second step
7- (bromomethyl-d) 2 ) -3-cyclopropyl-1, 5-naphthyridin-2 (1H) -one 6b
7-(bromomethyl-d 2 )-3-cyclopropyl-1,5-naphthyridin-2(1H)-one
Referring to the synthesis for 1h, 6b (white solid, 310mg, 69% yield) was obtained.
LC-MS m/z(ESI)＝281.1[M+1]。
Third step
(R) -5- (4- ((7-cyclopropyl-6-oxo-5, 6-dihydro-1, 5-naphthyridin-3-yl) methyl-d 2 ) Piperazin-1-yl) -N- (tetrahydrofuran-3-yl) picolinamide Compound 6
(R)-5-(4-((7-cyclopropyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl-d 2 )piperazin-1-yl)-N-(tetrahydrofuran-3-yl)picolinamide
Referring to the synthetic method of compound 2, compound 6 (white solid, 26mg, yield 49%) was obtained.
1 H NMR(400MHz,DMSO-d 6 )δ12.13(s,1H),8.38(d,2H),8.27(s,1H),7.83(d,1H),7.60(s,1H),7.40(d,2H),4.47-4.42(m,1H),3.87-3.79(m,2H),3.73-3.68(m,1H),3.59-3.55(m,1H),3.43-3.37(m,4H),2.56-2.54(m,4H),2.17-2.09(m,2H),1.97-1.91(m,1H),0.99-0.93(m,2H),0.82-0.80(m,2H)。
LC-MS m/z(ESI)＝477.2[M+1]。
Biological evaluation
PARP1, PARP2 Activity inhibition assay
The inhibitory activity of the compounds on PARP1 and PARP2 was measured by PARP1 chemiluminescence assay (Chemiluminescent assay, commercially available from BPS Bioscience, cat# 80551) and PARP2 chemiluminescence assay (Chemiluminescent assay, commercially available from BPS Bioscience, cat# 80552), respectively. The results were quantified using chemiluminescence, and the specific experimental protocol was as follows:
(1) The 96-well plate was coated overnight with 1 Xhistone mix (50. Mu.L/well);
(2) Discarding the coating liquid; adding a Blocking buffer 3 (200 mu L) into each well, and incubating for 90min at room temperature;
(3) Discarding the sealing liquid, and washing with PBST for 2 times; add 25. Mu.L of master mix (containing 2.5. Mu.L of 10 XPAR buffer, 2.5. Mu.L of 10X PARP Assay mixture, 5. Mu.L of activated DNA, 15. Mu.L of ddH 2O), 5. Mu.L of inhibitor (initial concentration of inhibitor 10. Mu.M, 8 diluted 1:5 fold), 20. Mu.L of enzyme (2 ng/. Mu.L); incubating for 1 hour at room temperature;
(4) Discarding liquid and washing with PBST for 2 times; 50. Mu.L of Streptavidin (strepavidin) -HRP Blocking buffer 3 (50-fold dilution) was added; incubating for 30min at room temperature;
(5) Discarding liquid and washing with PBST for 3 times; 100 μ L ELISA ECL Substrate A/B mix (50 μL each) was added;
(6) Detection results of enzyme-labeled instrument and IC (integrated circuit) by using GraphPad Prism 8 50 Is calculated by the computer.
The results show that the compound provided by the application has remarkable inhibitory activity on PARP1 and good selectivity relative to PARP 2.
PARP1/PARP2 capture (tracking) assay:
2.1 PARP1 capture (tracking) assay:
(1) A mixture of 4 XPRP 1 (purchased from BPS Bioscience under the trade designation 80501) and Mab anti GST-Tb (purchased from cisbio under the trade designation 61 GSTTLA) was prepared with a buffer, and 4. Mu.L/well of the mixture was added to a 384-well plate (purchased from Greiner under the trade designation 784075);
(2) 4 XDSB DNA probe-1 (purchased from general) was prepared with a buffer, and 4. Mu.L/well was added to a 384-well plate;
(3) Add 4. Mu.L/well inhibition (initial concentration 10. Mu.M, 10 diluted 1:5 fold) to 384 well plates and incubate at room temperature for 1h;
(4) 4 XNAD (purchased from Sigma Co., ltd., cat# 10127965001) was prepared with buffer, 4. Mu.L/well was added to 384 well plates and incubated at room temperature for 10min;
(5) The results were tested using TR-FRET, fitted with GraphPad 5.0, and IC50 calculations were performed.
