A tricyclic ubiquitin-specific protease 1 inhibitor and preparation method, use and pharmaceutical composition thereof

Abstract

The present application relates to the technical field of medicine, specifically relates to substituted tri-cyclic ubiquitin specific protease 1 (USP1) inhibitor compounds, pharmaceutically acceptable salts or stereoisomers thereof, pharmaceutical compositions and preparations containing the compounds, pharmaceutically acceptable salts or stereoisomers thereof, a method for preparing the compounds, pharmaceutically acceptable salts or stereoisomers thereof, and the use of the compounds, pharmaceutically acceptable salts or stereoisomers thereof in the preparation of drugs for treating and / or preventing diseases mediated by USP1 and related diseases.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to a tricyclic ubiquitin-specific protease 1 inhibitor, its preparation method, uses, and pharmaceutical composition. Background Technology

[0002] Ubiquitination is a reversible process involving the deubiquitinating enzyme (DUB) family, which regulates various cellular processes by deubiquitinizing substrates. DUBs are encoded by approximately 100 human genes and are divided into six families, the largest of which is the ubiquitin-specific protease (USP) family, comprising over 50 members. DUBs act on the ubiquitin-protease system, cleaving the isopeptide bond between lysine residues and the C-terminus of UBQ, influencing cell proliferation, cell cycle, apoptosis, DNA damage responses, tumor suppression, development, and metastasis.

[0003] USP1 (Ubiquitin-specific protease 1) is a member of the USP family, a cysteine ​​isopeptidase containing a triplet structure of Cys90, His593, and Asp751. Human USP1 consists of 785 amino acids. USP1 itself is inactive; it only acquires full enzymatic activity after binding to the cofactor UAF1 (USP1-associated factor 1, a cofactor containing a WD40 repeat sequence that binds to and regulates USP1 activity) to form a heterodimeric complex. This complex stabilizes the replication fork, plays 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 / ovarian cancer. The USP1 / UAF1 complex deubiquitinates monoubiquitinated PCNA (proliferating cell nuclear antigen) and monoubiquitinated FANCD2 (Fanconianemia group complementary group D2), both of which play important roles in the translesion DNA synthesis (TLS) and Fanconi anemia (FA) pathways, respectively. These two pathways are essential for repairing DNA damage caused by DNA cross-linking agents such as cisplatin and mitomycin C (MMC). The USP1 / UAF1 complex also deubiquitinates FANCI (Fanconi anemia complementation group I). The importance of these findings was further confirmed experimentally, namely that mice lacking USP1 are highly sensitive to DNA damage. Interestingly, USP1 expression 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. These findings suggest that USP1 is a promising target for chemotherapy in certain cancers.

[0005] Therefore, the development of novel USP1 inhibitors holds promise for providing entirely new options and treatment methods for a variety of malignant diseases, including cancer. Summary of the Invention

[0006] The purpose of this invention is to provide a novel USP1 inhibitor compound with good inhibitory activity against USP1. This type of compound exhibits good inhibitory activity against the USP1 kinase, thereby enhancing the body's immune response against various tumors. Furthermore, this type of compound can also be used to treat or prevent USP1-mediated diseases, especially cancer. This type of compound shows good inhibitory activity against various cancer cells and has good drug-like properties.

[0007] On the one hand, the present invention provides a compound of formula (I), its stereoisomers, geometric isomers, tautomers, or pharmaceutically acceptable salts:

[0008]

[0009] Wherein: the ring A is selected from unsubstituted or substituted phenyl or 5-6-membered heteroaryl groups;

[0010] The ring B is selected from unsubstituted or 5-6-membered heteroaryl groups that are substituted with 1-3 Q2 groups;

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

[0012] Each Q1 is independently selected from halogen, cyano, carboxyl, hydroxy, amino, sulfonamide, C1-C6 alkylamino, di(C1-C6 alkyl)amino, haloC1-C6 alkyl, haloC1-C6 alkoxy, C1-C6 alkoxy, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, carboxylC1-C6 alkyl, C1-C6 alkyl carbonyl, C1-C6 alkoxy carbonyl, C1-C6 alkyl aminoacyl, C1-C6 alkyl sulfonyl, C1-C6 alkyl sulfonamide, C1-C6 alkylamino sulfonyl, C1-C6 alkylamino sulfonyl, C1-C4 alkyl, C3-C 10 Cycloalkyl groups;

[0013] Each Q2 is independently selected from halogens;

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

[0015] Preferably, the present invention provides a compound of formula (I), a stereoisomer, geometric isomer, tautomer, or pharmaceutically acceptable salt thereof:

[0016] Wherein: the ring A is selected from unsubstituted or substituted with 1-3 Q1 groups, namely phenyl, pyrimidinyl, imidazole, or pyrazolyl.

[0017] The ring B is selected from unsubstituted or phenyl groups substituted with 1-3 Q2 groups.

[0018] The ring C is selected from imidazole groups that are unsubstituted or substituted with 1-3 Q3 groups.

[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 group.

[0020] Each Q2 is independently selected from halogens;

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

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

[0023]

[0024]

[0025]

[0026] On the other hand, the present invention also provides a method for preparing the compound, its stereoisomers, geometric isomers, and tautomers, comprising the following steps:

[0027]

[0028] (1) Compound B was prepared by cyclization of compound A with 2,5-dimethoxytetrahydrofuran.

[0029] (2) Compound B reacts with N,N'-carbonyldiimidazole to give compound C;

[0030] (3) Using cesium carbonate as a base, compound C reacts with benzyl chloride to give compound D;

[0031] (4) Under Suzuki reaction conditions, compound D is coupled with a ring-A substituted pinacol ester of borate or boric acid to obtain the compound, its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts.

[0032] In another aspect, the present invention also provides a pharmaceutical composition comprising the compound, its stereoisomers, geometric isomers, tautomers, or pharmaceutically acceptable salts, and optionally a pharmaceutically acceptable carrier and / or excipient; preferably, the pharmaceutical composition further comprises one or more active pharmaceutical ingredients, other than the compound, its stereoisomers, geometric isomers, tautomers, or pharmaceutically acceptable salts, for the prevention and / or treatment of cancer, immune diseases, cardiovascular diseases, viral infections, inflammation, metabolic / endocrine disorders, or neurological diseases; preferably, the pharmaceutical composition is a pharmaceutically acceptable pharmaceutical preparation for the prevention and / or treatment of cancer, immune diseases, cardiovascular diseases, viral infections, inflammation, metabolic / endocrine disorders, or neurological diseases.

[0033] In another aspect, the present invention also provides a pharmaceutical formulation comprising at least one of the compounds described herein or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier, diluent, or / or excipient; preferably, the pharmaceutical formulation is selected from the following dosage forms: parenteral formulations, such as injectable solutions or suspensions; enteral formulations, such as oral formulations, such as tablets or capsules; topical formulations, such as lotions, gels, ointments, emulsions, nasal formulations, suppositories, transdermal formulations, or ophthalmic formulations.

