8- and 6-Substituted Pyridopyrimidine Derivatives as KRAS Inhibitors

Abstract

The present invention relates to an inhibitor of Kirsten rat sarcoma virus (KRAS), more specifically, a compound represented by formula I, and a composition containing formula I, and a method of using a compound represented by formula I for the treatment or prevention of diseases, disorders, or medical conditions mediated through KRAS, particularly the KRAS variant G12C. TIFF2025521086000028.tif5157 Formula I

Description

Technical Field

[0001] Cross - reference to related applications This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 61 / 714,565, filed May 9, 2022, and U.S. Provisional Application No. 63 / 339,580, filed Mar. 15, 2023. The entire disclosure of the above applications is incorporated herein by reference. Technical field The present invention relates to inhibitors of Kirsten rat sarcoma virus (KRAS), and more particularly to pyridopyrimidine compounds, compositions and methods for the treatment or prevention of diseases, disorders, or conditions mediated through KRAS, particularly the KRAS variant G12C. Diseases include various cancers.

Background Art

[0002] Ras is a superfamily of small guanosine triphosphate (GTP)-binding proteins consisting of various isoforms. The Ras gene can mutate into a cancer gene associated with many cancers such as lung, pancreas, and colon. Ras is one of the most frequently mutated cancer genes. Kirsten rat sarcoma virus (KRAS), an isoform of Ras, is one of the most frequently mutated Ras genes, accounting for about 86% of all mutations. KRAS functions as an on / off switch for cell signaling. KRAS operates between an inactive (GDP-bound) state and an active (GTP-bound) state and is a proto-oncogene that controls various functions including cell proliferation. However, KRAS mutations cause uncontrolled cell proliferation and cancer. KRAS-4B is the main isoform in colon cancer (30 - 40%), lung cancer (15 - 20%), and pancreatic cancer (90%). (Liu, P. 2019, Acta Pharmaceutica Sinica B). Therefore, inhibitors of KRAS-GTP binding are potential therapeutic agents for the treatment of various cancers.

Summary of the Invention

Problems to be Solved by the Invention

[0003] Previous attempts to design KRAS inhibitors mostly ended in failure because of the high affinity of KRAS for GTP. However, recent approaches targeting the KRAS G12C mutation have shown to be more promising. This mutation is present in approximately 50% of lung cancers and approximately 10 - 20% of all KRAS G12 mutations. Since the cysteine residue of the mutation is located within the active site, the sulfhydryl functional group can form a covalent bond with a properly functionalized binding ligand (Liu, P. 2019, Acta Pharmaceutica Sinica B). Through this approach, irreversible covalent inhibitors of the KRAS G12C mutation have been identified and are currently in clinical trials. Considering that KRAS plays an important role as a driver in many malignancies, there is a need for new KRAS inhibitors with improved selectivity, safety, and efficacy.

Means for Solving the Problems

[0004] Summary of the invention In one aspect, the present invention provides formula I:

Chemical formula

[0005] In one aspect, the present invention relates to a pharmaceutical composition comprising a compound or salt represented by formula I together with a pharmaceutically acceptable carrier.

[0006] In one aspect, the present invention relates to a method of treating a disease, disorder, or medical condition of a patient, the method comprising providing a therapeutic agent to a patient in need thereof, wherein the therapeutic agent comprises a compound of formula I or a salt thereof.

[0007] These and other aspects will become apparent upon reading the following detailed description of the invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0008]

Figure 1

[0009] Detailed description of the invention Terms Compounds are described using standard nomenclature. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0010] The terms "a" and "an" are not intended to denote a limitation in quantity, but rather to indicate that at least one of the referenced items is present. The term "or" means "and / or". The terms "comprising", "having", "including", and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to").

[0011] The recitation of a range of values is intended only as a shorthand method of referring individually to each value within the range, unless otherwise indicated herein, and each individual value is incorporated herein as if it were individually recited herein. All endpoints of ranges are included within the range and can be combined independently.

[0012] All of the methods described in this specification can be performed in a suitable order unless otherwise indicated herein or unless otherwise clearly contradicted by the context. The use of any examples, or exemplary language (e.g., "such as") is merely for better illustration of the invention and does not limit the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention described herein. Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0013] Furthermore, the disclosure includes all variations, combinations, and rearrangements in which one or more limitations, elements, clauses, and descriptive terms of the recited claims are introduced into another claim. For example, a claim that depends on another claim can be modified to include one or more limitations from another claim that depends on the same base claim. When elements are presented as a list (e.g., in a Markush group format), each subgroup of the elements is also disclosed, and any element can be removed from the group.

[0014] All compounds are understood to include any possible isotopes of the atoms present in the compound. Isotopes include atoms having the same atomic number but different mass numbers, including heavy isotopes and radioactive isotopes. As a general example, without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 11 C, 13 C, and 14 C. Thus, the compounds disclosed herein may include heavy isotopes or radioactive isotopes within the structure of the compound or as substituents attached to the compound. Examples of useful heavy isotopes or radioactive isotopes include 18 F, 15 N, 18 O, 76 Br, 125 I and 131 are included.

[0015] All of the formulas disclosed herein include all pharmaceutically acceptable salts of such formulas.

[0016] The open-ended term "comprising" includes the intermediate and closed terms "consisting essentially of" and "consisting of".

[0017] The term "substituted" means that one or more hydrogens of the designated atom or group are replaced with a selected group from the designated group, provided that the normal valence of the designated atom is not exceeded. Combinations of substituents and / or variables are permitted only if such combinations result in a stable compound or a useful synthetic intermediate. A stable compound or stable structure means a compound that is separated from the reaction mixture and has sufficient robustness to be formulated as an effective therapeutic agent thereafter.

[0018] A dash ("-") that is not between two letters or symbols is used to indicate the point of attachment of a substituent.

[0019] "Alkyl" includes both branched and straight-chain saturated aliphatic hydrocarbon groups having the designated number of carbon atoms, generally from 1 to about 8 carbon atoms. The term C1-C6 alkyl as used herein refers to an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. Other embodiments include alkyl groups having from 1 to 8 carbon atoms, from 1 to 4 carbon atoms, or 1 or 2 carbon atoms, such as, for example, C1-C8 alkyl, C1-C4 alkyl, and C1-C2 alkyl. C0-C nWhen alkyl is used in combination with other groups such as, for example, -C0-C2 alkyl(phenyl), the group shown (in this case phenyl) is either directly bonded by a single covalent bond (C0 alkyl) or bonded by an alkyl chain having the specified number of carbon atoms (in this case 1, 2, 3, or 4 carbon atoms). Alkyl can also be bonded through other groups such as heteroatoms, such as -O-C0-C4 alkyl(C3-C7 cycloalkyl). Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, 3-methylbutyl, t-butyl, n-pentyl, and sec-pentyl.

[0020] "Alkoxy" refers to an alkyl group as defined above, in which the specified number of carbon atoms are covalently bonded and replaced by an oxygen bridge (-O-). Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy. Similarly, an "alkylthio" or "thioalkyl" group is an alkyl group as defined above, in which the specified number of carbon atoms are covalently bonded and replaced by a sulfur bridge (-S-). Similarly, "alkenyloxy", "alkynyloxy", and "cycloalkyloxy" each indicate a group substituted with an oxygen bridge (-O-).

[0021] "Halo" or "halogen" means fluoro, chloro, bromo, or iodo, and is defined herein to include all isotopes thereof, including heavy isotopes and radioactive isotopes. Examples of useful halo isotopes include 18 F, 76 Br, and 131 I. Further isotopes will be readily understood by those skilled in the art.

[0022] "Haloalkyl" means a branched and straight-chain alkyl group having a specified number of carbon atoms and usually substituted with one or more halogen atoms up to the maximum allowable number of halogen atoms. Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, 2-fluoroethyl, and pentafluoroethyl.

[0023] "Haloalkoxy" is a haloalkyl group as defined above bonded through an oxygen bridge (the oxygen of the alcohol radical).

[0024] "Peptide" means a molecule in which amino acids are linked in a chain via amide bonds (also called peptide bonds).

[0025] "Pharmaceutical composition" means a composition containing at least one active agent such as a compound or salt of formula II and at least one other substance such as a carrier. The pharmaceutical composition meets the standards of the US FDA's GMP (Good Manufacturing Practice) for human or non-human pharmaceuticals.

