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CN116444497A - Pyridazinone compound, preparation and application thereof - Google Patents

Pyridazinone compound, preparation and application thereof Download PDF

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Publication number
CN116444497A
CN116444497A CN202211557988.2A CN202211557988A CN116444497A CN 116444497 A CN116444497 A CN 116444497A CN 202211557988 A CN202211557988 A CN 202211557988A CN 116444497 A CN116444497 A CN 116444497A
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membered
alkyl
mmol
heterocycloalkyl
independently selected
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万惠新
王亚周
马金贵
王亚辉
查传涛
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Shanghai Lingda Biomedical Co ltd
Rudong Ringene Pharmaceuticals Co ltd
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Shanghai Lingda Biomedical Co ltd
Rudong Ringene Pharmaceuticals Co ltd
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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Abstract

The invention discloses a pyridazinone compound, a preparation method and application thereof, in particular to a pyridazinone compound shown in a general formula I, or pharmaceutically acceptable salt thereof, or enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, a preparation method and application thereof in pharmacy, wherein the definition of each group is described in the specification.

Description

Pyridazinone compound, preparation and application thereof
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and in particular relates to a pyridazinone compound which has better PARP7 inhibition activity and can be used for preparing therapeutic and preventive medicines for treating diseases related to PARP7 activity or expression or mutation.
Background
PARP, which is known as poly-ADP-ribosepolymerase, i.e., poly-ADP-ribose polymerase, is involved in a number of cellular processes including DNA repair, genomic stability, etc. The protein family consists of 17 members, all of which comprise a co-catalytic domain of about 230 amino acids. Four members of the family (PARP 1, 2, 5a and 5 b) can be attached to their target substrates to catalyze poly ADP-ribose (PAR) chain synthesis, the remaining members are called monoprop, except PARP13, which is only able to transfer a single ADP-ribose (MAR) moiety, whereas PARP13 appears to lack ADP-ribose transferase activity.
Lynparza (olapari) is a PARP inhibitor that was first marketed worldwide based on the DNA repair damage mechanism (DNAdamageresponse, DDR), and was approved by the FDA at an accelerated rate at month 12 of 2014. Currently there are 4 groups of PARP inhibitors worldwide on the market, including rucaparib (Lu Kapa ni), niraparib (nilaparib) and taazoparib (tazopanib), in addition to olaparib. In indications, PARP inhibitors have been approved and developed to treat diseases involving a number of solid tumors such as ovarian, pancreatic, fallopian tube, castration-resistant prostate, urothelial, small cell lung, breast, peritoneal, etc. However, more PARP inhibitors from the collection are currently focused on BRCA mutant tumor species.
The monoprp protein family plays a role in a variety of stress responses associated with the development of cancer, inflammatory and neurodegenerative diseases, and its member PARP7 has been shown to be overactive in tumors and plays a key role in cancer cell survival. Many cancer cells have been found to rely on PARP7 to achieve intrinsic cell survival, while PARP7 allows cancer cells to "harbor" outside the immune system. Inhibiting PARP7 is effective in inhibiting the growth of cancer cells and restoring interferon signaling, and in releasing cancer for evading the immune system, inhibiting the "brake" of the innate and adaptive immune mechanisms. PARP7 inhibitors exhibit durable tumor growth inhibition, potent antiproliferative activity, and interferon signaling recovery in several preclinical cancer models. The PARP7 inhibitor RBN2397 of RibonTherapeutics has been tested in phase I clinical trials.
Therefore, more special, efficient and low-toxicity therapeutic drugs with unique mechanisms are urgently needed to enter clinic aiming at tumors dependent on PARP7, and the discovery and search of efficient, low-toxicity and novel-structure PARP7 targeted drugs are a great hot field in industry.
Disclosure of Invention
One of the technical problems to be solved by the invention is to provide a novel PARP7 inhibitor for preparing tumor therapeutic drugs.
The scheme for solving the technical problems is as follows:
in a first aspect of the present invention there is provided a pyridazinone compound of the general formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, stereoisomer, solvate, polymorph or prodrug thereof,
wherein: x is independently selected from hydrogen, halogen, C1-C6 alkyl, cyano, C1-C6 alkoxy, C1-C6 alkylthio, 3-6 membered cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl; the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, 3-6 membered cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl may optionally be substituted with one or more R x Substituted, R x Independently selected from deuterium, halogen, amino, hydroxy, cyano, mono C1-C3 alkylamino, di C1-C3 alkylamino, C1-C3 alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkyl C1-C6 alkyl, the number of substituents being one or more;
Y 1 、Y 2 、Y 3 Independently selected from O, S (O) p 、NR y 、C(＝O)、C(＝O)O、C(＝O)NR y 、S(O) p NR y 、NR y C(＝O)NR y Wherein R is y Independently selected from hydrogen, C1-C6 alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl, said R y Optionally by one or more R y1 Substituted, R y1 Independently selected from deuterium, halogen, amino, hydroxy, cyano, C1-C3 monoalkylamino, C1-C3 dialkylamino, C1-C3 alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkyl-C1-C3 alkyl-; p is 0, 1 or 2;
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 each independently selected from hydrogen, halogen, cyano, nitro, amino, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-to 10-membered cycloalkyl or heterocycloalkyl, 5-to 12-membered aryl or heteroaryl, 3-to 10-membered cycloalkyl-C1-C3 alkyl-, 3-to 10-membered heterocycloalkyl-C1-C3 alkyl-, 6-to 12-membered aryl-C1-C3 alkyl-, 5-to 12-membered heteroaryl-C1-C3 alkyl-, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 alkyl sulfoxide, C1-C3 alkyl sulfone, C1-C3 alkanoyl, -C (=O) O-, -C (=O) NH-, sulfonylamino, sulfonylimino, ureido, sulfonylureido, guanido, amidino, carbamate, mono-C1-C3 alkyl-substituted amino, di-C1-C3 alkyl-substituted amino; the C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, 3-to 10-membered cycloalkyl or heterocycloalkyl, 5-to 12-membered aryl or heteroaryl, 3-to 10-membered cycloalkyl-C1-C3 alkyl-, 3-to 10-membered heterocycloalkyl-C1-C3 alkyl-, 6-to 12-membered aryl-C1-C3 alkyl-, 5-to 12-membered heteroaryl-C1-C3 alkyl-, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 alkyl sulfoxide, C1-C3 alkyl sulfone, C1-C3 alkanoyl may be substituted with one or more substituents selected from the group consisting of: halogen, deuterium, cyano, nitro, amino, hydroxy, C1-C6 alkyl, 3-to 10-membered cycloalkyl;
Or R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 Any two groups of the two groups can form a 3-10 membered saturated or unsaturated or partially unsaturated ring system through a carbon chain or a heteroatom;
alternatively, R 1 Or R is 2 Together with Ry and the atoms to which they are attached form a 4-10 membered heterocycloalkyl, i.e. R 1 Or R is 2 Together with the atoms to which they are attached, Y1 form a 4-10 membered heterocycloalkyl;
m and n are each independently selected from integers of 1 to 3;
Cy 1 independently selected from 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl, 4-12 membered spirocyclic group, 4-12 membered bridged ring group, 4-12 membered fused ring group;
Cy 2 independently selected from 6-10 membered aryl 4-10 membered saturated or partially unsaturated ring systems or 5-10 membered heteroaryl 4-10 membered saturated or partially unsaturated ring systems;
R 9 、R 10 each independently selected from one or more carbonyl, hydrogen, halogen, C1-C3 alkyl or halogenated C1-C3 alkyl, cyano, nitro, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 alkyl sulfoxide, C1-C3 alkyl sulfone, C1-C3 alkanoyl, 3-6 membered cycloalkyl or heterocycloalkyl, vinyl, ethynyl;
one or more (e.g., 1, 2, 3, 4, 5) hydrogen atoms on any of the above groups may be substituted with a substituent selected from the group consisting of: including but not limited to deuterium, halogen, hydroxy, amino, C1-C3 monoalkylamino, C1-C3 dialkylamino, C1-C3 alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkyl alkyl; wherein the heteroaryl group comprises 1 to 3 heteroatoms selected from the group consisting of: n, O, P or S, said heterocycloalkyl comprising 1 to 3 heteroatoms selected from the group consisting of: n, O, P or S, wherein the ring system comprises a spiro, bridged, fused, or other saturated or partially unsaturated ring system; the saturated or partially unsaturated ring system may optionally contain 1 to 3 heteroatoms selected from the group consisting of: n, O, P or S; the saturated or partially unsaturated ring system includes, but is not limited to, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl.
In some preferred embodiments, the compounds of formula (I), or pharmaceutically acceptable salts thereof, or enantiomers, diastereomers, tautomers, torsional isomers, solvates, polymorphs, or prodrugs thereof, are preferably compounds of formula (IIa-IIf),
wherein ring D is independently selected from: 5-12 membered monocyclic or polycyclic groups, said ring systems including but not limited to
Wherein a is terminal and Y 3 Are connected;
ring E is independently selected from:wherein the a end is connected with the pyridazine ring end of the mother nucleus;
ring F and ring G are each independently selected from 5-12 membered cycloalkyl or heterocycloalkyl, 5-10 membered aryl or heteroaryl;
R 15 、R 16 、R 17 each independently selected from hydrogen, halogen, C1-C3 alkyl or haloalkyl, cyano, nitro, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 alkyl sulfoxide, C1-C3 alkyl sulfone, C1-C3 alkanoyl, 3-to 6-membered cycloalkyl or heterocycloalkyl, vinyl, ethynyl;
in some preferred embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, cy 2 Is that
Wherein Z is 1 ，Z 2 Are independently selected from N and CR 11 M1, M2, M3 are each independently selected from- (CR) 12 R 13 )t-，-NR 14 -C (O) -, -O-, -S (O) q-, or-ch=ch-;
R 11 independently selected from hydrogen, halogen, C1-C3 alkyl or haloalkyl, cyano, nitro, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 alkyl sulfoxide, C1-C3 alkyl sulfone, C1-C3 alkanoyl, 3-to 6-membered cycloalkyl or heterocycloalkyl, vinyl, ethynyl;
R 12 、R 13 each independently selected from hydrogen, halogen, C1-C3 alkyl or haloalkyl, cyano, nitro, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 alkyl sulfoxide, C1-C3 alkyl sulfone, C1-C3 alkanoyl, 3-to 6-membered cycloalkyl or heterocycloalkyl, vinyl, ethynyl;
R 14 independently selected from hydrogen, C1-C3 haloalkyl, C1-C3 alkoxyC 1-C3 alkyl, C1-C3 hydroxyalkyl, substituted or unsubstituted amino-C1-C3 alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; the substituents in the substituted amino-C1-C3 alkyl are independently selected from one or more of the following groups: halogen, hydroxy, amino, C1-C3 monoalkylamino, C1-C3 dialkylamino, C1-C3 alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkyl C1-C3 alkyl;
t is independently selected from integers from 1 to 3; q is independently selected from integers from 0 to 2.
In some preferred embodiments, the compounds of formula (I), or pharmaceutically acceptable salts thereof, or enantiomers, diastereomers, tautomers, torsional isomers, solvates, polymorphs, or prodrugs thereof, are preferably of formula (III-1) or (III-2),
wherein X is preferably F, cl, br, CH 3 、CF 3 ；R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 Each independently is preferably selected from hydrogen, deuterium, fluorine, methyl, ethyl; a is preferably an integer from 0 to 6; z is Z 1 Preferably CH, C-F, C-Me, N.
In some preferred embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, is preferably of formula (IV-1), (IV-2), (IV-3), (IV-4), (IV-5) or (IV-6)
Therein X, R 10 、Z 1 And a is as described above.
In some preferred embodiments, when X is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C2-C6 alkenyl, C2-C6 alkynyl, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, vinyl, ethynyl; more preferably methyl, methoxy, methylthio;
in some preferred embodiments, when R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 Each independently selected from 3-10 membered cycloalkyl or heterocycloalkyl, 5-12 membered aryl or heteroaryl, 3-10 membered cycloalkyl-C1-C3 alkyl-, 3-10 membered heterocycloalkyl-C1-C3 alkyl-, 6-12 membered aryl-C1-C3 alkyl-, 5-12 membered heteroaryl-C1-C3 alkyl-, preferably 3-6 membered cycloalkyl or heterocycloalkyl, 5-8 membered aryl or heteroaryl, 3-6 membered cycloalkyl-C1-C3 alkyl-, 3-6 membered heterocycloalkyl-C1-C3 alkyl-, 6-10 membered aryl-C1-C3 alkyl-, 5-8 membered heteroaryl-C1-C3 alkyl-;
in some preferred embodiments, R 1 Or R is 2 When Ry and the atoms to which they are attached together form a 4-10 membered heterocycloalkyl, the 4-10 membered heterocycloalkyl is a 5-8 membered heterocycloalkyl.
In some preferred embodiments, R 1 Or R is 2 When Ry and the atoms to which they are attached together form a 4-10 membered heterocycloalkyl group, it is preferred thatWherein the a-terminal is attached to the parent pyridazine ring and the b-terminal is attached to the chain end.
In some preferred embodiments, cy 1 Preferably 5-8 membered cycloalkyl, 5-8 membered heterocycloalkyl, 5-8 membered spirocyclic group, 5-8 membered bridged cyclic group, 5-8 membered fused ring group; more preferably
Wherein b is terminal and Y 3 Connected with a terminal and Cy 2 Are connected;
in some preferred embodiments, cy 2 Preferably from 6-10 membered aryl and 5-8 membered saturated or partially unsaturated ring systems or from 5-10 membered heteroaryl and 5-8 membered saturated or partially unsaturated ring systems; more preferably 6-10 membered aryl-5-8 membered cycloalkyl, 6-10 membered aryl-5-8 membered heterocycloalkyl, 6-10 membered aryl-5-8 membered cycloalkenyl, 5-10 membered heteroaryl-5-8 membered cycloalkyl, 5-10 membered heteroaryl-5-8 membered heterocycloalkyl or 5-10 membered heteroaryl-5-8 membered cycloalkenyl; further preferred is
In some preferred embodiments, R 9 Independently preferably from 1 to 3H, F, -CF 3 、CN、CH 3 CH 2 -、CH 3 -、CH 3 O-、-CH 2 CN, the number is preferably 1-3.
In some preferred embodiments, R 10 Independently preferably from 1 to 3H, F, -CF 3 、CN、CH 3 CH 2 -、CH 3 -、CH 3 O-、-CH 2 CN。
The invention provides a method for preparing a compound of formula I, wherein an amide compound is formed through a condensation reaction of acid and amine:
preferably, the steps are carried out in respective solvents, and the solvents are selected from the group consisting of: water, methanol, ethanol, isopropanol, butanol, ethylene glycol methyl ether, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, toluene, methylene chloride, 1, 2-dichloroethane, acetonitrile, N-dimethylformamide, N-dimethylacetamide, dioxane, or a combination thereof.