[0034] The following are definitions of some of the terms used in this invention; other undefined terms have meanings known to those skilled in the art.

[0035] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0036] The term "halogenation" refers to the substitution of any hydrogen atom in a substituent by one or more identical or different halogens.

[0037] "Halogen" is as defined above.

[0038] When any variable (e.g., R) a R b When a group appears more than once in the composition or structure of a compound, its definition is independent in each case. For example, if a group is surrounded by two R... b Replaced, then each R b Each has its own independent options.

[0039] Term "C" m -C n "" refers to having an integer number of carbon atoms in the range mn. For example, "C1-C 10 "" means that the group can have 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms.

[0040] The term "alkyl" refers to a compound with the general formula C1. n H 2n+1 The alkyl group. This alkyl group can be straight-chain or branched. For example, the term "C1-C..." 10"Alkyl" should be understood to mean a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The alkyl group 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 "Alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-yl, 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 groups has the same definition as above. When an alkyl group is described as optionally substituted with an R group, this means that the alkyl group is optionally substituted with one or more R groups. When an alkoxy, alkylamino, and dialkylamino group is described as optionally substituted with an R group, this means that the alkoxy, alkylamino, and dialkylamino group is optionally substituted with one or more R groups. The "C1-C" mentioned herein 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".

[0041] 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 the target protein or polypeptide.

[0042] The term "tumor" includes, but is not limited to, solid tumors and hematologic malignancies, such as glioma, thyroid cancer, breast cancer, small cell lung cancer, non-small cell lung cancer, gastric cancer, colon cancer, gastrointestinal stromal cancer, pancreatic cancer, bile duct cancer, ovarian cancer, endometrial cancer, prostate cancer, kidney cancer, anaplastic large cell lymphoma, leukemia, multiple myeloma, mesothelioma, and melanoma, as well as combinations thereof.

[0043] The term "effective amount" refers to the amount of a compound or pharmaceutical composition described herein sufficient to achieve the intended application as described below, including but not limited to the treatment of a disease. Effective amounts may vary depending on: the intended application (in vivo or in vitro); or the individual being treated and the disease condition, such as the individual's weight and age, the severity of the disease; the route of administration, etc. Effective amounts can be readily determined by those skilled in the art.

[0044] "Optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility that the event or environment may or may not occur. For example, "optionally halogenated alkyl" means that a halogen may but does not have to be present, and the description includes the possibility that the alkyl group is halogenated and the possibility that the alkyl group is not halogenated.

[0045] The compounds described in this invention also include their isotope-labeled compounds. 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 a different atomic mass number than those normally found in nature. Examples of isotopes suitable for this 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.

[0046] Various solvates and hydrates of the compounds or their salts described in this invention, as well as their polymorphs, are also included within the scope of this invention.

[0047] The term "solvent" refers to a compound that also includes stoichiometric or non-stoichiometric solvents bound by non-covalent intermolecular forces. A solvate can be the disclosed compound or a pharmaceutically acceptable salt thereof. When the solvent is water, the solvate is a "hydrate". Pharmaceutically acceptable solvates and hydrates are, for example, complexes that may include, for example, one to about 100, one to about 10, one 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.

[0048] Prodrugs of the compounds described in this invention are also included within the scope of this invention. Some derivatives of the compounds described in this invention possess weak or no pharmacological activity, but when these derivatives are administered into the body, they can be converted into pharmacologically active compounds of this invention through processes such as hydrolysis and cleavage. These derivatives are called "prodrugs". Further information on the uses 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. E.B. Roche, American Pharmaceutical Association).

[0049] The compounds described in this invention include pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to a salt that is pharmaceutically acceptable and possesses the pharmacological activity required of the parent compound. Pharmaceutically acceptable salts are described in detail by Berge et al. in J. Pharma. Sci., 1977, 66, 1-19, which is incorporated herein by reference. The compounds described in this invention may contain sufficient acidic groups, sufficient basic groups, or both types of functional groups, and accordingly react with some inorganic or organic base, or inorganic and organic acid, to form pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, phosphates, monohydrophosphates, dihydrophosphates, metaphosphates, pyrophosphates, hydrochlorides, hydrobromates, hydroiodates, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptanates, propynates, oxalates, malonates, succinates, octanoates, sebates, fumarates, maleates, butyn-1,4-dicitates, hexyn-1,6-dicitates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, gamma-hydroxybutyrate, glycolate, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.

[0050] When used as a pharmaceutical, the compounds described herein are typically administered in the form of a pharmaceutical composition. Therefore, pharmaceutical compositions comprising the compounds described herein and pharmaceutically acceptable carriers, diluents, or excipients are also included within the scope of this invention. Carriers, excipients, and additives as used herein include any and all solvents, diluents or other liquid excipients, dispersants or suspending agents, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, etc., suitable for the desired particular dosage form. Various carriers for formulating pharmaceutically acceptable compositions and known techniques for their preparation are disclosed in Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988–1999, Marcel Dekker, New York, the contents of which are incorporated herein by reference.

[0051] The compositions of this invention can be administered via any route suitable for the condition to be treated. In particular, administration is possible via: parenteral administration, for example, as an injectable solution or suspension; enteral administration, for example, orally, in tablet or capsule form; topical administration, for example, as a lotion, gel, ointment, or emulsion, or via nasal or suppository form. Topical application is, for example, to the skin. Another form of topical administration is administration to the eye.

[0052] Pharmaceutical compositions can be administered in solid, semi-solid, liquid, or gaseous form, or may be in the form of dry powders, such as lyophilized forms. Pharmaceutical compositions can be packaged in easily deliverable forms, including, for example, solid dosage forms such as capsules, pouches, sachets, gelatin, paper, tablets, suppositories, granules, pills, lozenges, and tablets. The type of packaging will generally depend on the route of administration. Implantable, sustained-release formulations and transdermal formulations are also covered.

[0053] 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), buffers (e.g., phosphates), glycine, sorbic acid or potassium sorbate, mixtures of metaglycerides of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block copolymers, lanolin, sugars (e.g., lactose, glucose, and sucrose), and starches (e.g., corn starch). The composition may contain: potato starch, cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; tragacanth gum 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 buffer, as well as other non-toxic and compatible lubricants, such as sodium lauryl sulfate and magnesium stearate. Colorants, releasing agents, coating agents, sweeteners, flavorings and aromas, preservatives and antioxidants may also be present in the composition, at the discretion of the formulation personnel. Detailed Implementation

[0054] The following are specific embodiments of the present invention, which further describe the technical solution of the present invention. However, the scope of protection of the present invention is not limited to these embodiments. Any changes or equivalent substitutions that do not depart from the concept of the present invention are included within the scope of protection of the present invention.