[0026] "Carrier" means a diluent, excipient, or vehicle administered together with an active compound. "Pharmaceutically acceptable carrier" means a substance that is generally safe, non-toxic, and not otherwise undesirable for preparing pharmaceutical compositions, such as excipients, diluents, or vehicles, and includes carriers acceptable for veterinary use and human pharmaceutical use. "Pharmaceutically acceptable carrier" includes one or more such carriers.

[0027] "Patient" means a human or non-human animal in need of medical treatment. Medical treatment can include the treatment of existing conditions such as diseases or disorders, or diagnostic procedures. In some embodiments, the patient is a human patient.

[0028] "To provide" means to give, administer, sell, distribute (in the sense of delivering), transfer (whether for profit or not), manufacture, compound, or dispense.

[0029] "To treat" or "treatment" means administering to a patient an amount of an active compound sufficient to measurably reduce the symptoms of a disease, slow the progression of the disease, or cause regression of the disease. In certain embodiments, treatment of a disease can be initiated before a patient exhibits symptoms of the disease.

[0030] A "therapeutically effective amount" of a pharmaceutical composition means an amount that, when administered to a patient, is effective to produce a therapeutic effect such as improvement of symptoms, reduction of the progression of a disease, or regression of a disease.

[0031] A "therapeutic compound" means a compound that can be used for the diagnosis or treatment of a disease. The compound can be a small molecule, peptide, protein, or other type of molecule.

[0032] A significant change is a detectable change that is statistically significant in a parametric test of standard statistical significance, such as a Student's T-test, with p < 0.05.

[0033] Chemical description Compounds of the formulas disclosed herein may contain one or more asymmetric elements, such as stereocenters, stereogenic axes, e.g., asymmetric carbon atoms, and thus the compounds can exist in different stereoisomeric forms. These compounds can be, for example, racemates, atropisomers, or optically active forms. In the case of compounds having two or more asymmetric elements, these compounds can further be mixtures of diastereomers. In the case of compounds having an asymmetric center, all optical isomers in pure form and mixtures thereof are included. In such situations, a single enantiomer, i.e., an optically active form, can be obtained by asymmetric synthesis, synthesis from an optically pure precursor, or resolution of a racemate. Resolution of racemates and atropisomers can also be achieved by conventional methods such as crystallization in the presence of a resolving agent, or by chromatography, e.g., using a chiral HPLC column. All forms are contemplated herein, regardless of the method used to obtain them.

[0034] All forms of the active agent (e.g., solvates, optical isomers, enantiomeric forms, atropisomeric forms, polymorphs, free compounds, and salts) can be used alone or in combination.

[0035] The term "chiral" refers to a molecule having the property of not being superimposable on its mirror image.

[0036] "Stereoisomers" are compounds that have the same chemical structure but differ in the arrangement of atoms or groups in space.

[0037] "Diastereomers" are stereoisomers that have two or more chirality centers and are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral characteristics, and reactivity. A mixture of diastereomers can be separated by high-resolution analytical procedures such as electrophoresis, crystallization in the presence of a resolving agent, or chromatography using a chiral HPLC column.

[0038] "Enantiomer" refers to two stereoisomers of a compound that are mirror images and cannot be superimposed on each other. A 50:50 mixture of enantiomers is called a racemic mixture or racemic compound and can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

[0039] The definitions and rules of stereochemistry used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., New York. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. When describing an optically active compound, the prefixes D and L or R and S are used to indicate the absolute configuration of the chiral center of the molecule. The prefixes d and l or (+) and (-) are used to specify the sign of the rotation of plane-polarized light by the compound, and (-) or l means that the compound is levorotatory. A compound with the prefix (+) or d is dextrorotatory.

[0040] A "racemic mixture" or "racemic compound" is an equimolar (or 50:50) mixture of two enantiomeric species that are not optically active. A racemic mixture can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

[0041] A "chelating group" or "chelating agent" is a ligand group that can form two or more separate coordination bonds to a single central atom, usually a metal ion. The chelating groups disclosed herein are organic groups having a plurality of N, O, or S heteroatoms and having a structure in which two or more heteroatoms can form bonds to the same metal ion.

[0042] "Salt" includes derivatives of the disclosed compounds, and the parent compounds are modified by making inorganic and organic, non-toxic, acid or base addition salts. The salts of the compounds of the present invention can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of an appropriate base (such as Na, Ca, Mg, or K hydroxides, carbonates, bicarbonates, etc.) or by reacting the free base form of these compounds with a stoichiometric amount of an appropriate acid. Such reactions are usually carried out in water, an organic solvent, or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used when feasible. The salts of the compounds of the present invention also include solvates of the compounds and solvates of the salts of the compounds. In one embodiment, the compounds of the present invention are synthesized or isolated as trifluoroacetic acid (TFA) salts.

[0043] In one embodiment, the salt forms of the compounds of the present invention described above may include pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include conventional non-toxic salts and, for example, quaternary ammonium salts of parent compounds formed from non-toxic inorganic or organic acids. For example, conventional non-toxic acid salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc.; and acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, mesylic acid, esylic acid, besylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC-(CH2) nSalts prepared from organic acids such as -COOH (where n is 0 to 4) and the like can be mentioned. A list of additional suitable salts is described, for example, in G. Steffen Paulekuhn, et al., Journal of Medicinal Chemistry 2007, 50, 6665 and Handbook of Pharmaceutically Acceptable Salts: Properties, Selection and Use, P. Heinrich Stahl and Camille G. Wermuth, Editors, Wiley-VCH, 2002.

[0044] The compounds of the present invention are of formula I:

Chemical formula

[0045] In Formula I, A is optionally one or more of hydrogen, halogen, hydroxyl, C 1-6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -(C0-C6 alkyl)cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, NO2, cyano, CO2H, PO(OR 3 )2, POR 3 (OR 3 )、PO(R 4 )2、NH2、NH(C 1-6 alkyl) or N(C 1-6 alkyl)2-substituted aryl or heteroaryl; X is selected from O, NR 2 , S or CH2; Y and G are the same or different and are bromine, iodine, C 1-4 alkyl, C 1-4Perjuterol alkyl, -(C0-C2 alkyl) alkenyl, -(C0-C2 alkyl) alkynyl, -(C0-C2 alkyl) cycloalkyl, C 1-4 Haloalkyl, -O(C 1-4 Alkyl), -S(C 1-4 Alkyl), -(C0-C2 alkyl) cyano, or -O(C 1-4 Haloalkyl) selected from; Z is hydrogen, halogen, trifluoromethyl or C 1-6 Selected from alkyl; R 1 Is hydrogen, C1-C6 alkyl, -(C1-C6 alkyl)C 1-6 Alkoxy, -C0-C6 alkyl(cycloalkyl), C1-C6 haloalkyl, -(C1-C6 alkyl)CN or -(C1-C6 alkyl)P(O)R 2 R 3 Selected from; n is 1-3; Each R 2 Is H, C 1-6 Alkyl, C 3-6 Cycloalkyl or -(C1-C6 alkyl)P(O)R 2 R 3 Selected from; R 3 Is H, C 1-6 Alkyl or C 3-6 Selected from cycloalkyl; R 4 Is C 1-6 Alkyl, C 3-6 Selected from cycloalkyl or aryl.

[0046] In a preferred embodiment, the compound represented by formula I is represented by 1a-1z and 2a-2g, or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

Table 1

Table 2

Table 3

Table 4

[0047] Particularly preferred compounds of the present invention are 1d, 1f, 1n and 1z:

Chemical formula

[0048] In one embodiment, the present invention includes a pharmaceutical composition comprising any one of compound 1d, compound 1f, compound 1n, or compound 1z, or a salt, solvate, or prodrug thereof, together with a pharmaceutically acceptable carrier.

[0049] The compounds disclosed herein can be administered as pure chemical substances, but are preferably administered as pharmaceutical compositions. Accordingly, the present invention encompasses pharmaceutical compositions comprising a compound such as a compound represented by formula I or a pharmaceutically acceptable salt of the compound, together with at least one pharmaceutically acceptable carrier. The pharmaceutical composition can contain the compound or salt represented by the formula as the sole active agent, but preferably contains at least one additional active agent. As will be understood by those skilled in the art, various combinations of the compounds described by formula I can also be incorporated into the compositions and methods of the present invention. In certain embodiments, the pharmaceutical composition is in a unit dosage form and contains about 0.1 mg to about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about 800 mg, or about 200 mg to about 600 mg of the compound represented by formula I, and optionally about 0.1 mg to about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about 800 mg, or about 200 mg to about 600 mg of an additional active agent in a dosage form. The pharmaceutical composition can also include the molar ratio of the compound such as the compound represented by formula I to the additional active agent. For example, the pharmaceutical composition can include a molar ratio of the additional active agent to the compound represented by formula I of about 0.5:1, about 1:1, about 2:1, about 3:1, or from about 1.5:1 to about 4:1.