Preferably, the condensing agent combination is selected from the group consisting of: DCC (dicyclohexylcarbodiimide), DIC (diisopropylcarbodiimide), CDI (carbonyldiimidazole), EDCI (1-ethyl-3 (3-dimethylpropylamine) carbodiimide), HOAt (1-hydroxy-7-azabenzotriazole), HOBt (1-hydroxybenzotriazole), BOP (carbo condensing agent), pyBOP (1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate), HATU (2- (7-azabenzotriazol) -N, N' -tetramethylurea hexafluorophosphate), TBTU (benzotriazole tetramethyl tetrafluoroboric acid), and the like, or combinations thereof.
Preferably, the inorganic base is selected from the group consisting of: sodium hydride, potassium hydroxide, sodium acetate, potassium t-butoxide, sodium t-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, or a combination thereof; the organic base is selected from the group consisting of: pyridine, triethylamine, N, N-diisopropylethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), lithium hexamethyldisilazide, sodium hexamethyldisilazide, lutidine, or combinations thereof.
Preferably, the acid is selected from the group consisting of: hydrochloric acid, hydrofluoric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, formic acid, acetic acid, trifluoromethanesulfonic acid or combinations thereof.
The invention provides a class of preferred compounds of formula (I) including, but not limited to, the following structures:
it is another object of the present invention to provide a medicament for treating or preventing tumors and a composition thereof. The technical scheme for achieving the purpose is as follows:
a pharmaceutical composition for treating tumor comprises pyridazinone compound shown in the general formula (I), or pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, torsion isomer, solvate, polymorph or prodrug thereof and pharmaceutically acceptable carrier.
It is a further object of the present invention to provide the use of the above compounds. The technical scheme for achieving the purpose is as follows:
the pyridazinone compound shown in the general formula (I), or pharmaceutically acceptable salt thereof, or enantiomer, diastereomer, tautomer, torsionally isomer, solvate, polymorph or prodrug thereof is used for preparing medicaments for treating diseases related to PARP7 mutation, activity or expression quantity, in particular medicaments for treating tumors. The tumor is independently selected from non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, gastric cancer, intestinal cancer, bile duct cancer, brain cancer, leukemia, lymphoma, fibroma, sarcoma, basal cell carcinoma, glioma, renal cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal cancer, pancreatic cancer, etc.
The invention relates to a compound with the structural characteristics of a general formula (I), which can inhibit various tumor cells, especially can efficiently kill tumors related to abnormal PARP7 protein signal channels, and is a therapeutic drug with a brand-new action mechanism.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. The limited space is not described in any more detail herein.
Detailed Description
The inventor has prepared a class of pyridazinone compounds with novel structure shown in formula I through long-term and intensive research, and found that the pyridazinone compounds have better PARP7 protein inhibition activity, and the compounds have specific inhibition effect on PARP7 protein at very low concentration (which can be lower than 20 nM), and have quite excellent proliferation inhibition activity (IC 50 is less than 100 nM) on cells (such as H1373) related to PARP7 channels, so that the pyridazinone compounds can be used for treating related diseases such as tumors caused by PARP7 mutation or activity or expression quantity abnormality. Based on the above findings, the inventors have completed the present invention.
Terminology
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety unless otherwise indicated.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the inventive subject matter. In this application, the singular is used to include the plural unless specifically stated otherwise. It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the use of "or" means "and/or" unless stated otherwise. Furthermore, the terms "include," as well as other forms, such as "comprising," "including," and "containing," are not limiting.
Conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV/VIS spectroscopy, and pharmacological methods are employed unless otherwise indicated. Unless specifically defined otherwise, the terms used herein in the description of analytical chemistry, organic synthetic chemistry, and pharmaceutical chemistry are known in the art. Standard techniques may be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using the manufacturer's instructions for the kit, or in a manner well known in the art or in accordance with the teachings of the present invention. The techniques and methods described above may generally be practiced according to conventional methods well known in the art, based on a number of general and more specific descriptions in the literature cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by one skilled in the art to provide stable moieties and compounds.
When substituents are described by conventional formulas written from left to right, the substituents also include chemically equivalent substituents obtained when writing formulas from right to left. For example, -CH 2O-is equivalent to-OCH 2-.
The section headings used herein are for purposes of organizing articles only and should not be construed as limiting the subject matter. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, operating manuals, and treatises, are hereby incorporated by reference in their entirety.
Certain chemical groups defined herein are preceded by a simplified symbol to indicate the total number of carbon atoms present in the group. For example, C1-6 alkyl refers to an alkyl group as defined below having a total of 1 to 6 carbon atoms. The total number of carbon atoms in the reduced notation does not include carbon that may be present in a substituent of the group.
In addition to the foregoing, when used in the specification and claims of this application, the following terms have the meanings indicated below, unless specifically indicated otherwise.
In the present application, the term "halogen" refers to fluorine, chlorine, bromine or iodine; "hydroxy" refers to an-OH group; "hydroxyalkyl" refers to an alkyl group as defined below substituted with a hydroxy (-OH); "carbonyl" refers to a-C (=o) -group; "nitro" means-NO 2; "cyano" refers to-CN; "amino" means-NH 2; "substituted amino" refers to an amino group substituted with one or two alkyl, alkylcarbonyl, aralkyl, heteroaralkyl groups as defined below, e.g., mono-, di-, alkylamido, aralkylamino, heteroaralkylamino; "carboxy" refers to-COOH.
In the present application, as part of a group or other group (e.g. as used in halogen substituted alkyl groups or the like), the term "alkyl" means a straight or branched hydrocarbon chain group consisting of only carbon atoms and hydrogen atoms, free of unsaturated bonds, having, for example, from 1 to 12 (preferably from 1 to 8, more preferably from 1 to 6) carbon atoms and being linked to the remainder of the molecule by a single bond. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl, decyl and the like.
In the present application, the term "alkenyl" as part of a group or other group means a straight or branched hydrocarbon chain group consisting of only carbon and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and being linked to the rest of the molecule by a single bond, such as, but not limited to, ethenyl, propenyl, allyl, but-1-enyl, but-2-enyl, pent-1, 4-dienyl, and the like.
In this application, the term "alkynyl" as part of a group or other group means a straight or branched hydrocarbon chain group consisting of only carbon and hydrogen atoms, containing at least one triple bond and optionally one or more double bonds, having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and being attached to the remainder of the molecule by a single bond, such as, but not limited to, ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-en-4-ynyl, and the like.
In this application, as part of a group or other group, the term "cycloalkyl" means a stable, non-aromatic, mono-or polycyclic hydrocarbon group consisting of only carbon and hydrogen atoms, which may include fused ring systems, bridged ring systems, or spiro ring systems, having from 3 to 15 carbon atoms, preferably from 3 to 10 carbon atoms, more preferably from 3 to 8 carbon atoms, and which is saturated or unsaturated and may be attached to the remainder of the molecule by a single bond via any suitable carbon atom. Unless otherwise specifically indicated in the specification, carbon atoms in cycloalkyl groups may optionally be oxidized. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexanyl, cyclooctyl, 1H-indenyl, 2, 3-indanyl, 1,2,3, 4-tetrahydro-naphthyl, 5,6,7, 8-tetrahydro-naphthyl, 8, 9-dihydro-7H-benzocyclohepten-6-yl, 6,7,8, 9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9, 10-hexahydro-benzocyclooctenyl, fluorenyl, bicyclo [2.2.1] heptyl, 7-dimethyl-bicyclo [2.2.1] heptyl, bicyclo [2.2.1] heptenyl, bicyclo [ 2.2.2.2 ] octyl, bicyclo [3.1.1] heptyl, bicyclo [3.2.1] octyl, bicyclo [2.2.2] octenyl, bicyclo [ 2.1.1 ] octadienyl, adamantylene, and the like.
In this application, the terms "heterocyclyl", "heterocycloalkyl" and "heterocycloalkyl" are used interchangeably as part of a group or other group, and refer to a stable 3-to 20-membered non-aromatic cyclic group consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur. Unless specifically indicated otherwise in the present specification, a heterocyclyl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, which may include fused, bridged or spiro ring systems; the nitrogen, carbon or sulfur atoms in the heterocyclyl may optionally be oxidized; the nitrogen atom may optionally be quaternized; and the heterocyclyl may be partially or fully saturated. The heterocyclic group may be attached to the remainder of the molecule via a carbon atom or a heteroatom and by a single bond. In heterocyclyl groups containing fused rings, one or more of the rings may be aryl or heteroaryl as defined below, provided that the point of attachment to the remainder of the molecule is a non-aromatic ring atom. For the purposes of the present invention, heterocyclyl is preferably a stable 4-to 11-membered non-aromatic monocyclic, bicyclic, bridged or spiro ring group comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 4-to 8-membered (e.g. 4, 5, 6, 7, 8-membered) non-aromatic monocyclic, bicyclic, bridged or spiro ring group comprising 1 to 3 (e.g. 1, 2, 3) heteroatoms selected from nitrogen, oxygen and sulfur, wherein the nitrogen, carbon or sulfur atoms in the heterocyclyl may optionally be oxidized. Examples of heterocyclyl groups include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2, 7-diaza-spiro [3.5] nonan-7-yl, 2-oxa-6-aza-spiro [3.3] heptan-6-yl, 2, 5-diaza-bicyclo [2.2.1] heptan-2-yl, azetidinyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxacyclopentyl, tetrahydroisoquinolyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, quinolizinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indolinyl, octahydroindolyl, octahydroisoindolyl, pyrrolidinyl, pyrazolidinyl, phthalimidyl, and the like.
In the present application, the term "heterocyclylalkyl" refers to an alkyl group as defined above substituted with a heterocyclyl group as defined above.
In this application, the term "aryl" as part of a group or other group means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms, preferably having 6 to 10 carbon atoms. For the purposes of the present invention, aryl groups may be monocyclic, bicyclic, tricyclic or more ring systems, and may also be fused to cycloalkyl or heterocyclyl groups as defined above, provided that the aryl groups are linked to the remainder of the molecule by single bonds via atoms on the aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, fluorenyl, 2, 3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-benzoxazin-3 (4H) -one-7-yl, and the like.
In the present application, the term "arylalkyl" refers to an alkyl group as defined above substituted with an aryl group as defined above.
In this application, as part of a group or other group, the term "heteroaryl" means a 5-to 16-membered conjugated ring system group having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur within the ring. Unless otherwise specifically indicated in the present specification, heteroaryl groups may be monocyclic, bicyclic, tricyclic or more ring systems, and may also be fused to cycloalkyl or heterocyclyl groups as defined above, provided that heteroaryl groups are attached to the remainder of the molecule via an atom on an aromatic ring by a single bond. The nitrogen, carbon, or sulfur atoms in the heteroaryl group may optionally be oxidized; the nitrogen atom may optionally be quaternized. For the purposes of the present invention, heteroaryl groups are preferably stable 5-to 12-membered aromatic groups comprising 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably stable 5-to 10-membered aromatic groups comprising 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur or 5-to 6-membered aromatic groups comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolinyl, isoquinolinyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothienyl, oxatriazolyl, cinnolinyl, quinazolinyl, thiophenyl, indolizinyl, phenanthroline, isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6, 7-tetrahydrobenzo [ b ] thienyl, naphthyridinyl, [1,2,4] triazolo [4, 3-triazolo [1, 4] pyridazine, 3-1, 4-imidazo [1, 4] triazolo [1, 4, 3-triazolo [1, 4] pyridazine, 3-1, 4-imidazo [ 2,4] a ] 1, 4-imidazo [ 2, 4-a ] and the like.
In the present application, the term "heteroarylalkyl" refers to an alkyl group as defined above substituted with a heteroaryl group as defined above.
In the present application, the term "amido", "amido" includes-alkyl-CONH 2 as defined above or-CONH-alkyl as defined above or-CON (alkyl as defined above) 2. In this application, "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted aryl groups and unsubstituted aryl groups.
The terms "moiety", "structural moiety", "chemical moiety", "group", "chemical group" as used herein refer to a particular fragment or functional group in a molecule. Chemical moieties are generally considered to be chemical entities that are embedded or attached to a molecule.
"stereoisomers" refer to compounds that consist of the same atoms, are bonded by the same bonds, but have different three-dimensional structures. The present invention is intended to cover various stereoisomers and mixtures thereof.
When an olefinic double bond is contained in the compounds of the present invention, the compounds of the present invention are intended to include both E-and Z-geometric isomers unless otherwise specified.
"tautomer" refers to an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the invention are also intended to be included within the scope of the invention.
The compounds of the invention or pharmaceutically acceptable salts thereof may contain one or more chiral carbon atoms and thus may be produced in enantiomers, diastereomers and other stereoisomeric forms. Each chiral carbon atom may be defined as (R) -or (S) -, based on stereochemistry. The present invention is intended to include all possible isomers, as well as racemates and optically pure forms thereof. The compounds of the invention may be prepared by selecting racemates, diastereomers or enantiomers as starting materials or intermediates. Optically active isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.
Conventional techniques for preparing/separating individual isomers include chiral synthesis from suitable optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high performance liquid chromatography.
In the present application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
By "pharmaceutically acceptable acid addition salt" is meant a salt with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, and the like; organic acid salts include, but are not limited to, formate, acetate, 2-dichloroacetate, trifluoroacetate, propionate, hexanoate, octanoate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, adipate, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, alginate, ascorbate, salicylate, 4-aminosalicylate, naphthalenedisulfonate, and the like. These salts can be prepared by methods known in the art.
By "pharmaceutically acceptable base addition salt" is meant a salt formed with an inorganic or organic base that is capable of maintaining the bioavailability of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, the following: primary, secondary and tertiary amines, substituted amines including natural substituted amines, cyclic amines and basic ion exchange resins such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be prepared by methods known in the art.
"polymorphs" refer to the different solid crystalline phases of certain compounds of the present invention in the solid state due to the presence of two or more different molecular arrangements. Certain compounds of the present invention may exist in more than one crystal form, and the present invention is intended to include various crystal forms and mixtures thereof.
In general, crystallization will produce solvates of the compounds of the present invention. The term "solvate" as used herein refers to an aggregate comprising one or more molecules of a compound of the invention and one or more solvent molecules. The solvent may be water, in which case the solvate is a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present invention may exist as hydrates, including monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate, and the like, as well as the corresponding solvated forms. The compounds of the invention may form true solvates, but in some cases may also retain only adventitious water or a mixture of water plus a portion of the adventitious solvent. The compounds of the invention may be reacted in a solvent or precipitated or crystallized from a solvent. Solvates of the compounds of the present invention are also included within the scope of the present invention.