[0055] In the following embodiments, unless otherwise noted in the structural formula or chemical name, molecules with a single chiral center exist as a racemic mixture. Unless otherwise noted in the structural formula or chemical name, molecules with two or more chiral centers exist as a racemic mixture of diastereomers. The single enantiomer / diastereomer can be obtained by methods known to those skilled in the art.

[0056] Preparation method

[0057] The compounds described in this invention can be synthesized according to the synthetic schemes described herein and / or techniques well known in the art. For example, the compounds provided by this invention can be prepared according to the following general synthetic methods.

[0058] General Synthesis Method

[0059]

[0060] (1) Compound B was prepared by cyclization of compound A with 2,5-dimethoxytetrahydrofuran.

[0061] (2) Compound B reacts with N,N'-carbonyldiimidazole to give compound C;

[0062] (3) Using cesium carbonate as a base, compound C reacts with benzyl chloride to give compound D;

[0063] (4) Under Suzuki reaction conditions, compound D is coupled with a ring-A substituted pinacol ester of borate or boric acid to obtain the compound, its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts.

[0064] Example

[0065] Preparation Examples

[0066] The compounds described in this invention can be synthesized according to one or more synthetic schemes described herein and / or techniques well known in the art. Those skilled in the art will recognize that the synthetic methods of some embodiments described in detail herein can be readily applied to the synthesis of other embodiments. In some embodiments, the compounds described herein can be prepared by appropriate combinations of synthetic methods well known in the art. Many starting materials and other reagents are available from commercial suppliers, such as Alfaisa (China) Chemical Co., Ltd., or can be readily prepared using synthetic methods commonly used in the art.

[0067] 1 H NMR spectra are recorded on instruments operating at 400 MHz, 500 MHz, or 700 MHz. 1 ¹H NMR spectra were obtained in solution form (reported in ppm), using CDCl₃ (7.26 ppm), DMSO-d₆ (2.50 ppm), or the internal standard tetramethylsilane (0.00 ppm) as reference standards. When reporting peak multiplicity, the following abbreviations were used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad peak), dd (doublet), dt (doubletuplet). Coupling constants are given in Hertz (Hz).

[0068] When necessary, the (R)- and (S)-isomers of the non-limiting exemplary compounds, if present, can be separated by methods known to those skilled in the art, such as by forming diastereomer salts or complexes, which can be separated by, for example, crystallization; by forming diastereomeric derivatives, which can be separated by, for example, crystallization or chromatography; by selectively reacting one enantiomer with an enantiomer-specific reagent, thereby separating the modified and unmodified enantiomers; or by chromatographic separation in a chiral environment, for example, a chiral column. Alternatively, specific enantiomers can be prepared by asymmetric synthesis using optically active reagents, substrates, catalysts, or solvents, or by converting one enantiomer to another via asymmetric transformation.

[0069] 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 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" is... "Na2SO4" refers to sodium acetate, "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(diphenylphosphine)ferrocene]palladium dichloride, "Ar" refers to argon, "M" refers to volumetric molar concentration, "rt" refers to room temperature, "min" refers to minutes, "h" refers to hours, "mL" refers to milliliters, "mmol" refers to millimoles, "μM" refers to micromoles, "nM" refers to nanomoles, and "℃" refers to degrees Celsius.

[0070] Preparation of general intermediate C

[0071] Step 1: Preparation of 2-chloro-5-(1H-pyrrolo-1-yl)pyrimidin-4-amine (B)

[0072]

[0073] 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 with Ar, and reacted at 95 °C for 8 h. After cooling to room temperature, the mixture was extracted with EA (500 mL × 4). The combined organic layers were washed with water (500 mL × 3) and brine (500 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by rapid column chromatography (silica gel, PE / EA = 4:1, v / v) to give product B as a yellow solid (3.67 g, yield 47%).

[0074] 1H NMR (500MHz, DMSO-d6) δ7.99 (s, 1H), 6.94 (t, J = 2.1Hz, 2H), 6.28 (t, J = 2.1Hz, 2H).

[0075] LCMS m / z = 195.1 [M+H] +

[0076] Step 2: Preparation of 3-chloropyrrolo[1,2-f]pterodin-6(5H)-one (C)

[0077]

[0078] 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, product C, a yellow solid (2.60 g, yield 98%), was used directly in the next step without purification.

[0079] 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).

[0080] LCMS m / z = 221.1[M+H] +

[0081] Example 1 Preparation of 3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)5-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrrolo[1,2-f]pteridine-6(5H)-one (compound 1)

[0082]

[0083] Step 1: Preparation of methyl 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (I-1)

[0084] To a mixture of 3,3-dibromo-1,1,1-trifluoropropane-2-one (6.69 g, 24.8 mmol) in water (10 mL), NaOAc (2.03 g, 24.8 mmol) was added. The mixture was heated at 100 °C for 1 hour, then cooled to room temperature. Next, a solution of methyl 4-formylbenzoate (3.39 g, 20.7 mmol) in MeOH (93 mL) and NH4OH (21 mL) was added to the reaction mixture at room temperature. After 40 minutes, the reaction mixture was heated to 100 °C and stirred for 4 hours. The mixture was quenched with H2O (50 mL) and extracted with EA (500 mL × 4). The combined organic layers were washed with water (500 mL × 3) and brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by rapid column chromatography (silica gel, PE / EA = 5:1, v / v) to give product I-1 as a yellow solid (2.42 g, yield 44%).

[0085] LCMS m / z = 271.1 [M+H] +

[0086] Step 2: Preparation of methyl 4-((1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (I-2)

[0087] Compound I-1 (2.42 g, 9 mmol) was dissolved in 200 mL of ACN at room temperature, followed by the sequential addition of isopropyl iodine (2.29 g, 13.5 mmol) and cesium carbonate (8.8 g, 29 mmol). The mixture was heated to 90 °C and reacted overnight. After cooling to room temperature, the mixture was extracted with EA (500 mL × 4). The combined organic layers were washed with water (500 mL × 3) and brine (500 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by rapid column chromatography (silica gel, PE / EA = 8:1, v / v) to give product I-2 as a yellow solid (1.81 g, yield 64%).

[0088] LCMS m / z = 313.1 [M+H] +

[0089] Step 3: Preparation of (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (I-3)

[0090] At 0°C, DIBAL-H (30 mL, 30 mmol, 1 M hexane solution) was added to a solution of compound I-2 (1.81 g, 5.8 mmol) in THF (40 mL) via syringe. After addition, the mixture was stirred at 0°C for 20 min, followed by a 30 min warming to room temperature. TLC analysis indicated the reaction was complete. The mixture was then quenched with ice water (10 mL) and the pH was adjusted to 5 with dilute HCl. Extraction was performed using 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 rapid column chromatography (silica gel, PE / EA = 1:1, v / v) to give product I-3 as a white solid (1.4 g, 90.4% yield).