2.2 PARP2 capture (tracking) assay:
(1) A mixture of 4 XPRP 2 (purchased from BPS Bioscience under the trade designation 80502) and Mab anti GST-Tb (purchased from cisbio under the trade designation 61 GSTTLA) was prepared with a buffer, and 4. Mu.L/well of the mixture was added to a 384-well plate (purchased from Greiner under the trade designation 784075);
(2) 4 XPAR 2probe2 (purchased from general Co.) was prepared with buffer and added to a 384 well plate at 4. Mu.L/well;
(3) Add 4. Mu.L/well inhibition (initial concentration 10. Mu.M, 10 diluted 1:5 fold) to 384 well plates and incubate at room temperature for 45min;
(4) 4 XNAD (purchased from Sigma Co., ltd., cat# 10127965001) was prepared with buffer, 4. Mu.L/well was added to 384 well plates and incubated at room temperature for 10min;
(5) The results were tested using TR-FRET, fitted with GraphPad 5.0, and IC50 calculations were performed.
Note that: comparative example 1 was J.Med. Chem (2021), 64 (19), 14498-14512, compound 25, which was obtained according to the preparation method of compound 25.
The results show that the compound provided by the application has remarkable inhibitory activity on PARP1 capture (trapping) and has good selectivity relative to PARP2 capture (trapping).
DLD1 BRCA2-/-cell proliferation inhibition assay
DLD-1 BRCA2 (-/-) cells (purchased from Horizon Discovery Ltd. Co.) were cultured in 1640 (10% FBS,1% PS) medium at 37℃under 5% CO 2 . When the cells grew to the logarithmic growth phase, the cells were resuspended and diluted to 15000/mL with 1640 medium. 40nL of test compound (final concentration 10. Mu.M, 2. Mu.M, 400nM,80nM,16nM,3.2nM,0.64nM,0.128nM,0.0256nM,0.00512 nM) was added to each well of 384 Kong Baiban (Perkinelmer) using an Echo pipettor; control 1 (0.1% dmso added) and control 2 (blank medium) were set up in 2 replicates per concentration gradient. Subsequently 384 Kong Baiban (PerkinElmer) was added to 40 μl (600) of cell suspension per well (control group 2 was not added with cells).
Placing the 384 well plate in CO 2 Incubator (37 ℃,5% CO) 2 ) The culture was continued for 7 days, and 384-well plates were removed and left at room temperature for 30 minutes. mu.L of Celltiter Glo detection solution was added to each well, and the plate shaking machine was shaken for 2 minutes and left at room temperature for 30 minutes. Chemiluminescent values were measured using a microplate reader (Perkinelmer; enVision).
Curve fitting was performed with GraphPad Prism 8.0 and IC was calculated 50 . Detection results of enzyme-labeled instrument and IC (integrated circuit) by using GraphPad Prism 8 50 Is calculated by the computer.
Numbering of compounds DLD1 BRCA 2-/-cell IC50 (nM)
Compound 1 2.00
The results show that the compound has obvious inhibition effect on the proliferation of DLD1 BRCA 2-/-cells.
MDA-MB-436 cell proliferation inhibition experiment
MDA-MB-436 cells (supplier ATCC) were cultured in DMEM medium (10% FBS,1% PS) at 37℃under 5% CO 2 . When the cells grew to the logarithmic growth phase, the cells were resuspended and diluted to 1500 cells/ml with DMEM medium. The test compound (final concentration: 10000nM,2000nM,400nM,80nM,16nM,3.2nM,0.64nM,0.128nM,0.0256nM,0.00512 nM) was added at 40. Mu.L per well in 384 well plates; control 1 (0.1% dmso added) and control 2 (blank medium) were set up in 2 replicates per concentration gradient. Subsequently 40. Mu.L of cell suspension was added to 384 well plates (control group 2 was without cells).
The 384-well plate was placed in an incubator (37 ℃,5% CO) 2 ) After 7 days of continuous culture, 384 well plates were removed and allowed to stand at room temperature for 30min. Adding 30 mu L Celltiter Glo assay kit detection liquid into each hole, vibrating for 3min by using a vibration plate machine, and standing for 30min at room temperature. Chemiluminescent values were measured using a microplate reader (Perkinelmer; enVision).