The invention also includes prodrugs of the above compounds. In this application, the term "prodrug" means a compound that can be converted into a biologically active compound of the invention under physiological conditions or by solvolysis. Thus, the term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of a compound of the invention. Prodrugs may not be active when administered to an individual in need thereof, but are converted in vivo to the active compounds of the present invention. Prodrugs are typically rapidly converted in vivo to the parent compounds of the present invention, for example, by hydrolysis in blood. Prodrug compounds generally provide solubility, histocompatibility, or sustained release advantages in mammalian organisms. Prodrugs include known amino protecting groups and carboxyl protecting groups.
In this application, "pharmaceutical composition" refers to a formulation of a compound of the invention with a medium commonly accepted in the art for delivery of biologically active compounds to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote the administration of organisms, facilitate the absorption of active ingredients and further exert biological activity.
The term "pharmaceutically acceptable" as used herein refers to a material (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention, and is relatively non-toxic, i.e., the material can be administered to an individual without causing an adverse biological reaction or interacting in an adverse manner with any of the components contained in the composition.
In this application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonizing agent, solvent, or emulsifying agent that is approved by the relevant government regulatory agency as acceptable for human or livestock use.
The "tumor", "cell proliferation abnormality related disease", and the like of the present invention include, but are not limited to, leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, pancreatic cancer, lung squamous carcinoma, lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, cervical cancer, ovarian cancer, intestinal cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, renal cancer, oral cancer, and the like.
The terms "prevent", "preventing" and "preventing" as used herein include reducing the likelihood of a patient from developing or worsening a disease or condition.
The term "treatment" and other similar synonyms as used herein include the following meanings:
(i) Preventing the occurrence of a disease or disorder in a mammal, particularly when such mammal is susceptible to the disease or disorder, but has not been diagnosed as having the disease or disorder;
(ii) Inhibiting the disease or disorder, i.e., inhibiting its progression;
(iii) Alleviating a disease or condition, i.e., causing the state of the disease or condition to subside; or alternatively
(iv) Alleviating symptoms caused by the disease or condition.
The term "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" as used herein refers to an amount of at least one agent or compound that is sufficient to alleviate one or more symptoms of the disease or disorder being treated to some extent after administration. The result may be a reduction and/or alleviation of signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is required to provide clinically significant relief from a disorder. Effective amounts suitable in any individual case can be determined using techniques such as a dose escalation test.
The terms "administering," "administering," and the like as used herein refer to a method capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. In preferred embodiments, the compounds and compositions discussed herein are administered orally.
The terms "pharmaceutical combination", "co-administration", "administration of other treatments", "administration of other therapeutic agents" and the like as used herein refer to a pharmaceutical treatment obtained by mixing or combining more than one active ingredient, which includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity or single dosage form. The term "ambulatory combination" refers to the simultaneous administration, co-administration, or sequential administration of at least one compound described herein and at least one synergistic formulation as separate entities to a patient at variable intervals. These also apply to cocktail therapies, for example, administration of three or more active ingredients.
It will also be appreciated by those skilled in the art that in the methods described below, the intermediate compound functional groups may need to be protected by appropriate protecting groups. Such functional groups include hydroxyl, amino, mercapto and carboxylic acid. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl groups (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino and guanidino groups include t-butoxycarbonyl, benzyloxycarbonyl and the like. Suitable mercapto-protecting groups include-C (O) -R "(wherein R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl, and the like. Suitable carboxyl protecting groups include alkyl, aryl or aralkyl esters.
Protecting groups may be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The protecting group may also be a polymeric resin.
The invention will be further illustrated with reference to specific examples. It should be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples, in which specific conditions are not noted, are generally in accordance with conventional conditions, or in accordance with the conditions recommended by the manufacturer. Percentages and parts are weight percentages and parts unless otherwise indicated.
Intermediate preparation
Intermediate A1: 5-chloro-4- (trifluoromethyl) -2- ((2- (trimethylsilyl) ethoxy) methyl) pyridazin-3 (2H) -one
Step one: sodium hydride (7.56 g,189.1 mmol) was added to N, N-dimethylformamide (300 mL) of 4, 5-dibromopyridazin-3 (2H) -one (40.0 g,157.6 mmol) under ice-bath cooling, and the reaction mixture was reacted at room temperature for 1 hour. 2- (trimethylsilyl) ethoxymethyl chloride (28.91 g,173.4 mmol) was then added with ice-bath cooling. The reaction mixture was allowed to continue at room temperature for 2 hours. LCMS detects complete conversion of starting material. The reaction mixture was diluted with ethyl acetate (200 mL), and the organic phase was washed with saturated brine. The separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=10:1) to give intermediate compound (45 g) as a pale yellow solid. LCMS (ESI) m/z 384.9/386.9[ M+H ] ] + 。 1 H NMR(400MHz,CDCl 3 )δ7.82(s,1H),5.49(s,2H),3.76-3.69(m,2H),1.00-0.93(m,2H),0.01(s,9H).
Step two: lithium chloride (567 mg,13.51 mmol) was added to N-methylpyrrolidone (20 mL) of the above intermediate (5.16 g,13.51 mmol) at ice-bath cooling. The reaction mixture was reacted at 95℃for 4 hours. TLC detected the basic reaction was complete. Ethyl acetate (200 mL) was added to the reaction mixture, and the organic phase was washed with saturated brine (100 mL). The separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=10:1) to give the compound as a white oil (4.35 g). LCMS (ESI) m/z 341/339[ M+H ]] + 。 1 H NMR(400MHz,CDCl 3 )δ7.74(s,1H),5.50(s,2H),3.78-3.63(m,2H),1.02-0.88(m,2H),0.01(s,9H).
Step three: to N-methylpyrrolidone (200 mL) as the intermediate compound (40 g,118.35 mmol) was added copper iodide (4.51 g,23.67 mmol), methyl 2, -difluoro-2-fluorosulfonylacetate (68.15 g,335.04 mmol) at room temperature, and the reaction mixture was reacted at 100℃for 2 hours. The reaction mixture was diluted with ethyl acetate (500 mL), and the organic phase was washed with saturated brine (300 mL). The separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=50:1) to give intermediate A1 (26 g) as a white oil. LCMS (ESI) m/z 329.1[ M+H ] ] + 。 1 H NMR(400MHz,CDCl 3 )δ7.80(s,1H),5.46(s,2H),3.81-3.63(m,2H),1.01-0.88(m,2H),0.00(s,9H).
Intermediate A2: (S) -3- (2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) isopropoxy) propanoic acid
Step one: methyl acrylate (8.6 g,99.93 mmol) was added to a solution of (S) -1-hydroxy-2-carbamoyl tert-butyl ester (3.5 g,19.99 mmol) and cesium carbonate (13.02 g,39.97 mmol) in acetonitrile (100 mL) at room temperature. The reaction mixture was reacted at room temperature for 16 hours. TLC detected the reaction product as the predominant product. Dilute reaction with dichloromethane (100 mL)The reaction mixture was washed with brine (50 mL). The separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10:1) to give intermediate compound (2.17 g) as a colorless oil. LCMS (ESI) m/z 262.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO)δ6.61(d,J＝7.3Hz,1H),3.65-3.53(m,6H),3.29-3.26(m,1H),3.14(m,1H),2.53(m,2H),1.37(s,9H),0.97(d,J＝6.7Hz,3H)。
Step two: to a solution of the above intermediate (2.1 g,8.04 mmol) in methanol (30 mL) was added hydrochloric acid/methanol solution (4M, 5mL,20 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to give a crude compound (1.5 g) as a pale yellow solid. LCMS (ESI) m/z 162.0[ M+H ]] + 。
Step three: n, N-diisopropylethylamine (1.4 g,10.8 mmol) was added to ethanol (10 mL) of the above intermediate (1.3 g,8.02 mmol) and intermediate A1 (2.63 g,8.02 mmol) at room temperature, and the reaction mixture was reacted at 70℃for 2 hours. LCMS detected the reaction product as the predominant product. The reaction solution was concentrated under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (eluent: dichloromethane/methanol=20:1) to obtain an anhydrous oily intermediate (1.8 g). LCMS (ESI) m/z 454.2[ M+H ] ] + 。 1 H NMR(400MHz,CDCl 3 )δ7.68(s,1H),5.83(m,1H),5.41-5.34(m,2H),3.94(m,1H),3.78-3.60(m,7H),3.49-3.45(m,1H),2.59-2.56(t,J＝6.0Hz,2H),1.31(d,J＝7.2Hz,3H),0.97(m,2H),0.01(s,9H)。
Step four: trifluoroacetic acid (5 mL) was added to dichloromethane (20 mL) of the above intermediate compound (1.8 g,3.97 mmol) at room temperature, and the reaction mixture was reacted at 20 degrees for 2 hours. The trifluoroacetic acid was removed by concentration under reduced pressure. After the residue was dissolved in 1, 4-dioxane (5 mL), an aqueous potassium carbonate solution (4M, 3mL,12 mmol) was added. The reaction mixture was stirred at 60℃for 2 hours with continued heating. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10:1) to give an intermediate compound (500 mg) as a white solid. LCMS (ESI) m/z 454.2[ M+H ]] + 。
Step five: an aqueous solution (1.5 mL) of lithium hydroxide (89 mg,3.869 mmol) was added to the above at room temperatureIn methanol (1.5 mL) as an intermediate compound (250 mg,0.774 mmol), the reaction mixture was reacted at 20℃for 1 hour. LCMS detected complete reaction. The solvent was removed by concentration under reduced pressure, and the crude product was isolated by HPLC to give intermediate compound A2 (200 mg) as a white solid. LCMS (ESI) m/z 310.1[ M+H ]] + 。
Intermediate A3: (S) -3- (2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) pyrrol-2-yl) methoxy) propanoic acid
Step one (S) -2- (hydroxymethyl) pyrrole-1-carboxylic acid tert-butyl ester (20 g,99.37 mmol), methyl acrylate (43 g,496.85 mmol) and cesium carbonate (97 g,298.11 mmol) were dissolved in acetonitrile (200 mL) at room temperature. The reaction mixture was reacted at room temperature for 2 hours. The reaction mixture was filtered and the filter cake was washed with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and the separated organic phases were concentrated under reduced pressure. The crude product obtained was chromatographed on a column of silica gel (eluent: petroleum ether/ethyl acetate=4:1) to give intermediate compound (10 g) as a white solid. LCMS (ESI) m/z 288.2[ M+H ] + 。 1 H NMR(400MHz,CDCl 3 )δ3.99–3.80(m,1H),3.77–3.65(m,5H),3.57(d,J＝12.6Hz,1H),3.38–3.23(m,3H),2.56(t,J＝6.3Hz,2H),1.93–1.79(m,4H),1.46(s,9H).
Step two hydrochloric acid/1, 4-dioxane (20 mL) was added to the above intermediate compound (10 g,34.80 mmol) in methanol (100 mL). The reaction mixture was reacted at room temperature for 2 hours. LCMS detected the product as the dominant. The reaction solution was concentrated under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (eluent: dichloromethane/methanol=10:1) to obtain a brown solid intermediate compound (8.0 g). LCMS (ESI) m/z 188.2[ M+H ]] + 。
Step three: n, N-diisopropylethylamine (885 mg,6.84 mmol) was added to the above intermediate compound (1.1 g,5.57 mmol), intermediate compound A1 (2.2 g,6.84 mmol) in ethanol (10 mL) at room temperature, and the reaction mixture was reacted at 70℃for 2 hours. LCMS detected completion of the reaction. Concentrating the organic phase under reduced pressure, and collecting residueSilica gel column chromatography (eluent: dichloromethane/methanol=20:1) afforded intermediate compound (1 g) as a colorless oil. LCMS (ESI) m/z 480.2[ M+H ]] + 。 1 HNMR(400MHz,CDCl 3 )δ7.92(s,1H),5.45(d,J＝9.8Hz,1H),5.31(d,J＝9.8Hz,1H),4.37(dd,J＝6.9,4.3Hz,1H),3.74-3.56(m,9H),3.49-3.33(m,2H),2.51(t,J＝6.1Hz,2H),2.29-2.19(m,1H),2.08-1.93(m,1H),1.76-1.61(m,2H),0.97(m,2H),-0.00(s,9H).
Step four: trifluoroacetic acid (5 mL) was added to dichloromethane (10 mL) of the above intermediate compound (1 g,2.09 mmol) at room temperature, and the reaction mixture was reacted at room temperature for 2 hours. LCMS detected complete reaction. Trifluoroacetic acid was removed by concentration under reduced pressure, and the obtained residue was dissolved in 1, 4-dioxane (3 mL) and then aqueous ammonia (3 mL) was added. The reaction mixture was stirred at 60℃for 2 hours with continued heating. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10:1) to give an intermediate compound (700 mg) as a white solid. LCMS (ESI) m/z 350.0[ M+H ] ] + 。
Step five: an aqueous solution (10 mL) of lithium hydroxide (180 mg,4.3 mmol) was added dropwise to a solution of the above intermediate compound (300 mg,0.86 mmol) in methanol (10 mL). The reaction mixture was reacted at room temperature for 2 hours. LCMS detected complete reaction of starting material, and concentrated under reduced pressure to remove solvent, affording crude pale yellow solid intermediate compound A3 (280 mg). LCMS (ESI) m/z 336.1[ M+H ]] + 。
Example preparation method
Example 1: (S) -5- ((1- (3- (4- (6, 7-dihydro-5H-cyclopenta [ d ] pyrimidin-2-yl) piperazin-1-yl) -3-oxopropoxy) propan-2-yl) amino-4- (trifluoromethyl) pyridazin-3 (2H) -one
Step one Zinc powder (5.5 g,84.6 mmol) was added to 2, 4-dichloro-6, 7-dihydro-5H-cyclopenta [ d ] at room temperature]Pyrimidine (4.0 g,21.2 mmol), ammonia (14 mL,105.8 mmol) in ethanol (30 mL). The reaction mixture was reacted at 60℃for 16 hours. LCMS detected complete reaction of starting materialAll of them. The reaction was diluted with ethyl acetate (50 mL), then filtered through celite, and the filtrate was concentrated under reduced pressure. The crude product obtained was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=4:1) to give intermediate compound (1.7 g) as a white solid. LCMS (ESI) m/z 155.1[ M+H ]] + 。 1 HNMR(400MHz,DMSO)：δ8.53(m,1H),2.92(m,4H),2.16-2.03(m,2H)。
Step two: N-Boc-piperazine (4.23 g,22.7 mmol) was added to the above intermediate compound (500 mg,3.25 mmol), N, N-diisopropylethylamine (2.94 g,22.7 mmol) in tetrahydrofuran (8 mL) at room temperature. The reaction mixture was reacted at 70℃for 2 hours. LCMS detected completion of the reaction. The organic solvent was removed by concentration under reduced pressure, and the reaction mixture was diluted with ethyl acetate (100 mL) and the organic phase was washed with saturated sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=2:1) to give intermediate compound (500 mg) as a white solid. LCMS (ESI) m/z 305.2[ M+H ] ] + . 1 H NMR(400MHz,CDCl 3 )δ8.12(s,1H),3.84-3.70(m,4H),3.55-3.41(m,4H),2.80(m,4H),2.15-2.01(m,2H),1.49(s,9H).