[0091] LCMS m / z = 285.1 [M+H] +

[0092] Step 4: Preparation of (4-(chloromethyl)phenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazolium (I-4)

[0093]

[0094] Compound I-3 (0.95 g, 1.76 mmol) was dissolved in DCE (10 mL), and thionyl chloride (1.19 g, 10.00 mmol) was added at room temperature. The mixture was stirred for 2 hours. The solution was concentrated under reduced pressure to obtain compound I-4, which was used directly in the next step.

[0095] LCMS m / z = 303.2[M+H] +

[0096] Step 5: Preparation of 3-chloro-5-(4-(1-isopropyl-4-trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrrolo[1,2-f]pteridin-6(5H)-one (I-5)

[0097]

[0098] A mixture of compound C (440 mg, 2 mmol) and compound I-4 (606 mg, 2 mmol) in DMF (50 mL) was stirred at 60 °C for 4 h. After cooling to room temperature, the mixture was extracted with EA (100 mL × 4). The combined organic layers were washed with water (100 mL × 3) and brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by rapid column chromatography (silica gel, PE / EA = 2:1, v / v) to give product I-5 as a yellow solid (409 mg, yield 42%).

[0099] 1H NMR (400MHz, DMSO-d6) δ9.45(s,1H),8.40(dd,J=2.9,1.4Hz,1H),8.16(d,J=1.4Hz,1H),7.50(s, 4H), 7.24 (dd, J=3.9, 1.4Hz, 1H), 6.83 (dd, J=3.9, 2.8Hz, 1H), 5.47 (s, 2H), 1.38 (d, J=6.6Hz, 6H).

[0100] LCMS m / z = 487.3 [M+H] +

[0101] Step Six: Preparation of 3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)5-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrrolo[1,2-f]pteridin-6(5H)-one (Compound 1)

[0102]

[0103] 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), followed by the addition of (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). The mixture was refluxed overnight under argon protection. After cooling to room temperature, the mixture was extracted with EA (20 mL × 4). The combined organic layers were washed with water (20 mL × 3) and brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by rapid column chromatography (silica gel, PE / EA = 1:2, v / v) to give compound 1 as a white solid (251 mg, yield 84%).

[0104] 1 H NMR (400MHz, DMSO-d6) δ9.66(s,1H),8.67(s,1H),8.47-8.42(m,1H),8.15(s,1H),7.47(s,4H),7.24(d,J=3.7Hz,1H),6.84(t,J=3.5Hz,1H),5.5 4(s,2H),4.41(p,J=6.6Hz,1H),3.82(s,3H),1.75(tt,J=8.6,4.8Hz,1H ),1.37(d,J=6.6Hz,6H),1.03–0.95(m,2H),0.73(dt,J=7.8,3.5Hz,2H).

[0105] LCMS m / z = 601.2[M+H]+

[0106] Example 2 Preparation of 5-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-3-(2-isopropylphenyl)pyrrolo[1,2-f]pteridine-6(5H)-one (compound 2)

[0107]

[0108] Compound 2 was prepared from compound I-5 and (2-isopropylphenyl)boronic acid according to step six of Example 1. 1 HNMR(700MHz,DMSO-d6)δ9.63(s,1H),8.45-8.42(m,1H),8.15(s,1H),7.58(d,J=7.7Hz,1H),7.49(d,J=8.0Hz,2H),7.45-7.40(m,4H),7.30-7 .23(m,2H),6.86-6.82(m,1H),5.61(s,2H),4.42(hept,J=6.7Hz,1H),3.52(hept,J=7.0Hz,1H),1.36(d,J=6.7Hz,6H),1.00(d,J=6.8Hz,6H).

[0109] LCMS m / z = 571.2 [M+H] +

[0110] Example 3 Preparation of 5-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-3-(2-methoxyphenyl)pyrrolo[1,2-f]pteridine-6(5H)-one (compound 3)

[0111]

[0112] Compound 3 was prepared from compound I-5 and (2-methoxyphenyl)boronic acid according to step six of Example 1. 1H NMR(700MHz,DMSO-d6)δ9.58-9.55(m,1H),8.39(ddt,J=4.4,2.9,1.4Hz,1H),8.15 (s,1H),7.67(dd,J=7.5,1.8Hz,1H),7.56-7.49(m,4H),7.46(tdd,J=8.9,4.7,2.0 Hz,1H),7.16(dd,J=8.5,3.7Hz,1H),7.08-7.03(m,1H),6.82(dq,J=4.0,2.6Hz,1H ),5.60(s,2H),4.43(hept,J=6.7Hz,1H),3.72(s,3H),1.37(d,J=6.6Hz,6H).LCMS m / z = 559.2 [M+H] +

[0113] Example 4 Preparation of 3-(2-cyclopropylphenyl)-5-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrrolo[1,2-f]pteridine-6(5H)-one (compound 4)

[0114]

[0115] Compound 4 was prepared from compound I-5 and (2-cyclopropylphenyl)boronic acid according to step six of Example 1. 1 H NMR(700MHz,DMSO-d6)δ9.64(s,1H),8.44(dd,J=2.9,1.4Hz,1H),8.16(d,J=1 .3Hz,1H),7.67(dd,J=7.7,1.5Hz,1H),7.50-7.45(m,2H),7.35(td,J=7.6,1.5 Hz,1H),7.29-7.24(m,2H),7.00(dd,J=8.0,1.2Hz,1H),5.62(s,2H),4.42(he pt,J=6.7Hz,1H),2.42-2.35(m,1H),1.37(d,J=6.7Hz,6H),0.52-0.44(m,4H).

[0116] LCMS m / z = 569.2 [M+H] +

[0117] Example 5 Preparation of 5-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-3-(2-methoxy-6-methylphenyl)pyrrolo[1,2-f]pteridine-6(5H)-one (compound 5)

[0118]

[0119] Compound 3 was prepared from compound I-5 and (2-methoxy-6-methylphenyl)boronic acid according to step six of Example 1.

[0120] 1 H NMR (700MHz, DMSO-d6) δ9.60(s,1H),8.42(dd,J=2.8,1.4Hz,1H),8.16(d,J=1.4Hz,1H),7.46(q,J=8.3Hz,4H),7.30(t,J=8.0Hz,1H),7.24(dd,J= 3.9,1.4Hz,1H),6.95(d,J=8.3Hz,1H),6.88-6.82(m,2H),5.52(s,2H),4 .40(hept,J=6.7Hz,1H),3.63(s,3H),1.85(s,3H),1.37(d,J=6.7Hz,6H).

[0121] LCMS m / z = 573.2 [M+H] +

[0122] Example 6 Preparation of 5-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-3-(2-(trifluoromethoxy)phenyl)pyrrolo[1,2-f]pteridine-6(5H)-one (compound 6)

[0123]

[0124] Compound 6 was prepared from compound I-5 and (2-(trifluoromethoxy)phenyl)boronic acid according to step six of Example 1.