The detection results were curve-fitted with GraphPad Prism 8 and IC was calculated 50 。
Numbering of compounds MDA-MB-436 cell IC50 (nM)
Comparative example 2 ＞10000
Compound 1 4.96
Compound 4 24.68
Note that: comparative example 2 is compound 62 of patent WO200905337, which is obtained according to the preparation method of compound 62.
The results show that the compound has obvious inhibition effect on MDA-MB-436 cell proliferation.
5. In vivo pharmacokinetic experiments in mice
(1) Test animals: ICR male mice, 5-6 weeks old, were purchased from Chengdu laboratory animals Inc.;
(2) Test object preparation: precisely weighing a proper amount of comparative example 1 and compound 1 to prepare a transparent and clear solution with the concentration of 0.3mg/mL, wherein the solvent is 5% DMSO+30% HP-beta-CD;
(3) Dosing and blood sampling for animals: each mouse was given comparative example 1 and Compound 1 by gavage at a dose of 3mg/kg, respectively, with 3 mice per group. According to the conditions that before administration (0 h), 5min, 15min, 0.5h, 1h, 2h, 4h, 6h, 8h and 24h are carried out after administration, 10 blood sampling time points respectively pass through the eye socket vein Cong Caixie 0.1.1 mL, and blood samples are centrifuged for 10min at 2000g at 4 ℃, so that blood plasma is collected for subsequent detection;
(4) The LC-MS/MS method is adopted to measure the concentration of the proto-drug in the blood plasma, and the Winnol 8.2 non-atrioventricular model is adopted to calculate the main pharmacokinetic parameters.
Note that: comparative example 1 was J.Med. Chem (2021), 64 (19), 14498-14512, compound 25, which was obtained according to the preparation method of compound 25.
The results show that the compounds of the application show significantly better pharmacokinetic profile in mice than the control.
While the specification describes in detail specific embodiments of the present application, those skilled in the art will recognize that the foregoing embodiments are illustrative and not to be construed as limiting the application, and that many variations and modifications of the application may be made without departing from the spirit of the application, which is intended to fall within the scope of the appended claims.

Claims (8)

  1. A compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof:
    wherein:
    R 1 is C 3-8 Cycloalkyl or C 3-8 Heterocycloalkyl, said C 3-8 Heterocycloalkyl comprises 1 to 4 heteroatoms selected from N, O and S;
    l is-NH-, -CO-, or- (CR) L1 R L2 ) n -；
    R L1 、R L2 Each independently is H or C 1-6 Alkyl, said C 1-6 Alkyl is optionally substituted with 1 or more substituents selected from halogen, hydroxy and cyano;
    a is a 4 to 12 membered heterocycle which is a 4 to 12 membered monocyclic ring, a 5 to 12 membered spiro ring, a 4 to 12 membered fused ring or a 4 to 12 membered bridged ring, said 4 to 12 membered heterocycle comprising 1 to 4 heteroatoms selected from N, O and S;
    R 2 h, C of a shape of H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or C 3-8 Heterocycloalkyl, said C 3-8 Heterocycloalkyl comprises 1 to 4 heteroatoms selected from N, O and S; the C is 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or C 3- 8 Heterocycloalkyl is optionally substituted with 1 or more groups selected from halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and C 3-8 Substituents of heterocycloalkyl groups;
    n is 1 or 2;
    optionally, the compound of formula (I) is substituted with 1 or more deuterium.
  2. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the R 1 Is that
  3. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein L is-CH 2 -、-CH(CH 3 ) -or-CD 2 -。
  4. A compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein a is
  5. A compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2 Is an oxetanyl, azetidinyl, methyl, ethyl or propyl group; the oxetanyl, azetidinyl, methyl, ethyl or propyl groups are optionally substituted with one or more substituents selected from methyl, methoxy and hydroxy.
  6. A compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, which is:
    optionally, the compound is substituted with 1 or more deuterium.
  7. A pharmaceutical composition comprising:
    (1) A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or stereoisomer thereof;
    (2) Optionally one or more other active ingredients; and
    (3) Pharmaceutically acceptable carriers and/or excipients.
  8. Use of a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt or stereoisomer thereof or a pharmaceutical composition according to claim 7 for the preparation of an antitumor drug.
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