Step three: hydrochloric acid/1, 4-dioxane (1M, 10 mL) was added to a 1, 4-dioxane solution (10 mL) of the above intermediate compound (500 mg,1.64 mmol) at room temperature. The reaction mixture was reacted at room temperature for 4 hours. LC-MS detection reaction was complete. The 1, 2-dioxane solvent was removed by concentration under reduced pressure, the residue was slurried with diethyl ether (10 mL) and the solid product filtered off. The resulting solid product was dried to give the intermediate compound (380 mg) as a pale yellow solid. LCMS (ESI) m/z 205.1[ M+H ]] + 。 1 H NMR(400MHz,DMSO)δ9.41(s,2H),8.25(s,1H),4.01-3.95(m,4H),3.15(s,4H),2.80(m,4H),2.03(m,2H)。
Step four: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (112 mg,0.58 mmol) was added to a solution of the above intermediate compound (70 mg,0.29 mmol), intermediate A2 (90 mg,0.29 mmol), 1-hydroxybenzotriazole (79 mg,0.58 mmol) and N, N-diisopropylethylamine (75 mg,0.58 mmol) in N, N-dimethylformamide (3 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. Concentrating the reaction solution under reduced pressure to obtainThe crude product was purified by HPLC to give example 1 compound as a white solid (4.1 mg). LCMS (ESI) m/z 496.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO)δ12.44(s,1H),8.19(s,1H),7.91(s,1H),6.26(m,1H),4.15(m,1H),3.77-3.61(m,6H),3.48(m,6H),2.81-2.72(m,4H),2.58(m,2H),1.99(m,2H),1.15(d,J＝6.5Hz,3H).
Example 2: (S) -6-methyl-2- (4- (3- (2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propanoyl) piperazin-1-yl) -6, 7-dihydro-5H-pyrrolo [3,4-d ] pyrimidin-5-one
Step one liquid bromine (2.72 g,17.0 mmol) was added to an acetic acid solution (30 mL) of 4-methyl-2- (methylthio) pyrimidine-5-carbonate (4.0 g,18.9 mmol) at room temperature. The reaction mixture was heated to 60 degrees and reacted for 2 hours. The reaction mixture was diluted with ethyl acetate (100 mL), and then washed with saturated brine. The separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography to give the compound as a white solid (3.54 g). LCMS (ESI) m/z 292.9[ M+H ]] + 。 1 H NMR(400MHz,DMSO)δ9.04(s,1H),4.86(s,2H),4.36(m,2H),2.59(s,3H),1.35(m,3H)。
Step two A solution of methylamine in tetrahydrofuran (2M, 22.6mL,45.2 mmol) was added to a solution of the above intermediate compound (3.54 g,12.2 mmol) in tetrahydrofuran (20 mL) at room temperature. The reaction mixture was reacted at room temperature for 2 hours. LCMS detected complete reaction. The solvent was removed by concentration under reduced pressure, and the crude product obtained was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=4:1 to 1:1) to give an intermediate compound (960 mg) as a white solid. LCMS (ESI) m/z 196.1[ M+H ]] + 。 1 H NMR(400MHz,DMSO)δ8.88(s,1H),4.53(s,2H),3.06(s,3H),2.59(s,3H)。
Step three, m-chloroperoxybenzoic acid (978 mg,5.67 mmol) was added to dichloromethane (5 mL) of the above intermediate compound (850 mg,4.36 mmol) at room temperature. The reaction mixture was reacted at room temperature for 1 hour. LCMS detected complete reaction. Two reaction liquids After dilution of methyl chloride (20 mL), the mixture was washed twice with sodium sulfite solution (20 mL). The mixture was washed once with saturated aqueous sodium bicarbonate. The separated organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure, and the obtained crude product was dissolved in 1, 4-dioxane (10 mL) and used directly for the next reaction. N-Boc piperazine (1.62 g,8.72 mmol) was added to a 1, 4-dioxane solution of the crude compound prepared above at room temperature. The reaction mixture was heated to 50 degrees and reacted for 1 hour. LC-MS detects the reaction, most of the starting material is converted to the desired product. The reaction mixture was diluted with methylene chloride (50 mL) and washed with saturated aqueous sodium chloride (50 mL). The separated organic phase was dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=2:1) to give an intermediate compound (155 mg) as a pale yellow solid. LCMS (ESI) m/z 334.1[ M+H ]] + 。 1 HNMR(400MHz,CDCl 3 )δ8.67(s,1H),4.21(s,2H),3.97-3.84(m,4H),3.55-3.50(m,4H),3.13(s,3H),1.49(s,9H)。
Step four trifluoroacetic acid (2 mL) was added to dichloromethane (5 mL) of the above intermediate compound (153 mg,0.459 mmol) at room temperature. The reaction mixture was reacted at 20℃for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with methylene chloride (20 mL) and washed twice with saturated aqueous sodium bicarbonate (20 mL). The separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20:1) to give the compound as a white solid (80 mg). LCMS (ESI) m/z 234.1[ M+H ] ] + 。 1 HNMR(400MHz,CDCl 3 ):δ8.66(s,1H),4.21(s,2H),3.98-3.88(m,4H),3.13(s,3H),3.00-2.88(m,4H)。
Step five 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (131 mg,0.69 mmol) was added to a solution of the above intermediate compound (80 mg,0.34 mmol), intermediate compound A2 (106 mg,0.34 mmol), N, N-diisopropylethylamine (89 mg,0.69 mmol) and 1-hydroxybenzotriazole (93 mg,0.69 mmol) in N, N-dimethylformamide (3 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. To the reaction mixture was added water (5 mL), and the mixture was extracted three times with ethyl acetate (20 mL). The combined organic phases are concentrated under reduced pressureThe crude product was concentrated by HPLC to give example 2 compound as a white solid (3.9 mg). LCMS (ESI) m/z 525.1[ M+H ]] + 。 1 HNMR(400MHz,DMSO)δ12.42(s,1H),8.62(s,1H),7.90(s,1H),7.38-6.94(m,2H),6.26(m,1H),4.36(s,2H),4.22-4.09(m,1H),3.83(m,4H),3.74-3.66(m,2H),3.57-3.52(m,4H),2.99(s,3H),2.59(t,J＝6.4Hz,2H),1.15(d,J＝6.5Hz,3H)。
Example 3: (S) -2- (4- (3- (2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propanoyl) piperazin-1-yl) -6, 7-dihydro-5H-cyclopenta [ d ] pyrimidin-5-one
Step one: n-bromosuccinimide (3.05 g,17.13 mmol) and azobisisobutyronitrile (0.256 g,1.56 mmol) were added to a solution of 2-chloro-6, 7-dihydro-5H-cyclopenta [ d ] pyrimidine (2.15 g,15.58 mmol) in 1, 2-dichloroethane (80 mL) at room temperature. The reaction mixture was reacted at 80℃for 2 hours. LCMS detected completion of the reaction, and the reaction mixture was concentrated under reduced pressure to give the crude product which was used directly in the next step.
Step two: after the crude product concentrated in the previous step was dissolved in ethylene glycol dimethyl ether (60 mL), silver carbonate (8.6 g,31.19 mmol) and water (3 mL) were added. The reaction mixture was heated to 70 ℃ for 2 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10:1 to 1:1) to give a pale yellow solid compound (1.3 g). LCMS (ESI) m/z 171.2[ M+H ]] + 。 1 HNMR(400MHz,CDCl 3 ):δ8.59(s,1H),5.39(t,J＝6.0Hz,1H),3.17(m,1H),2.94(m,1H),2.68-2.56(m,1H),2.20(m,1H),2.12-2.00(m,1H)。
Step three: potassium fluoride (4.44 g,76.5 mmol) was added to a DMSO solution (20 mL) of the above intermediate compound (1.3 g,7.65 mmol) and N-boc piperazine (2.85 g,15.29 mmol) at room temperature. The reaction mixture was reacted at 120℃for 2 hours. LCMS detected the reaction was essentially complete. Ethyl acetate (100 mL) was added to the reaction solution, followed by washing twice with water (50 mL), and the separated organic phase was driedDried over sodium sulfate and the filtrate concentrated under reduced pressure. The crude product obtained was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=1:1) to give the compound as a white solid (1.77 g). LCMS (ESI) m/z 321.2[ M+H ]] + 。 1 HNMR(400MHz,CDCl 3 ):δ8.32(s,1H),5.23(s,1H),3.90-3.78(m,4H),3.54-3.45(m,4H),3.00(m,1H),2.72(m,1H),2.45(m,1H),1.96(m,1H),1.83(m,1H),1.49(s,9H).
Step four: manganese dioxide (2.88 g,33.13 mmol) was added to a solution of the above intermediate compound (1.71 g,5.34 mmol) in methylene chloride (50 mL) at room temperature. The reaction mixture was reacted at 40℃for 16 hours. LCMS detected complete reaction. After the reaction solution was filtered through celite, it was washed with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: ethyl acetate/methanol=20:1) to give a white solid compound (1.3 g). LCMS (ESI) m/z 319.2[ M+H ] ] + 。 1 HNMR(400MHz,CDCl 3 ):δ8.67(s,1H),4.02-3.95(m,4H),3.57-3.48(m,4H),3.02-2.94(m,2H),2.66-2.61(m,2H),1.50(s,9H).
Step five: a solution of hydrochloric acid/1, 4-dioxane (1M, 4 mL) was added to a solution of the above intermediate compound (0.37 g,1.16 mmol) in 1, 4-dioxane (10 mL) at room temperature. The reaction mixture was reacted at room temperature for 2 hours. LCMS detected the reaction was essentially complete. The reaction mixture was concentrated under reduced pressure, and the residue was slurried with diethyl ether (5 mL), and the filtered solid was dried to give a crude intermediate compound (0.28 g) as white. LC-MS (ESI) m/z 219.0[ M+H ]] + 。 1 HNMR(400MHz,DMSO):δ9.67(s,2H),8.69(s,1H),4.25-4.10(m,4H),3.19(s,4H),3.03-2.93(m,2H),2.67-2.55(m,2H).
Step six: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (520 mg,2.72 mmol) was added to a solution of intermediate compound A2 (280 mg,0.91 mmol), the above intermediate compound (264 mg,0.91 mmol) and 1-hydroxybenzotriazole (367 mg,2.72 mmol) in N, N-dimethylformamide (10 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the obtained crude product was purified by HPLC to give a white solid (42 mg) of the compound of example 3. LCMS (ESI) m/z 510.4[ M+H ]] + 。 1 HNMR (400 mhz, dmso): δ12.43 (s, 1H), 8.65 (s, 1H), 7.91 (s, 1H), 6.27 (m, 1H), 4.21-4.10 (m, 1H), 3.96-3.80 (m, 4H), 3.74-3.62 (m, 2H), 3.60-3.53 (m, 4H), 3.49 (d, j=5.4 hz, 2H), 3.00-2.90 (m, 2H), 2.60 (t, j=6.4 hz, 2H), 2.57-2.52 (m, 2H), 1.15 (d, j=6.5 hz, 3H). Example 4: (S) -5- ((1- (3- (4- (5, 5-dioxo-6, 7-dihydrothieno [3, 2-d)) ]Pyrimidin-2-yl) -piperazin-1-yl) -3-isopropoxy-propan-2-yl-amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one
Step one: zinc powder (2.6 g,38.64 mmol) was added to 2, 4-dichloro-6, 7-dihydrothieno [3,2-d ] at room temperature]Pyrimidine (2.0 g,9.66 mmol), ammonia (4.6 g,38.64 mmol) in ethanol (10 mL). The reaction mixture was reacted at 60 degrees for 16 hours. The reaction was diluted with ethyl acetate (100 mL) and the organic phase was washed with saturated sodium chloride solution (50 mL). The separated organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (eluent: dichloromethane/methanol=10:1) to give an intermediate compound (1.42 g) as a white solid. LCMS (ESI) m/z 173.1[ M+H ]] + 。
Step two: the intermediate compound (1.05 g,6.08 mmol) was dissolved in dimethyl sulfoxide (10 mL) under nitrogen protection, N-boc piperazine (2.3 g,12.16 mmol) and potassium fluoride (3.5 g,60.8 mmol). The reaction mixture was reacted at 100℃for 2 hours. The reaction was diluted with ethyl acetate (100 mL) and the organic phase was washed with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=4:1) to give an intermediate compound (1.3 g) as a white solid. LCMS (ESI) m/z 323.1[ M+H ] ] + 。 1 H NMR(400MHz,CDCl 3 ):δ8.07(s,1H),3.78-3.72(m,4H),3.51-3.46(m,4H),3.32(m,2H),3.18(m,2H),1.48(s,9H)。
Step three: metropropolyoxybenzoic acid (69 mg,10.1 mmol) was added to the above intermediate compound (1.3 g,4.0 mmol) in methylene chloride (15 mL) under nitrogen. The reaction mixture was reacted at room temperature for 2 hours. The reaction solution is treated by saturated sodium carbonate waterAfter the solution washing, the solution is washed by a sodium thiosulfate aqueous solution and finally washed by a saturated sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=2:1) to give an intermediate compound (1.1 g) as a white solid. LCMS (ESI) m/z 355.1[ M+H ]] + 。 1 HNMR(400MHz,CDCl 3 ):δ8.63(s,1H),3.97-3.90(m,4H),3.50(m,6H),3.26(m2H),1.49(s,9H)。
Step four: hydrochloric acid/1, 4-dioxane solution (1M, 5mL,5 mmol) was added to a dichloromethane solution (5 mL) of the above intermediate compound (1.1 g,3.10 mmol) at room temperature. The reaction mixture was reacted at room temperature for 4 hours. LCMS detected completion of the reaction. The reaction solution was concentrated under reduced pressure, and the crude product was slurried with anhydrous diethyl ether (10 mL), and the filtered solid was dried to give a white solid intermediate compound (800 mg). LCMS (ESI) m/z 255.1[ M+H ]] + 。 1 H NMR(400MHz,DMSO):δ9.42(s,1H),8.91(s,1H),4.16-3.98(m,4H),3.61(t,J＝7.1Hz,2H),3.29(t,J＝7.1Hz,2H),3.18(s,4H)。
Step five: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (62 mg,0.61 mmol) was added to the above intermediate compound (250 mg,0.31 mmol), intermediate compound A2 (151 mg,0.46 mmol), 1-hydroxybenzotriazole (62 mg,0.46 mmol) in N, N-dimethylformamide (5 mL) at room temperature, and the reaction mixture was reacted for 16 hours. The reaction solution was concentrated directly under reduced pressure, and the residue was purified by HPLC to give a white solid, the compound of example 4 (61 mg). LCMS (ESI) m/z 546.3[ M+H ] ] + 。 1 H NMR(400MHz,DMSO):δ12.44(s,1H),8.84(s,1H),7.91(s,1H),6.27(m,1H),4.15(m,1H),3.83(m,4H),3.69-3.56(m,8H),3.26(t,J＝7.1Hz,2H),2.59(m,2H),1.15(d,J＝6.5Hz,3H).