[0125] 1 H NMR (700MHz, DMSO-d6) δ9.64(s,1H),8.43(dd,J=2.9,1.5Hz,1H),8.14(s,1H),7.98(dd,J=7.8,1.8Hz,1H),7.64(tt,J=7.8,2.0Hz,1H),7.54(t d,J=7.2,3.1Hz,1H),7.52-7.46(m,5H),7.27-7.23(m,1H),6.86-6.81( m,1H),5.61(s,2H),4.45-4.36(m,J=6.6Hz,1H),1.35(d,J=6.6Hz,6H).

[0126] LCMS m / z = 613.1 [M+H] +

[0127] Example 7 Preparation of 3-(2,6-dimethoxyphenyl)-5-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrrolo[1,2-f]pteridine-6(5H)-one (compound 7)

[0128]

[0129] Compound 7 was prepared from compound I-5 and (2,6-dimethoxyphenyl)boronic acid according to step six of Example 1.

[0130] 1 H NMR (700MHz, DMSO-d6) δ9.56 (s, 1H), 8.39 (dd, J = 2.9, 1.5Hz, 1H), 8.15 (d, J = 1. 3Hz,1H),7.51(d,J=8.4Hz,2H),7.47(d,J=8.3Hz,2H),7.39(t,J=8.4Hz,1H),7 .21(dd,J=4.0,1.4Hz,1H),6.81(dd,J=3.9,2.8Hz,1H),6.77(d,J=8.5Hz,2H), 5.50(s,2H),4.41(hept,J=6.6Hz,1H),3.63(s,6H),1.36(d,J=6.6Hz,6H).LCMS m / z=589.2[M+H] +

[0131] Example 8 Preparation of 5-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-3-(2-ethylphenyl)pyrrolo[1,2-f]pteridine-6(5H)-one (compound 8)

[0132]

[0133] Compound 8 was prepared from compound I-5 and (2-ethylphenyl)boronic acid according to step six of Example 1.

[0134] 1H NMR (700MHz, DMSO-d6) δ9.63(d,J=1.2Hz,1H),8.44(dt,J=2.6,1.3Hz,1H),8.15(d,J=1.3 Hz,1H),7.73(dd,J=7.7,1.5Hz,1H),7.51-7.46(m,2H),7.44(d,J=8.1Hz,2H),7.39(td,J =7.4,1.6Hz,1H),7.30(dd,J=8.5,7.2Hz,2H),7.25(dd,J=3.8,1.5Hz,1H),5.61(s,2H),4 .41(h,J=6.7Hz,1H),2.78(q,J=7.5Hz,2H),1.36(d,J=6.8Hz,7H),0.93(t,J=7.5Hz,3H).

[0135] LCMS m / z = 556.2 [M+H] +

[0136] Example 9 Preparation of 3-(2-(dimethylamino)phenyl)-5-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrrolo[1,2-f]pteridine-6(5H)-one (compound 9)

[0137]

[0138] Compound 9 was prepared from compound I-5 and (2-(dimethylamino)phenyl)boronic acid according to step six of Example 1.

[0139] 1 H NMR(700MHz,DMSO-d6)δ9.58(s,1H),8.41(dd,J=2.9,1.4Hz,1H),8.16(d,J=1.3Hz,1H ),7.54-7.48(m,4H),7.44(dd,J=7.5,1.7Hz,1H),7.35-7.30(m,1H),7.24(dd,J=3.9, 1.4Hz,1H),7.02(d,J=8.3Hz,1H),6.91(td,J=7.3,1.1Hz,1H),6.83(ddd,J=3.8,2.7, 0.9Hz,1H),5.57(s,2H),4.42(hept,J=6.7Hz,1H),2.48(s,6H),1.37(d,J=6.6Hz,6H).

[0140] LCMS m / z = 572.2 [M+H] +

[0141] Example 10 Preparation of 3-(2-acetylphenyl)-5-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrrolo[1,2-f]pteridine-6(5H)-one (compound 10)

[0142]

[0143] Compound 8 was prepared from compound I-5 and (2-acetylphenyl)boronic acid according to step six of Example 1. 1 H NMR (700MHz, DMSO-d6) δ9.47(s,1H),8.31(dd,J=2.8,1.4Hz,1H),8.04-7.98(m,2H),7.52-7.44(m,2H),7.38(s,4H),7.35(dd,J=7.2, 1.6Hz,1H),7.14(dd,J=3.7,1.3Hz,1H),6.75-6.71(m,1H),5.48(s,2H),4.31(hept,J=6.7Hz,1H),2.15(s,3H),1.24(d,J=6.7Hz,6H).

[0144] LCMS m / z = 556.2 [M+H] +

[0145] Example 11 Preparation of 3-(2-(methoxyyl)phenyl)-5-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrrolo[1,2-f]pteridine-6(5H)-one (compound 11)

[0146]

[0147] Compound 8 was prepared from compound I-5 and (2-(methoxyyl)phenyl)boronic acid according to step six of Example 1.

[0148] 1 H NMR(700MHz, DMSO-d6)δ9.58(s,1H),8.40(dd,J=3.0,1.4Hz,1H),8.13(d,J=1.4Hz,1H),8.00(dd,J=7.7,1.3Hz,1H),7.68-7.57(m,3H),7.52-7.47 (m,4H),7.25(dd,J=3.9,1.4Hz,1H),6.84(ddd,J=4.0,2.9,1.0Hz,1H),5.60(s,2H),4.41(hept,J=6.6Hz,1H),3.63(s,3H),1.35(d,J=6.6Hz,6H).

[0149] LCMS m / z = 587.2 [M+H] +

[0150] Example 12 Preparation of 5-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-3-(1-methyl-1H-pyrazol-5-yl)pyrrolo[1,2-f]pteridine-6(5H)-one (compound 12)

[0151]

[0152] Compound 12 was prepared from compound I-5 and 1-methyl-1H-pyrazole-5-boronic acid pinacol ester according to step six of Example 1.

[0153] 1 H NMR (400MHz, DMSO-d6) δ9.58(d,J=1.0Hz,1H),8.42(dd,J=2.7,1.4Hz,1H),8.14(d,J=1.6Hz,1H),7.51(d,J=3.1Hz,5H),7.26(d,J =3.9Hz,1H),7.00(d,J=1.9Hz,1H),6.85(t,J=3.4Hz,1H),5.63(s,2H),4.42(p,J=6.7Hz,1H),4.10(s,3H),1.36(d,J=6.6Hz,6H).

[0154] LCMS m / z = 533.2 [M+H] +

[0155] Example 13 Preparation of 3-(1H-imidazol-1-yl)-5-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrrolo[1,2-f]pteridin-6(5H)-one (compound 13)

[0156]

[0157] A mixture of compound I-5 (972 mg, 2 mmol) and imidazole (272 mg, 4 mmol) in DMF (50 mL) was stirred at 60 °C for 4 h. After cooling to room temperature, the mixture was extracted with EA (100 mL × 4). The combined organic layers were washed with water (100 mL × 3) and brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by rapid column chromatography (silica gel, PE / EA = 2:1, v / v) to give compound 12 as a white solid (829 mg, 80% yield).

