Pyrrolo-pteridinone ubiquitin specific protease 1 inhibitor as well as preparation method, application and pharmaceutical composition of pyrrolo-pteridinone ubiquitin specific protease 1 inhibitor

Abstract

The invention relates to the technical field of medicines, in particular to a substituted pyrrolo pteridinone ubiquitin specific protease 1 (USP1) inhibitor compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, a pharmaceutical composition containing the compound, the pharmaceutically acceptable salt thereof, or the stereoisomer thereof, and a preparation containing the compound, the pharmaceutically acceptable salt thereof, or the stereoisomer thereof. The invention relates to a compound, a pharmaceutically acceptable salt or a stereoisomer thereof, a method for preparing the compound, the pharmaceutically acceptable salt or the stereoisomer thereof, and application of the compound, the pharmaceutically acceptable salt or the stereoisomer thereof in preparation of drugs for treating and / or preventing USPl-mediated diseases and related diseases.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology and relates to a pyrrolopteridinone ubiquitin-specific protease 1 inhibitor and a preparation method, use and pharmaceutical composition thereof. Background Art

[0002] Ubiquitination is a reversible process involving a family of deubiquitinating enzymes (DUBs) that regulate various cellular processes by deubiquitinating substrates. DUBs are encoded by approximately 100 human genes and are divided into six families, the largest of which is the ubiquitin-specific proteases (USPs) with more than 50 members. DUBs act in the ubiquitin-protease system to cleave the isopeptide bond between lysine and the C-terminus of UBQ, affecting cell proliferation, cycle, apoptosis, DNA damage response, tumor suppression, occurrence, and metastasis.

[0003] USP1 (Ubiquitin specific protease 1) is a member of the USP family and is a cysteine ​​isopeptidase containing a tripartite structure of Cys90, His593 and Asp751. Human USP1 consists of 785 amino acids. USP1 itself is inactive and can only obtain complete enzyme activity after combining with the auxiliary factor UAF1 (USP1-associated factor 1, a auxiliary factor containing WD40 repeat sequences that binds and regulates USP1 activity) to form a heterodimeric complex, stabilize replication forks, play a role in DNA damage repair, and is located in the cell nucleus.

[0004] USP1 is highly expressed in cancers such as breast cancer and ovarian cancer, and its expression is also elevated in other cancers. USP1 overexpression is associated with BRCA1 deficiency in breast cancer / ovarian cancer. The USP1 / UAF1 complex deubiquitinates monoubiquitinated PCNA (proliferating cell nuclear antigen) and monoubiquitinated FANCD2 (Fanconianemia group complementary group D2), two proteins that play important roles in the translesion DNA synthesis (TLS) and Fanconi anemia (FA) pathways, respectively. These two pathways are required for the repair of DNA damage caused by DNA crosslinking agents such as cisplatin and mitomycin C (MMC). The USP1 / UAF1 complex also deubiquitinates FANCI (Fanconi anemia complementation group l). The importance of these findings was further confirmed by experiments showing that mice lacking USP1 are highly sensitive to DNA damage. Interestingly, the expression of USP1 is significantly increased in many cancers. Blocking USP1 to inhibit DNA repair can induce apoptosis in multiple myeloma cells and enhance the sensitivity of lung cancer cells to cisplatin, suggesting that USP1 is a promising target for chemotherapy of certain cancers.

[0005] Therefore, the development of novel USP1 inhibitors is expected to provide new options and treatments for the treatment of a variety of malignant diseases including tumors. Summary of the invention

[0006] The object of the present invention is to provide a USP1 inhibitor compound with novel structure and good inhibitory activity against USP1. Such compounds have good inhibitory activity against USP1 kinase, thereby enhancing the body's immune effect against various tumors. Furthermore, such compounds can also be used to treat or prevent related diseases mediated by USP1, especially cancer. Such compounds have good inhibitory effects on various cancer cells and have good drugability.

[0007] In one aspect, the present invention provides a compound represented by formula (I), its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts:

[0008]

[0009] Wherein: the ring A is selected from phenyl or 5-6 membered heteroaryl which is unsubstituted or substituted by 1-3 Q1;

[0010] The ring B is selected from phenyl or 5-6 membered heteroaryl which is unsubstituted or substituted by 1-3 Q2;

[0011] The ring C is selected from phenyl or 5-6 membered heteroaryl which is unsubstituted or substituted by 1-3 Q3;

[0012] Each Q1 is independently selected from halogen, cyano, carboxyl, hydroxyl, amino, sulfonylamino, C1-C6 alkylamino, di(C1-C6 alkyl)amino, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, C1-C6 alkoxy, hydroxy C1-C6 alkyl, amino C1-C6 alkyl, carboxyl C1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, C1-C6 alkylaminoacyl, C1-C6 alkylamido, C1-C6 alkylsulfonyl, C1-C6 alkylsulfonylamino, C1-C6 alkylaminosulfonyl, C1-C4 alkyl, C3-C6 alkyl, C4-C6 alkyl, C5-C6 alkyl, C6-C6 alkylamino, C6-C6 alkylsulfonyl, C1-C6 alkylsulfonylamino, C1-C6 alkylaminosulfonyl, C1-C4 alkyl, C3-C6 alkyl, C6-C6 alkyl, C6-C6 alkylamino, C1-C6 alkylsulfonyl, C1-C6 alkylsulfonylamino, C1-C6 alkylaminosulfonyl, C1-C4 alkyl, C3-C6 alkyl, C6-C6 alkyl 10 cycloalkyl;

[0013] Each Q2 is independently selected from halogen;

[0014] Each Q3 is independently selected from halogen, C1-C4 alkyl, and halogenated C1-C6 alkyl.

[0015] Preferably, the present invention provides a compound represented by formula (I), its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts:

[0016] Wherein: the ring A is selected from phenyl, pyrimidinyl, imidazolyl, pyrazolyl which is unsubstituted or substituted with 1-3 Q1;

[0017] The ring B is selected from phenyl which is unsubstituted or substituted by 1-3 Q2;

[0018] The ring C is selected from pyrazolyl which is unsubstituted or substituted with 1-3 Q3;

[0019] Each Q1 is independently selected from halogen, carboxyl, hydroxyl, cyano, nitro, amino, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, carboxymethyl, carboxyethyl, C1-C4 alkyl, C3-C 10 cycloalkyl;

[0020] Each Q2 is independently selected from halogen;

[0021] Each Q3 is independently selected from halogen, monofluoromethyl, difluoromethyl, trifluoromethyl, and C1-C4 alkyl.