[0050] The compounds disclosed in this specification can be administered in dosage unit formulations containing conventional pharmaceutically acceptable carriers by oral, topical, parenteral, inhalation or spray, sublingual, transdermal, buccal, rectal, eye drops, or other means. The pharmaceutical compositions can be formulated in any pharmaceutically useful form, such as, for example, aerosols, creams, gels, pills, capsules, tablets, syrups, transdermal patches, or eye drops. Some dosage forms, such as tablets and capsules, are subdivided into unit dosages of appropriate size containing an appropriate amount of the active ingredient, for example, an amount effective to achieve the desired purpose.

[0051] The carriers include excipients and diluents, and are of sufficiently high purity and sufficiently low toxicity to be suitable for administration to the patient under treatment. The carrier may be inert or may itself have medicinal effects. The amount of carrier used in combination with the compound is an amount sufficient to provide a practical amount of the substance for administration per unit dose of the compound.

[0052] The types of carriers include, but are not limited to, binders, buffers, colorants, diluents, disintegrants, emulsifiers, flavoring agents, flow promoters, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents. Some carriers may be classified into multiple classes. For example, vegetable oils can be used as lubricants in some formulations and as diluents in other formulations. Examples of pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered tragacanth, malt, gelatin, talc, and vegetable oils. Any active agent can be included in the pharmaceutical composition, provided that it does not substantially interfere with the activity of the compounds of the present invention.

[0053] The pharmaceutical compositions / combinations can be formulated for oral administration. These compositions contain from 0.1 to 99 weight percent (wt%) of the compound of formula III and usually contain at least about 5 weight percent of the compound represented by formula I. Some embodiments contain from about 25 weight percent to about 50 weight percent, or from about 5 weight percent to about 75 weight percent, of the compound represented by formula I.

[0054] Treatment method The compounds represented by Formula I, as well as pharmaceutical compositions containing such compounds, are useful for the diagnosis or treatment of diseases, disorders, or medical conditions mediated via KRAS, particularly the KRAS variant G12C, and include various cancers such as glioma (glioblastoma), acute myeloid leukemia, acute myeloid leukemia, myelodysplastic / myeloproliferative neoplasms, sarcoma, chronic myelomonocytic leukemia, non-Hodgkin lymphoma, astrocytoma, melanoma, non-small cell lung cancer, cholangiocarcinoma, chondrosarcoma, colon cancer or pancreatic cancer.

[0055] According to the present invention, a method for treating a KRAS-mediated disease or medical condition comprises providing a therapeutically effective amount of a compound represented by Formula I to a patient in need thereof. In one embodiment, the patient is a mammal, more specifically a human. As will be understood by those skilled in the art, the present invention also encompasses methods for treating non-human patients such as pet animals, e.g., cats, dogs, and livestock.

[0056] The therapeutically effective amount of the pharmaceutical composition is preferably an amount sufficient to reduce or ameliorate the symptoms of the disease or condition. For example, in the case of a KRAS-mediated disease, the therapeutically effective amount may be an amount sufficient to reduce or ameliorate the cancer. The therapeutically effective amount of the compounds or pharmaceutical compositions described herein also provides a sufficient concentration of the compound represented by Formula I when administered to a patient. The sufficient concentration is preferably the concentration of the compound in the patient's body required to prevent or treat the disease. Such amounts can be confirmed experimentally, for example, by assaying the blood concentration of the compound, or theoretically by calculating bioavailability.

[0057] According to the present invention, the treatment methods disclosed herein include administering to a patient a specific dosage of a compound or group of compounds represented by Formula I. The dosage level of each compound is from about 0.1 mg to about 140 mg per kilogram of body weight per day, which is useful for the treatment of the above symptoms (from about 0.5 mg to about 7 g per patient per day). The amount of compound that can be combined with a carrier material to produce a single dosage form will vary depending on the patient to be treated and the particular method of administration. Dosage unit forms generally contain from about 1 mg to about 500 mg of each active compound. In certain embodiments, a patient is provided with from 25 mg to 500 mg, or from 25 mg to 200 mg, of the compound represented by Formula I per day. The frequency of administration may also vary depending on the compound used and the particular disease being treated. However, for the treatment of most KRAS-mediated diseases and disorders, a dosing schedule of up to 4 times a day can be used, and in certain embodiments, a dosing schedule of once or twice a day is used.

[0058] However, it will be understood that the specific dosage level for a particular patient will depend on various factors such as the activity of the specific compound used, age, body weight, general health, gender, diet, time of administration, route of administration, rate of excretion, combination of drugs, and the severity of the particular disease being treated.

[0059] The compound represented by Formula I may be administered alone (i.e., as the sole therapeutic agent in a dosing regimen) or in combination with another active agent to treat or prevent KRAS-mediated diseases and conditions such as various cancers. One or more compounds represented by Formula I may be administered in conjunction with the dosing regimen of one or more other active agents such as anti-cancer cytotoxic agents. In one embodiment, a method for treating or diagnosing KRAS-mediated cancer in a mammal includes administering to the mammal a therapeutically effective amount of a compound represented by Formula I, optionally in combination with one or more additional active ingredients.

[0060] As will be understood by those skilled in the art, the treatment methods provided herein are useful for the treatment of non-human mammals, including veterinary uses such as the treatment of livestock such as cows, sheep, dairy cows, goats, pigs, and the treatment of pets (companion animals) such as dogs and cats.

[0061] For diagnostic or research uses, various mammals such as rodents (such as mice, rats, hamsters), rabbits, primates, pigs such as inbred pigs are suitable subjects. Further, for in vitro uses such as in vitro diagnostic and research uses, body fluids (such as blood, plasma, serum, interstitial fluid, saliva, feces, and urine) and cell and tissue samples from the above subjects are suitable.

[0062] In one embodiment, the present invention provides a method for treating a disease, disorder, or medical condition (including various cancers) mediated through KRAS, particularly the KRAS variant G12C, in a patient identified as in need of treatment, the method comprising administering to the patient an effective amount of a compound of Formula I. The compounds represented by Formula I provided herein can be administered alone or in combination with one or more other active agents.

[0063] In another embodiment, a method for treating or diagnosing a KRAS-mediated disease or condition further comprises administering to a patient in need of such treatment a compound of Formula I in combination with one or more additional compounds, wherein at least one of the additional compounds is an active agent. The one or more additional compounds include additional therapeutic compounds including anti-cancer therapeutic compounds such as doxorubicin, paclitaxel, docetaxel, cisplatin, camptothecin, temozolomide, avastin, herceptin, erbitux.

Example

[0064] Chemical synthesis The synthesis of the compounds of the present invention is illustrated by a series of steps shown in Reaction Schemes 1-6. Reaction Scheme 1 shows that Y and G are hydrogen and X is O, NR 2、or S, shows the synthesis of examples of formula I (i.e., 10a - 10c). In reaction scheme 1, when commercially available compounds 3 and 4 are reacted in a solvent such as acetonitrile in the presence of a base such as DIPEA, 5 is formed. Reacting 6a - 6c with a base such as sodium hydride, Hunig's base, K2CO3 or a Cs2CO3 / DABCO mixture, and then treating with 5 at room temperature or elevated temperature in a polar aprotic solvent such as N-methyl-2-pyrrolidone, compounds 7a - 7c are formed respectively. Compounds 9a - 9c can be prepared using a standard Suzuki coupling method between compounds 7a - 7c and 8 in a solvent mixture such as 1,4-dioxane and water. Removing the Boc protecting group of 9a - 9c under acidic conditions such as anhydrous HCl in 1,4-dioxane, and then acylating the deprotected product with an α,β-unsaturated acid chloride such as acryloyl chloride in a solvent such as methylene chloride containing a base such as triethylamine, when Y and G are hydrogen and X is O, NR 2 、or S, the corresponding compounds of formula 10a - 10c are formed.