[0158] 1H NMR (400MHz, DMSO-d6) δ9.49(s,1H),8.60(s,1H),8.40(s,1H),8.14(s,1H),7.96(s,1H),7.59(d,J=7.4Hz,2H) ,7.50(d,J=7.7Hz,2H),7.26(s,1H),7.14(s,1H),6.83(s,1H),5.63(s,2H),4.42(s,1H),1.35(d,J=6.4Hz,5H).

[0159] LCMS m / z = 519.2 [M+H] +

[0160] Example 14 Preparation of 3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)5-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrrolo[1,2-f]pteridine-6(5H)-one (compound 14)

[0161]

[0162] Step 1: Preparation of methyl 4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (I-6)

[0163] Compound I-6 was prepared from compound I-1 and iodoethane according to the method in step two of Example 1.

[0164] LCMS m / z = 299.1 [M+H] +

[0165] Step 2: Preparation of (4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (I-7)

[0166] Compound I-7 was prepared from compound I-6 according to step three of Example 1.

[0167] LCMS m / z = 271.1 [M+H] +

[0168] Step 3: Preparation of (4-(chloromethyl)phenyl)-1-ethyl-4-(trifluoromethyl)-1H-imidazolium (I-8)

[0169] Compound I-8 was prepared from compound I-7 according to step four of Example 1.

[0170] LCMS m / z = 289.2 [M+H] +

[0171] Step 4: Preparation of 3-chloro-5-(4-(1-ethyl-4-trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrrolo[1,2-f]pteridin-6(5H)-one (I-9)

[0172]

[0173] Compound I-9 was prepared from compound C and compound I-8 according to step five of Example 1.

[0174] 1 H NMR(700MHz, DMSO-d6)δ9.43(s,1H),8.37(dd,J=2.9,1.4Hz,1H),8.01(d,J=1.3Hz,1H),7.60-7.55(m,2H),7.52-7.48(m ,2H),7.25(dd,J=4.0,1.4Hz,1H),6.83(dd,J=3.9,2.8Hz,1H),5.47(s,2H),4.06(q,J=7.2Hz,2H),1.30(t,J=7.3Hz,3H).

[0175] LCMS m / z = 473.1 [M+H] +

[0176] Step 5: Preparation of 3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)5-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrrolo[1,2-f]pteridin-6(5H)-one (compound 14)

[0177]

[0178] Compound 14 was prepared from compound I-9 and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid according to step six of Example 1.

[0179] 1H NMR (700MHz, DMSO-d6) δ9.64(s,1H),8.67(s,1H),8.44(dd,J=2.8,1.4Hz,1H),8.01(d,J= 1.4Hz,1H),7.54(d,J=8.2Hz,2H),7.46(d,J=8.2Hz,2H),7.25(dd,J=3.9,1.4Hz,1H),6.84 (dd,J=3.9,2.8Hz,1H),5.53(s,2H),4.04(q,J=7.3Hz,2H),3.82(s,3H),1.75(tt,J=8.3,4 .6Hz,1H),1.29(t,J=7.2Hz,3H),0.99(dq,J=6.4,3.4Hz,2H),0.74(dt,J=8.2,3.4Hz,2H).

[0180] LCMS m / z = 587.2 [M+H] +

[0181] Example 15 Preparation of 5-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-3-(2-isopropylphenyl)pyrrolo[1,2-f]pteridine-6(5H)-one (compound 15)

[0182]

[0183] Compound 15 was prepared from compound I-9 and (2-isopropylphenyl)boronic acid according to step six of Example 1. 1 H NMR(700MHz, DMSO-d6)δ9.64(s,1H),8.44(dd,J=2.8,1.4Hz,1H),8.00(d,J=1.5Hz,1H),7.60-7.53(m,3H),7.46-7.40(m,4H),7.30-7.23(m, 2H), 6.84 (dd, J = 3.9, 2.8Hz, 1H), 5.60 (s, 2H), 4.04 (q, J = 7.3Hz, 2H), 3.54 (hept, J = 6.8Hz, 1H), 1.28 (t, J = 7.2Hz, 3H), 1.02 (d, J = 6.9Hz, 6H).

[0184] LCMS m / z = 557.2 [M+H] +

[0185] Example 16 Preparation of 5-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-3-(2-methoxyphenyl)pyrrolo[1,2-f]pteridine-6(5H)-one (compound 16)

[0186]

[0187] Compound 16 was prepared from compound I-9 and (2-methoxyphenyl)boronic acid according to step six of Example 1. 1 H NMR(700MHz,DMSO-d6)δ8.40(dd,J=2.8,1.4Hz,1H),8.00(d,J=1.3Hz,1H),7.66(dd,J=7.6 ,1.8Hz,1H),7.59-7.55(m,2H),7.53(d,J=8.3Hz,2H),7.46(ddd,J=8.9,7.3,1.8Hz,1H),7. 22(dd,J=3.9,1.4Hz,1H),7.16(dd,J=8.5,1.0Hz,1H),7.05(td,J=7.4,1.0Hz,1H),6.82(dd ,J=3.9,2.8Hz,1H),5.58(s,2H),4.04(q,J=7.2Hz,2H),3.72(s,3H),1.28(t,J=7.2Hz,3H).

[0188] LCMS m / z = 545.2 [M+H] +

[0189] Example 17 Preparation of 3-(2-cyclopropylphenyl)-5-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrrolo[1,2-f]pteridine-6(5H)-one (compound 17)

[0190]

[0191] Compound 17 was prepared from compound I-9 and (2-cyclopropylphenyl)boronic acid according to step six of Example 1. 1 H NMR(700MHz,DMSO-d6)δ9.64(s,1H),8.45(dd,J=2.9,1.4Hz,1H),8.00(d,J=1.3Hz,1H), 7.65(dd,J=7.7,1.5Hz,1H),7.56-7.52(m,2H),7.42(d,J=8.2Hz,2H),7.34(td,J=7.6,1. 5Hz,1H),7.28-7.23(m,2H),7.00(dd,J=7.9,1.2Hz,1H),6.85(dd,J=3.8,2.8Hz,1H),4.0 4(q,J=7.3Hz,2H),2.38(tt,J=8.6,5.4Hz,1H),1.28(t,J=7.3Hz,3H),0.53-0.44(m,4H).

[0192] LCMS m / z = 555.2 [M+H] +

[0193] Example 18 Preparation of 3-(2-(dimethylamino)phenyl)-5-(4-(1-ethyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrrolo[1,2-f]pteridine-6(5H)-one (compound 18)

[0194]

[0195] Compound 18 was prepared from compound I-9 and (2-(dimethylamino)phenyl)boronic acid according to step six of Example 1.