[0022] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof, including but not limited to:

[0023]

[0024]

[0025] On the other hand, the present invention also provides a method for preparing the compound, its stereoisomers, geometric isomers, and tautomers, which comprises the following steps:

[0026]

[0027] (1) Compound A is used as a starting material to prepare compound B via 2,5-dimethoxytetrahydrofuran cyclization;

[0028] (2) Compound B reacts with N,N'-carbonyldiimidazole to obtain Compound C;

[0029] (3) Using cesium carbonate as a base, compound C reacts with a benzyl chloride compound to obtain compound D;

[0030] (4) Under Suzuki reaction conditions, compound D is coupled with a boronic acid pinacol ester or boronic acid substituted on the A ring to obtain the compound, its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts.

[0031] In another aspect, the present invention also provides a pharmaceutical composition, which comprises the compound, its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts, and optionally a pharmaceutically acceptable carrier and / or excipient; preferably, the pharmaceutical composition also comprises one or more active pharmaceutical ingredients for preventing and / or treating cancer, immune diseases, cardiovascular diseases, viral infections, inflammation, metabolic / endocrine dysfunction or neurological diseases other than the compound, its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts; preferably, the pharmaceutical composition is a pharmaceutically acceptable pharmaceutical preparation for preventing and / or treating cancer, immune diseases, cardiovascular diseases, viral infections, inflammation, metabolic / endocrine dysfunction or neurological diseases.

[0032] On the other hand, the present invention also provides a pharmaceutical preparation, which comprises at least one of the compounds or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier, diluent or / and excipient; preferably, the pharmaceutical preparation is selected from the following pharmaceutical dosage forms: parenteral preparations, such as injection solutions or suspensions; enteral preparations, such as oral preparations, such as tablets or capsules; topical preparations, such as lotions, gels, ointments, emulsions, nasal preparations, suppositories, transdermal preparations or ophthalmic preparations.

[0033] Some of the terms used in the present invention are defined below, and other undefined terms have meanings known to those skilled in the art.

[0034] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0035] The term "halo" means that any hydrogen in a substituent may be replaced by one or more halogens which may be the same or different.

[0036] "Halogen" is as defined above.

[0037] When any variable (such as R a , R b ) occurs more than once in the composition or structure of a compound, its definition is independent in each case. For example, if a group is represented by 2 R b is replaced, then each R b All have independent options.

[0038] The term "C m -C n ", refers to an integer number of carbon atoms in the range of mn. For example, "C1-C 10 ” means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, or 10 carbon atoms.

[0039] The term "alkyl" refers to a group of the formula C n H 2n+1 The alkyl group may be straight chain or branched. For example, the term "C1-C 10The term “alkyl” is understood to mean a straight-chain or branched, saturated, monovalent hydrocarbon radical having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The alkyl radical is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc.; the term “C 1-6 The term "alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, and dialkylamino has the same definition as above. When alkyl is described as being optionally substituted with an R group, this means that the alkyl is optionally substituted with one or more R groups. When alkoxy, alkylamino, and dialkylamino are described as being optionally substituted with an R group, this means that the alkoxy, alkylamino, and dialkylamino are optionally substituted with one or more R groups. The "C1-C 10 "Alkyl" may include "C1-C6 alkyl", "C1-C4 alkyl", "C1-C3 alkyl" or "C1-C2 alkyl", and the "C1-C6 alkyl" may further include "C1-C4 alkyl", "C1-C3 alkyl" or "C1-C2 alkyl".

[0040] The term "inhibitor" refers to a compound or agent that can inhibit the biological function of a target protein or polypeptide, such as inhibiting the activity or expression of a target protein or polypeptide.

[0041] The term "tumor" includes, but is not limited to, solid tumors and hematological tumors, such as glioma, thyroid cancer, breast cancer, small cell lung cancer, non-small cell carcinoma, gastric cancer, colon cancer, gastrointestinal stromal cancer, pancreatic cancer, bile duct cancer, ovarian cancer, endometrial cancer, prostate cancer, renal cancer, anaplastic large cell lymphoma, leukemia, multiple myeloma, mesothelioma and melanoma, and combinations thereof, etc.

[0042] The term "effective amount" refers to an amount of a compound or pharmaceutical composition described herein sufficient to achieve the intended application described below, including but not limited to disease treatment. The effective amount may vary depending on: the intended application (in vivo or in vitro); or the individual and disease condition being treated, for example, the individual's weight and age, the severity of the disease; the mode of administration, etc. The effective amount can be easily determined by a person of ordinary skill in the art.

[0043] "Optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "alkyl optionally substituted with halogen" means that halogen may but need not be present, and the description includes instances where alkyl is substituted with halogen and instances where alkyl is not substituted with halogen.

[0044] The compounds described in the present invention also include isotope-labeled compounds thereof. The term "isotope-labeled compound" refers to a compound in which one or more atoms are replaced by atoms having the same atomic number but an atomic mass number different from the atomic mass number commonly found in nature. Examples of isotopes suitable for the present invention include, but are not limited to: hydrogen isotopes 2H and 3H; carbon isotopes 11C, 13C and 14C; chlorine isotope 36Cl; fluorine isotope 18F; iodine isotopes 123I and 125I; nitrogen isotopes 13N and 15N; oxygen isotopes 15O, 17O and 18O; phosphorus isotope 32P and sulfur isotope 35S.

[0045] Various solvates and hydrates of the compounds or salts thereof described in the present invention and polymorphs thereof are also included in the scope of the present invention.

[0046] The term "solvate" refers to a compound that also includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. The solvate can be a disclosed compound or a pharmaceutically acceptable salt thereof. When the solvent is water, the solvate is a "hydrate". Pharmaceutically acceptable solvates and hydrates are complexes that can include, for example, 1 to about 100, or 1 to about 10, or 1 to about 2, about 3, or about 4 solvent or water molecules. The term "polymorph" refers to a compound that exists in two or more different crystalline forms.

[0047] Prodrugs of the compounds described in the present invention are also included in the scope of the present invention. Certain derivatives of the compounds described in the present invention have weaker pharmacological activity or no pharmacological activity themselves, but when these derivatives are administered into the body or onto the body, they can be converted into pharmacologically active compounds described in the present invention by means such as hydrolysis and cleavage, and these derivatives are called "prodrugs". Further information on the use of prodrugs can be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. EB Roche, American Pharmaceutical Association).