[0065] Reaction Scheme 1

Chemical formula

[0066] Reaction scheme 2 is such that Y or G is fluorine and X is O, NR 2、or S, showing the synthesis of examples of formula I (i.e., 18a-c and 19a-c). When commercially available 7-bromopyrido[3,2-d]pyrimidine-2,4-diol (11) is oxidized with urea-hydrogen peroxide complex in an aprotic solvent such as DMF at 0 °C in the presence of trifluoroacetic anhydride, N-oxide 12 is obtained. Subsequently, when 12 is reacted with POCl3 in the presence of Hunig's base, a ca. 1:1 mixture of trichloro compounds 13a and 13b is formed. Treatment of the 13a / 13b mixture with 4 in a solvent such as acetonitrile in the presence of Hunig's base gives the corresponding products 14a and 14b, which can be separated by chromatography. Treatment of 6a-6c with a base such as sodium hydride, Hunig's base, K2CO3 or Cs2CO3 / DABCO mixture, followed by reaction of 14a and 14b in a polar aprotic solvent such as N-methyl-2-pyrrolidone at room temperature or elevated temperature gives compounds 15a and 15b, respectively. Reaction of 15a and 15b with a fluoride source such as potassium fluoride or cesium fluoride at elevated temperature in a polar aprotic solvent such as DMSO gives the corresponding fluorine products 16a and 16b. Compounds 17a and 17b can be prepared using the standard Suzuki coupling method between compounds 16a and 16b and 8 in a solvent mixture such as 1,4-dioxane and water. Under acidic conditions such as anhydrous HCl in 1,4-dioxane, the Boc protecting groups of 17a and 17b are removed. Subsequently, the deprotected product is acylated with an α,β-unsaturated acid chloride such as acryloyl chloride in a solvent such as methylene chloride containing a base such as triethylamine, where either Y or G is fluorine and X is O, NR 2 、or S, the corresponding compounds 18a-c and 19a-c of formula I are formed.

[0067] Reaction Scheme 2

Chemical formula

[0068] Reaction formula 3 is such that Y is hydrogen, G is fluorine, and X is O, NR 2、or S, shows the synthesis of examples of formula I (i.e., 31a - 31c). When commercially available 3,5 - dibromo - 4 - fluoropyridine or 3,5 - dichloro - 4 - fluoropyridine (20) is reacted with (1Z)-N-[(methylsulfonyl)oxy] - ethanimidoyl chloride (21; CAS number 1228558 - 17 - 5) according to the general procedure described by P. S. Fier (J. Am. Chem. Soc. 2017, 139(28), 9499 - 9736), 3,5 - dihalo - 4 - fluoropicolinonitrile (22) is obtained. Alternatively, compound 22 can be prepared by oxidizing 20 with H2O2 - urea complex in the presence of trifluoroacetic anhydride, followed by treating the corresponding N - oxide with trimethylsilyl cyanide in the presence of dimethylcarbamoyl chloride in a solvent such as dichloromethane. As generally described in WO2021117767A1, the product 23 is obtained by regioselective Suzuki coupling of 22 with boronic acid 8. Subsequently, 23 is reacted with 2,4 - dimethoxybenzylamine (24) while heating in a suitable solvent such as 1,4 - dioxane in the presence of Hunig's base according to the procedure described in WO2021041671A1 to obtain compound 25. Alternatively, 25 can also be prepared by a backward Hartwig amination procedure between 23 and 24 under standard conditions. 25 is subjected to a Pinner reaction in methanol in the presence of HCl at - 78 °C to 0 °C, and then the intermediate iminoester is hydrolyzed in the presence of saturated aqueous NaHCO3 to obtain compound 26. 26 is reacted with trichloroacetyl isocyanate at 0 °C, followed by treatment with anhydrous ammonia in methanol and warming to room temperature to obtain compound 27. When 27 is reacted with POCl3 at high temperature in the presence of Hunig's base, the corresponding 2,4 - dichloro - 8 - fluoropyrido[3,2 - d]pyrimidine derivative 28 is obtained. When compound 28 is reacted with 4 in a solvent such as acetonitrile in the presence of Hunig's base, 29 is obtained.When 6a - 6c are treated with a suitable base such as potassium fluoride, Hunig's base, K2CO3 or Cs2CO3 / DABCO mixture in neat 6a - 6c or in a suitable aprotic solvent and then reacted with 29 at a high temperature, compounds 30a - 30c are obtained respectively. Alternatively, 30a can also be produced by coupling 6a and 29 with Pd(OAc)2 at a high temperature in toluene in the presence of BINAP and Cs2CO3. The Boc protecting groups of 30a - 30c are removed under acidic conditions such as anhydrous HCl in 1,4 - dioxane. The corresponding deprotected products are acylated with an α,β - unsaturated acid chloride such as acryloyl chloride in an aprotic solvent such as methylene chloride containing a base such as triethylamine, to produce a compound represented by formula I (i.e., 31a - 31c) where Y is hydrogen, G is fluorine, and X is O, NR2, or S.

[0069] Reaction Scheme 3

Chemical formula

[0070] Reaction Scheme 4 shows that Y is hydrogen, G is hydrogen, halogen, C 1-4 alkyl, -(C0 - C2 alkyl) alkenyl, -(C0 - C2 alkyl) alkynyl, -(C0 - C2 alkyl) cycloalkyl, C 1-4 haloalkyl, -O(C 1-4 alkyl), -S(C 1-4 alkyl), -(C0 - C2 alkyl) cyano, or -O(C 1-4 haloalkyl), and X is O, NR 2、or S, shows the synthesis of an example of Formula I. Oxidizing 32 with a urea-hydrogen peroxide complex in the presence of trifluoroacetic anhydride, followed by treatment with dimethylcarbamoyl chloride and trimethylsilyl cyanide gives nitrile 33. Compound 34 can be prepared using the standard Suzuki coupling method of 33 and 8. Reacting 34 with 2,4-dimethoxybenzylamine (35) at high temperature gives compound 36. Subjecting 36 to the Pinner reaction in methanol in the presence of HCl at -78 °C to 0 °C, followed by hydrolysis of the intermediate imino ester in the presence of saturated aqueous NaHCO3 gives ester 37. Reacting 37 with trichloroacetyl isocyanate at 0 °C, followed by treatment with anhydrous ammonia in methanol and warming to room temperature gives diol 38. Reacting 38 with POCl3 at high temperature in the presence of Hunig's base gives dichloro compound 39. Reacting compound 39 with 4 in a solvent such as acetonitrile in the presence of Hunig's base gives 40. Treating 6a - 6c with a suitable base such as potassium fluoride, Hunig's base, K2CO3 or Cs2CO3 / DABCO mixture, neat 6a - 6c or in a suitable aprotic solvent, followed by reacting with 40 at high temperature gives compounds 41a - 41c, respectively. Alternatively, 6a and 40 can also be coupled with Pd(OAc)2 at high temperature in toluene in the presence of BINAP and Cs2CO3 to produce 41a. Removing the Boc protecting group of 41a - 41c under acidic conditions such as anhydrous HCl in 1,4-dioxane. Acylating the corresponding deprotected product with an α,β-unsaturated acid chloride such as acryloyl chloride in an aprotic solvent such as methylene chloride containing a base such as triethylamine, where Y is hydrogen and G is hydrogen, halogen, C 1-4 alkyl, -(C0-C2 alkyl)alkenyl, -(C0-C2 alkyl)alkynyl, -(C0-C2 alkyl)cycloalkyl, C 1-4 haloalkyl, -O(C 1-4 alkyl), -S(C 1-4 alkyl), -(C0-C2 alkyl)cyano, or -O(C 1-4 haloalkyl), where X is O, NR 2、Or either S, the compound represented by formula I (i.e., 42a - 42c) is produced.