Example 5:2- (4- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propanoyl) piperazin-1-yl) -6, 7-dihydro-5H-cyclopenta [ d ] pyrimidine-5-carbonitrile
Step one: to 5-bromo-2-chloro-6, 7-dihydro-5H-cyclopenta [ d ] at room temperature]To a solution of pyrimidine (1 g,4.28 mmol) in N, N-dimethylformamide (10 mL) was added potassium cyanide (800 mg,12.3 mmol). The reaction mixture was heated to 60 degrees and stirred overnight. LCMS detection reaction was safe. The reaction mixture was diluted with ethyl acetate (100 mL), washed twice with water (50 mL) and once with saturated brine. The separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude white solid intermediate compound (330 mg). LCMS (ESI) m/z 180.0[ M+H ]] + 。
Step two: the above intermediate compound (330 mg,1.84 mmol), N-boc piperazine (685 mg,3.68 mmol), potassium fluoride (1.07 g,18.4 mmol) was dissolved in dimethyl sulfoxide (5 mL) at room temperature. The reaction mixture was reacted at 100℃for 2 hours. The reaction was diluted with ethyl acetate (100 mL) and the organic phase was washed with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=4:1) to give an intermediate compound (220 mg) as a white solid. LCMS (ESI) m/z 330.1[ M+H ] ] + 。 1 H NMR(400MHz,CDCl 3 ):δ8.31(s,1H),4.04(m,1H),3.84-3.81(m,4H),3.51-3.47(m,4H),3.02-2.81(m,2H),2.58-2.36(m,2H),1.49(s,9H)。
Step three: hydrochloric acid/1, 4-dioxane solution (1M, 3mL,3 mmol) was added to a dichloromethane solution (5 mL) of the above intermediate compound (210 mg,0.64 mmol) at room temperature. The reaction mixture was reacted at room temperature for 2 hours. LCMS detected completion of the reaction. The reaction solution was concentrated under reduced pressure, and the crude product was slurried with anhydrous diethyl ether (10 mL), and the filtered solid was dried to give a white solid intermediate compound (89 mg). LCMS (ESI) m/z 230.3[ M+H ]] + 。 1 HNMR(400MHz,CDCl 3 ):δ8.31(s,1H),4.05-4.01(m,1H),3.96-3.79(m,4H),3.04-2.97(m,4H),2.88-2.81(m,4H),2.55(m,1H),2.44-2.32(m,1H)。
Step four: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (149 mg,0.78 mmol) was added to the above intermediate compound (89 mg,0.39 mmol), intermediate compound A2 (317 mg,0.59 mmol), 1-hydroxybenzotriazole (118 mg,0.87 mmol) in N, N-dimethylformamide (10 mL) at room temperature, and the reaction mixture was reacted for 16 hoursWhen (1). The reaction solution was concentrated under reduced pressure, and the residue was purified by HPLC to give a white solid, the compound of example 5 (23 mg). LCMS (ESI) m/z 521.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO):δ12.34(s,1H),8.38(s,1H),7.91(s,1H),6.28-6.25(m,1H),4.38-4.34(m,1H),4.14(m,1H),3.75-3.65(m,6H),3.50-3.48(m,7H),2.90-2.82(m,2H),2.61-2.53(m,2H),2.49-2.22(m,1H),1.15(d,J＝6.4Hz,3H)。
Example 6: (S) -5- ((1- (3-oxo-3- (4- (5, 6,7, 8-tetrahydroquinazolin-2-yl) piperazin-1-yl) propoxy) propan-2 yl) amino) 4- (trifluoromethyl) pyridazin-3 (2H) -one
Step one: zinc powder (1.28 g,19.7 mmol) was added to ethanol (25 mL) of 2, 4-dichloro-5, 6,7, 8-tetrahydroquinazoline (1 g,4.92 mmol) and aqueous ammonia (4 mL,24.6 mmol) at room temperature. The reaction mixture was reacted at 60℃for 16 hours under nitrogen protection. LCMS detected complete reaction. The reaction was diluted with methanol (50 mL), filtered through celite, and the filtrate concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=4:1) to give intermediate compound as a white solid (700 mg).
LCMS(ESI)m/z:169.2[M+H] + 。 1 HNMR(400MHz,CDCl 3 ):δ8.28(s,1H),2.88(m,2H),2.74(m,2H),1.86(m,4H)。
Step two: potassium fluoride (3.64 g,62.6 mmol) was added to the above intermediate compound (0.7 g,4.17 mmol) and N-Boc piperazine (2.33 g,12.5 mmol) in dimethyl sulfoxide (25 mL) at room temperature. The reaction mixture was reacted at 120℃for 1 hour. LCMS detection showed complete reaction. The reaction was diluted with ethyl acetate (100 mL) and washed twice with water (50 mL). The separated organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure, and the obtained crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10:1) to give an intermediate compound (1.02 g) as a white solid. LCMS (ESI) m/z 319.2[ M+H ]] + 。 1 HNMR(400MHz,CDCl 3 ):δ8.01(s,1H),3.80-3.61(m,4H),3.54-3.40(m,4H),2.62(m,4H),1.85-1.74(m,4H),1.48(s,9H)。
Step three: hydrochloric acid/1, 4-dioxane solution (2M, 5mL,10 mmol) was added to dichloromethane (5 mL) of the above intermediate compound (1.02 g,3.204 mmol) at room temperature. The reaction mixture was reacted at room temperature for 2 hours. LCMS detection showed complete reaction. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10:1) to give the compound (700 mg). LCMS (ESI) m/z 219.3[ M+H ]] + 。 1 HNMR(400MHz,DMSO):δ8.27(s,1H),4.52(m,4H),3.84-3.69(m,4H),2.83-2.69(m,4H),1.65(m,4H)。
Step four: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (581 mg,3.03 mmol) was added to the above intermediate compound (220 mg,1.01 mmol), intermediate A2 (313 mg,1.01 mmol), 1-hydroxybenzotriazole (410 mg,3.03 mmol) in N, N-dimethylformamide (10 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. Ethyl acetate (100 mL) was added to the reaction mixture, which was then washed twice with water (20 mL). The separated organic phase was concentrated under reduced pressure and the resulting crude product was prepared by HPLC to afford the compound of example 6 as a white solid (24 mg). LCMS (ESI) m/z 510.2[ M+H ] ] + 。 1 HNMR(400MHz,DMSO):δ12.3(br.s,1H),8.08(s,1H),7.91(s,1H),6.27(m,1H),4.14(m,1H),3.67(m,6H),3.48(m,6H),2.66-2.52(m,7H),1.72(m,4H),1.15(d,J＝6.4Hz,3H)。
Example 7: 5-fluoro-2- (4- (3- ((S) -2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4 yl) amino) propoxy) propan-yl) piperazin-1-yl) -6, 7-dihydro-5H-cyclopenta [ d ] pyrimidine-5-carbonitrile
Step one: to 4- (5-oxo-6, 7-dihydro-5H-cyclopenta [ d ] at room temperature]To a solution of pyrimidin-2-yl) piperazine-1-carbonyl tert-butyl ester (258 mg,0.81 mmol) in anhydrous dichloromethane (20 mL) was added anhydrous aluminum trichloride (21 mg,0.16 mmol). Then cooled to 0℃and trimethylcyanosilane (201 mg,2.03 mmol) was slowly added dropwise. The reaction mixture was reacted at room temperature under nitrogen protectionAnd 6 hours. LCMS detected complete reaction. The reaction mixture was added to a saturated aqueous sodium hydrogencarbonate solution (30 mL), and the separated organic phase was washed once with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was isolated and purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=3:1) to give intermediate compound as a white solid (150 mg). LCMS (ESI) m/z 346.2[ M+H ]] + 。 1 HNMR(400MHz,CDCl 3 ):δ8.63(s,1H),4.05-3.93(m,4H),3.57-3.48(m,4H),3.05-2.91(m,2H),2.61-2.53(m,2H),1.49(s,9H).
Step two: to a solution of the intermediate compound (150 mg,0.43 mmol) in methylene chloride (20 mL) was added diethylaminosulfur trifluoride (350 mg,2.17 mmol) at room temperature. The reaction mixture was reacted at 60℃for 5 hours. LCMS detection showed complete reaction. The reaction mixture was slowly added to saturated aqueous sodium bicarbonate (30 mL) and then extracted twice with ethyl acetate (60 mL). The combined organic phases were washed twice with water (50 mL). The separated organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure, and the obtained crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5:1) to give an intermediate compound (80 mg) as a white solid. LCMS (ESI) m/z 348.2[ M+H ] ] + 。 1 HNMR(400MHz,CDCl 3 ):δ8.79(s,1H),4.03-3.91(m,4H),3.55-3.46(m,4H),3.15-2.93(m,2H),2.65-2.53(m,2H),1.49(s,9H).
Step three: hydrochloric acid/1, 4-dioxane solution (2M, 0.5mL,1 mmol) was added to dichloromethane (5 mL) of the above intermediate compound (80 mg,0.23 mmol) at room temperature. The reaction mixture was reacted at room temperature for 30 minutes. LCMS detection showed complete reaction. The reaction solution was concentrated under reduced pressure to give a crude intermediate compound (40 mg) as a yellow solid. LCMS (ESI) m/z 248.2[ M+H ]] + 。
Step four: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (31 mg,0.16 mmol) was added to the above intermediate compound (40 mg,0.16 mmol), intermediate compound A2 (75 mg,0.23 mmol), 1-hydroxybenzotriazole (25 mg,0.18 mmol) in N, N-dimethylformamide (5 mL) at room temperature, and the reaction mixture was reacted for 16 hours. The reaction solution is directly concentrated under reduced pressure, and the residue is prepared and purified by HPLCTo a white solid, example 7 compound (7 mg). LCMS (ESI) m/z 539.2[ M+H ]] + 。 1 HNMR(400MHz,DMSO):δ12.3(s,1H),8.85(s,1H),7.93(s,1H),6.25(m,1H),4.15(m,1H),3.85-3.81(m,4H),3.65-3.58(m,6H),3.56(m,2H),3.26(m,2H),2.59(m,2H),1.15(d,J＝6.4Hz,3H).
Example 8:5- (((2S) -1- (3- (4- (5-fluoro-5- (trifluoromethyl) -6, 7-dihydro-5H-cyclopenta [ d ] pyrimidin-2-yl) piperazin-1-yl) -3-oxopropoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one
Step one: to 4- (5-oxo-6, 7-dihydro-5H-cyclopenta [ d ] at room temperature]To a solution of pyrimidin-2-yl) piperazine-1-carbonyl-tert-butyl ester (318 mg,1.0 mmol) and (trifluoromethyl) trimethylsilane (356 mg,2.5 mmol) in anhydrous tetrahydrofuran (20 mL) was slowly added tetrabutylammonium fluoride (1 MinTHF,0.5mL,0.5 mmol). The reaction mixture was reacted at room temperature for 6 hours under nitrogen protection. LCMS detected complete reaction. The reaction mixture was added to saturated aqueous sodium bicarbonate (30 mL) and then extracted with ethyl acetate (100 mL). The separated organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=3:1) to give intermediate compound (110 mg) as a white solid. LCMS (ESI) m/z 389.2[ M+H ] ] + 。 1 HNMR(400MHz,CDCl 3 ):δ8.68(s,1H),4.05-3.93(m,4H),3.57-3.48(m,4H),3.11-2.95(m,2H),2.65-2.58(m,2H),1.49(s,9H).
Step two: to a solution of the intermediate compound (100 mg,0.26 mmol) in methylene chloride (20 mL) was added diethylaminosulfur trifluoride (350 mg,2.17 mmol) at room temperature. The reaction mixture was reacted at 80℃for 5 hours. LCMS detection showed complete reaction. The reaction mixture was slowly added to saturated aqueous sodium bicarbonate (30 mL) and then extracted with ethyl acetate (100 mL). The separated organic phase was washed with water (50 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The crude product obtained is subjected to silica gel column chromatography (eluent: petroleum ether/acetic acid)Ethyl ester=4:1) to afford the intermediate compound as a white solid (60 mg). LCMS (ESI) m/z 391.2[ M+H ]] + 。 1 HNMR(400MHz,CDCl 3 ):δ8.79(s,1H),4.05-3.91(m,4H),3.53-3.46(m,4H),3.15-2.95(m,2H),2.71-2.58(m,2H),1.51(s,9H).
Step three: hydrochloric acid/1, 4-dioxane solution (2M, 0.5mL,1 mmol) was added to dichloromethane (5 mL) of the above intermediate compound (60 mg,0.15 mmol) at room temperature. The reaction mixture was reacted at room temperature for 30 minutes. LCMS detection showed complete reaction. The reaction solution was concentrated under reduced pressure to give a crude intermediate compound (40 mg) as a yellow solid. LCMS (ESI) m/z 291.0[ M+H ]] + 。
Step four: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (29 mg,0.15 mmol) was added to the above intermediate compound (40 mg,0.14 mmol), intermediate compound A2 (75 mg,0.23 mmol), 1-hydroxybenzotriazole (20 mg,0.15 mmol) in N, N-dimethylformamide (5 mL) at room temperature, and the reaction mixture was reacted for 12 hours. The reaction solution was concentrated directly under reduced pressure, and the residue was purified by HPLC to give a white solid, the compound of example 8 (2 mg). LCMS (ESI) m/z 539.2[ M+H ] ] + 。 1 HNMR(400MHz,DMSO):δ12.3(s,1H),8.85(s,1H),7.93(s,1H),6.25(m,1H),4.13(m,1H),3.85-3.81(m,4H),3.68-3.58(m,6H),3.56(m,2H),3.26(m,2H),2.58(m,2H),1.19(d,J＝6.4Hz,3H).