[0048] The compounds of the present invention include pharmaceutically acceptable salts thereof. The term "pharmaceutically acceptable salt" refers to a salt that is pharmaceutically acceptable and has the pharmacological activity required by the parent compound. Berge et al. describe pharmaceutically acceptable salts in detail in J.Pharma.Sci., 1977, 66, 1-19, which is incorporated herein by reference. The compounds of the present invention may contain sufficient acidic groups, sufficient basic groups, or both types of functional groups, and react with some inorganic or organic bases, or inorganic and organic acids to form pharmaceutically acceptable salts accordingly. Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, hydrochlorides, hydrobromides, hydroiodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, gamma-hydroxybutyrates, glycolates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.

[0049] When the compounds of the present invention are used as drugs, they are usually administered in the form of pharmaceutical compositions. Therefore, pharmaceutical compositions comprising the compounds of the present invention and pharmaceutically acceptable carriers, diluents or excipients are also included in the scope of the present invention. The carriers, adjuvants, and excipients used herein include any and all solvents, diluents or other liquid excipients, dispersants or suspending agents, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid adhesives, lubricants, etc. suitable for the desired specific dosage form. In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York, various carriers for preparing pharmaceutically acceptable compositions and known techniques for their preparation are disclosed, and their contents are all incorporated herein by reference.

[0050] The composition of the invention can be administered by any route suitable for the condition to be treated. In particular, it can be administered parenterally, for example in the form of an injectable solution or suspension; enterally, for example orally, for example in the form of tablets or capsules; topically, for example in the form of a lotion, gel, ointment or cream or in the form of a nasal or suppository. Topical application is, for example, application to the skin. Another form of topical administration is administration to the eye.

[0051] The pharmaceutical composition can be administered in solid, semisolid, liquid or gaseous form, or can be in a dried powder, such as a lyophilized form. The pharmaceutical composition can be packaged in a form that is convenient for delivery, including, for example, solid dosage forms such as capsules, sachets, cachets, gelatin, paper, tablets, suppositories, pellets, pills, lozenges and pastilles. The type of packaging will generally depend on the route of administration. Implantable sustained-release formulations are also contemplated, as well as transdermal formulations.

[0052] Some examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates), glycine, sorbic acid or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block copolymers, lanolin, sugars (e.g., lactose, glucose, and sucrose), starches (e.g., corn starch and potato starch), cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; tragacanth powder; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols, such as propylene glycol or polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; and phosphate buffers, as well as other nontoxic compatible lubricants, such as sodium lauryl sulfate and magnesium stearate. Colorants, release agents, coating agents, sweeteners, flavoring and fragrance agents, preservatives and antioxidants may also be present in the composition according to the judgment of the formulator. DETAILED DESCRIPTION

[0053] The following are specific embodiments of the present invention, which further describe the technical solution of the present invention, but the protection scope of the present invention is not limited to these embodiments. Any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the protection scope of the present invention.

[0054] In the following examples, unless otherwise noted by structural formula or chemical name, molecules with a single chiral center exist as racemic mixtures. Unless otherwise noted by structural formula or chemical name, those molecules with two or more chiral centers exist as racemic mixtures of diastereomers. Single enantiomers / diastereomers can be obtained by methods known to those skilled in the art.

[0055] Preparation method

[0056] The compounds described in the present invention can be synthesized according to the synthesis schemes herein and / or techniques well known in the art. For example, the compounds provided by the present invention can be prepared according to the following general synthesis methods.

[0057] General synthetic method

[0058]

[0059] (1) Compound A is used as a starting material to prepare compound B via 2,5-dimethoxytetrahydrofuran cyclization;

[0060] (2) Compound B reacts with N,N'-carbonyldiimidazole to obtain Compound C;

[0061] (3) using cesium carbonate as a base, compound C reacts with a benzyl chloride compound to obtain compound D;

[0062] (4) Under Suzuki reaction conditions, compound D is coupled with a boronic acid pinacol ester or boronic acid substituted on the A ring to obtain the compound, its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts.

[0063] Example

[0064] Preparation Example

[0065] The compounds described herein can be synthesized according to one or more synthesis schemes and / or techniques well known in the art. It will be appreciated by those skilled in the art that the synthesis methods of certain embodiments described in detail in the present invention can be easily adapted to synthesize other embodiments. In some embodiments, the compounds described herein can be prepared by an appropriate combination of synthesis methods well known in the art. Many starting materials and other reagents can be purchased from commercial suppliers, such as Alfa Aesar (China) Chemical Co., Ltd., or easily prepared using synthesis methods commonly used in the art.

[0066] 1 H NMR spectra were recorded on instruments operating at 400 MHz, 500 MHz or 700 MHz. 1 H NMR spectra were obtained as solutions (reported in ppm) using CDCl3 (7.26 ppm) or DMSO-d6 (2.50 ppm) or internal tetramethylsilane (0.00 ppm) as reference standards. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), dd (double of doublets), dt (double of triplets). Coupling constants are given in Hertz (Hz).

[0067] If desired, the (R)- and (S)-isomers of the non-limiting exemplary compounds, if present, can be resolved by methods known to those skilled in the art, such as by forming diastereomeric salts or complexes, which can be separated by, for example, crystallization or chromatography, by forming diastereomeric derivatives, which can be separated by, for example, crystallization or chromatography, by selectively reacting one enantiomer with an enantiomer-specific reagent, followed by separation of the modified and unmodified enantiomers, or by chromatographic separation in a chiral environment, such as a chiral chromatographic column. Alternatively, a specific enantiomer can be prepared by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.

[0068] In the following preparation methods and examples, "H2O" refers to water, "PE" refers to petroleum ether, "EA" refers to ethyl acetate, "MeOH" refers to methanol, "EtOH" refers to ethanol, "ACN" refers to acetonitrile, "DMF" refers to N,N-dimethylformamide, "NH4OH" refers to aqueous ammonia, "DMSO-d6" refers to deuterated dimethyl sulfoxide, "DCM" refers to dichloromethane, "DCE" refers to 1,2-dichloroethane, "THF" refers to tetrahydrofuran, "HCl" refers to hydrochloric acid, "DIBAL-H" refers to diisobutylaluminum hydride, "DIEA" refers to N,N-diisopropylethylamine, and "NaOAc" refers to refers to sodium acetate, “Na2SO4” refers to sodium sulfate, “K2CO3” refers to potassium carbonate, “Cs2CO3” refers to cesium carbonate, “Na2CO3” refers to sodium carbonate, “Pd(PPh3)4” refers to tetrakis(triphenylphosphine)palladium, “PdCl2(dppf)” refers to [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, “Ar” refers to argon, “M” refers to molarity, “rt” refers to room temperature, “min” refers to minute, “h” refers to hour, “mL” refers to milliliter, “mmol” refers to millimole, “μM” refers to micromolar, “nM” refers to nanomolar, and “℃” refers to degrees Celsius.