[0071] Reaction Scheme 4

Chemical formula

[0072] Reaction step formula 5 shows the synthesis of an example of formula I (i.e., 46) where Y and G are hydrogen, halogen, C 1-4 alkyl, -(C0 - C2 alkyl) alkenyl, -(C0 - C2 alkyl) alkynyl, -(C0 - C2 alkyl) cycloalkyl, C 1-4 haloalkyl, -O(C 1-4 alkyl), -S(C 1-4 alkyl), -(C0 - C2 alkyl) cyano, or -O(C 1-4 haloalkyl), and X is methylene. By reacting acetylene 44 with a strong base such as sodium hydride, the corresponding acetylide anion is produced, which reacts with 43 to obtain 45. Alternatively, compound 45 can be obtained by Sonogashira coupling of 43 and 44 using a Pd catalyst such as Pd(dppf)2Cl2. Catalytic hydrogenation of 45 followed by removal of the Boc group under acidic conditions such as TFA in dichloromethane gives the corresponding amine, which is then reacted with acryloyl chloride in a solvent such as methylene chloride containing a base such as triethylamine, and a compound represented by formula I (i.e., 46) can be produced where Y and G are each hydrogen, halogen, C 1-4 alkyl, C0 - C2 alkenyl, C0 - C2 alkynyl, -(C0 - C2 alkyl) cycloalkyl, C1 - 4 haloalkyl, -O(C 1-4 alkyl), -S(C 1-4 alkyl), C0 - C2 cyano, or -O(C 1-4 haloalkyl), and X is methylene.

[0073] Reaction Scheme 5

Chemical formula

[0074] Reaction formula 6 is such that Y is hydrogen, halogen, C 1-4 alkyl, -(C0-C2 alkyl) alkenyl, -(C0-C2 alkyl) alkynyl, -(C0-C2 alkyl) cycloalkyl, C 1-4 haloalkyl, -O(C 1-4 alkyl), -S(C 1-4 alkyl), -(C0-C2 alkyl) cyano, or -O(C 1-4 haloalkyl), G is hydrogen, and X is O, NR 2、or S, shows the synthesis of an example (i.e., 46) of Formula I. Nitration of picolinic acid 47 with nitric acid in concentrated sulfuric acid gives the corresponding nitro compound 48. Esterification of 48 with catalytic sulfuric acid in methanol produces methyl ester 49 under reflux. Reduction of the nitro group of 49 with tin(II) chloride dihydrate in the presence of hydrochloric acid in an alcohol such as ethanol gives the corresponding amino derivative 50. Hydrolysis of the ester moiety of 50 in a wet solvent such as acetonitrile or THF containing 6% water (v / v) in the presence of LiBr and triethylamine gives carboxylic acid 51 (S. Karlsson et al, Tet. Lett. 2007 48, 2497 - 2499). Treatment of 51 with HATU and ammonium chloride in the presence of sodium bicarbonate in a polar aprotic solvent such as DMF produces the corresponding carboxamide derivative 52. Reaction of 52 with triphosgene (bis(trichloromethyl) carbonate) at 5 °C in an aprotic solvent such as 1,4 - dioxane, followed by heating at 110 °C, gives the 7 - bromopyrido[3,2 - d]pyrimidin - 2,4(1H,3H) - dione derivative 53. Reaction of 53 with phosphorus oxychloride at 120 °C in the presence of Hunig's base gives the corresponding dichloro derivative 54. Reaction of 54 with 4 in the presence of Hunig's base in a solvent such as acetonitrile gives 55. Treatment of 6a - 6c with a suitable base such as sodium hydride, Hunig's base, K2CO3 or Cs2CO3 / DABCO mixture, followed by reaction with 55 at high temperature, gives compounds 56a - 56c respectively. Alternatively, 56a can also be generated by coupling 6a and 55 with Pd(OAc)2 at high temperature in toluene in the presence of BINAP and Cs2CO3. Compounds 57a - 57c can be prepared using the standard Suzuki coupling method between 56a - 56c and 8. Removal of the Boc protecting group of 57a - 57c under acidic conditions such as anhydrous HCl in 1,4 - dioxane, followed by acylation of the corresponding deprotected product with an α,β - unsaturated acid chloride, such as acryloyl chloride, in an aprotic solvent such as methylene chloride containing a base such as triethylamine, gives Y is hydrogen, halogen, C 1-4Alkyl, -(C0-C2 alkyl) alkenyl, -(C0-C2 alkyl) alkynyl, -(C0-C2 alkyl) cycloalkyl, C 1-4 Haloalkyl, -O(C 1-4 Alkyl), -S(C 1-4 Alkyl), -(C0-C2 alkyl) cyano, or -O(C 1-4 Haloalkyl), where G is hydrogen and X is O, NR 2 , or S, and a compound represented by formula I (i.e., 58a-58c) is produced.

[0075] Reaction Scheme 6

Chemical Structure

[0076] Abbreviations and acronyms In this application, the following abbreviations and acronyms can be used: ACN = Acetonitrile; anhyd. = Anhydrous; aq. = Aqueous; B2pin2 = Bis(pinacolato)diboron; Boc = tert-Butoxycarbonyl; BTC = Triphosgene (Bis(trichloromethyl) carbonate) n-Bu3P = Tri-n-butylphosphine; Compd = Compound; d = Day; DABCO = 1,4-Diazabicyclo[2.2.2]octane; DCM = Dichloromethane; DIEA = DIPEA = N,N-Diisopropylethylamine = Hunig's base; DMF = N,N-Dimethylformamide; DMSO = Dimethyl sulfoxide; DMA = N,N-Dimethylacetamide; dppf = 1,1'-Bis(diphenylphosphino)ferrocene EtOAc = Ethyl acetate; equiv = equivalent; Ex; Example h = time; HATU = 1 - [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate LiHMDS = Lithium bis(trimethylsilyl)amide [LiN(SiMe3)2]; MeOH = methanol; NMP = N-methyl-2-pyrrolidone; min = minute; Pd(dppf)Cl2 = [1,1’-Bis(diphenylphosphino)ferrocene]dichloropalladium(II); PE = petroleum ether; RT = room temperature; satd. = saturated solution; TEA = triethylamine; TFA = trifluoroacetic acid; TFAA = trifluoroacetic anhydride; THF = tetrahydrofuran; TMSCN = trimethylsilyl cyanide.

[0077] Examples The concept of the present invention is explained from the viewpoints of exemplary principles and embodiments. However, those skilled in the art will understand that changes can be made and the described things can be replaced with equivalents without departing from the scope and spirit of the disclosure defined by the following examples.

Example

[0078] 2 - ((S) - 4 - (7 - (8 - chloronaphthalen - 1 - yl) - 2 - (((S) - 1 - methylpyrrolidin - 2 - yl)methoxy)pyrido[3,2 - d]pyrimidin - 4 - yl) - 1 - (2 - fluoroacryloyl)piperazin - 2 - yl)acetonitrile (1a)

Chem.

[0079] Reaction Scheme 7

Chem.

[0080] tert - butyl (S) - 4 - (7 - bromo - 2 - chloropyrido[3,2 - d]pyrimidin - 4 - yl) - 2 - (cyanomethyl)piperazine - 1 - carboxylate (60) A mixture of 7-bromo-2,4-dichloropyrido[3,2-d]pyrimidine (3, Hal = Br; CAS number 1215074-41-1; 1.00 g, 3.61 mmol) and tert-butyl (2S)-2-(cyanomethyl)piperazine-1-carboxylate (59; CAS number 1589565-36-5; 0.90 g, 3.97 mmol) in anhydrous 1,4-dioxane (9.0 mL) was slowly added dropwise with diisopropylethylamine (1.90 mL, 10.8 mmol) while stirring at room temperature. After 1 hour, the reaction mixture was concentrated in vacuo and the crude product was purified by silica gel column chromatography eluting with a gradient of 5 - 50% ethyl acetate in hexane to afford 1.64 g (98%) of tert-butyl (S)-4-(7-bromo-2-chloropyrido[3,2-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (60) as a pale yellow solid: HPLC-MS (ES + ) m / z MH + = 467.

[0081] tert - butyl (S) - 4 - (7 - bromo - 2 - (((S) - 1 - methylpyrrolidin - 2 - yl)methoxy)pyrido[3,2 - d]pyrimidin - 4 - yl) - 2 - (cyanomethyl)piperazine - 1 - carboxylate (62) A mixture of tert-butyl (S)-4-(7-bromo-2-chloropyrido[3,2-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (60; 500 mg, 1.07 mmol) and (S)-(1-methylpyrrolidin-2-yl)methanol (61; CAS number 34381-71-0; 0.20 mL, 1.60 mmol) in anhydrous 1,4-dioxane (6.0 mL) was treated with K2CO3 (443 mg, 3.21 mmol), and the reaction mixture was heated at 90 °C with stirring for 16 h under a N2 atmosphere. The reaction mixture was cooled to room temperature and concentrated in vacuo, and the crude product was purified by silica gel column chromatography eluting with a gradient of 0 - 10% MeOH in DCM to afford 370 mg (63%) of tert-butyl (S)-4-(7-bromo-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[3,2-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (62) as an off-white solid: HPLC-MS (ES + ) m / z MH + = 546.