Example 9: (S) -5- ((1- (3- (4-7H-cyclopenta [ d ] pyrimidin-2-yl) piperazin-1-yl) -3-oxopropoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one
Step one: to 5-bromo-2-chloro-6, 7-dihydro-5H-cyclopenta [ d ] at room temperature]To a solution of pyrimidine (250 mg,1.07 mmol) in N, N-dimethylformamide (10 mL) was added 1, 8-diazabicyclo undec-7-ene (600 mg,3.94 mmol). The reaction mixture was heated to 80 degrees and stirred overnight. LCMS detection reaction was safe. The reaction was diluted with ethyl acetate (100 mL) and washed twice with water (50 mL). The separated organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude white productColor solid intermediate compound (130 mg). LCMS (ESI) m/z 153.0[ M+H ]] + 。
Step two: potassium fluoride (500 mg,8.6 mmol) was added to the above intermediate compound (130 mg,0.86 mmol) and N-Boc piperazine (284 mg,2.6 mmol) in dimethyl sulfoxide (10 mL) at room temperature. The reaction mixture was reacted at 120℃for 1 hour. LCMS detection showed complete reaction. The reaction was diluted with ethyl acetate (100 mL) and washed twice with water (50 mL). The separated organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure, and the obtained crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10:1) to give an intermediate compound (80 mg) as a white solid. LCMS (ESI) m/z 303.2[ M+H ] ] + 。 1 HNMR(400MHz,CDCl 3 ):δ8.43(s,1H),6.57-6.52(m,1H),6.23-6.03(m,1H),3.80-3.61(m,4H),3.54-3.40(m,4H),3.22(m,2H),1.53(s,9H)。
Step three: hydrochloric acid/1, 4-dioxane solution (2M, 0.5mL,1 mmol) was added to dichloromethane (5 mL) of the above intermediate compound (80 mg,0.26 mmol) at room temperature. The reaction mixture was reacted at room temperature for 30 minutes. LCMS detection showed complete reaction. The reaction solution was concentrated under reduced pressure to give a crude intermediate compound (40 mg) as a yellow solid. LCMS (ESI) m/z 203.2[ M+H ]] + 。
Step four: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (60 mg,0.31 mmol) was added to the above intermediate compound (40 mg,0.20 mmol), intermediate compound A2 (100 mg,0.32 mmol), 1-hydroxybenzotriazole (40 mg,0.30 mmol) in N, N-dimethylformamide (5 mL) at room temperature, and the reaction mixture was reacted for 12 hours. The reaction solution was concentrated directly under reduced pressure, and the residue was purified by HPLC to give a white solid, the compound of example 9 (10 mg). LCMS (ESI) m/z 494.2[ M+H ]] + 。 1 HNMR(400MHz,DMSO)δ12.4(s,1H),8.19(s,1H),7.91(s,1H),6.65-6.56(m,1H),6.26-6.13(m,2H),4.15(m,1H),3.78-3.62(m,6H),3.48-3.45(m,6H),2.71-2.62(m,2H),1.15(d,J＝6.5Hz,3H).
Example 10: (S) -5- ((1- (3- (4- (5, 5-difluoro-6, 7-dihydro-5H-cyclopenta [ d ] pyrimidin-2-yl) piperazin-1-yl) -3-oxopropoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one
Step one: 4- (5-oxo-6, 7-dihydro-5H-cyclopenta [ d ] at room temperature]A reaction mixture of pyrimidin-2-yl) piperidine-1-carbonyl tert-butyl ester (318 mg,1.0 mmol) and diethylaminosulfur trifluoride (1.2 g,7.44 mmol) was heated to 80℃and reacted for 10 hours. LCMS detection showed complete reaction. The reaction mixture was slowly added to saturated aqueous sodium bicarbonate (100 mL) and then extracted with ethyl acetate (100 mL). The separated organic phase was washed with water (50 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=4:1) to give intermediate compound (65 mg) as a white solid. LCMS (ESI) m/z 341.2[ M+H ] ] + 。 1 HNMR(400MHz,CDCl 3 ):δ8.46(s,1H),3.89-3.87(m,4H),3.53-3.48(m,4H),2.94-2.92(m,2H),2.57-2.54(m,2H),1.49(s,9H).
Step two: hydrochloric acid/1, 4-dioxane solution (2M, 0.5mL,1 mmol) was added to dichloromethane (5 mL) of the above intermediate compound (61 mg,0.18 mmol) at room temperature. The reaction mixture was reacted at room temperature for 30 minutes. LCMS detection showed complete reaction. The reaction solution was concentrated under reduced pressure to give a crude intermediate compound (43 mg) as a yellow solid. LCMS (ESI) m/z 241.0[ M+H ]] + 。
Step three: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (31 mg,0.16 mmol) was added to the above intermediate compound (40 mg,0.17 mmol), intermediate compound A2 (75 mg,0.23 mmol), 1-hydroxybenzotriazole (25 mg,0.18 mmol) in N, N-dimethylformamide (5 mL) at room temperature, and the reaction mixture was reacted for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by HPLC to give a white solid, example 10 compound (4 mg). LCMS (ESI) m/z 532.2[ M+H ]] + 。 1 HNMR(400MHz,DMSO):δ12.3(s,1H),8.55(s,1H),7.93(s,1H),6.25(m,1H),4.13(m,1H),3.85-3.81(m,4H),3.68(m,2H),3.60-3.58(m,4H),3.56(m,2H),3.26(m,2H),2.59(m,2H),1.15(d,J＝6.4Hz,3H).
Example 11:5- (((2S) -1- (3- (4- (5-fluoro-6, 7-dihydro-5H-cyclopenta [ d ] pyrimidin-2-yl) piperazin-1-yl) -3-oxopropoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one
Step one: to 5-bromo-2-chloro-6, 7-dihydro-5H-cyclopenta [ d ] at room temperature]To a solution of pyrimidine (250 mg,1.07 mmol) in acetonitrile (10 mL) was added silver fluoride (315 mg,2.5 mmol). The reaction mixture was heated to 80 degrees and stirred for 3 hours. LCMS detection reaction was safe. The reaction was diluted with ethyl acetate (100 mL) and washed twice with water (50 mL). The separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude white solid intermediate compound (60 mg). LCMS (ESI) m/z 173.0[ M+H ] ] + 。
Step two: potassium fluoride (100 mg,1.7 mmol) was added to the above intermediate compound (60 mg,0.35 mmol) and N-Boc piperazine (130 mg,0.7 mmol) in dimethyl sulfoxide (5 mL) at room temperature. The reaction mixture was reacted at 120℃for 1 hour. LCMS detection showed complete reaction. The reaction was diluted with ethyl acetate (50 mL) and washed twice with water (30 mL). The separated organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure, and the obtained crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10:1) to give an intermediate compound (20 mg) as a white solid. LCMS (ESI) m/z 323.2[ M+H ]] + 。
Step three: hydrochloric acid/1, 4-dioxane solution (2M, 0.5mL,1 mmol) was added to the above intermediate compound (20 mg,0.06 mmol) in dichloromethane (5 mL) at room temperature. The reaction mixture was reacted at room temperature for 10 minutes. LCMS detection showed complete reaction. The reaction solution was concentrated under reduced pressure to give a crude intermediate compound (12 mg) as a yellow solid. LCMS (ESI) m/z 223.0[ M+H ]] + 。
Step four: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (12 mg,0.06 mmol) was added to the above intermediate compound (12 mg,0.05 mmol), intermediate compound A2 (31 mg,0.1 mmol), 1-hydroxybenzotriazole (10 mg,0.07 mmol) in N, N-dimethylformamide (5 mL) at room temperature, and the reaction mixture was reacted for 10 hours. Reverse-rotation The reaction solution was concentrated under reduced pressure, and the residue was purified by HPLC to give a white solid, example 11 compound (2 mg). LCMS (ESI) m/z 514.2[ M+H ]] + 。 1 HNMR(400MHz,DMSO):δ12.3(s,1H),8.45(s,1H),7.95(s,1H),6.25(m,1H),4.58(m,1H),4.13(m,1H),3.85-3.81(m,4H),3.68-3.58(m,6H),3.56(m,2H),3.26(m,2H),2.59(m,2H),1.21(d,J＝6.4Hz,3H).
Example 12: (S) -5- ((1- (3- (4- (5, 6-dihydro-4H-cyclopenta [ d ] thiazol-2-yl) piperazin-1-yl) -3-oxopropoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one
Step one: to 5, 6-dihydro-4H-cyclopenta [ d ] at room temperature]To a solution of thiazole-2 amine (300 mg,2.14 mmol) and N-Boc-N, N-bis (2-bromoethyl) amine (702 mg,2.14 mmol) in N, N-dimethylformamide (20 mL) was added sodium hydrogen (60% oil viscosity, 200mg,5.0 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was quenched with ice water (50 mL), the reaction was extracted with ethyl acetate (100 mL), the separated organic phase was concentrated under reduced pressure, and the crude product obtained was purified by column on silica gel (eluent: petroleum ether/ethyl acetate=4:1) to give intermediate compound (230 mg) as a white solid. LCMS (ESI) m/z 310.2[ M+H ]] + 。
Step two: hydrochloric acid/1, 4-dioxane solution (2M, 0.5mL,1 mmol) was added to dichloromethane (5 mL) of the above intermediate compound (130 mg,0.42 mmol) at room temperature. The reaction mixture was reacted at room temperature for 30 minutes. LCMS detection showed complete reaction. The reaction solution was concentrated under reduced pressure to give a crude intermediate compound (150 mg) as a yellow solid. LCMS (ESI) m/z 210.0[ M+H ] ] + 。
Step three: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (62 mg,0.32 mmol) was added to the above intermediate compound (60 mg,0.29 mmol), intermediate compound A2 (155 mg,0.5 mmol), 1-hydroxybenzotriazole (46 mg,0.34 mmol) in N, N-dimethylformamide (10 mL) at room temperature, and the reaction mixture was reacted for 10 hours. The reaction solution is directly concentrated under reduced pressure, and the residue is prepared and purified by HPLC to obtain whiteColoured solid example 12 compound (8 mg). LCMS (ESI) m/z 501.2[ M+H ]] + 。 1 HNMR(400MHz,DMSO):δ12.5(s,1H),7.91(s,1H),6.27(m,1H),4.60(m,1H),4.15-4.06(m,2H),3.65-3.33(m,8H),2.99(m，1H),2.76-2.40(m,7H),1.77(m，2H),1.17(d,J＝6.4Hz,3H).
Example 13: (S) -5- ((1- (3- (4- (5, 5-difluoro-5H-cyclopenta [ d ] pyrimidin-2-yl) piperazin-1-yl) -3-oxopropoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one
Step one: 4- (5-hydroxy-6, 7-dihydro-5H-cyclopenta [ d ] under nitrogen]A reaction mixture of pyrimidin-2-yl) piperidine-1-carbonyl tert-butyl ester (500 mg,1.56 mmol) and diethylaminosulfur trifluoride (1.2 g,7.44 mmol) was heated to 70℃and reacted for 16 hours. LCMS detection showed complete reaction. The reaction mixture was slowly added to saturated aqueous sodium bicarbonate (50 mL) and then extracted with ethyl acetate (100 mL). The separated organic phase was washed with water (50 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=4:1) to give intermediate compound (27 mg) as a white solid. LCMS (ESI) m/z 339.2[ M+H ] ] + 。 1 HNMR(400MHz,CDCl 3 ):δ8.26(s,1H),6.71(m,1H),6.64(m,1H),3.91-3.89(m,4H),3.52-3.49(m,4H),1.49(s,9H).
Step two: hydrochloric acid/1, 4-dioxane solution (2M, 0.5mL,1 mmol) was added to dichloromethane (5 mL) of the above intermediate compound (25 mg,0.07 mmol) at room temperature. The reaction mixture was reacted at room temperature for 30 minutes. LCMS detection showed complete reaction. The reaction solution was concentrated under reduced pressure to give a crude intermediate compound (10 mg) as a yellow solid. LCMS (ESI) m/z 239.0[ M+H ]] + 。
Step three: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (10 mg,0.05 mmol) was added to the above intermediate compound (10 mg,0.04 mmol), intermediate compound A2 (23 mg,0.07 mmol), 1-hydroxybenzotriazole (8 mg,0.06 mmol) in N, N-dimethyl at room temperatureIn dimethylformamide (5 mL), the reaction mixture was reacted for 16 hours. The reaction solution was concentrated directly under reduced pressure, and the residue was purified by HPLC to give a white solid, the compound of example 13 (2.5 mg). LCMS (ESI) m/z 530.2[ M+H ]] + 。 1 HNMR(400MHz,DMSO):δ12.3(s,1H),8.44(s,1H),7.91(s,1H),7.04-6.99(m,2H),6.29-6.25(m,1H),4.16(m,1H),3.84-3.66(m,6H),3.54-3.48(m,6H),2.59-2.57(m,2H),1.15(d,J＝6.4Hz,3H).
Example 14: (S) -5- ((1- (3- (4- (5, 6-dihydrofuro [2,3-d ] pyrimidin-2-yl) piperazin-1-yl) -3-oxopropoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one
Step one: potassium fluoride (200 mg,3.4 mmol) was added to 2-chloro-5, 6-dihydrofuro [2,3-d ] at room temperature]Pyrimidine (200 mg,1.28 mmol) and N-Boc piperazine (280 mg,1.5 mmol) in dimethyl sulfoxide (5 mL). The reaction mixture was reacted at 120℃for 1 hour. LCMS detection showed complete reaction. The reaction was diluted with ethyl acetate (50 mL) and washed twice with water (30 mL). The separated organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10:1) to give an intermediate compound (100 mg) as a white solid. LCMS (ESI) m/z 307.2[ M+H ] ] + 。
Step two: hydrochloric acid/1, 4-dioxane solution (2M, 0.5mL,1 mmol) was added to the above intermediate compound (50 mg,0.16 mmol) in dichloromethane (5 mL) at room temperature. The reaction mixture was reacted at room temperature for 10 minutes. LCMS detection showed complete reaction. The reaction solution was concentrated under reduced pressure to give a crude intermediate compound (30 mg) as a yellow solid. LCMS (ESI) m/z 207.0[ M+H ]] + 。
Step three: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (40 mg,0.21 mmol) was added to the above intermediate compound (30 mg,0.15 mmol), intermediate compound A2 (100 mg,0.32 mmol), 1-hydroxybenzotriazole (27 mg,0.20 mmol) in N, N-dimethylformamide (5 mL) at room temperature, and the reaction mixture was reacted for 10 hours. Reaction liquidThe residue was purified by HPLC to give the compound of example 14 as a white solid (5 mg). LCMS (ESI) m/z 514.2[ M+H ]] + 。 1 HNMR(400MHz,DMSO):δ12.44(s,1H),8.64(s,1H),7.92(s,1H),6.25(m,1H),4.15(m,1H),3.83(m,4H),3.69-3.56(m,8H),3.26(t,J＝7.1Hz,2H),2.69(m,2H),1.15(d,J＝6.8Hz,3H).