[0069] Preparation of general intermediate C

[0070] Step 1 Preparation of 2-chloro-5-(1H-pyrrol-1-yl)pyrimidin-4-amine (B)

[0071]

[0072] 2-Chloro-4,5-diaminopyrimidine (5.78 g, 40 mmol), 2,5-dimethoxytetrahydrofuran (5.29 g, 40 mmol) and p-methylphenylsulfonic acid hydrate (6 g, 40 mmol) were dissolved in dioxane (200 mL), protected by Ar, reacted at 95 ° C for 8 h, cooled to room temperature, and extracted with EA (500 mL × 4). The combined organic layer was washed with water (500 mL × 3) and brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, PE / EA = 4:1, v / v) to obtain product B as a yellow solid (3.67 g, yield 47%).

[0073] 1H NMR (500MHz, DMSO-d6) δ7.99 (s, 1H), 6.94 (t, J = 2.1Hz, 2H), 6.28 (t, J = 2.1Hz, 2H).

[0074] LCMS m / z=195.1[M+H] +

[0075] Step 2 Preparation of 3-chloropyrrolo[1,2-f]pteridin-6(5H)-one (C)

[0076]

[0077] A mixture of compound B (2.33 g, 12 mmol) and N,N'-carbonyldiimidazole (2.33 g, 12 mmol) in toluene was refluxed overnight under an Ar atmosphere. After cooling to room temperature, the mixture was filtered, and the residue was washed with PE and H2O (50 mL×3). After drying, the product C was obtained as a yellow solid (2.60 g, yield 98%), which was used directly in the next step without purification.

[0078] 1 H NMR (400MHz, DMSO-d6) δ12.36 (s, 1H), 9.33 (d, J = 31.8Hz, 1H), 7.14 (d, J = 4.5Hz, 1H), 6.76 (s, 1H).

[0079] LCMS m / z=221.1[M+H] +

[0080] Example 1 Preparation of 3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)5-(4-(3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)pyrrolo[1,2-f]pteridin-6(5H)-one (Compound 1)

[0081]

[0082] Step 1 Preparation of methyl 4-(3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)benzoate (I-1) and methyl 4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoate (I-2)

[0083]

[0084] A mixture of methyl 4-hydrazinobenzoate (2.5 g, 15.02 mmol), 1,1,1-trifluoropentane-2,4-dione (3.1 g, 20.12 mmol), sodium acetate (2.5 g, 30.48 mmol) and acetic acid (10 mL) was stirred at 120 ° C for 1 h. After cooling to room temperature, the reaction solution was concentrated and purified by flash column chromatography (silica gel, PE / EA=5:1, v / v) to give a yellow oily substance of I-1 (1.3 g, 94% yield) and a ~1:2 mixture of I-2 (2.8 g, 94% yield). LCMS m / z=285.1 [M+H] +

[0085] Step 2 Preparation of (4-(3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol (I-3)

[0086] At 0°C, DIBAL-H (30 ml, 30 mmol, 1 M in toluene) was added to a solution of compound I-1 (1.65 g, 5.8 mmol) in THF (40 ml) by syringe. After addition, the reaction was stirred at 0°C for 20 minutes, and then allowed to warm to room temperature over 30 minutes. After TLC analysis indicated that the reaction was complete, the mixture was quenched with ice water (10 mL), and the pH was adjusted to 5 with dilute HCl solution. Extracted with EA (200 mL×4). The combined organic layers were washed with water (200 mL×3) and brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, PE / EA=1:1, v / v) to give product I-3 as a white solid (1.3 g, yield 90.4%).

[0087] LCMS m / z=257.1[M+H] +

[0088] Step 3 Preparation of 1-(4-(chloromethyl)phenyl)-3-methyl-5-(trifluoromethyl)-1H-pyrazole (I-4)

[0089]

[0090] Compound I-3 (0.45 g, 1.76 mmol) was dissolved in DCE (10 mL), thionyl chloride (1.19 g, 10.00 mmol) was added at room temperature, stirred for 2 hours, and concentrated under reduced pressure to obtain compound I-4, which was used directly in the next step.

[0091] LCMS m / z=275.1[M+H] +

[0092] Step 4 Preparation of 3-chloro-5-(4-(3-methyl-5-trifluoromethyl)-1H-pyrazol-1-yl)benzyl)pyrrolo[1,2-f]pteridin-6(5H)-one (I-5)

[0093]

[0094] A mixture of compound C (440 mg, 2 mmol) and compound I-4 (512 mg, 2 mmol) in DMF (50 mL) was stirred at 60 ° C for 4 h. Cooled to room temperature, extracted with EA (100 mL × 4). The combined organic layer was washed with water (100 mL × 3) and brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, PE / EA=2:1, v / v) to give product I-5 as a white solid (385 mg, yield 42%).

[0095] 1 H NMR(700MHz,DMSO-d6)δ9.43(s,1H),8.38(dd,J=2.8,1.5Hz,1H),7.54-7.49(m,2H),7.43-7.39(m,2 H),7.25(dd,J=3.9,1.4Hz,1H),6.92(s,1H),6.83(dd,J=3.9,2.8Hz,1H),5.47(s,2H),2.27(s,3H).

[0096] LCMS m / z=459.3[M+H] +

[0097] Step 5 Preparation of 3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)5-(4-(3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)pyrrolo[1,2-f]pteridin-6(5H)-one (Compound 1)

[0098]

[0099] Compound I-5 (0.23 g, 0.5 mmol) was dissolved in a mixed solvent of 1,4-dioxane (10 mL) and water (2 mL), and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boric acid (0.12 g, 0.6 mmol), sodium carbonate (0.06 g, 0.6 mmol) and Ph(PPh3)4 (0.06 g, 0.05 mmol) were added in sequence, and refluxed overnight under argon protection. Cooled to room temperature, extracted with EA (20 mL×4). The combined organic layer was washed with water (20 mL×3) and brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, PE / EA=1:2, v / v) to obtain compound 1 as a white solid (240 mg, yield 84%).

[0100] 1 H NMR(700MHz,DMSO-d6)δ9.64(s,1H),8.67(s,1H),8.43(dd,J=2.8,1.4Hz,1 H),7.50-7.46(m,2H),7.40-7.35(m,2H),7.24(dd,J=3.9,1.4Hz,1H),6.91( s,1H),6.84(dd,J=3.9,2.8Hz,1H),5.53(s,2H),3.81(s,3H),2.26(s,3H), 1.75(tt,J=8.3,4.6Hz,1H),0.99(dq,J=6.1,3.4Hz,2H),0.78-0.72(m,2H).