[0196] 1 H NMR(700MHz,DMSO-d6)δ9.57(s,1H),8.40(dd,J=2.9,1.5Hz,1H),8.00(d,J=1.3Hz,1H),7.58 -7.53(m,2H),7.52-7.48(m,2H),7.43(dd,J=7.5,1.7Hz,1H),7.32(ddd,J=8.5,7.2,1.7Hz,1H ),7.24(dd,J=3.9,1.4Hz,1H),7.01(dd,J=8.3,1.1Hz,1H),6.91(td,J=7.4,1.1Hz,1H),6.83( dd,J=3.9,2.8Hz,1H),5.56(s,2H),4.04(q,J=7.3Hz,2H),2.48(s,6H),1.28(t,J=7.3Hz,3H).

[0197] LCMS m / z = 558.2 [M+H] +

[0198] Example 19 Preparation of 3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrrolo[1,2-f]pteridin-6(5H)-one (compound 19)

[0199]

[0200] Step 1: Preparation of methyl 4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzoate (I-10)

[0201] Compound I-10 was prepared from compound I-1 and iodomethane according to the method in step two of Example 1.

[0202] LCMS m / z = 285.1 [M+H] +

[0203] Step 2: Preparation of (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (I-11)

[0204] Compound I-11 was prepared from compound I-10 according to step three of Example 1.

[0205] LCMS m / z = 257.1 [M+H] +

[0206] Step 3: Preparation of (4-(chloromethyl)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazolium (I-12)

[0207] Compound I-12 was prepared from compound I-11 according to step four of Example 1.

[0208] LCMS m / z = 275.2 [M+H] +

[0209] Step 4: Preparation of 3-chloro-5-(4-(1-methyl-4-trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrrolo[1,2-f]pteridin-6(5H)-one (I-13)

[0210]

[0211] Compound I-13 was prepared from compound C and compound I-12 according to step five of Example 1.

[0212] 1 H NMR(700MHz,DMSO-d6)δ9.41(s,1H),8.36(dd,J=2.8,1.4Hz,1H),7.90(d,J=1.4Hz,1H),7.67–7.62(m,2H) ,7.48(d,J=8.1Hz,2H),7.24(dd,J=4.0,1.4Hz,1H),6.82(dd,J=4.0,2.8Hz,1H),5.45(s,2H),3.74(s,3H).

[0213] LCMS m / z = 459.1 [M+H] +

[0214] Step 5: Preparation of 3-(4-cyclopropyl-6-methoxypyrimidin-5-yl)5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrrolo[1,2-f]pteridin-6(5H)-one (compound 19)

[0215]

[0216] Compound 19 was prepared from compound I-13 and (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid according to step six of Example 1.

[0217] 1 H NMR(400MHz,DMSO-d6)δ9.65(d,J=1.9Hz,1H),8.67(s,1H),8.44(dq,J=2.6,1.3Hz, 1H),7.91(t,J=1.3Hz,1H),7.65-7.57(m,2H),7.46(d,J=8.2Hz,2H),7.24(dd,J=3. 9,1.4Hz,1H),6.84(td,J=3.4,1.2Hz,1H),5.52(s,2H),3.82(s,3H),3.73(s,3H),1 .75(tt,J=8.2,4.6Hz,1H),1.00(dq,J=6.0,3.6Hz,2H),0.75(dt,J=8.3,3.4Hz,2H).

[0218] LCMS m / z = 573.2 [M+H] +

[0219] Example 20 Preparation of 5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-3-(2-isopropylphenyl)pyrrolo[1,2-f]pteridine-6(5H)-one (compound 20)

[0220]

[0221] Compound 20 was prepared from compound I-13 and (2-isopropylphenyl)boronic acid according to step six of Example 1. 1H NMR(700MHz, DMSO-d6)δ9.64(s,1H),8.43(dd,J=3.0,1.5Hz,1H),7.90(d,J=1.3Hz,1H),7.65-7.61(m,2H),7.60-7.56(m,1H),7.46-7 .40(m,5H),7.30-7.22(m,2H),6.84(dd,J=3.9,2.8Hz,1H),5.59(s,2H),3.73(s,3H),3.55(hept,J=6.8Hz,1H),1.03(d,J=6.8Hz,6H).

[0222] LCMS m / z = 543.2 [M+H] +

[0223] Example 21 Preparation of 5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-3-(2-methoxyphenyl)pyrrolo[1,2-f]pteridine-6(5H)-one (compound 21)

[0224]

[0225] Compound 21 was prepared from compound I-13 and (2-methoxyphenyl)boronic acid according to step six of Example 1. 1 H NMR (700MHz, DMSO-d6) δ9.56 (s, 1H), 8.39 (dd, J = 2.8, 1.4Hz, 1H), 7.90 (d, J = 1.3 Hz,1H),7.70-7.64(m,3H),7.53(d,J=8.2Hz,2H),7.46(ddd,J=8.7,7.3,1.8Hz, 1H),7.22(dd,J=4.0,1.4Hz,1H),7.16(dd,J=8.3,1.0Hz,1H),7.06(td,J=7.5,1 .0Hz,1H),6.82(dd,J=3.9,2.8Hz,1H),5.58(s,2H),3.73(d,J=4.3Hz,6H).LCMS m / z = 531.2 [M+H] +

[0226] Example 22 Preparation of 3-(2-cyclopropylphenyl)-5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrrolo[1,2-f]pteridine-6(5H)-one (compound 22)

[0227]

[0228] Compound 22 was prepared from compound I-13 and (2-cyclopropylphenyl)boronic acid according to step six of Example 1. 1 H NMR (700MHz, DMSO-d6) δ9.64 (s, 1H), 8.44 (dd, J=2.8, 1.5Hz, 1H), 7.91 (d, J= 1.3Hz,1H),7.68-7.60(m,3H),7.42(d,J=8.1Hz,2H),7.34(td,J=7.6,1.5Hz, 1H),7.28-7.22(m,2H),7.00(dd,J=7.8,1.3Hz,1H),6.84(dd,J=4.0,2.7Hz,1 H),5.60(s,2H),3.73(s,3H),2.39(tt,J=8.5,5.4Hz,1H),0.55-0.45(m,4H).

[0229] LCMS m / z = 541.2 [M+H] +

[0230] Example 23 Preparation of 5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-3-(2-methoxy-6-methylphenyl)pyrrolo[1,2-f]pteridine-6(5H)-one (compound 23)

[0231]

[0232] Compound 23 was prepared from compound I-13 and (2-methoxy-6-methylphenyl)boronic acid according to step six of Example 1.

[0233] 1 H NMR(700MHz, DMSO-d6)δ9.59(s,1H),8.42(dd,J=2.9,1.4Hz,1H),7.91(d,J=1.3Hz,1H),7.63-7.59(m,2H),7.43(d,J=8.2Hz,2H),7.30(t ,J=8.0Hz,1H),7.24(dd,J=3.9,1.4Hz,1H),6.94(d,J=8.3Hz,1H),6.90-6.81(m,2H),5.51(s,2H),3.73(s,3H),3.63(s,3H),1.86(s,3H).