[0082] tert - butyl (S) - 4 - (7 - (8 - chloronaphthalen - 1 - yl) - 2 - (((S) - 1 - methylpyrrolidin - 2 - yl)methoxy)pyrido[3,2 - d]pyrimidin - 4 - yl) - 2 - (cyanomethyl)piperazine - 1 - carboxylate (64) (S)-tert-Butyl 4-(7-bromo-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[3,2-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (62; 450 mg, 0.825 mmol), 2-(8-chloronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (63; 950 mg, 3.30 mmol), and a mixture of K2CO3 (494 mg, 3.30 mmol) in 1,4-dioxane (7.0 mL) and water (0.9 mL) were degassed with N2 by sparging while stirring for 20 min. Tetrakis(triphenylphosphine)palladium(0) (143 mg, 0.123 mmol) was added and the reaction mixture was degassed again with N2 while stirring for an additional 15 min. The reaction mixture was heated at 80 °C for 16 h while stirring under a N2 atmosphere, cooled to room temperature, diluted with ethyl acetate, and then filtered through celite. The filtrate was washed with saturated aqueous NaCl solution (3 times), dried (MgSO4), filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography eluting with a gradient of 0–15% MeOH in DCM to give 130 mg (25%) of (S)-tert-butyl 4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[3,2-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (64) as an off-white solid: HPLC-MS (ES + ) m / z MH + = 628; 11H NMR (300 MHz, CDCl3) δ 8.54 (dd, J = 3.2, 1.2 Hz, 1H), 7.97 (dd, J = 8.2, 1.1 Hz, 1H), 7.91 (d, J = 2.2 Hz, 1H), 7.89 (dd, J = 7.0, 1.2 Hz, 1H), 7.60 - 7.53 (m, 2H), 7.47 - 7.40 (m, 2H), 5.97 (br s, 1H), 5.35 (br s, 1H), 4.69 (br s, 1H), 4.55 - 4.47 (m, 1H), 4.35 - 4.25 (m, 1H), 4.15 (br s, 1H), 3.62 (br s, 1H), 3.26 (br s, 2H), 3.14 - 3.08 (m, 1H), 2.94 - 2.86 (m, 1H), 2.79 - 2.61 (m, 2H), 2.50 (s, 3H), 2.35 - 2.24 (m, 1H), 2.15 - 2.00 (m, 1H), 1.92 - 1.76 (m, 3H), 1.52 (s, 9H).

[0083] 2 - ((S) - 4 - (7 - (8 - chloronaphthalen - 1 - yl) - 2 - (((S) - 1 - methylpyrrolidin - 2 - yl)methoxy)pyrido[3,2 - d]pyrimidin - 4 - yl)piperazin - 2 - yl)acetonitrile hydrochloride (1:3) (65) A mixture of tert-butyl (S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[3,2-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate (64; 160 mg, 0.255 mmol) and 4 M HCl (2.0 mL) was stirred at room temperature under a N2 atmosphere. After 1 hour, the reaction mixture was concentrated under vacuum to give 180 mg (93%) of 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[3,2-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile hydrochloride (1:3) (65) as an off-white solid: HPLC-MS (ES + ) m / z MH + = 528; 11H NMR (300 MHz, DMSO-d6) δ 11.1 (br s, 1H), 10.3 (br s, 2H), 8.68 (d, J = 1.6 Hz, 1H), 8.22 (dd, J = 7.2, 1.1 Hz, 1H), 8.14 (dd, J = 8.1, 1.2 Hz, 1H), 8.08 (d, J = 2.1 Hz, 1H), 7.77 - 7.67 (m, 2H), 7.65 - 7.53 (m, 2H), 4.91 - 4.74 (m, 2H), 4.23 (br s, 2H), 3.92 - 3.83 (m, 2H), 3.74 - 3.66 (m, 1H), 3.51 - 3.43 (m, 2H), 3.28 (br s, 4H), 3.18 - 3.05 (m, 1H), 2.96 (d, J = 4.7 Hz, 3H), 2.36 - 2.22 (m, 1H), 2.14 - 1.77 (m, 4H).

[0084] 2 - ((S) - 4 - (7 - (8 - chloronaphthalen - 1 - yl) - 2 - (((S) - 1 - methylpyrrolidin - 2 - yl)methoxy)pyrido[3,2 - d]pyrimidin - 4 - yl) - 1 - (2 - fluoroacryloyl)piperazin - 2 - yl)acetonitrile (1a) A mixture of 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[3,2-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile hydrochloride (1:3) (65; 100 mg, 0.157 mmol), 2-fluoroprop-2-enoic acid (66; CAS number 430-99-9; 28 mg, 0.314 mmol), and oven-dried 4 Å molecular sieves (132 mg) in EtOAc (2.0 mL) was treated with diisopropylethylamine (0.22 mL, 1.26 mmol), and the reaction mixture was stirred at room temperature. After 5 minutes, 1-propanephosphonic anhydride solution (T3P, 0.33 mL, 0.471 mmol, 50% ethyl acetate solution) was added, and the reaction mixture was stirred at room temperature. After 20 minutes, the reaction mixture was diluted with EtOAc, washed with 5% aqueous NaHCO3 (3 times), dried (MgSO4), filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography eluting with a gradient of 10 - 100% EtOAc containing 1% Et3N (v / v) in DCM to give 2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[3,2-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile (1a) as an off-white solid (40 mg, 35%): HPLC-MS (ES + ) m / z MH + = 600; 1 H NMR (300 MHz, CDCl3) δ 8.57 (dd, J = 2.1, 1.3 Hz, 1H), 7.98 (dd, J = 8.2, 1.2 Hz, 1H), 7.93 (d, J = 2.1 Hz, 1H), 7.90 (dd, J = 8.1, 1.2 Hz, 1H), 7.60 - 7.54 (m, 2H), 7.48 - 7.40 (m, 2H), 5.44 (d, J = 47.8 Hz, 1H), 5.26 (dd, J = 13.3, 3.6 Hz, 1H), 4.65xA), 2.56 (s, 3H), 2.44 - 2.30 (m, 1H), 2.18 - 2.03 (m, 1H), 1.95 - 1.52 (m, 10H).

[0085] The intermediate 71 produced as shown in Reaction Scheme 8 is useful for producing a compound having an 8-methyl substituent.

[0086] Reaction Scheme 8 [Chemical formula]

[0087] 5 - bromo - 3 - nitro - 4 - methylpicolinonitrile (68) To a solution of 2,5-dibromo-3-nitro-4-methylpyridine (67; 5.04 g, 17.0 mmol) in propionitrile (34 mL) was added copper(I) cyanide (1.83 g, 20.4 mmol) with stirring at room temperature. The resulting suspension was heated to reflux with rapid stirring for 4 days under a nitrogen atmosphere. The cooled reaction mixture was extracted with a mixture of water and ethyl acetate and then filtered through celite. Next, the phases of the filtrate were separated, and the ethyl acetate extract was washed with saturated NaCl (aqueous solution), dried (CaSO4), and evaporated to give 3.9 g of a crude product as a dark brown oil. This was purified by silica gel chromatography eluting with a gradient of 1 - 5% EtOAc in hexane to give 3.1 g of a yellow solid. This material was recrystallized from heptane to give 2.7 g of 5-bromo-3-nitro-4-methylpicolinonitrile (68) as a white powder. HPLC-MS (ES - ) m / z [M-H] - = 240, 242; 1 1H NMR (300 MHz, DMSO) δ 9.18 (s, 1H), 2.52 (s, 3H); 13 13C NMR (75 MHz, DMSO) δ 154.9, 149.7, 143.5, 129.8, 125.9, 114.0, 19.4.