[0101] LCMS m / z=573.2[M+H] +

[0102] Example 2 Preparation of 5-(4-(3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-3-(2-isopropylphenyl)pyrrolo[1,2-f]pteridin-6(5H)-one (Compound 2)

[0103]

[0104] According to the method of step 5 in Example 1, compound 2 was prepared from compound 1-5 and (2-isopropylphenyl)boronic acid.

[0105] 1H NMR(700MHz,DMSO-d6)δ9.63(d,J=1.0Hz,1H),8.43(dt,J=2.8,1.1Hz,1H),7.58-7.53(m,1H),7.46-7.37(m,6H),7.29-7.2 3(m,2H),6.91(d,J=2.2Hz,1H),6.84(ddd,J=4.0,2.7,1.4Hz,1H),5.60(s,2H),3.53(hept,J=6.9Hz,1H),2.26(s,3H).LCMS m / z=543.2[M+H] +

[0106] Example 3 Preparation of 5-(4-(3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-3-(2-methoxyphenyl)pyrrolo[1,2-f]pteridin-6(5H)-one (Compound 3)

[0107]

[0108] According to the method of step 5 in Example 1, compound 3 was prepared from compound 1-5 and (2-methoxyphenyl)boronic acid.

[0109] 1 H NMR (700MHz, DMSO-d6) δ9.57 (s, 1H), 8.40 (dd, J = 2.8, 1.4Hz, 1H), 7.61 (dd, J = 7. 6,1.8Hz,1H),7.56-7.52(m,2H),7.50-7.43(m,1H),7.41(d,J=8.3Hz,2H),7.23 (dd,J=3.8,1.5Hz,1H),7.15(d,J=8.3Hz,1H),7.03(t,J=7.4Hz,1H),6.91(s,1H ),6.82(ddd,J=3.9,2.8,1.2Hz,1H),5.58(s,2H),3.69(s,3H),2.26(s,3H).LCMS m / z=531.2[M+H] +

[0110] Example 4 Preparation of 3-(2-cyclopropylphenyl)-5-(4-(3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)pyrrolo[1,2-f]pteridin-6(5H)-one (Compound 4)

[0111]

[0112] According to the method of step 5 in Example 1, compound 4 was prepared from compound 1-5 and (2-cyclopropylphenyl)boronic acid.

[0113] 1 H NMR (700MHz, DMSO-d6) δ9.63 (s, 1H), 8.44 (dd, J=2.9, 1.5Hz, 1H), 7.62 (dd, J=7 .7,1.5Hz,1H),7.48-7.42(m,2H),7.40-7.32(m,3H),7.27-7.21(m,2H),7.00( d,J=7.8Hz,1H),6.91(s,1H),6.84(ddd,J=4.0,2.7,1.0Hz,1H),5.61(s,2H),2 .39(tt,J=8.5,5.4Hz,1H),2.26(s,3H),0.55-0.49(m,2H),0.49-0.44(m,2H).

[0114] LCMS m / z=541.2[M+H] +

[0115] Example 5 Preparation of 5-(4-(3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-3-(2-(trifluoromethoxy)phenyl)pyrrolo[1,2-f]pteridin-6(5H)-one (Compound 5)

[0116]

[0117] According to the method of step 5 in Example 1, compound 5 was prepared from compound 1-5 and (2-(trifluoromethoxy)phenyl)boronic acid.

[0118] 1 H NMR (700MHz, DMSO-d6) δ9.65(s,1H),8.44(dd,J=2.8,1.4Hz,1H),7.92(dd,J=7.7,1.8Hz,1H),7.64(td,J=7.8,1.8Hz,1H),7. 55-7.48(m,4H),7.40-7.36(m,2H),7.25(dd,J=3.8,1.4Hz,1H),6.90(s,1H),6.84(t,J=3.3Hz,1H),5.61(s,2H),2.25(s,3H).

[0119] LCMS m / z=585.1[M+H] +

[0120] Example 6 Preparation of 3-(2-(dimethylamino)phenyl)-5-(4-(3-methyl-5-(trifluoromethyl)-1H-pyrazol-2-yl)benzyl)pyrrolo[1,2-f]pteridin-6(5H)-one (Compound 6)

[0121]

[0122] According to the method of step 5 in Example 1, compound 6 was prepared from compound 1-5 and (2-(dimethylamino)phenyl)boronic acid.

[0123] 1 H NMR (700MHz, DMSO-d6) δ9.57 (s, 1H), 8.40 (dd, J=2.8, 1.4Hz, 1H), 7.43-7.38 (m, 3H), 7.31 (ddd, J=8.5, 7.2, 1.7Hz, 1H), 7.24 (dd, J= 3.9,1.4Hz,1H),7.00(dd,J=8.3,1.0Hz,1H),6.93-6.87(m,2H),6.83(dd,J=3.9,2.7Hz,1H),5.55(s,2H),2.45(s,6H),2.26(s,3H).

[0124] LCMS m / z=544.2[M+H] +

[0125] Example 7 Preparation of 3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)5-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)pyrrolo[1,2-f]pteridin-6(5H)-one (Compound 7)

[0126]

[0127] Step 1 Preparation of (4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol (I-6)

[0128] According to the method of step 2 in Example 1, compound I-6 was prepared from compound I-2.

[0129] LCMS m / z=257.1[M+H] +

[0130] Step 2 Preparation of 1-(4-(chloromethyl)phenyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole (I-7)

[0131] According to the method of step 3 in Example 1, compound I-7 was prepared from compound I-6.

[0132] LCMS m / z=275.1[M+H] +

[0133] Step 3 Preparation of 3-chloro-5-(4-(5-methyl-3-trifluoromethyl)-1H-pyrazol-1-yl)benzyl)pyrrolo[1,2-f]pteridin-6(5H)-one (I-8)

[0134]

[0135] According to the method of step 4 in Example 1, compound I-8 was prepared from compound I-7.

[0136] 1 H NMR (700MHz, DMSO-d6) δ9.42 (s, 1H), 8.37 (dd, J = 2.9, 1.4Hz, 1H), 7.57-7.49 (m, 4H), 7.24 ( dd,J=4.0,1.4Hz,1H),6.83(dd,J=3.9,2.8Hz,1H),6.73(s,1H),5.48(s,2H),2.32(s,3H).