Example 15: (S) -2- (4- (3- (2- ((6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) amino) propoxy) propanoyl) piperazin-1-yl) furo [2,3-d ] pyrimidin-5 (6H) -one
Step one: to a solution of ethyl 2-glycolate (677 mg,6.51 mmoL) in tetrahydrofuran (50 mL) was added sodium hydrogen (60%, 280mg,7.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes. To the reaction solution was added a solution of ethyl 4-chloro-2- (methylthio) pyrimidine-5-carboxylate (1.5 g,6.47 mmol) in tetrahydrofuran (10 mL) under ice-bath cooling. The reaction mixture was stirred at room temperature for 4 hours. LCMS detection showed complete reaction. The reaction was quenched by addition of ice water (100 mL) and then extracted with ethyl acetate (100 mL). The separated organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5:1) to obtain an intermediate compound (1.6 g) as a white solid. LCMS (ESI) m/z 301.0[ M+H ] ] + 。
Step two: to a solution of the above intermediate (1.6 g,5.33 mmol) in methylene chloride (50 mL) was added m-chloroperoxybenzoic acid (1.08 g,6.26 mmol) under ice-bath cooling. The reaction mixture was stirred at room temperature for 3 hours. LC-MS detection reaction was complete. To the reaction mixture was added saturated aqueous sodium bicarbonate (50 mL). The separated organic phase was washed once with saturated brine, saturated aqueous sodium thiosulfate solution and water. The separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude pale yellow solid intermediate compound (1.2 g). LCMS (ESI) m/z 317.0[ M+H ]] + 。
Step three: potassium fluoride (771 mg,13.4 mmol) was added at room temperature) To the above intermediate compound (1.2 g,3.80 mmol) and N-Boc piperazine (707 mg,3.8 mmol) in dimethyl sulfoxide (20 mL). The reaction mixture was reacted at 120℃for 2 hours. LCMS detection showed complete reaction. The reaction was diluted with ethyl acetate (200 mL) and washed twice with water (100 mL). The separated organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5:1) to obtain an intermediate compound (1.4 g) as a white solid. LCMS (ESI) m/z 439.2[ M+H ] + 。
Step four: to the above intermediate (1.3 g,2.97 mmol) N, N-dimethylformamide (20 mL) was added potassium tert-butoxide (673 mg,6.0 mmol) under ice-bath cooling. The reaction mixture was stirred at zero degrees for 30 minutes. LC-MS detection reaction was complete. To the reaction solution was added a saturated aqueous ammonium chloride solution (100 mL), followed by extraction with ethyl acetate (150 mL). The separated organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3:1) to obtain an intermediate compound (540 mg) as a white solid. LCMS (ESI) m/z 393.2[ M+H ]] + 。
Step five: to methanol (10 mL) of the above intermediate (540 mg,1.38 mmol) was added concentrated hydrochloric acid (5 mL) under ice-bath cooling. The reaction mixture was stirred at 60 degrees for 1 hour. The reaction solution was concentrated under reduced pressure, and dried to give a crude white solid intermediate compound (260 mg). LCMS (ESI) m/z 221.0[ M+H ]] + 。
Step six: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (100 mg,0.52 mmol) was added to the above intermediate compound (100 mg,0.45 mmol), intermediate compound A2 (250 mg,0.81 mmol), 1-hydroxybenzotriazole (68 mg,0.51 mmol) in N, N-dimethylformamide (5 mL) at room temperature, and the reaction mixture was reacted for 10 hours. The reaction solution was concentrated directly under reduced pressure, and the residue was purified by HPLC to give a white solid, the compound of example 15 (18 mg). LCMS (ESI) m/z 512.2[ M+H ] ] + 。 1 HNMR(400MHz,DMSO):δ12.3(s,1H),8.64(s,1H),7.98(s,1H),6.27(m,1H),5.28(s,2H),4.17(m,1H),3.85(m,4H),3.75-3.36(m,8H),1.15(d,J＝6.8Hz,3H)。
Referring to the synthetic methods of examples 1-15, the following example compounds were synthesized using starting materials of different substituents instead of 2- (piperazin-1-yl) -cyclopenta [ d ] pyrimidine.
Example 21: (S) -2- (4- (3- ((1- (6-oxo-5- (trifluoromethyl) -1, 6-dihydropyridazin-4-yl) pyrrol-2-yl) methoxy) propionyl) piperidin-1-yl) -6, 7-dihydro-5H-cyclopenta [ d ] pyrimidin-5-one
Step one: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (483 mg,2.52 mmol) was added to intermediate A3 (280 mg,0.84 mmol), 2- (piperazin-1-yl) -6, 7-dihydro-5H-cyclopenta [ d) at room temperature]Pyrimidine-5-one hydrochloride (183 mg,0.84 mmol), 1-hydroxybenzotriazole (340 mg,2.52 mmol) in N, N-dimethylformamide (10 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction was diluted with ethyl acetate (100 mL) and washed twice with water (30 mL). The separated organic phase was concentrated under reduced pressure and the resulting crude product was purified by HPLC to afford the compound of example 21 as a white solid (15 mg). LCMS (ESI) m/z 536.2[ M+H ]] + 。 1 HNMR(400MHz,DMSO):δ12.35(s,1H),8.66(s,1H),8.01(s,1H),4.52(m,1H),3.89(m,4H),3.64(m,2H),3.53(m,6H),3.39-3.18(m,2H),2.95(m,2H),2.57-2.53(m,4H),2.08(m,1H),1.88(m,1H),1.63(m,2H)。
Referring to the synthetic procedure of example 21, the following example compounds were synthesized using starting materials of different substituents instead of 2- (piperazin-1-yl) -cyclopenta [ d ] pyrimidine.
Referring to the synthetic methods of examples 1-15, the following example compounds were synthesized using starting materials of different substituents instead of 2- (piperazin-1-yl) -cyclopenta [ d ] pyrimidine.
Referring to the synthetic procedure of example 21, the following example compounds were synthesized using starting materials of different substituents instead of 2- (piperazin-1-yl) -cyclopenta [ d ] pyrimidine.
Referring to the synthetic methods of examples 1-15, the following example compounds were synthesized using starting materials of different substituents instead of 2- (piperazin-1-yl) -cyclopenta [ d ] pyrimidine.
Referring to the synthetic procedure of example 21, the following example compounds were synthesized using starting materials of different substituents instead of 2- (piperazin-1-yl) -cyclopenta [ d ] pyrimidine.
Example 61: (S) -5- ((1- (3- (4- (7, 7-dimethyl-7H-pyrano [2,3-d ] pyrimidin-2-yl) piperazin-1-yl) -3-oxopropoxy) propan-2-yl) amino) -4- (trifluoromethyl) pyridazin-3 (2H) -one
Step one: to a solution of ethyl 3-hydroxy-3-methylbutanoate (951 mg,6.50 mmoL) in tetrahydrofuran (50 mL) was added sodium hydrogen (60%, 280mg,7.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes. To the reaction solution was added a solution of ethyl 4-chloro-2- (methylthio) pyrimidine-5-carboxylate (1.5 g,6.47 mmol) in tetrahydrofuran (10 mL) under ice-bath cooling. The reaction mixture was stirred at room temperature for 4 hours. LCMS detection showed complete reaction. The reaction was quenched by addition of ice water (100 mL) and then extracted with ethyl acetate (100 mL). The separated organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5:1) to obtain a white solid intermediate compound (1.3 g). LCMS (ESI) m/z 343.0[ M+H ] ] + 。
Step two: to a solution of the above intermediate (1.3 g,2.92 mmol) in methylene chloride (50 mL) was added m-chloroperoxybenzoic acid (0.54 g,3.13 mmol) under ice-bath cooling. The reaction mixture was stirred at room temperature for 3 hours. LC-MS detection reaction was complete. To the reaction mixture was added saturated aqueous sodium bicarbonate (50 mL). The separated organic phase was washed once with saturated brine, saturated aqueous sodium thiosulfate solution and water. The separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude pale yellow solid intermediate compound (920 mg). LCMS (ESI) m/z 359.0[ M+H ]] + 。
Step three: potassium fluoride (771 mg,13.4 mmol) was added to the above intermediate compound (0.92 g,2.57 mmol) and N-benzyl piperazine at room temperatureOxazine (460 mg,2.61 mmol) in dimethyl sulfoxide (20 mL). The reaction mixture was reacted at 120℃for 2 hours. LCMS detection showed complete reaction. The reaction was diluted with ethyl acetate (200 mL) and washed twice with water (100 mL). The separated organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5:1) to obtain an intermediate compound (0.85 g) as a white solid. LCMS (ESI) m/z 471.2[ M+H ] ] + 。
Step four: to the above intermediate (0.85 g,1.81 mmol) in N, N-dimethylformamide (20 mL) was added potassium tert-butoxide (673 mg,6.0 mmol) under ice-bath cooling. The reaction mixture was stirred at zero degrees for 30 minutes. LC-MS detection reaction was complete. To the reaction solution was added a saturated aqueous ammonium chloride solution (100 mL), followed by extraction with ethyl acetate (150 mL). The separated organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3:1) to give an intermediate compound (550 mg) as a white solid. LCMS (ESI) m/z 425.2[ M+H ]] + 。
Step five: concentrated hydrochloric acid (5 mL) was added to ethanol (10 mL) of the above intermediate (450 mg,1.17 mmol) under ice-bath cooling. The reaction mixture was stirred at 60 degrees for 1 hour. The reaction solution was concentrated under reduced pressure, and dried to give a crude white solid intermediate compound (280 mg). LCMS (ESI) m/z 353.0[ M+H ]] + 。
Step six: sodium borohydride (61 mg,1.6 mmol) was added to ethanol (10 mL) of the intermediate (280 mg,0.79 mmol) under ice-bath cooling. The reaction mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (20 mL), washed twice with water (5 mL), and the separated organic phase was concentrated under reduced pressure to give a crude white solid intermediate compound (240 mg). LCMS (ESI) m/z 355.0[ M+H ] ] + 。
Step seven: to a toluene solution (20 mL) of the above intermediate (240 mg,0.68 mmol) was added p-toluenesulfonic acid monohydrate (21 mg,0.11 mmol). The reaction mixture was heated to 100 degrees and stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (20 mL) and washed with water (5 mL). Concentrating the separated organic phase under reduced pressure to obtain crude white solidA somatic intermediate compound (160 mg). LCMS (ESI) m/z 337.0[ M+H ]] + 。
Step eight: to the intermediate compound (160 mg,0.47 mmol) above in dichloromethane (4 mL) was added 1-chloroethyl chloroformate (100 mg,1.05 mmol) at room temperature, and the reaction mixture was reacted at 40℃for 2 hours. The reaction mixture was concentrated and dissolved in methanol (5 mL), and the reaction was continued at 50℃for 2 hours. The reaction solution was concentrated directly, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10:1) to give an intermediate compound (55 mg) as a white solid. LCMS (ESI) m/z 247.1[ M+H ]] + 。
Step nine: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (50 mg,0.26 mmol) was added to the above intermediate compound (55 mg,0.22 mmol), intermediate compound A2 (123 mg,0.4 mmol), 1-hydroxybenzotriazole (32 mg,0.26 mmol) in N, N-dimethylformamide (5 mL) at room temperature, and the reaction mixture was reacted for 10 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by HPLC to give a white solid, example 61 compound (15 mg). LCMS (ESI) m/z 538.2[ M+H ] ] + 。 1 HNMR(400MHz,DMSO)δ12.35(s,1H),8.63(s,1H),7.91(s,1H),6.36(m,1H),6.27(m,1H),5.93-5.77(m,1H),4.25-4.04(m,1H),3.70-3.49(m,8H),2.71(m,2H),2.58(m,2H),2.36(m,2H),1.15(d,J＝6.4Hz,3H),0.96(s,6H).
With reference to the synthetic methods of example 61 or example 21, the following example compounds were synthesized using starting materials of different substituents instead of 2- (piperazin-1-yl) -cyclopenta [ d ] pyrimidine.
Test example 1: test for H1373 cell proliferation inhibition Activity
1) Well conditioned NCI-H1373 cells (ATCC) were digested, centrifuged, resuspended, counted and seeded in 96 well plates (Corning) with 1000 cells per well.
2) Incubator pre-culture for 24h (37 ℃,5% CO) 2 ) After that, the compound of the example was given at different concentrations for 144 hours; the experimental and control groups were each provided with 6 duplicate wells, and control wells with DMSO solvent added and blank wells without cells added (pure medium).
3) After the treatment of the medicines, cellTiter is usedAnd (5) detecting the cell viability by a luminescence method. The plates were equilibrated to room temperature before measurement and 50 uLCellTiter-/well was added>Reagents (Promega) were mixed on an orbital shaker for 2 minutes to induce cell lysis, incubated for 60 minutes at room temperature to stabilize the luminescence signal, and then luminescence values were recorded on Envision (PerkinElmer).
4) Cell viability inhibition (%) = [ a ] was calculated (DMSO) -A (dosing) ]/[A (DMSO) -A (blank) ]×100％。(A (dosing) : absorbance of wells with cells and drug solution; a is that (blank) : absorbance of wells with medium without cells; a is that (DMSO) : absorbance of wells plated with cells and added DMSO). Experiments were repeated three times and the Graghpad software was counted.
Results: most of the compounds of the examples have strong cell proliferation inhibition activity, the IC50 is less than 1uM, and the cell proliferation inhibition activity IC50 of some of the compounds of the examples is even less than 100nM, and the specific results are shown in the following table:
( The activity of the compounds in the table is expressed by letters: a represents IC50 less than or equal to 100nM, B represents 100nM < IC50 less than or equal to 1000nM, C represents IC50>1000nM )
Test example 2: PARP7 enzymatic biochemical assay
Biochemical experimental scheme:
1. coating: 384 well plates were coated with 25 ul/well 1xhistone overnight;
2. closing: washing 384-well plates with PBST, adding 50 ul/well blocking solution, and blocking for 1 hour at room temperature;
3. compound dilution: the compounds were diluted in a 1:3 ratio for 10 concentrations, starting at 100nM;
4. enzyme reaction: enzyme was added to assaybuffer, biotin-NAD + After incubation reaction with different concentrations of compounds under certain conditions, 384 well plates were washed with PBST,
5. luminescence reading: incubation with 25 μLStre-HRP for 1 hour at room temperature, PBS wash 3 times, then QuantaRedEnhance for 10 minutes, termination of the reaction, rapid reading with an ELISA reader at Ex550/Em 620;
IC 50 : refers to the concentration of the compound at which PARP7 enzyme activity is 50% inhibited.