[0088] 3 - amino - 5 - bromo - 4 - methylpicolinamide (69) Ammonium hydroxide (5.0 mL) was added to a stirred aqueous (10 mL) suspension of 5-bromo-3-nitro-4-methylpicolinonitrile (68; 1.20 g, 5.0 mmol). The flask was sealed with a septum cap and the suspension was stirred rapidly at room temperature. After 3 h, powdered sodium sulfite (4.8 g, 27.3 mmol) was added portionwise to the suspension over 15 min and the mixture was stirred at room temperature for 2.5 h. The resulting yellow solid was separated by filtration, washed with water and dried to give 511 mg of a crude product contaminated with approximately 25% of 6-bromo-7-methyl-1,2-dihydro-3H-pyrazolo[4,3-b]pyridin-3-one. This material was purified by silica gel chromatography eluting with a gradient of 0–5% MeOH in DCM to give 328 mg of 3-amino-5-bromo-4-methylpicolinamide (69) as a white solid: HPLC-MS (ES + ) m / z MH + = 230, 232; 1 H NMR (300 MHz, DMSO) δ 7.99 (s, 1H), 7.89 (s, 1H), 7.45 (s, 1H), 7.15 (bs, 2H), 2.25 (s, 3H): 13 C NMR (75 MHz, DMSO) δ 170.5, 146.7, 136.6, 132.1, 127.7, 126.1, 17.0.

[0089] 7 - bromo - 8 - methylpyrido[3,2 - d]pyrimidine - 2,4 - diol (70) (270 mg, 0.9 mmol) was added to a stirred solution of 3-amino-5-bromo-4-methylpicolinamide (69; 209 mg, 0.9 mmol) in anhydrous 1,4-dioxane (18 mL) and the mixture was heated to reflux under nitrogen for 2 h. The cooled reaction mixture was partitioned between ammonium hydroxide and ethyl acetate. The resulting insoluble white precipitate was isolated by filtration, washed with water and air dried on the filter paper to give 151 mg of 7-bromo-8-methylpyrido[3,2-d]pyrimidine-2,4-diol (70). HPLC-MS (ES + ) m / z MH + = 256, 258; 11H NMR (300 MHz, DMSO) δ 8.39 (s, 1H), 7.74 (bs, 2H), 2.43 (s, 3H). 13 13C NMR (75 MHz, DMSO) δ 162.1, 152.2, 144.2, 142.1, 135.2, 131.0, 127.4, 17.3.

[0090] 7 - bromo - 2,4 - dichloro - 8 - methylpyrido[3,2 - d]pyrimidine (71) A stirred mixture of 7-bromo-8-methylpyrido[3,2-d]pyrimidine-2,4-diol (70; 1.24 g, 4.8 mmol) and triethylammonium hydrochloride (2.7 g, 19.3 mmol) in a 50 mL round-bottom flask was treated with phosphoryl chloride (22.5 mL, 241.4 mmol), and the mixture was heated to reflux for 4 h. The resulting black solution was cooled, and water was slowly added at 0 °C to carefully quench the reaction. After the addition was complete, the product was extracted with ethyl acetate. The ethyl acetate extract was washed with saturated NaCl (aq), dried (CaSO4), and concentrated in vacuo to give 2.8 g of 7-bromo-2,4-dichloro-8-methylpyrido[3,2-d]pyrimidine (71) as a light brown solid, which was used without purification: HPLC-MS (ES + ) m / z MH + = 294.

[0091] The intermediate 77 prepared as shown in Reaction Scheme 9 is useful for preparing compounds having an 8-chloro substituent.

[0092] Reaction Scheme 9

Chemical Structure

[0093] Methyl 3 - amino - 5 - bromo - 6 - iodopicolinate (73) N-Iodosuccinimide (5.88 g, 26.0 mmol) was added to a stirred suspension of methyl 3-amino-5-bromopicolinate (72; CAS number 1072448-08-8; 5.0 g, 21.7 mmol) in acetic acid (12.6 mL), and the mixture was stirred at 50 °C. After 5 days, the mixture was cooled to room temperature and slowly pipetted into saturated aqueous NaHCO3 and stirred at room temperature. After 2 hours, the precipitated solid was filtered and washed with EtOAc to give 2 g of methyl 3-amino-5-bromo-6-iodopicolinate (73) as an off-white solid. The aqueous layer was extracted with EtOAc (3 times), washed with saturated aqueous NaHCO3 (2 times), 2% aqueous Na2S2O5 (3 times), dried (MgSO4), filtered, and concentrated. After standing overnight, additional solid precipitated from the filtrate. The solid was recrystallized from EtOAc to give 1.0 g of methyl 3-amino-5-bromo-6-iodopicolinate (73) as an off-white solid. The product from the extract was purified by silica gel column chromatography eluting with a gradient of 10% - 40% ethyl acetate in hexane to give 1.13 g of methyl 3-amino-5-bromo-6-iodopicolinate (73) as an off-white solid: HPLC-MS (ES + ) m / z [M + H + = 357, 359; 1 H NMR (300 MHz, CDCl3) δ 7.28 (s, 1H), 5.81 (br s, 2H), 3.94 (s, 3H).

[0094] Methyl 3 - amino - 5 - bromo - 4 - chloro - 6 - iodopicolinate (74) N-Chlorosuccinimide (2.76 g, 20.6 mmol) was added to a stirred solution of methyl 3-amino-5-bromo-6-iodopicolinate (73; 1.53 g, 20.6 mmol) in N-methyl-2-pyrrolidone (20 mL). The mixture was placed in a metal heating mantle preheated to 80 °C and stirred at 80 °C. After 30 minutes, the red-orange mixture was quickly removed from the heat source and diluted with EtOAc. The mixture was washed with saturated aqueous NaCl solution (5 times), dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with dichloromethane to give 460 mg of methyl 3-amino-5-bromo-4-chloro-6-iodopicolinate (74) as a fluffy white solid: HPLC-MS (ES + ) m / z [M+H + = 391, 393, 395; 1 1H NMR (300 MHz, CDCl3) δ 6.45 (br s, 2H), 3.97 (s, 3H).

[0095] Methyl 3 - amino - 5 - bromo - 4 - chloropicolinate (75) Zinc powder (51 mg, 0.79 mmol) was added to a stirred suspension of methyl 3-amino-5-bromo-4-chloro-6-iodopicolinate (74; 102 mg, 0.26 mmol) in acetic acid (2.4 mL), and the resulting dark green mixture was stirred at room temperature. After 4 days, the mixture formed a yellow-brown suspension and an additional 14.4 mg of zinc powder was added. The mixture was stirred at room temperature for 16 hours, then poured into saturated aqueous NaHCO3 solution and extracted with ethyl acetate (3 times), dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with a gradient of 0% to 10% EtOAc in DCM to give 30 mg of methyl 3-amino-5-bromo-4-chloropicolinate (75) as an off-white solid: HPLC-MS (ES + ) m / z [M+H + = 265, 267, 269; 1 1H NMR (300 MHz, CDCl3) δ 8.16 (s, 1H), 6.45 (br s, 2H), 3.99 (s, 3H).

[0096] 3-Amino-5-bromo-4-chloropicolinamide (76) A mixture of methyl 3-amino-5-bromo-4-chloropicolinate (75; 200 mg, 0.753 mmol) and a methanol solution of anhydrous ammonia (4.0 mL, 7 N) was stirred at room temperature in a sealed flask. After 16 h, a white suspension formed and the reaction mixture was concentrated under vacuum to give 188 mg of 3-amino-5-bromo-4-chloropicolinamide (76) as a white solid: HPLC-MS (ES + ) m / z [M+H + = 250, 252, 254; 1 H NMR (300 MHz, DMSO-d6) δ 8.09 (br s, 1H), 8.01 (s, 1H), 7.63 (br s, 1H), 7.41 (br s, 2H).

[0097] 7-Bromo-8-chloropyrido[3,2-d]pyrimidine-2,4-diol (77) Triphosgene (223 mg, 0.751 mmol) was added to a stirred solution of 3-amino-5-bromo-4-chloropicolinamide (76; 188 mg, 0.751 mmol) in anhydrous 1,4-dioxane (7.0 mL) and the mixture was heated to reflux under nitrogen. After 5 h, additional triphosgene (227 mg) was added and the mixture was heated to reflux for 16 h, cooled to room temperature and then concentrated in vacuo. The crude solid was triturated with EtOAc, washed with EtOAc to give 166 mg of 7-bromo-8-chloropyrido[3,2-d]pyrimidine-2,4-diol (77) as a grey solid: HPLC-MS (ES + ) m / z [M+H + = 276, 278, 280; [M-H + = 274, 276, 278; 1 H NMR (300 MHz, DMSO-d6) δ 11.8 (br s, 1H), 11.1 (br s, 1H), 8.66 (s, 1H).