[0137] LCMS m / z=459.3[M+H] +

[0138] Step 4 Preparation of 3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)5-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)pyrrolo[1,2-f]pteridin-6(5H)-one (Compound 7)

[0139]

[0140] According to the method of step five in Example 1, compound 7 was prepared from compound I-8 and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid.

[0141] 1 H NMR (700MHz, DMSO-d6) δ9.64(s,1H),8.68(s,1H),8.43(dd,J=2.8,1.4Hz,1H),7.53-7.46(m,4H),7.25(dd,J=3.9,1.4Hz,1H),6.84(dd,J=3.9 ,2.8Hz,1H),6.73(s,1H),5.53(s,2H),3.83(s,3H),2.30(s,3H),1.75 (tt,J=8.2,4.7Hz,1H),1.00(dq,J=6.3,3.5Hz,2H),0.78-0.73(m,2H).

[0142] LCMS m / z=573.2[M+H] +

[0143] Example 8 Preparation of 5-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-3-(2-isopropylphenyl)pyrrolo[1,2-f]pteridin-6(5H)-one (Compound 8)

[0144]

[0145] According to the method of step 5 in Example 1, compound 8 was prepared from compound 1-8 and (2-isopropylphenyl)boronic acid.

[0146] 1 H NMR(700MHz,DMSO-d6)δ9.64(s,1H),8.44(dd,J=2.9,1.4Hz,1H),7.60-7.56(m,1H),7.51-7.40(m,6H),7.30-7.23(m,2H) ,6.84(dd,J=3.9,2.8Hz,1H),6.73(s,1H),5.61(s,2H),3.54(hept,J=6.8Hz,1H),2.30(s,3H),1.02(d,J=6.8Hz,6H).LCMS m / z=543.2[M+H] +

[0147] Example 9 Preparation of 5-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-3-(2-methoxyphenyl)pyrrolo[1,2-f]pteridin-6(5H)-one (Compound 9)

[0148]

[0149] According to the method of step 5 in Example 1, compound 9 was prepared from compound 1-8 and (2-methoxyphenyl)boronic acid.

[0150] 1 H NMR(700MHz,DMSO-d6)δ9.56(s,1H),8.39(dd,J=2.8,1.4Hz,1H),7.66(dd,J=7.6,1 .8Hz,1H),7.60-7.56(m,2H),7.53-7.49(m,2H),7.46(ddd,J=8.8,7.4,1.8Hz,1H), 7.23(dd,J=3.9,1.4Hz,1H),7.16(dd,J=8.5,0.9Hz,1H),7.06(td,J=7.4,1.0Hz,1H ),6.82(dd,J=3.9,2.8Hz,1H),6.73(s,1H),5.59(s,2H),3.73(s,3H),2.30(s,3H).

[0151] LCMS m / z=531.2[M+H] +

[0152] Example 10 Preparation of 3-(2-cyclopropylphenyl)-5-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)pyrrolo[1,2-f]pteridin-6(5H)-one (Compound 10)

[0153]

[0154] According to the method of step 5 in Example 1, compound 10 was prepared from compound 1-8 and (2-cyclopropylphenyl)boronic acid.

[0155] 1 H NMR(700MHz,DMSO-d6)δ9.63(s,1H),8.44(dd,J=2.8,1.4Hz,1H),7.65(dd,J=7.7,1 .5Hz,1H),7.48(s,4H),7.35(td,J=7.6,1.5Hz,1H),7.28-7.23(m,2H),7.00(dd,J= 7.8,1.2Hz,1H),6.84(dd,J=3.9,2.8Hz,1H),6.73(s,1H),5.61(s,2H),2.39(tt,J= 8.5,5.4Hz,1H),2.30(s,3H),0.53(dt,J=10.3,2.8Hz,2H),0.49-0.44(m,2H).LCMS m / z=541.2[M+H] +

[0156] Example 11 Preparation of 5-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-3-(2-methoxy-6-methylphenyl)pyrrolo[1,2-f]pteridin-6(5H)-one (Compound 11)

[0157]

[0158] According to the method of step 5 in Example 1, compound 11 was prepared from compound 1-8 and (2-methoxy-6-methylphenyl)boronic acid.

[0159] 1H NMR (700MHz, DMSO-d6) δ9.59(s,1H),8.42(dd,J=2.8,1.4Hz,1H),7.48(d,J=1.1Hz,4H),7.29(t,J=8.0Hz,1H),7.24(dd,J=4.0,1.4Hz,1H), 6.94(d,J=8.3Hz,1H),6.86(d,J=7.7Hz,1H),6.83(dd,J=3.9,2.8Hz,1H),6.73(s,1H),5.52(s,2H),3.63(s,3H),2.29(s,3H),1.86(s,3H).

[0160] LCMS m / z=545.2[M+H] +

[0161] Example 12 Preparation of 5-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)-3-(2-(trifluoromethoxy)phenyl)pyrrolo[1,2-f]pteridin-6(5H)-one (Compound 12)

[0162]

[0163] According to the method of step 5 in Example 1, compound 12 was prepared from compound 1-8 and (2-(trifluoromethoxy)phenyl)boronic acid.

[0164] 1 H NMR(700MHz,DMSO-d6)δ9.65(s,1H),8.44(dd,J=2.9,1.4Hz,1H),7.99(dd,J=7.7,1.8Hz,1H),7.64(td,J=7.7,1.8Hz,1H) ,7.58-7.46(m,6H),7.25(dd,J=3.9,1.4Hz,1H),6.84(dd,J=3.9,2.8Hz,1H),6.72(s,1H),5.62(s,2H),2.28(s,3H).LCMS m / z=585.1[M+H] +

[0165] Example 13 Preparation of 3-(2,6-dimethoxyphenyl)-5-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)pyrrolo[1,2-f]pteridin-6(5H)-one (Compound 13)

[0166]

[0167] According to the method of step 5 in Example 1, compound 13 was prepared from compound 1-8 and (2,6-dimethoxyphenyl)boronic acid.

[0168] 1 H NMR(700MHz, DMSO-d6)δ9.55(s,1H),8.38(dd,J=2.7,1.5Hz,1H),7.57-7.52(m,2H),7.51-7.47(m,2H),7.38(t,J=8.4Hz,1 H),7.21(dd,J=3.9,1.4Hz,1H),6.80(dd,J=3.9,2.8Hz,1H),6.76(d,J=8.5Hz,2H),6.73(s,1H),3.64(s,6H),2.29(s,3H).