[0234] LCMS m / z = 545.2 [M+H] +

[0235] Example 24 Preparation of 5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-3-(2-(trifluoromethoxy)phenyl)pyrrolo[1,2-f]pteridine-6(5H)-one (compound 24)

[0236]

[0237] Compound 24 was prepared from compound I-13 and (2-(trifluoromethoxy)phenyl)boronic acid according to step six of Example 1.

[0238] 1 H NMR (700MHz, DMSO-d6) δ9.64(s,1H),8.43(dd,J=2.9,1.5Hz,1H),8.14(s,1H),7.98(dd,J=7.8,1.8Hz,1H),7.64(tt,J=7.8,2.0Hz,1H),7.54(t d,J=7.2,3.1Hz,1H),7.52-7.46(m,5H),7.27-7.23(m,1H),6.86-6.81( m,1H),5.61(s,2H),4.45-4.36(m,J=6.6Hz,1H),1.35(d,J=6.6Hz,6H).

[0239] LCMS m / z = 585.1 [M+H] +

[0240] Example 25 Preparation of 3-(2,6-dimethoxyphenyl)-5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrrolo[1,2-f]pteridine-6(5H)-one (compound 25)

[0241]

[0242] Compound 25 was prepared from compound I-13 and (2,6-dimethoxyphenyl)boronic acid according to step six of Example 1.

[0243] 1 H NMR (400MHz, DMSO-d6) δ9.55(s,1H),8.37(dd,J=2.9,1.4Hz,1H),7.90(d,J=1.4Hz,1H),7.66–7.59(m,2H),7.50(d,J=8 .2Hz,2H),7.39(t,J=8.4Hz,1H),7.20(dd,J=3.9,1.3Hz,1H),6.83–6.73(m,3H),5.49(s,2H),3.73(s,3H),3.64(s,6H).

[0244] LCMS m / z = 561.2 [M+H] +

[0245] Example 26 Preparation of 3-(2-(dimethylamino)phenyl)-5-(4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)pyrrolo[1,2-f]pteridine-6(5H)-one (compound 26)

[0246]

[0247] Compound 26 was prepared from compound I-13 and (2-(dimethylamino)phenyl)boronic acid according to step six of Example 1.

[0248] 1 H NMR (700MHz, DMSO-d6) δ9.57(s,1H),8.40(t,J=1.8Hz,1H),7.90(s,1H),7.64(d,J=8.1Hz,2H),7.50(d,J=8.0Hz,2H),7.45(d,J=7.6Hz,1H),7.32( t,J=7.7Hz,1H),7.24(d,J=3.9Hz,1H),7.02(d,J=8.3Hz,1H),6.92(t,J= 7.4Hz, 1H), 6.83 (t, J = 3.3Hz, 1H), 5.55 (s, 2H), 3.73 (s, 3H), 2.48 (s, 6H).

[0249] LCMS m / z = 544.2 [M+H] +

[0250] Pharmacological activity evaluation

[0251] Example 27 Biochemical detection of USP1 activity

[0252] The efficacy of the compounds of this invention against USP1 was evaluated using an in vitro kinase assay. The experiment employed the Fluorescence assay method. Compound sample powder was dissolved in DMSO to prepare a stock solution. This stock solution was diluted 100-fold to the required initial concentration and then transferred to 384-well Echo plates (Echo Qualified 384-Well Polypropylene Microplate 2.0, Clear, Flat Bottom). The compound was serially diluted to the set concentration points using an automated micropipette (Precision PRC384U). Wells on the Echo plate containing only DMSO were used for negative and positive control wells. 200 nmL of the 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 consisted of 50 mM Tirs-HCl (pH 7.8), 0.5 mM EDTA, 0.01% BSA, 0.01% Tween-20, 1 mM DTT, and ddH2O. 10 μL of reaction buffer containing His6-USP1 / His6-UAF1 was added to each of the compound wells and negative control wells in a 384-well plate. For the positive control wells, 10 μL of reaction buffer without His6-USP1 / His6-UAF1 was added to each well, and the plate was incubated at room temperature for 60 minutes. Then, 10 μL of reaction buffer containing the substrate Ubiquitin Rhodamine 110 Protein was added to each well. The final reaction volume was 20 μL. The final concentrations of each component in the reaction system were as follows: His6-USP1 / His6-UAF1 = 0.05 nM, Ubiquitin Rhodamine 110 Protein = 300 nM, and DMSO concentration = 1%. After adding the substrate solution, immediately place the reaction plate in a Paradigm microplate reader and read the signal change values ​​(Ex480 / Em540) over 30 minutes.

[0253] The inhibition percentage is calculated based on the following formula:

[0254] Inhibition rate (%) = (maximum value - sample value) / (maximum value - minimum value) × 100%.

[0255] Copy the values ​​from the ELISA reader and calculate the slope value, where the maximum value represents the negative control reading and the minimum value represents the positive control reading. Use Y = Bottom + (Top - Bottom) / (1 + (IC)) 50 The formula / X)^HillSlope) is fitted to a curve to obtain IC. 50 Value, Y is the inhibition rate, and X is the compound concentration.

[0256] Table 1: USP1 activity of the compounds disclosed herein in USP1 assay.

[0257] Example <![CDATA[USP1 IC 50 (nM)]]> Example <![CDATA[USP1 IC 50 (nM)]]> 1 4.4 14 5.0 2 8.5 15 4.8 3 68 16 27 4 31 17 10 5 36 18 8.1 6 89 19 5.9 7 11 20 13 8 93 21 32 9 14 22 15 10 339 24 32 11 161 25 15 12 >10000 26 8.3 13 >10000 .

Claims

1. A compound of formula (I), its stereoisomers, geometric isomers, tautomers, or pharmaceutically acceptable salts: in: The ring A is selected from phenyl, pyrimidinyl, imidazolyl, and pyrazolyl groups that are unsubstituted or substituted with 1-3 Q1 groups; The ring B is selected from phenyl groups that are either unsubstituted or substituted with 1-3 Q2 groups; The ring C is selected from imidazole groups that are unsubstituted or substituted with 1-3 Q3 groups; 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 groups; Each Q2 is independently selected from halogens; Each Q3 is independently selected from halogens, monofluoromethyl, difluoromethyl, trifluoromethyl, and C1-C4 alkyl groups.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

3. A pharmaceutical composition comprising at least one compound of any one of claims 1-2 or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier and / or excipient.

4. The pharmaceutical composition according to claim 3, further comprising a pharmaceutically active ingredient other than the compound or a pharmaceutically acceptable salt thereof.

5. The use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, or the pharmaceutical composition according to claim 3 or 4, in the preparation of a medicament for treating diseases related to USP1.

6. Use of the compound according to any one of claims 1-2 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 3 or 4, in the preparation of a medicament for the prevention and / or treatment of tumors.

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