[0098] Nucleotide exchange assay The biological activity of the examples was measured in a KRAS G12C / SOS1 nucleotide exchange assay performed by Reaction Biology Corporation, 1 Great Valley Parkway, Suite 2 Malvern, PA 19355, USA. In this assay, the SOS1-mediated exchange of Bodipy-GDP to GTP observed with KRAS G12C was evaluated.

[0099] Compounds were tested at 10 concentrations in a 3-fold serial dilution at an initial concentration of 10 μM for the examples and MRTX-849 (reference standard), and at an initial concentration of 5 μM for ARS-1620 (reference standard) in an IC 50 mode. The pre-incubation time of the compounds was 30 minutes at room temperature, and curve fitting was performed when the activity at the highest concentration of the compound was less than 65%.

[0100] Reaction buffer: 40 mM HEPES 7.4, 10 mM MgCl2, 1 mM DTT 0.002% Triton X100, 0.5 DMSO.

[0101] Protein: SOS1 (RBC catalog number MSC-11-502). Recombinant human SOS1 (Genbank accession number NM_005633.3; aa 564-1049, expressed in E. coli with a C-terminal StrepII. MW = 60.59 kDa).

[0102] KRAS G12C: Recombinant human KRAS (Genbank accession number NM_033360.3; aa 2-169, expressed in E. coli with an N-terminal TEV-cleavable his-tag. MW 21.4 kDa). KRAS is pre-loaded with a 5-fold excess of Bodipy-GDP. The excess Bodipy-GDP is separated from the loaded protein using a spin desalting column.

[0103] Final concentration:KRAS-bodipy-GDP was 0.125 μM; SOS1 was 70 nM; and GTP was 25 μM.

[0104] Reaction procedure: Inject 10 μL of 1.5 x KRAS solution in freshly prepared reaction buffer into the reaction well. 1. Use acoustic technology (Echo550; nanoliter range) to deliver the compound in 100% DMSO into the buffer. 2. Incubate the compound at room temperature for 30 minutes. 3. Prepare 3x (SOS1 + GTP) solution with reaction buffer. 4. Inject 5 μL of SOS1+GTP solution into the reaction well (if no SOS1 control, inject only GTP into column 1). 5. Measure the decrease in fluorescence signal with a PHERAstar plate reader (BMG Labtech; Ex / Em = 485 / 520) equipped with real-time reaction monitoring function, and monitor the progress of the reaction at room temperature for 30 minutes.

[0105] Data analysis (for covalent compounds): The dRFU value at each compound concentration was calculated by subtracting the fluorescence (RFU) at the end of the 30-minute reaction from the initial fluorescence measured immediately before the addition of the SOS1 / GTP mixture. The fluorescence data was normalized using the following equation and fitted to a "1-phase exponential decay" equation using GraphPad prism software. The plateau was not constrained, and the IC 50 value was calculated using the dRFU value.

[0106]

Number

[0107] The signal minus background (SOS1 protein wells were not used as background) was converted to % activity relative to the DMSO control. Data were analyzed using GraphPad Prism 4 with "Sigmoid Dose Response (Variable slope)"; four parameters of the Hill slope. Constraints were a lower limit (constant of 0) and an upper limit (must be less than 120).

[0108] Results:

Table 5

[0109] Pharmacokinetics of Example 1 in male CD-1 mice The pharmacokinetic profile of Example 1 (Compound 1a) was measured in male CD-1 mice by WuXi AppTec Co., Ltd., 1318 Wuzhong Avenue, Wuzhong District, Suzhou, China, 215104. The results shown in the following table clearly indicate that the oral bioavailability in male CD-1 mice of Example 1 is 28.8%.

Table 6

Claims

1. Formula I: 【Chemical 1】 Formula I [Wherein, A is selected from optionally one or more hydrogens, halogens, hydroxyls, C 1-6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -(C 0 -C 6 alkyl)cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, NO 2 , cyano, CO 2 H, PO(OR 3 ) 2 , POR 3 (OR 3 ), PO(R 4 ) 2 , NH 2 , NH(C 1-6 alkyl) or N(C 1-6 alkyl) 2 aryl or heteroaryl substituted with; X is selected from O, NR 2 , S or CH 2 ; Y and G are the same or different and are selected from bromine, iodine, C 1-4 alkyl, C 1-4 perdeuteroalkyl, -(C 0 -C 2 alkyl)alkenyl, -(C 0 -C 2 alkyl)alkynyl, -(C 0 -C 2 alkyl)cycloalkyl, C 1-4 haloalkyl, -O(C 1-4 alkyl), -S(C 1-4 alkyl), -(C 0 -C 2 alkyl)cyano, or -O(C 1-4 haloalkyl); Z is selected from hydrogen, halogen, trifluoromethyl or C 1-6 alkyl; R 1 is selected from hydrogen, C 1 -C 6 -alkyl, -(C 1 -C 6 -alkyl)C 1-6 -alkoxy, -C 0 -C 6 -alkyl(cycloalkyl), C 1 -C 6 -haloalkyl, -(C 1 -C 6 -alkyl)CN or -(C 1 -C 6 -alkyl)P(O)R 2 R 3 ; n is 1 - 3; Each R 2 is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl or -(C 1 -C 6 alkyl)P(O)R 2 R 3 and is selected therefrom; R 3 is selected from H, C 1-6 alkyl or C 3-6 cycloalkyl; R 4 is C 1-6 alkyl, C 3-6 selected from cycloalkyl or aryl] a compound represented by or a salt, solvate, or prodrug thereof.

2. The compound represented by Formula I is a compound selected from the following 1b - 1z and 2a - 2g: 【Table 1】 【Table 2】 【Table 3】 【Table 4】 or a salt, solvate, or prodrug thereof, the compound or salt according to Claim 1.

3. A pharmaceutical composition comprising the compound according to any one of Claims 1 to 2, or a salt, solvate, or prodrug thereof, together with a pharmaceutically acceptable carrier.

4. A method of treating a disease, disorder, or medical condition of a patient, comprising the step of providing a therapeutic agent to a patient in need thereof, wherein the therapeutic agent comprises the compound according to any one of Claims 1 to 3, or a salt, solvate, or prodrug thereof.

5. The method according to Claim 4, wherein the disease, disorder, or medical condition of the patient comprises various cancers.

6. The method according to Claim 5, wherein the disease, disorder, or medical condition of the patient is mediated via KRAS.

7. The method according to Claim 6, wherein the disease, disorder, or medical condition is mediated via KRAS, particularly the KRAS variant G12C.

8. The method according to Claim 6, wherein the cancer is selected from glioma (glioblastoma), acute myeloid leukemia, acute myeloid leukemia, myelodysplastic / myeloproliferative neoplasm, sarcoma, chronic myelomonocytic leukemia, non - Hodgkin lymphoma, astrocytoma, melanoma, non - small cell lung cancer, cholangiocarcinoma, chondrosarcoma, colon cancer or pancreatic cancer.

9. The method according to any one of Claims 4 to 8, further comprising administering at least one additional therapeutic agent to a patient in need thereof.

10. The compound represented by Formula I is compound 1d, 1f, 1n and 1z: [Chemical Formula 2] or a compound according to Claim 2, selected from a salt, solvate, or prodrug thereof.

11. The method according to Claim 4, comprising the step of providing the pharmaceutical composition according to Claim 11 to a patient in need thereof.

12. The method according to Claim 4, wherein the disease, disorder, or medical condition comprises various cancers.

13. The method according to Claim 12, wherein the disease, disorder, or medical condition is mediated via KRAS.

14. The method according to Claim 13, wherein the disease, disorder, or medical condition is mediated via the KRAS variant G12C.

15. The method according to claim 13, wherein the cancer is selected from glioma (glioblastoma), acute myeloid leukemia, acute myeloid leukemia, myelodysplastic / myeloproliferative neoplasm, sarcoma, chronic myelomonocytic leukemia, non-Hodgkin lymphoma, astrocytoma, melanoma, non-small cell lung cancer, cholangiocarcinoma, chondrosarcoma, colon cancer or pancreatic cancer.

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