[0169] LCMS m / z=561.2[M+H] +

[0170] Example 14 Preparation of 3-(2-(dimethylamino)phenyl)-5-(4-(5-methyl-4-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)pyrrolo[1,2-f]pteridin-6(5H)-one (Compound 14)

[0171]

[0172] According to the method of step 5 in Example 1, compound 14 was prepared from compound 1-8 and (2-(dimethylamino)phenyl)boronic acid.

[0173] 1 H NMR(700MHz, DMSO-d6)δ9.57(s,1H),8.41(dd,J=2.9,1.4Hz,1H),7.59-7.47(m,4H),7.44(dd,J=7.7,1.7Hz,1H),7.38-7.26(m,1H),7 .26-7.22(m,1H),7.01(d,J=8.2Hz,1H),6.91(t,J=7.4Hz,1H),6.86-6.79(m,1H),6.73(s,1H),5.56(s,2H),2.49(s,6H),2.30(s,3H).

[0174] LCMS m / z=544.2[M+H] +

[0175] Example 15 Preparation of 3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-(3-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)pyrrolo[1,2-f]pteridin-6(5H)-one (Compound 15)

[0176]

[0177] Step 1 Preparation of methyl 3-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoate (I-9)

[0178] According to the method of step 1 in Example 1, compound I-9 was prepared from methyl 3-fluoro-4-hydrazinobenzoate.

[0179] 1 H NMR (400MHz, DMSO-d6) δ8.04-7.93(m,2H),7.82(t,J=7.8Hz,1H),6.83(s,1H),3.91(d,J=5.0Hz,3H),2.24(d,J=3.3Hz,3H).

[0180] LCMS m / z=303.1[M+H] +

[0181] Step 2 Preparation of 3-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol (I-10)

[0182]

[0183] According to the method of step 2 in Example 1, compound I-10 was prepared from compound I-9.

[0184] 1 H NMR (400MHz, DMSO-d6) δ7.66(t,J=8.1Hz,1H),7.51-7.40(m,2H),6.75(s,1H),5.44(t,J=5.7Hz,1H),4.63(d,J=5.7Hz,2H),2.37(s,3H).

[0185] LCMS m / z=275.1[M+H] +

[0186] Step 3 Preparation of 1-(4-(chloromethyl)-2-fluorophenyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole (I-11)

[0187] According to the method of step 3 in Example 1, compound I-11 was prepared from compound I-10.

[0188] 1 H NMR (400MHz, DMSO-d6) δ7.64(dd,J=4.8,3.1Hz,2H),7.51(td,J=8.3,1.8Hz,1H),6.77(s,1H),4.87(s,2H),2.21(s,3H).

[0189] LCMS m / z=293.1[M+H] +

[0190] Step 4 Preparation of 3-chloro-5-(3-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)pyrrolo[1,2-f]pteridin-6(5H)-one (I-12)

[0191]

[0192] According to the method of step 4 in Example 1, compound I-12 was prepared from compound I-11.

[0193] 1 H NMR(400MHz,DMSO-d6)δ9.42(s,1H),8.40-8.35(m,1H),7.63-7.50(m,2H),7.44- 7.37(m,1H),7.28-7.22(m,1H),6.95-6.67(m,2H),5.49(s,2H),2.19(s,3H).LCMS m / z=477.3[M+H] +

[0194] Step 5 Preparation of 3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)5-(3-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)pyrrolo[1,2-f]pteridin-6(5H)-one (Compound 15)

[0195]

[0196] According to the method of step five in Example 1, compound 15 was prepared from compound 1-12 and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid.

[0197] 1H NMR (400MHz, DMSO-d6) δ9.64 (s, 1H), 8.67 (s, 1H), 8.44 (dd, J = 2.9, 1.4Hz, 1H), 7. 60-7.47(m,2H),7.37(dd,J=8.2,1.8Hz,1H),7.25(dd,J=3.9,1.4Hz,1H),6.84(dd ,J=3.9,2.8Hz,1H),6.76(s,1H),5.54(s,2H),3.82(s,3H),2.17(s,3H),1.76(tt ,J=8.2,4.6Hz,1H),1.00(dq,J=6.1,3.6Hz,2H),0.76(dt,J=8.2,3.4Hz,2H).LCMS m / z=591.1[M+H] +

[0198] Example 16 Preparation of 3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-5-(2-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)pyrrolo[1,2-f]pteridin-6(5H)-one (Compound 16)

[0199]

[0200] Step 1 Preparation of methyl 2-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoate (I-13)

[0201] According to the method of step 1 in Example 1, compound I-13 was prepared from methyl 2-fluoro-4-hydrazinobenzoate.

[0202] 1 H NMR (400MHz, DMSO-d6) δ8.06(t,J=8.2Hz,1H),7.71(dd,J=11.6,2.1Hz,1H),7.61(dd,J=8.5,2.1Hz,1H),6.83(s,1H),3.89(s,3H),2.45(s,3H).

[0203] LCMS m / z=303.1[M+H] +

[0204] Step 2 Preparation of 2-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol (I-14)

[0205]

[0206] According to the method of step 2 in Example 1, compound I-14 was prepared from compound I-13.

[0207] 1 H NMR(400MHz, DMSO-d6)δ7.57(t,J=8.0Hz,1H),7.47-7.38(m,1H),7.35(dd,J=8.2, 1.7Hz,1H),6.76(s,1H),5.52(t,J=5.7Hz,1H),4.62(d,J=5.7Hz,2H),2.20(s,3H).

[0208] LCMS m / z=275.1[M+H] +

[0209] Step 3 Preparation of 1-(4-(chloromethyl)-3-fluorophenyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole (I-15)

[0210] According to the method of step 3 in Example 1, compound I-15 was prepared from compound I-14.

[0211] 1 H NMR (400MHz, DMSO-d6) δ7.74(t,J=8.2Hz,1H),7.68-7.56(m,1H),7.49(td,J=8.8,2.1Hz,1H),6.77(s,1H),4.87(s,2H),2.40(s,3H).

[0212] LCMS m / z=293.1[M+H] +

[0213] Step 4 Preparation of 3-chloro-5-(2-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)pyrrolo[1,2-f]pteridin-6(5H)-one (I-16)

[0214]

[0215] According to the method of step 4 in Example 1, compound I-16 was prepared from compound I-15.