Results: most of the compounds of the examples have strong PARP7 enzyme activity inhibition activity, the IC50 is less than 10nM, the cell proliferation inhibition activity IC50 of some of the compounds of the examples is even less than 1nM, and the specific results are shown in the following table:
numbering device IC50 Numbering device IC50 Numbering device IC50
Control RBN-2397 0.74nM 1 0.76nM 3 0.77nM
4 0.94nM 6 1.28nM 11 0.75nM
14 1.2nM 15 1.3nM 22 0.75nM
27 0.79nM 33 0.98nM 34 0.95nM
35 0.87nM 37 1.1nM 38 0.62nM
41 1.0nM 42 0.81nM 46 0.82nM
Test example 3: ADMET test of example Compounds
(1) Metabolic stability test: metabolic stability incubation was performed with 150 μl of liver microsomes (final concentration 0.5 mg/mL) containing NADPH (final concentration 1 mM), 1 μl of test compound and positive control midazolam or negative control atenolol, and the reaction was stopped with tinidazole-containing acetonitrile at 0min, 5min, 10min, 20min and 30min, vortexed for 10min, centrifuged at 15000rmp for 10min, and 50 μl of supernatant was sampled in 96 well plates. The metabolic stability of the compounds was calculated by measuring the relative decrease in the drug substance.
Results: the compound of the embodiment of the invention has higher stability to liver microsomes of various species (rats, mice, dogs, monkeys, humans), and has a half-life longer than 30min, as in the compounds 6 and 34 of the embodiment, and the like.
Test example 4: test of pharmacokinetic parameters of example Compounds in mice
The 6 male SPF-class Balb c mice (Shanghai Sipule-BiKai laboratory animals) were divided into two groups and the test compounds were formulated as appropriate solutions or suspensions; one group is administered by intravenous injection and one group is administered orally. Blood was collected via jugular vein puncture, each sample was collected at about 0.2 mL/time point, heparin sodium was anticoagulated, and the blood collection time points were as follows: 5, 15 and 30min,1, 2, 4, 6, 8 and 24h before and after administration; blood samples were collected and placed on ice, and plasma was centrifuged (centrifugation conditions: 8000 rpm, 6 min, 2-8 ℃) and stored at-80℃prior to analysis of the collected plasma. Plasma samples were analyzed by LC-MS/MS.
According to the blood concentration data of the medicine, respectively calculating the pharmacokinetic parameters AUC of the test sample by using a pharmacokinetic calculation software WinNonlin5.2 non-atrioventricular model 0-t 、AUC 0-∞ 、MRT 0-∞ 、C max 、T max 、T 1/2 And V d Isoparametric parameters, mean and standard deviation. In addition, the bioavailability (F) will be calculated by the following formula.
For samples with concentrations below the lower limit of quantification, the samples sampled before Cmax is reached should be calculated as zero values when pharmacokinetic parameter calculations are performed, when C is reached max The sample points should be calculated as unqualified (BLQ) later.
The results of the mouse PK data of example 6 are as follows
：F＝(AUC INF-PO *Dose IV )/(SUC INF-IV *Dose PO )*100％
All documents mentioned in this application are incorporated by reference as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the claims appended hereto.

Claims (10)

1. A pyridazinone compound represented by general formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsionally isomer, solvate, polymorph or prodrug thereof,
wherein,,
wherein: x is independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, 3-6 membered cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl; the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, 3-6 membered cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl may optionally be substituted with one or more R x Substituted, R x Independently selected from deuterium, halogen, amino, hydroxy, cyano, mono-C1-C3 alkylamino, di-C1-C3 alkylamino, C1-C3 alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkyl-C1-C6 alkyl, the number of substituents being one or more;
Y 1 、Y 2 、Y 3 Independently selected from O, S (O) p 、NR y 、C(＝O)、C(＝O)O、C(＝O)NR y 、S(O) p NR y 、NR y C(＝O)NR y Wherein R is y Independently selected from hydrogen, C1-C6 alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl, said R y Optionally by R y1 Substituted, R y1 Independently selected from deuterium, halogen, amino, hydroxy, cyano, C1-C3 monoalkylamino, C1-C3 dialkylamino, C1-C3 alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkyl-C1-C3 alkyl-, substituent R y1 One or more of the numbers; p is 0, 1 or 2;
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 independently selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-to 10-membered cycloalkyl or heterocycloalkyl, 5-to 12-membered aryl or heteroaryl, 3-to 10-membered cycloalkyl-C1-C3 alkyl-, 3-to 10-membered heterocycloalkyl-C1-C3 alkyl-, 6-to 12-membered aryl-C1-C3 alkyl-, 5-to 12-membered heteroaryl-C1-C3 alkyl-, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 alkyl sulfoxide, C1-C3 alkyl sulfone, C1-C3 alkyl acyl, carbonyl, -C (=O) O-, -C (=O) NH-, sulfonylamino, sulfonylimino, ureido, sulfonylureido, guanidino, amidineA radical, a carbamate radical, a mono-C1-C3 alkyl-substituted amino radical, a di-C1-C3 alkyl-substituted amino radical; the C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, 3-to 10-membered cycloalkyl or heterocycloalkyl, 5-to 12-membered aryl or heteroaryl, 3-to 10-membered cycloalkyl-C1-C3 alkyl-, 3-to 10-membered heterocycloalkyl-C1-C3 alkyl-, 6-to 12-membered aryl-C1-C3 alkyl-, 5-to 12-membered heteroaryl-C1-C3 alkyl-, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 alkyl sulfoxide, C1-C3 alkyl sulfone, C1-C3 alkanoyl may be substituted with one or more substituents selected from the group consisting of: halogen, deuterium, cyano, nitro, amino, hydroxy, C1-C6 alkyl, 3-to 10-membered cycloalkyl;
Or R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 Any two groups of the two groups can form a 3-10 membered saturated or unsaturated or partially unsaturated ring system through a carbon chain or a heteroatom;
alternatively, R 1 Or R is 2 Together with Ry and the atoms to which they are attached, form a 4-10 membered heterocycloalkyl;
m and n are each independently selected from integers of 1 to 3;
Cy 1 independently selected from 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl, 4-12 membered spirocyclic group, 4-12 membered bridged ring group, 4-12 membered fused ring group;
Cy 2 independently selected from a 6-10 membered aryl 4-10 membered saturated or partially unsaturated ring system, or a 5-10 membered heteroaryl 4-10 membered saturated or partially unsaturated ring system;
R 9 、R 10 each independently selected from one or more carbonyl, hydrogen, halogen, C1-C3 alkyl or halogenated C1-C3 alkyl, cyano, nitro, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 alkyl sulfoxide, C1-C3 alkyl sulfone, C1-C3 alkanoyl, 3-6 membered cycloalkyl or heterocycloalkyl, vinyl, ethynyl;
one or more (e.g., 1, 2, 3, 4, 5) hydrogen atoms on any of the above groups may be substituted with a substituent selected from the group consisting of: including but not limited to deuterium, halogen, hydroxy, amino, C1-C3 monoalkylamino, C1-C3 dialkylamino, C1-C3 alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkyl C1-C3 alkyl; wherein the heteroaryl group comprises 1 to 3 heteroatoms selected from the group consisting of: n, O, P or S, said heterocycloalkyl comprising 1 to 3 heteroatoms selected from the group consisting of: n, O, P or S, said ring system comprising a spiro, bridged, fused, or other saturated or partially unsaturated ring system.
2. The pyridazinone compound represented by the formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, wherein the pyridazinone compound represented by the formula (I) has the following general formula,
wherein ring D is independently selected from: 5-12 membered monocyclic or polycyclic groups, said ring systems including but not limited to
Wherein a is terminal and Y 3 Are connected;
ring E is independently selected from:wherein the a end is connected with the pyridazine ring end of the mother nucleus;
ring F and ring G are each independently selected from 5-12 membered cycloalkyl or heterocycloalkyl, 5-10 membered aryl or heteroaryl;
R 15 、R 16 、R 17 are each independently selected from hydrogen, halogen, C1-C3 alkyl or haloalkyl, cyano, nitro, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 alkylsulfoxide, C1-C3 alkylsulfonyl, C1-C3 alkylAcyl, 3-6 membered cycloalkyl or heterocycloalkyl, vinyl, ethynyl.
3. The pyridazine compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, wherein: cy (Cy) 2 Is that
Wherein Z is 1 ，Z 2 Are independently selected from N and CR 11 M1, M2, M3 are each independently selected from- (CR) 12 R 13 )t-，-NR 14 -C (O) -, -O-, -S (O) q-, or-ch=ch-;
R 11 independently selected from the group consisting of hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, cyano, nitro, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 alkylsulfoxide, C1-C3 alkylsulfonyl, C1-C3 alkanoyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, vinyl, and ethynyl;
R 12 、R 13 each independently selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, cyano, nitro, C1-C3 alkoxy, C1-C3 alkylthio, C1-C3 alkylsulfoxide, C1-C3 alkylsulfonyl, C1-C3 alkanoyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, vinyl or ethynyl;
R 14 independently selected from hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyC 1-C3 alkyl, C1-C3 hydroxyalkyl, substituted or unsubstituted amino-C1-C3 alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; the substituents in the substituted amino-C1-C3 alkyl are independently selected from one or more of the following groups: halogen, hydroxy, amino, C1-C3 monoalkylamino, C1-C3 dialkylamino, C1-C3 alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkyl C1-C3 alkyl;
t is independently selected from integers from 1 to 3; q is independently selected from integers from 0 to 2.
4. The pyridazine compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, wherein: the pyridazinone compound shown in the formula (I) has a general formula shown in the following (III-1) or (III-2),
wherein X is preferably F, cl, br, CH 3 、CF 3 ；R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 Each independently is preferably selected from hydrogen, deuterium, fluorine, methyl, ethyl; a is preferably an integer from 0 to 6; z is Z 1 Preferably CH, C-F, C-Me, N.
5. The pyridazine compound represented by the formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, wherein the compound represented by the formula (I) has the general formula (IV-1), (IV-2), (IV-3), (IV-4), (IV-5) or (IV-6),
therein X, R 9 、R 10 、Z 1 And a is as claimed in claim 1.
6. The pyridazine compound represented by the formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof,
When X is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C2-C6 alkenyl, C2-C6 alkynyl, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, vinyl, ethynyl are preferred; more preferably methyl, methoxy, methylthio;
alternatively, when said R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 Each independently selected from 3-10 membered cycloalkyl or heterocycloalkyl, 5-12 membered aryl or heteroaryl, 3-10 membered cycloalkyl-C1-C3 alkyl-, 3-10 membered heterocycloalkyl-C1-C3 alkyl-, 6-12 membered aryl-C1-C3 alkyl-, 5-12 membered heteroaryl-C1-C3 alkyl-, preferably 3-6 membered cycloalkyl or heterocycloalkyl, 5-8 membered aryl or heteroaryl, 3-6 membered cycloalkyl-C1-C3 alkyl-, 3-6 membered heterocycloalkyl-C1-C3 alkyl-, 6-10 membered aryl-C1-C3 alkyl-, 5-8 membered heteroaryl-C1-C3 alkyl-;
alternatively, when said R 1 Or R is 2 When taken together with Ry and the atoms to which they are attached, form a 4-10 membered heterocycloalkyl, said 4-10 membered heterocycloalkyl is a 5-8 membered heterocycloalkyl;
alternatively, R 1 Or R is 2 When Ry and the atoms to which they are attached together form a 4-10 membered heterocycloalkyl, the 4-10 membered heterocycloalkyl is preferably
Wherein a terminal is linked to the parent pyridazine ring and b terminal is linked to the chain end;
alternatively, cy 1 Preferably 5-8 membered cycloalkyl, 5-8 membered heterocycloalkyl, 5-8 membered spirocyclic group, 5-8 membered bridged cyclic group, 5-8 membered fused ring group; more preferably
Wherein b is terminal and Y 3 Connected with a terminal and Cy 2 Are connected;
alternatively, R 9 Preferably H, F, -CF 3 、CN、CH 3 CH 2 -、CH 3 -、CH 3 O-、-CH 2 CN。
Alternatively, cy 2 Preferably from 6-10 membered aryl and 5-8 membered saturated or partially unsaturated ring systems or from 5-10 membered heteroaryl and 5-8 membered saturated or partially unsaturated ring systems; more preferably 6-10 membered aryl-5-8 membered cycloalkyl, 6-10 membered aryl-5-8 membered heterocycloalkyl, 6-10 membered aryl-5-8 membered cycloalkenyl, 5-10 membered heteroaryl-5-8 membered cycloalkyl, 5-10 membered heteroaryl-5-8 membered heterocycloalkyl or 5-10 membered heteroaryl-5-8 membered cycloalkenyl; further preferred is
Alternatively, Y 3 is-C (=o) -;
alternatively, R 10 Preferably selected from H, F, -CF 3 、CN、CH 3 CH 2 -、CH 3 -、CH 3 O-、-CH 2 CN；
Alternatively, X, Y 1 、Y 2 、Y 3 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、Cy 1 、Cy 2 The m, n groups are each independently the corresponding groups in the compounds 1 to 64 prepared in the examples.
7. A compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsionally isomer, solvate, polymorph or prodrug thereof, wherein it is any one of the following compounds:
8. a process for the preparation of a pyridazinone compound of formula (I) according to any one of claims 1-7, comprising the steps of: in a solvent, generating an amide compound through condensation reaction of acid and amine,
Therein, X, Y 1 、Y 2 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、Cy 2 The method of any one of claims 1-7.
9. A pharmaceutical composition comprising an effective amount of a pyridazinone compound according to any one of claims 1-7 or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph or prodrug thereof, according to formula (I), and a pharmaceutically acceptable carrier.
10. Use of a pyridazinone compound according to any one of claims 1-7 or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, torsionally isomer, solvate, polymorph or prodrug thereof according to formula (I) or a pharmaceutical composition according to claim 9 for the preparation of a PARP7 inhibitor, for the preparation of a medicament for the treatment of a disease associated with PARP7 mutation, activity or expression level, in particular a medicament for the treatment of tumors. The tumor is independently selected from non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, gastric cancer, intestinal cancer, bile duct cancer, brain cancer, leukemia, lymphoma, fibroma, sarcoma, basal cell carcinoma, glioma, renal cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal cancer, pancreatic cancer, etc.
CN202211557988.2A 2022-01-14 2022-12-06 Pyridazinone compound, preparation and application thereof Pending CN116444497A (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112424188A (en) * 2018-04-30 2021-02-26 里邦医疗公司 Pyridazinones as PARP7 inhibitors
WO2021087018A1 (en) * 2019-10-30 2021-05-06 Ribon Therapeutics, Inc. Pyridazinones as parp7 inhibitors
WO2021087025A1 (en) * 2019-10-30 2021-05-06 Ribon Therapeutics, Inc. Pyridazinones as parp7 inhibitors

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112424188A (en) * 2018-04-30 2021-02-26 里邦医疗公司 Pyridazinones as PARP7 inhibitors
WO2021087018A1 (en) * 2019-10-30 2021-05-06 Ribon Therapeutics, Inc. Pyridazinones as parp7 inhibitors
WO2021087025A1 (en) * 2019-10-30 2021-05-06 Ribon Therapeutics, Inc. Pyridazinones as parp7 inhibitors

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