[0216] 1H NMR(400MHz, DMSO-d6)δ9.43(s,1H),8.38(dd,J=2.9,1.4Hz,1H),7.59(dd,J=10.7,2.0Hz,1H),7.42(t,J=8.2Hz,1H),7 .32(dd,J=8.3,2.1Hz,1H),7.26(dd,J=4.0,1.4Hz,1H),6.87-6.81(m,1H),6.76(s,1H),5.49(s,2H),2.36(s,3H).LCMS m / z=477.3[M+H] +

[0217] Step 5 Preparation of 3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)5-(2-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)pyrrolo[1,2-f]pteridin-6(5H)-one (Compound 16)

[0218]

[0219] According to the method of step five in Example 1, compound 16 was prepared from compound 1-16 and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid.

[0220] 1 H NMR (400MHz, DMSO-d6) δ9.65 (s, 1H), 8.66 (s, 1H), 8.45 (dd, J = 2.8, 1.4Hz, 1H), 7 .55(dd,J=10.8,2.1Hz,1H),7.36(t,J=8.2Hz,1H),7.30-7.24(m,2H),6.85(dd,J =3.9,2.8Hz,1H),6.76(s,1H),5.54(s,2H),3.79(s,3H),2.33(s,3H),1.74(tt, J=8.2,4.6Hz,1H),0.98(dq,J=6.1,3.6Hz,2H),0.72(dt,J=8.2,3.3Hz,2H).LCMS m / z=591.1[M+H] +

[0221] Pharmacological activity evaluation

[0222] Example 44 Biochemical Detection of USP1 Activity

[0223] The potency of the compounds of the present invention against USP1 was evaluated using an in vitro kinase assay. The experiment used the Fluorescence assay method. The compound sample powder was dissolved in DMSO to prepare a compound stock solution, which was diluted to 100 times the starting concentration required for the experiment and then transferred to a 384-well Echo plate (Echo Qualified 384-Well Polypropylene Microplate 2.0, Clear, Flat Bottom). The compound was gradiently diluted to the set number of concentration points using an automatic microporous pipette (Precision PRC384U). The wells on the Echo plate containing only DMSO were used to set the negative control wells and positive control wells in the experiment. 200 nL of compound was transferred from the diluted Echo 384-well plate to the 384-well reaction plate using an ultrasonic nanoliter liquid handling system (Echo550). The kinase buffer includes 50mM Tirs-HCl (pH=7.8), 0.5mM EDTA, 0.01% BSA, 0.01% Tween-20, 1mM DTT, and ddH2O. The reaction buffer containing His6-USP1 / His6-UAF1 is added to the compound wells and negative control wells of the 384-well reaction plate, 10uL per well. For the positive control wells, the reaction buffer without His6-USP1 / His6-UAF1 is added, 10uL per well, and incubated at room temperature for 60 minutes. Then, the reaction buffer containing the substrate Ubiquitin Rhodamine 110 Protein is added, 10uL per well. The final reaction volume is 20uL. The final concentrations of the components in the reaction system are as follows: His6-USP1 / His6-UAF1=0.05nM, Ubiquitin Rhodamine110Protein=300nM, DMSO concentration ratio=1%. After adding the substrate solution, the reaction plate was immediately placed in the Paradigm microplate reader to read the signal change value (Ex480 / Em540) within 30 minutes.

[0224] The percentage inhibition was calculated based on the following formula:

[0225] Inhibition rate (%) = (maximum value - sample value) / (maximum value - minimum value) × 100%.

[0226] Copy the values ​​from the microplate reader and calculate the slope value, where the maximum value refers to the reading of the negative control and the minimum value refers to the reading of the positive control. Use Y = Bottom + (Top-Bottom) / (1 + (IC 50 / X)^HillSlope) formula is fitted into a curve to obtain IC 50 Value, Y is the inhibition rate, and X is the concentration of the compound.

[0227] Table 1: USP1 activity of compounds of the present disclosure in the USP1 assay.

[0228]

[0229]

Claims

1. A compound represented by formula (I), its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts: in: The ring A is selected from phenyl or 5-6 membered heteroaryl which is unsubstituted or substituted by 1-3 Q1; The ring B is selected from phenyl or 5-6 membered heteroaryl which is unsubstituted or substituted by 1-3 Q2; The ring C is selected from phenyl or 5-6 membered heteroaryl which is unsubstituted or substituted by 1-3 Q3; Each Q1 is independently selected from halogen, cyano, carboxyl, hydroxyl, amino, sulfonylamino, C1-C6 alkylamino, di(C1-C6 alkyl)amino, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, C1-C6 alkoxy, hydroxy C1-C6 alkyl, amino C1-C6 alkyl, carboxyl C1-C6 alkyl, C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, C1-C6 alkylaminoacyl, C1-C6 alkylamido, C1-C6 alkylsulfonyl, C1-C6 alkylsulfonylamino, C1-C6 alkylaminosulfonyl, C1-C4 alkyl, C3-C6 alkyl, C4-C6 alkyl, C5-C6 alkyl, C6-C6 alkylamino, C6-C6 alkylsulfonyl, C1-C6 alkylsulfonylamino, C1-C6 alkylaminosulfonyl, C1-C4 alkyl, C3-C6 alkyl, C6-C6 alkyl, C6-C6 alkylamino, C1-C6 alkylsulfonyl, C1-C6 alkylsulfonylamino, C1-C6 alkylaminosulfonyl, C1-C4 alkyl, C3-C6 alkyl, C6-C6 alkyl 10 cycloalkyl; Each Q2 is independently selected from halogen; Each Q3 is independently selected from halogen, C1-C4 alkyl, and halogenated C1-C6 alkyl.

2. The compound according to claim 1, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt, in: The ring A is selected from phenyl, pyrimidinyl, imidazolyl, pyrazolyl which are unsubstituted or substituted with 1-3 Q1; The ring B is selected from phenyl which is unsubstituted or substituted by 1-3 Q2; The ring C is selected from pyrazolyl which is unsubstituted or substituted with 1-3 Q3; Each Q1 is independently selected from halogen, carboxyl, hydroxyl, cyano, nitro, amino, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, aminomethyl, carboxymethyl, carboxyethyl, C1-C4 alkyl, C3-C 10 cycloalkyl; Each Q2 is independently selected from halogen; Each Q3 is independently selected from halogen, monofluoromethyl, difluoromethyl, trifluoromethyl, and C1-C4 alkyl.

3. The compound according to any one of claims 1 to 2, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt, wherein the compound is selected from:

4. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable carrier and / or excipient.

5. The pharmaceutical composition according to claim 4, further comprising a pharmaceutically active ingredient other than the compound or a pharmaceutically acceptable salt thereof.

6. Use of the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 4 or 5, in the preparation of a drug for treating a disease associated with USP1.

7. Use of the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 4 or 5 in the preparation of a medicament for preventing and / or treating tumors.

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